including extensive Appendices addressing
COMMON
PROBLEMATIC CONDITIONS, MEDICationS AND NUTRITIONAL SUPPLEMENTS,
botanicals AS COMPLEMENTARY ADJUNCTS WITH DRUGS
by Francis Brinker, N.D.
Copyright 2010
All rights reserved
Nothing from this document may be reproduced for sale or distribution in any form.
Last update July 13, 2010
Combining herbal use with medications
should only be done after consultation with a knowledgeable physician.
Preliminary research data on potentially beneficial combinations of herbals and
drugs is provided to educate pharmacists and physicians and encourage further clinical
research. Information provided in this book is not intended as recommending
self treatment or to replace instructions provided by one’s own doctor or
health care provider.
Introduction
+
The content on this site is
presented to supplement the information found in the third edition of the
book. By this means the database can be
enlarged, enhanced and updated without the user having to annually purchase a
new printed edition largely containing information already provided in the
previous edition or subscribing to an online updating service. The format for this site is consistent with
that found in the book, so that herbs and appendix categories can be easily
accessed by the same arrangement as in the printed text. The page numbers for
the updates indicate where in the book the associated information can be found,
while additions are identified as "NEW." The added reference
citations begin with 1100. Citations for
lower reference numbers are found in the book. Changes in scientific binomials
and standardized common names used here are now based on the second edition of Herbs
of Commerce (2000).
Since the
information on this site presupposes familiarity with the content in the book,
it must be understood in that context. The content on this site must be
recognized as inadequate without access to what has been published in the 3rd
edition. However, abbreviated versions
of prior referenced statements about the contraindications or the drug
interactions are included at the beginning of an addition to identify the
context of the addition. Listed below are important terms, abbreviations, and
symbols used in the book and/or on this site, followed by a Table of those
herbs and appendix sections to which additions have been made.
Regarding herbal
contraindications, many bridge the empirical vs. speculative designations, with
greater evidence provided by one or the other, though a combination of factors
often contribute. The method of determining such designations is imprecise, and
what is described as a speculative contraindication for self-prescribing by the
general public (the method employed for this text and web site) may in some
cases be more accurately described as a precaution for an expert prescriber
educated in botanical medicine (as indicated in other texts primarily intended
for professional use). Potential
risks from contraindications or adverse interactions can be uncertain in regard
to the actual degree of risk due to conflicting evidence. For this reason, in
such cases the inclusion of contradictory data in a separate indented paragraph
prefixed with the word, “However,” has been used as a means of emphasing the
equivocal nature of the extant evidence for some controversial
contraindications or interactions.
As
stand-alone evidence of drug interactions with herbals, laboratory studies in vivo with animals in
Category II. and/or
with in
vitro cell or tissue
cultures in Category III. are insufficient to extrapolate the findings to
humans with certainty. The reasons for this are many. For one, animals and
their intestinal bacterial flora differ from humans in their abilities to
digest, absorb, and/or metabolize the many different types of components found
in any complex botanical preparation. Similar but distinct problems exists with
in vitro laboratory studies utilizing cell organelles, cell
cultures, tissues, or isolated organs. The systemic exposure of living tissues
to complex solutions extracted from plants following intestinal absorption does
not involve the same chemical content and proportions as is found in laboratory
conditons where cells and tissues are exposed to the complete extract. Clinical
case reports or case series appear to be of more real value in determining an
herbal effect than extrapolating laboratory data to a clinical setting. In the
absence or preferably in the context of controlled clinical studies, combining
all types of preclinical evidence based on similar preparations facilitates a
more complete and, hopefully, a more dependable assessment.
When herbal
influence on drug pharmacokinetics is discussed, the term “bioavailability” is
often used as a short-hand term to describe the total Area Under the
concentration-time Curve (AUC). Though the total time that the drug
concentration is monitored may vary from a few hours to a few days depending
upon the study, this general term is applied to conveniently indicate when the
overall average circulating serum level of the drug has been significantly
altered. Results
reported here as "significant" are deemed so based on statistical
significance demonstrated by a P value of < 0.05, at most. However,
statistical significance in changes to biological markers does not guarantee a
clinically significant effect when it comes to assessing therapeutic outcomes.
The
following terms are used to describe the different means of determining
botanical effects.
The
categorization of I, II, III and IV is used to rank potential herb-drug
interactions according to their probable pertinence based on the strongest
degree of evidence available.
Where
contradicting data exists for a particular item in any category, this is noted
by an indentation, and the sentence will begin with the word, “However.”
I. human studies – published
research done on healthy individuals
human
clinical studies – published research from therapeutic trials on patients
being treated for a condition
empirical – traditional knowledge or consensus based on
experience from extensive use
human
case reports – published individual responses to using herbal products
human
case series – published responses from several patients using a preparation
of the same herb
II. in animals (types listed) – laboratory
tests using live animals (in vivo)
and various modes of administering the herb or herbal component(s)
III. ex vivo –laboratory interaction
finding on cells, tissue, or organs from animals or humans who were
administered the herbal agent (as contrasted to in vivo when studies are done on the living organisms themselves)
in vitro –laboratory interaction
finding with cell or tissue samples from animals or humans
speculative
– using pharmacological evidence from in
vitro research, animal studies, or human studies to infer probable or
potential interactions or effects in humans
IV. [dubious interactions] shown in brackets with the drugs underlined rather than in bold type are
based on preliminary findings, speculation, inaccurate information, and/or
false assumptions that have been contradicted by established evidence.
Abbreviations
for the various modes of administration are used as follows:
IM (intramuscular) – injected into a
large skeletal muscle
IP (intraperitoneal) – injected into
the peritoneal cavity
IV (intravenous) – injected into a vein
PO (per
os) – by mouth; orally or through a feeding tube; b.i.d. = 2x/day,
t.i.d. = 3x/day
SC (subcutaneous) – injected under the skin
ADDITIONAL
INFORMATION BASED ON THE FOLLOWING IS AVAILABLE FOR THE LISTED HERBS AND
APPENDICES:
+ denotes new contraindication(s) and/or
interaction(s) not previously listed in the book for the herb
^ denotes new herb with contraindication(s) and/or
interaction(s) in body of text or an entirely new appendix section
Ä denotes use of new
standardized common name from second edition of Herbs of Commerce
If none of the above are present in the list below,
elaborations have been made to information already included in the book.
An asterisk (*) in front of an herb’s
scientific name denotes toxic effects from over-consumption of that herb or a
major active component.
Where [CORRECTION:] appears before numbers or
information in ALL CAPS, it denotes correction of an error found in the book.
The following list are those
herbs that are either new or for which updates or new information has been
added.
Agar +
Agave ^
Alfalfa +
American
ginseng +
Andrographis ^
Anise +
Apricot ^
Arjun ^
Arnica +
Artichoke +
Ashwagandha +
Asparagus +
Astragalus
Bacopa ^
Barberry +
Basil +
Beebalm ^
Beth root ^
Bilberry
Birch +
Bitter
melon +
Bitter
orange +
Black
chokeberry ^
Black
cohosh +
Black
cumin ^
Black
currant ^
Bladder
kelp ^
Bladderwrack +
Blue cohosh +
Blue
flag ^
Blue
vervain ^
Bloodroot +
Boldo +
Borage
+
Boswellia ^
Bromelain +
Burdock +
Butcher's broom ^
Butternut ^
Cajeput ^
Calendual +
California spikenard ^
Camphor bark +
Caraway ^
Cascara sagrada
Cassia cinnamon + Ä See Cassia
Cat’s claw +
Cayenne
Celandine
+
Celery
+
Chamomile,
German +
Ä See Chamomile
Chamomile,
Roman Ä See Roman Chamomile
Chaste
tree +
Chickweed ^
Chicory +
Chinese
cucumber ^
Chinese skullcap ^ Ä
Cinchona +
Cinnamon +
Clove +
Cocoa +
Coffee
Comfrey +
Copaiba ^
Coptis ^
Cordyceps +
Corydalis ^
Cotton +
Couch
grass Ä See Triticum.
Cranberry ^
Cranesbill ^
Crucifers
Cumin ^
Dan
shen
Dandelion +
Devil’s
claw
Dill +
Dog
rose ^
Dong
quai +
Dulse +
Dyer’s
broom +
Eastern
red cedar ^
Eleuthero
Ephedra
Eucalyptus
European pennyroyal ^
European vervain ^
Evening primrose +
False unicorn root ^
Fennel +
Fenugreek +
Feverfew
Flax
Forsythia ^
Fragrant
angelica ^
French
maritime pine ^
Garlic
+
Ginger
+
Ginkgo
Ginseng + Ä See Asian ginseng
Goat’s rue ^
Goldenrod ^ Ä For Solidago virgaurea see European goldenrod.
Goldenseal
+
Gotu
kola +
Grapes ^
Grapefruit +
Guar
gum +
Guarana
Guggul ^
Gurmar + Ä See Gymnema
Hawthorn +
Henna ^
Hops +
Horse chestnut +
Horseradish
+
Horsetail +
Iboga
+
Inmortal
^
Ipecac
+
Jamaica
dogwood +
Job’s
tears ^
Jujube
seeds ^
Kava
+
Konjac
Kudzu +
Kutaki Ä
Lavender Ä See English lavender.
Lemongrass +
Licorice +
Life
root
Lobelia
+
Lomatium ^
Lycium ^
Maca ^
Maitake +
Makandi +
Mangosteen ^
Marijuana + See Cannabis.
Marshmallow +
Mate
Meadowsweet +
Milk
thistle +
Muirapuama ^
Mustard
Myrrh +
Nard ^
Neem ^
Nutmeg +
Oat +
Ocotillo ^
Olive +
Orange ^
Oregon grape +
Osha ^
Papain
Passion flower +
Pennyroyal Ä See American pennyroyal.
Peppermint +
Periwinkle Ä See Lesser periwinkle.
Petasites +
Plantain Ä For Plantago lanceolata see
English plantain.
Pleurisy root +
Poke ^
Pomegranate +
Prickly ash
Prickly pear
Psoralea ^
Psyllium
Puncture vine ^
Purslance ^
Quassia (Jamaican) ^
Quassia (Surinam) ^
Queen Ann’s lace Ä See Wild carrot
Raspberry +
Red
clover +
Rehmania +
Reishi +
Rhatany ^
Rhodiola ^
Rhubarb,
Chinese Ä See Chinese rhubarb
Royal
sun agaricus ^
Sage +
Schizandra +
Scotch broom
Scouring rush ^
Sea buckthorn ^
Senna +
Sesame ^
Shepherd’s purse +
Shrub aloe ^
Small spikenard ^
Soy +
Spikenard ^
St.
John’s wort +
Stevia ^
Stinging
nettles +
Sweet
annie ^
Sweet
clover
Szechuan
lovage ^
Szechuan
pepper ^
Tea +
Tea
tree ^
Thuja +
Thunder
god vine ^
Thyme
+
Tobacco +
Turkey
tail +
Turmeric +
Tylophora ^
Uva
ursi
Valerian
+
Vetiver ^
Watercress +
Wheat ^
Wild
cherry Ä See Black cherry
Wild
lettuce +
Wild
marjoram See Oregano
Wild
yam +
Willow +
Wintergreen ^
Witch
hazel +
Wormwood +
Yarrow +
Yellow dock ^
APPENDIX SECTIONS WITH NEW
HERBALS, DATA OR SECTIONS ADDED:
A.2.1 Carrot family
A.4 In Acute Inflammation of the
Urinary Tract
A.4.1 Medicinal Plants Containing Urinary Irritants
A.4.2 Medicinal Plants Containing Soluble Oxalates
A.5 In Gastrointestinal
Irritation
A.5.1 Herbals That Can Upset the GI Tract
A.6
In Hypothyroid Conditions or Euthyroid Goiter
A.6.2
Antigoitrogens
A.7.1 Herbals With Toxic Potential
B.1.1.b.i Selective Precipitation of Alkaloids and
Minerals by Tannins
B.1.3 No Influence on Drug Absorption in Humans ^
B.2 Potentiating Cardiotonic Medicines
B.2.2.b
Potentiation by Kaliuretics and/or Diuretics
B.3 Potentiating Sedative or Tranquilizing
Medicines
B.3.1 Hypnotic and/or
Anxiolytic Drug Enhancement
B.4 Modigying Blood Sugar in Insulin-Dependent
Diabetics
B.5 Modifying the Effects of Anticoagulants
B.7 Modifying Enzyme Activities in Metabolic
Conversions
B.7.1.a Modulation by Phase I &/or Phase II
Enzymes &/or Other Clearance Factors
B.7.1.c Influence on Aryl hydrocarbon Receptor (AhR) ^
B.7.2.a Influence on CYP 1A2 Metabolic Conversion of Substrates
B.7.2.b Influence on CYP 2E1 Metabolic Conversion of Substrates
B.7.2.c Influence on CYP 3A4 Metabolic Conversion of Substrates
B.7.2.d
Influence on CYP 2C9 Metabolic
Conversion of Substrates ^
B.7.2.e
Influence on CYP 2C19
Metabolic Conversion of Substrates ^
B.7.2.f
Influence on CYP 2D6 Metabolic
Conversion of Substrates ^
B.7.3.a Influence on Glutathione S-Transferase
Activity or its Isozyme Levels
B.7.3.b
Influence on Activity and/or Content of UDP-Glucuronosyltransferases
[UGT]
B.7.3.c
Influence on NADPH-Quinone Reductase [QR] (DT-Diaphorase) Activity
and/or Content
B.7.3.d
Influence on Epoxide Hydrolase (Epoxide Hydratase)[EH] Activity
B.7.4.a Aromatase
(CYP19) Conversion of Testosterone to 17b-Estradiol
B.7.4.b 5a-Reductase Conversion of
Testosterone to Dihydrotestosterone
B.7.4.d 11b-Hydroxysteroid
Dehydrogenase type 2 Conversion of Cortisol to Cortisone
B.7.4.e 17b-Hydroxysteroid Dehydrogenase
types 1, 3 or 5 Conversion of Androstenedione to Testosterone
B.7.4.f 17b-Hydroxysteroid
Dehydrogenase type 2 Conversion of Testosterone to Androstenedione or Estradiol
to Estrone ^
B.7.4.g 17b-Hydroxysteroid Dehydrogenase
type 1 Conversion of Estrone to Estradiol
^
B.7.4.h 3b-Hydroxysteroid
Dehydrogenase type 1 or 2 Conversion of DHEA to Androstenedione and/or
Pregnenolone to Progesterone ^
B.7.5 Herbal
Monoamine Oxidase –A &/or –B Inhibitors
C.1 During Pregnancy
C.1.1
Herbals That May Impact the Uterus or Fetal Development
D.1
Drug and Mineral Interactions with Vitamin Supplements
D.1.5 Vitamin B6 (Pyridoxine,
Pyridoxamine, Pyridoxal) / Drug Interactions
D.1.5.a Vitamin B6-Rich Herb and Vegetable
Sources
D.1.7 Folic Acid / Drug Interactions
D.1.8 Vitamin C (Ascorbic Acid, Ascorbates) / Drug
Interactions
D.1.10.a
Vitamin E-Rich Plant Sources
D.2 Drug and Vitamin Interactions with Mineral
Supplements
D.2.1 Calcium
/ Drug Interactions
D.2.1.a
Calcium-Rich Herb and Vegetable
Sources
D.2.2.a
Copper-Rich Herb and Vegetable Sources
D.2.4 Iron (as Ferrous Sulfate) / Drug Interactions
D.2.4.a Iron-Rich Herb and Vegetable Sources
D.2.5.a Magnesium-Rich Herb and Vegetable Sources
D.2.6.a Manganese-Rich Herb and Vegetable Sources
D.2.7.a Potassium-Rich Herb and Vegetable Sources
E.1. Potentially Beneficial Combinations of Herbals with Drugs [formerly Addendum]
E.2. Herbal Aids for Modifying Substance Abuse ^
E.4. Enhancing Chemotherapy and Chemoprevention or
Reducing the Adverse Effects ^
E.6. Herbals and
Anti-infectious Agents ^
1100. – 2708.
Introduction
There are many possible meanings of
the word “herb.” Taken in its broadest medicinal sense, it commonly refers to
all plants and/or plant parts. Traditionally, it has been applied to the
above-ground part of non-woody plants, excluding their roots and/or rhizomes.
The term is used in this text with this intended meaning, to describe the part
of the plant used for many of the botanicals included herein. In the culinary
arts an herb is distinguished from spices as referring primarily to aromatic
leaves, in contrast to seeds, bark, or roots/rhizomes. In all of these cases,
the word is intended to be understood as the whole part of the fresh or dried
plant, characteristically including its fiber content.
For the purposes of understanding
the title of this book in all of its ramifications, the concept of “herb”
incorporates chemically complex derivatives of all plant parts. This extended
application of the term is in consideration of the majority of studies using
only derivatives of the medicinal parts of plants. These extractives include,
for example, juices, teas, tinctures, volatile oils, and other fractions that
are physically or chemically removed from the fresh or dried plant parts. These
preparations are more properly referred to as botanicals or “herbals”, the
terms now employed in the text. Since these commercial derivatives are commonly
consumed, it is important to acknowledge the specific forms used in studies
when this is adequately described in published research.
By extension, major active components of the plants have been used to
help understand the pharmacology of the extracts and whole herbs. Discussion of
isolated phytochemicals should not be taken to imply that the pharmacology of a
commonly used extract or herb is identical to that of a single compound that
these may contain. Rather, the activity of an isolated compound is simply one
contributing factor to the overall effect derived from using the extract or
herb. The same case can be made in regard to a subfraction or even commonly
used extracts, when compared to the whole herb itself. At each level of growing
complexity (from isolate to subfraction to extract to herb) the influence of
the isolate in relation to the overall effect diminishes both in quality and quantity.
Nevertheless, it remains useful to consider specific pharmacological
research regarding the activity of isolates, subfractions, and extracts, when
considering the effects of the herb itself. For this reason, research data from
all of these forms are used as evidence in this book to help document the
probability of specific outcomes. This remains a useful approach as long as it
is understood that direct application of the findings for a specific
preparation apply only to that preparation and dose; other correlations
necessarily fall short.
The term “bioequivalence” is a relative concept, in that certain
extractives or derivatives of an herb have more or less similarity to one
another, depending on each one’s unique phytochemical content and proportions.
Bioequivalency certainly cannot be assumed to strictly corrlate with an initial
amount of plant material from which many variable preparations can be made.
Though the inherent variability in content and complexity of “similar”
preparations may be unsettling for the scientific purist, it should be no more
uncomfortable than considering the fact that each person who uses a herb or its
extract is also genetically and biochemically unique in their own peculiar
response to the remedy. It is knowledge of the general similarities regarding
pathophysiology, pharmacology and therapeutic responses in conjunction with an
understanding of the individual distinctions between both preparations used and
patients using them that comprise the challenging art of medical practice.
These are facts that must be acknowledged and addressed in each case, to
optimize the safety and efficacy of the intervention. The same relative
significance can be applied to different quantities consumed of the exact same
preparation. While an accepted therapeutic dose and duration can be completely
safe, increasing its consumption in amount and/or length of use beyond its
acknowledged safe limitations can lead to undesirable adverse effects.
Therefore, in addition to characterizing the form used in scientific studies it
is important to describe the dosage used.
In some cases, animal and in vitro evidence can provide either
contradictory or supporting evidence to help assess the likelihood of
interaction report(s) involving botanicals and drugs or in establishing
mechanistic evidence for contraindication rationales.As stand-alone evidence,
laboratory studies with animals (in vivo) and/or with cell cultures (in vitro)
are insufficient to extrapolate the findings to oral dosing in humans. The reasons
for this are many. Animals differ from one another and from humans in their
abilities to digest, absorb, and/or metabolize the many different types of
components found in any complex botanical preparation. Animal studies often
utilize exaggerated doses to produce an effect that is more readily observed or
measure biochemically, but this exposure also may not correlate with typical
human dosage. In many animal studies on botanicals the use of injections helps
to maintain a consistent and reliable dosage, but systemic bioavailability of
the complete phytochemical complex does not accurately represent the partial
systemic exposure that follows digestion and absorption with oral dosing in
humans.
Similar
but distinct problems exists with laboratory studies utilizing cell cultures or
isolated organs. The exposure of living tissues to complex solutions extracted
from plants following intestinal absorption does not involve the same content
and proportion as is found in laboratory conditons where cells and tissues are
exposed to the complete extract. The pre- and postabsorption conversion of
various phytochemicals in the extract, potentially involving both activation
and/or deactivation from digestion and metabolism, does not occur to nearly the
same extent in cell monocultures and the nonreactive in vitro glass
environment. The concentration tested in vitro also often greatly exceed tissue
exposure in vivo. These issues call into question many of the so-called
“mechanisms of actions” that supply the basis for theoretical indications,
contraindications and interactions on which many speculate. In the case of
these in vitro laboratory studies, more may be learned about potential
mechanisms by studying the contribution of isolated components found in the
herbs and/or extracts, so long as the particular isolate has been shown to
absorbed systemically and is bioavailable in the sustained concentrations as
tested in the lab. The only direct application of herb or extract in vitro lab
data might be their local use on superficial tissues, i.e, the skin or mucosa,
or on associated microbial growth on these surfaces.
Contraindications
and Drug Interactions
AGAR p. 27
^ Gelidium spp.
thallus
Drug Interactions
III. + 1)
May inhibit absorption of oral drugs
such as aspirin, digitalis
and other cardiac glycosides, antibiotics,
and anticoagulants if administered
concurrently (speculative)150
AGAVE NEW
^ Agave
americana plant, juice
Contraindications
1) Pregnancy
(empirical)2 due to its emmenagogue and abortifacient effects
(empirical)74
ALFALFA p.
27
Medicago sativa
plant
Drug Interactions
I. + 2)
A kidney transplant patient maintained on azathioprine and cyclosporin
for 16 years suffered severe acute rejection after taking alfalfa and black
cohosh (Cimicifuga racemosa) for 6 weeks, though serum cyclosporine
levels were not altered. Anti-T-cell immunoglobulin and steroid helped control
transplant rejection. Immunostimulation through T-cell activition by alfalfa’s
l-canavanine is suspected as contributing to the kidney rejection (PO in human
case report).1553
II. 1)
CORRECTION: increase rate of metabolism of ETHOXYCOUMARIN
in the liver by increasing the activity of hepatic microsomal
mixed-function oxidase reactions (PO in mice)103
III. + 3) The cytotoxic effect of gemcitabine,
a standard drug for pancreatic cancer, on pancreatic cancer cells was inhibited
in the presence of coumestrol and genistein even when used at 2.5 times higher
concentration (in vitro)1681
ALOE p. 29
Aloe vera = Aloe
barbadensis gel (not the dried sap)
Contraindications
+ 2)
Allergic hypersensitivity to aloe preparations such as contact
dermatitis (empirical).1890
+ 3)
Pregnancy without professional advice (speculative) due to uterine
stimulant, abortifacient, and/or teratogenic effects (in vitro, PO in
rat study).1890
Drug Interactions
IV. + 1)
Following extensive bleeding in the surgical removal of a large hemangioma, this
effect was attributed in part to a possible interaction between sevoflurane
and the consumption of 4 tablets per day for two weeks of Aloe vera (PO
in human case report). It was not known whether the aloe tablets were a whole
herb product or contained an extract, nor were the tablets analyzed for
constituent or to detect potential adulterants. Sevoflurance inhibits COX
activity and TXA2, impairs platelets, and prolongs bleeding, while
aloe was suspected of contributing by reducing prostaglandin synthesis.1785
This speculation was based on a study of a water extract and successive
fractions with n-hexane, benzene, ethyl acetate, chloroform, acetone, and 96%
ethanol from Aloe vera dried gel. Only the water extract of the gel
reduced PGE2 production (in vitro).1786
ALOES p.
29
*Aloe vera,
Aloe ferox, or Aloe perryi dried leaf latex or sap
(not the gel)
Contraindications
8) Do not take during intestinal obstruction due to stimulation of peristalsis by the
anthroquinones (empirical).4,6,150,401
Causes of obstruction include stenosis and atony.1890
+ 13) Allergic hypersensitivity to
aloe preparations such as contact dermatitis (empirical)1890
+ 14)
Do not take if there is known dehydration due to depletion of water and
electrolytes (empirical).1890
Drug Interactions
IV. + 1) Following extensive bleeding in the surgical removal of a
large hemangioma, this effect was attributed in part to a possible interaction
between sevoflurane and the consumption of 4 tablets per day for two
weeks of Aloe vera (PO in human case report). It was not known whether
the aloe tablets were a whole herb product or contained an extract, nor were
the tablets analyzed for constituent or to detect potential adulterants.
Sevoflurance inhibits COX activity and TXA2, impairs platelets, and
prolongs bleeding, while aloe was suspected of contributing by reducing
prostaglandin synthesis.1785 This speculation was based on a study
of a water extract and successive fractions with n-hexane, benzene, ethyl
acetate, chloroform, acetone, and 96% ethanol from Aloe vera dried gel.
Only the water extract of the gel reduced PGE2 production (in
vitro).1786
AMERICAN
GINSENG p.
30
Panax quinquefolius root
Contraindications
1) Estrogenic activity, especially of alcoholic root
extracts, may be present in large part due to zearalenone and its metabolites
from Fusariam fungal contamination (in vitro).1695 In
addition estrogen-independent stimulation of human breast cancer cell
proliferation with the alcoholic extract (in vitro)1664
suggests that regular consumption of the root or its alcoholic extracts should
be avoided in those with a history of breast cancer (speculative)
Drug Interactions
I. + 1)
3 grams or more of the powdered root given prior to a glucose challenge reduced
blood sugar levels in seven type 2 diabetics whose condition was being treated
with sulfonylureas or a combination
of these and metformin (PO in human
study).1114
In 12 nondiabetic subjects 3 grams of the dried
cultivated root tended to lower plasma glucose at 90 minutes during a 75-gram
oral GTT, but the same dose of wild root raised blood sugar after 120 minutes
(PO in human study).1713 From 3-9 grams of the ground root improved glucose
tolerance following a 25 gram glucose challenge in 10 nondiabetics (PO in human
study).1685 However, different batches of the root from the same
supplier that differed in ginsenoside ratios were not consistent in reducing
blood sugar of normal subjects under the same experiemental conditions (PO in
human study).1596 Roots grown in Wisconsin have shown wide
variability in total and individual ginsenoside content from those grown in
Illinois.1714
A water extract of the root has been shown to
significantly lower blood sugar, probably due to the activity of several
glycans (IP in mice).1574
An alcoholic extract of the berries at 150 mg/kg daily in
diabetics also lowers fasting blood sugar and improves overall glucose
tolerance while lowering body weight (IP in mice).1704
+ 2)
2 grams of encapsulated powdered root for 3 weeks in healthy subjects
significantly reduced blood levels and anticoagulant effect of warfarin
(PO in human study). The peak INR decreased along with peak plasma warfarin,
compared to placebo.1600
II. + 1)
Hot water extract at 400 mg/100 gm given 10 minutes prior to ethanol delayed the effects of ethanol
on the righting reflex and reduced its plasma levels, probably due to the
additive effect of slowing of gastric emptying by alcohol and American ginseng extract or ginsenosides (PO in mice)1117
+ 2) The saponin fraction enhanced phenylephrine
vasoconstrictor effect (in vitro)1550
III. 1) Standardized extract synergistically increased suppression
of estrogen-dependent cancerous breast cells when combined with tamoxifen, cytoxan, doxorubicin, taxol
and methotrexate (in vitro).981
Tumor inhibition may be due in part to the
antiangiogenic activity of its predominant ginsenoside Rb1, the opposite effect
associated with Rg1 (in vitro, SC in mice)1686 However, an
alcoholic extract stimulated growth in the MCF-7 human breast cancer cell line
(in vitro), though it showed no estrogenic activity in failing to induce
transactivation of alpha- or beta-estrogen receptors (in vitro) or
increase uterine weight after 4 days (PO in mice).1664
In 3 digoxin immunoassays, an aqueous
American ginseng extract increased the digoxin measurement results for the
fluorescence polarization immunoassay (in vitro). Using the
microparticle enzyme immunoassay, this extract significantly lowered the serum
digoxin measurement (in vitro). No effect was found on the measurement
done by Tina-quant (in vitro).1995
AMERICAN PENNYROYAl
[formerly PENNYROYAL] p. 159
Ä *Hedeoma pulegioides plant
ANDROGRAPHIS NEW
^ Andrographis
paniculata
plant
Contraindications
1) Pregnancy due to its abortifacient effects
(empirical),150 antifertility effect in females at high doses (in
mice),777 and fetal damage (in animals)1890
2) Gastric hyperacidity such as duodenal ulcers
and esophageal reflux (empirical).1890
Drug Interactions
III. 1) Avoid long-term use with immunosuppressive drugs (speculative)1890 due to the activation of immunocompetent cells by its extract and component andrographolide (in vitro).1967
2) Caution should be used when taking with antiplatelet or anticoagulant medications (speculative),1890 since it inhibits platelet aggregation after consumption by cardiovascular disease patients (ex vivo).404,1890
ANISE p.
31
Pimpinella anisum
seed/fruit
Contraindications
+ 3)
CNS toxicity following consumption the tea, especially in nursing
mothers and/or their breast fed infants (PO in human case reports)1141
+ 4)
Pregnancy (speculative)150 probably due to its estrogenic
effects of its essential oil component anethole14 and the antagonism
of testosterone and progesterone by anise seed oil (injected in rats)1312
APRICOT NEW
^ Prunus armeniaca seed
(Ch. xing ren)
Contraindications
1) Self prescribing due to potential for adverse
effects from cyanogenic glycosides (speculative)150
2) Children due to increased vulnerability to
toxic and lethal effects from cyanogenic glycosides (empirical)150
Drug Interactions
II. + 1)
The absorption of sulfasalazine was increased 2- to 4-fold when taken with
apricot extract (PO in rats).2287
ARJUN NEW
^ Terminalia
arjuna bark
(Manipuri: Maiyokpha;
Tamil: Marutu; Malayalam: Nirmarutu; Kannada: Nirmatti)
I. 1) An extract given at
500 mg 3 times/day for 2 weeks improved symptoms of patients with Class IV refractory chronic
congestive heart failure compared to placebo, when given in a crossover design
to 12 patients taking digoxin, along with the diuretic drugs furosemide, and
spironolactone (PO in human clinical study). In addition, vasodilator prescriptions included 8 for enalapril,
3 for captopril, 1 for nifedipine, and 3 for isosorbide dinatrate. Antiarrhythmic medication amiodarone was used by 2 patients, while
all were administered potassium supplements. In an open continuation of the
trial for a mean of 24 months signs and symptoms continued improving for 2-3
months and were maintained throughout the study, while diuretic dosages were
reduced for all and other doses were kept flexible. After 4 months 9 patients
were at Class II and 3 at class III.2661
ARNICA p.
31
Arnica montana flowers
Contraindications
+ 6)
Internally by nursing mothers and not applied topically to the nipple,
due to potential toxicity to the infant (empirical).1890
ARTICHOKE p.
32
Cynara solymus leaves
Contraindications
1) Allergic
hypersensitivity to artichoke or other Asteracea [Compositae] family plants
(empirical),6,17,401,777,1890
though the likelihood of globe artichoke
preparations producing an allergic response is very low (empirical).1890
A man and a woman who handled artichokes in their
occupations suffered seasonal allergic eruptions and urticaria, respectively,
and tested positive to patch or skin prick tests, especially to the stem,
leaves, and their fuzz (TP in human case reports).1974,1975
2) Bile duct obstruction, due to its cholagogue
effect (empirical)6,17,401,777,1890
and its choleretic activity as shown with a single
1.9 gram dose of its 4.5-5:1 strength extract (PO in human study).1270
Drug Interactions
III. 1) It may enhance cholesterol-lowering
agents, due to additive effects (speculative).777
Tablets with 450 mg of a 25-35:1 aqueous extract
reduced total cholesterol, LDL cholesterol, and LDL/HDL ratio (PO in human
clinical study).1271
ASHWAGANDHA p. 33
Withania somnifera
root
Drug Interactions
II. + 2)
After 10 days of using 100 mg/kg of a commercial root extract, tolerance to morphine
analgesia was inhibited, and morphine dependence was blocked (PO in mice
study), suggesting that it could be of use in opiate addiction1277
+ 3)
Leucopenia induced by cyclophosphamide was significantly reduced by
ashwagandha methanolic extract (IP in mice). So, the intended cytotoxic
activity of this chemotherapeutic agent and its efficacy in treating cancer may
be diminished (speculative).1583
However, when 4/5 of the
total ashwagandha root extract
was combined with 1/5 Tinospora cordifolia stem extract or the
alkaloid-free polar ashwagandha extract
was given in cyclophosphamide-treated ascitic sarcoma, not only did the
extracts provide myelo- and immuno-protective activity, but the drug’s
antitumor activty was not altered when compared to cyclophosphamide given alone
(PO in mice).2217
Also, 20 mg daily for 5 days of the methanolic
extract was shown to reduce bladder damage caused by cyclophosphamide
metabolites, one of the leading causes of adverse effects from this drug (IP in
mice). Rather than severe inflammation and hemorrhage 4-48 hours after the
drug, when given the extract the bladder morphology was normal, the elevated
serum and urine protein levels were normalized, while the lowered liver and
bladder glutathione levels were enhanced.1279
However, the
discontinuity effects caused by cyclophosphamide on the GI mucous membrane with
bleeding spots in the lower esophagus and upper stomach were not affected by
ashwagandha extract, suggesting the extract’s inability to protect against general
cyclophosphamide cytotoxicity (PO in mice).1278
100 mg/kg root extract given for 15 days with
cyclophosphamide, azathioprin and prednisolone prevented the
myelosuppressive activity of these drugs by increasing the hemoglobin, red
blood cell and platelet counts for all three groups, and the white blood cell
count for the cyclophosphamide and prednisolone groups (PO in mice). The
response was different for azathioprin and prednisolone than with
cyclophosphamide in that it reflected more of a direct response of the immune
system to ashwagandha, rather than indirect modulation or interference with the
drug’s immunosuppressive action.1278
+ 4)
Pretreatment with 100 mg/kg extract enhanced the antiepileptic effects of diazepam
and clonazepam when convulsions were induced by lithium-pilocarpine
model (PO in rats)1290
+ 5) Adverse effects such as orofacial dyskinesia and poor memory retention induced by reserpine and associated with brain lipid peroxidation have been reversed dose-dependently by chronic use of ashwagandha root extract (PO in rats).1855
+ 6)
Increased levels of pertussis antibodies were detected after 100 mg/kg of a
water extract was given daily for 15 days after receiving a Diphtheria,
Pertussis, Tetanus [DPT] vaccine (PO in mice). When immunized
animals were challenged on day 14 with intracerebral pertussis, morbidity and
mortality were reduced in those that had been treated with the extract.2006
+ 7)
A decrease in benzo(a)pyrene-induced lung tumor markers AHH, GGT, and LDH in
the serum and lungs by paclitaxel was further decreased when ashwaganha
ethanol extract 400 mg/kg once weekly for 4 weeks was added to paclitaxel
treatment (PO in mice). Likewise, a further reduction of lung glycoprotein
markers was also noted with the combination, compared with use of paclitaxel
alone.2218
+ 8)
Catalepsy induced by haloperidol was reduced dose-dependently when an
ashwagandha water extract was given 30 minutes prior to haloperidol in the
acute study and for 6 days prior in the chronic study (PO in mice). The
reduction in catalepsy was correlated with superoxide dismutase levels in the
brain, indicating that the antioxidant activity of the extract could have
contributed to its effect.2295
9) In 3 digoxin immunoassays, 3 liquid hydroalcoholic extracts were fed to animals,
and the serum was tested and produced significant false positive apparent
digoxin concentrations (PO in mice). These results were confirmed for digoxin
with fluorescence polarization immunoassay but not for carbamazepine,
phenytoin, phenobarbital, valproic acid, procainamide, N-acetyl procainamide,
theophylline, gentamicin, tobramycin, acetaminophen, or salicylate (in vitro).2665 A 60-65% ethanolic
ashwagandha extract increased the digoxin measurement results for the
fluorescence polarization immunoassay (in vitro). Using the
microparticle enzyme immunoassay, this extract significantly lowered the serum
digoxin measurement (in vitro). No effect was found on the measurement
done by Tina-quant (in vitro).1995
asian GINSENG [Formerly GINSENG.] p. 107
Panax ginseng
root
Contraindications
1) High blood
pressure (empirical, human case report)150,361,404,777
However, 200 mg of a ginseng extract standardized to
4% ginsensosides reduced diastolic blood pressure 2 hours after ingestion.1298
2) Acute asthma
(empirical)404,777,1308
or other inflammation (empirical)1308
3) Acute infections404,777
accompanied by fever (empirical)1308
4) Excessive menstruation
or nose bleeds (empirical)777
due to platelet aggregation inhibition by
ginsenoside Rg1 (in vitro)1196 and ginseng
lipophilic fraction (in vitro, ex vivo),
and prolonged time of fibrinogen conversion to fibrin (ex vivo)
following a 25 mg dose of the lipophilic fraction (PO in rats)1194
However, 10 adults taking a
proprietary Asian ginseng product at the manufacturer’s recommended dose for 2
weeks had no increase in coagulation time in ADP and epinephrine assays of
intrinsic and extrinsic platelet function, respectively (ex vivo), but
the product was not analyzed for its phytochemical content.2262
+ 5)
Headaches, palpitations or strong pulse, or insomnia since
ginseng can cause these in some people (empirical)1308
+ 6)
Anxiety, nervousness or emotional imbalance due to its
enhancement of the sympathetic nervous system (speculative),1308 or
in those with clinical affective disorders such as major depression
who may experience a manic state (PO in human case report)27,560,1461
+ 7)
Pregnancy due to possible estrogenic effects (speculative)1308
Estrogenic activity, especially of alcoholic extracts,
may be present in large part due to zearalenone and its metabolites from Fusariam
fungal contamination (in vitro).1695
One study of 88 pregnant women suggested an increase risk
of adverse fetal outcome (PO in human study).1509
Ginsenoside Rb1 at concentrations of 30-50
mcg/ml increased teratogenic effects in whole rat embryos (in vitro),1485
results with uncertain implications for women taking the whole root or complex
extracts in typical doses.
+ 8)
Brittle type 1 diabetes (speculative)893 because of the hypoglycemic
effect in diabetic patients (PO in human clinical study),109
probably due to the glycans of ginseng roots known as panaxans (IP in mice)567-569
and/or ginsenoside Rb2 that lowered blood sugar in diabetics (IP in
rats).72
However, the anti-hyperglycemic activity was
not confirmed as a hypoglycemic effect, since doses ranging from 1 to 9 grams
of powdered root in a randomized, multiple-crossover design did not
significantly affect plasma glucose or insulin following an oral glucose
tolerance test (PO in human study). Rather, the 2-hour plasma glucose was
significantly higher in pooled results.1612 Also, effects in 12
nondiabetic subjects on 75-gram oral glucose tolerance test responses to 3
grams of dried root varied according the type of ginseng. The dried whole root
was found to raise plasma glucose, whereas Asian-red ginseng steam-treated root
had no effect (PO in human study).1713 Compound K, the main gut
bacterial metabolite of protopanaxadiols, enhances glucose transport rate,
while the major protopanaxatriol Rg1 inhibits glucose transport across
intestinal cells (in vitro) These act by modulating the sodium/glucose
cotransporter 1 gene expression (in vitro).2043
An alcoholic extract of the berries at 150 mg/kg daily in
diabetics also lowers fasting blood sugar and improves overall glucose
tolerance while lowering body weight and plasma cholesterol levels (IP in
mice). The antihyperglycemic activity, but not the anti-obesity effect, is due
in large part to ginsenoside Re.1705
+ 9)
Use at least one week, and definitely in the 24 hours, prior to surgery
due to short term potential for hypoglycemia and long term potential for
decreased coagulation leading to hemorrhage (speculative).1309,1310
The hypoglycemic effect appears to be due to the glycans of ginseng roots known
as panaxans (IP in mice).567-569 Diminished coagulation may be
attributed to panaxynol, ginseng lipophilic fraction, and some ginsenosides’s
antiplatelet activity (in vitro410,565,1194,
1196 and lipophilic fraction ex vivo1194), and
prolonging time of fibrinogen conversion to fibrin by ginsenoside Ro (in
vitro)565 and ginseng lipophilic fraction (ex vivo) following a 25 mg dose of
the lipophilic fraction (PO in rats),1194 and the potent platelet
activating factor antagonism of several ginsenosides (in vitro).718
However, 10 adults taking a
proprietary Asian ginseng product at the manufacturer’s recommended dose for 2
weeks had no increase in coagulation time in ADP and epinephrine assays of
intrinsic and extrinsic platelet function, respectively (ex vivo), but
the product was not analyzed for its phytochemical content.2262
Drug
Interactions
I. 1) Caffeine with
large amounts of “ginseng” led to hypertension, nervousness, diarrhea, skin
eruptions and insomnia in 14 subjects (PO in human case series).108
Caffeine metabolism by CYP 1A2 was not affected when
1.5 gm of ginseng standardized to 5% ginsensosides was consumed daily for 4
weeks. CYP 2D6, 2E1, and 3A4 were also unaffected (PO in human study).1328
3) Phenelzine
produced manic-like symptoms with the use of ginseng (human case reports).26,27
However, the “Natrol High”
product that supposedly contained Asian ginseng in one report26
actually contained the generically- and phytochemically-distinct eleuthero or
“Siberian ginseng” (Eleutherococcus senticosus) as part of a combination
product. Positive identification of ginseng and its causality in the other
report was not established. This interaction was still assessed as possible due
to the evidence in latter report, while the former was described as unevaluable
based upon its inadequate data.1239
+ 5) When 5.4 gm of red Korean ginseng were
taken daily with zidovudine by HIV-1 infected patients for 4-6 years, it
effectively maintained their CD4+ T cell counts and delayed development of
resistance mutations to zidovudine (PO in human clinical study).1335
In addition to zidovudine, red ginseng use with nucleoside reverse
transcriptase inhibitor (NRTI) didanosine lowered resistance
mutations, but not for lamivudine, and no multinucleoside drug resistance
mutations were detected (PO in human clinical study).1336
+ 6)
Following surgical removal of stage III gastric cancer in 42 patients, 4.5
grams daily of red ginseng powder doubled 5-year and overall survival rates and
improved CD3 and CD4 levels compared to placebo, while patients were also given
chemotherapy with 5-fluorouracil and cisplatin (PO in human
clinical study).1382
+ 7)
200 mg daily of the standardized extract G 115 given 4 weeks prior and 8 weeks
after a polyvalent influenza vaccine resulted in significantly fewer
cases of influenza and the common cold during the 8 weeks following vaccination
than in the group receiving placebo. The antibody titers and natural killer
cell activity were also much higher in those receiving the extract, along with
no significant differences in adverse effects (PO in human clinical study).408
+ 8)
200 mg/day of uncharacterized "ginseng" for 18 days inhibited
metabolism of CYP 3A4 substrate nifedipine, as indicated by increased
peak plasma concentration of 29% (PO in humans).1728
However, daily doses for 28
days of 1.5 gm Asian ginseng standardized to 5% ginsenosides failed to alter
the metabolism of CYP 3A4 substrate midazolam in humans (PO in human study).1328
Likewise, 200 mg/day for 14 days of ginseng extract standardized to 4%
ginsenosides failed to alter cortisol metabolism in 20 subjects (PO in human
study).1811
+ 9)
A woman treated for major depression with clomipramine and haloperidol
became manic with the use of 300 mg/day of a ginseng root extract (PO in human
case report).1461
Clomipramine is a substrates for CYP 2D6, while
haloperidol is a substrate for CYP 3A4. A daily dose of 1.5 grams of an Asian
ginseng product standardized to 5% ginsenosides inhibited metabolism of the
substrate debrisoquin CYP 2D6 by 7% and an uncharacteried product inhibited CYP
3A4 as shown by increasing the peak plasma concentration of substrate
nifedipine by 29% (PO in human studies),1728,1808 though
standardized ginseng extracts with other 3A4 substrates showed no altered
bioavailability (PO in human studies).1328,1811
10) [Previously III.2.] Warfarin anticoagulant
activity was reduced as the INR fell from 3.1 to 1.4 following several weeks of
taking ginseng extract G 115 capsules 3 times daily (PO in speculative human
case report). Two weeks after the extract was discontinued, the INR returned to
3.3.110
Nonetheless, in a diabetic man with aortic valve
prosthesis, a thrombus interfered with the artificial leaflets valve in
conjunction with a reduction of INR to 1.4 in spite of increasing warfarin
dosage, following use of an undisclosed commercial ginseng product used at an
unreported dose for an indefinite time (PO in human case report).1986
However, a study of 25
ischemic stroke patients given warfarin with or without 1.5 grams/day of an
11:1 aqueous ginseng extract for 2 weeks did not result in any differences in
INR or prothrombin time between the two groups (PO in human clinical study).2326
When 1 gram solid Korean red ginseng aqueous extract daily was given for 6
weeks to patients using warfarin, there were no significant changes in INR
after 3 or 6 weeks, compared to placebo (PO in human clinical trial).2625
Furthermore, an open-label 3-way crossover randomized trial with 12 healthy
subjects found that ginseng extract daily providing 53.6 mg ginsenosides
derived from 3 grams of the root given 7 days before and after a single
warfarin dose does not affect warfarin clearance, INR, or platelet aggregation
(PO in human study).1578 In this study the apparent clearance was
increased by 14%, but this seems unlikely to have clinical significance
(speculative).2016
+ 11)
A randomized, double-blind, crossover trial using Korean ginseng rootlets in
capsules at doses of 2 grams 3 times daily before meals for 12 weeks in 19
patients with well-controlled diabetes type 2 treated with diet plus hypoglycemic
drugs alone or in combination in 14, including sulfonylurea in 10, metformin
in 9, rosiglitazone in 2, and acarbose in 1; this resulted in
reduction in oral glucose tolerance test indices by 8-11% and plasma insulin by
33-38% (PO in human clinical study). It also increased insulin sensitivity
indices by 33% compared to placebo. The rootlets had total ginsenoside
concentration of 1.92% with content of protopanaxadiols Rb1 0.48%, Rc 0.29%,
and Rb2 0.25%, along with protopanaxatriols Rg1 0.51% and Rf 0.23%.2042
Ginseng extract’s anti-hyperglycemic effect was
shown in non-insulin-dependent diabetic patients when 200 mg daily was given
orally for 8 weeks (PO in human clinical study).109 Ginseng extract
G115 at single doses of 200 mg and 400 mg reduced fasting blood glucose levels
in 30 healthy young adults after 60, 90 and 120 minutes (PO in human study).2153
However, the
anti-hyperglycemic activity was not confirmed as a hypoglycemic effect in
healthy subjects, since doses ranging from 1 to 9 grams of powdered root in a
randomized, multiple-crossover design did not significantly affect plasma
glucose or insulin following an oral glucose tolerance test (PO in human
study). Rather, the 2-hour plasma glucose was significantly higher in pooled
results.1612 When given with a 25-gram glucose drink to 27 healthy
subjects, 200 mg of G115 actually raised blood sugar levels after 1 hour but
had no effect after 2 hours, compared to controls (PO in human study).2153
Also, effects on
75-gram oral glucose tolerance test responses in 12 nondiabetic subjects given
3 grams of dried root varied according the type of ginseng. The dried whole
root was found to raise plasma glucose, whereas Asian-red ginseng steam-treated
root had no effect (PO in human study).1713 Compound K, the main gut
bacterial metabolite of protopanaxadiols, enhances glucose transport rate,
while the major protopanaxatriol Rg1 inhibits glucose transport across
intestinal cells (in vitro) These act by modulating the sodium/glucose
cotransporter 1 gene expression (in vitro).2043
II. + 3)
Extract G115 increased intestinal clearance of the active metabolite albendazole sulfoxide (IV in rats)1711
+ 4) An acidic polysaccharide fraction of red ginseng, derived from the marc following 85% ethanol extraction, combined with paclitaxel increased life span with transplanted sarcoma 180 by 29-43% at 25 mg/kg and reduced B16 melanoma tumor weight by 76% at 100 mg/kg, compared to the results from using paclitaxel alone (IP in mice)1721
+ 5)
The use of the 5 grams/day of the root as a decoction for 30 days along with doxorubicin
(adriamycin) given by intraperitoneal injection over a 2-week period reduced
the physical and biochemical signs of heart failure associated with the drug
(PO in rats).2257
III. + 1) Insulin dosage may need adjusting (speculative) because of ginseng extract’s hypoglycemic effect in diabetic patients (PO in human clinical study).109
Effects in 12 nondiabetic subjects on 75-gram oral
glucose tolerance test responses to 3 grams of dried root varied according the type of
ginseng and the protopanaxadiol to protopanaxatriol ratio. The dried whole root
was found to raise plasma glucose, whereas Asian-red ginseng steam-treated root
had no effect (PO in human study). The Asian-red protopanaxadiol content and
ratio were greater.1713
A randomized study found that while 6 grams Korean red
ginseng root body and water extract were ineffective in reducing glycemia from
a 50-gram glucose tolerance test, the rootlets were effective (PO in human
study). A dose of 2 grams of rootlets was found to be equally effective, and
the ginsenoside Rb1 was identified as the sole predictor of effects on
postprandial glucose.1977
However, another study with 27 young healthy
subjects showed that the extract G115 at single 200 mg doses lowered fasting
blood sugar from 60-120 minutes compared to placebo, but when given with a
drink containing 25 grams of glucose it raised blood glucose levels more than
when glucose was given alone (PO in human study).2018
An ethanolic extract of ginseng berries that differed in
ginsenoside proportions had an even greater anti-hyperglycemic and anti-obesity
effects than the root extract (IP in mice).1597 The alcoholic
extract of the berries at 150 mg/kg daily in diabetics also lowers fasting
blood sugar and improves overall glucose tolerance while lowering body weight
and plasma cholesterol levels (IP in mice). The antihyperglycemic activity, but
not the anti-obesity effect, is due in large part to ginsenoside Re.1705
2) [See IV. 2)]
+ The
synergistic cytotoxic effect of the chemotherapy drug mitomycin C
combined with ginseng component panaxytriol was shown on gastric carcinoma MK-1
cells (in vitro).1712
3) [Formerly IV. 1)] Using 5 digoxin
immunoassays on 2 liquid Asian ginseng extracts and 1 capsule, one liquid
increased the digoxin concentration results only for the fluorescence
polarization immunoassay (in vitro, ex vivo with rats, ex vivo with
humans). Using the microparticle enzyme immunoassay, the liquid extract
significantly lowered the serum digoxin measurement (ex vivo with
humans).1352,1995
IV. 1) [See III. 3]
ASPARAGUS p.
34
Asparagus racemosus root
Drug
Interactions
II. + 1)
Increased levels of pertussis antibodies were detected after 100 mg/kg of a
water extract was given daily for 15 days after receiving a Diphtheria,
Pertussis, Tetanus [DPT] vaccine (PO in mice). When immunized
animals were challenged on day 14 with intracerebral pertussis, morbidity and
mortality were reduced in those that had been treated with the extract.2006
ASTRAGALUS p.
34
Astragalus
membranaceus root
Contraindications
+ 2)
Allergic hypersensitiviy or autoimmune conditions, since they may
be aggravated due to immunostimulating polysaccharides (speculative).409
+ 3)
Following organ transplantation due to immunostimulating polysaccharides
(speculative).409
Drug Interactions
I. 1) The effects of recombinant interferon-a1
were therapeutically enhanced with an astragalus preparation that improved the
outcome in chronic viral cervicitis associated with human papillomavirus type
16 and herpes simplex virus type 2 (human clinical study).2359
+ 2) A meta-analysis compiled
34 randomized trials that combined astragalus herbal formulas with chemotherapy
regimens based on cisplatin for non-small-cell lung cancer in 2,815
patients. The data showed that chemotherapy plus oral astragalus formulas such as
Jin Fu Kang, or Ai Di Zhu She Ye injections containing astragalus used 8
studies, improved outcomes versus chemotherapy alone (PO or IV in human
clinical studies). Seven studies (529 patients) showed reduced risk of death
after 6 months, twelve (940 patients) after 12 months, nine (768 patients)
after 24 months, and six (556 patients) after 36 months. One of the studies
reducing this risk from 12-36 months used astragalus alone, rather than in a
formula. Tumor response rate favored the combination with herbs in 29 of 30
studies reporting this data, including two with astragalus alone. Karnofsky
performance status was stabilized or improved in one study with astragalus
alone, two studies with Jin Fu Kang, four studies with Ai Di Zhu She Ye, and
five studies with other astragalus formulas, totaling 1,095 patients.1851
Astragalus decoction enhanced immune function by increasing proliferation of
spleen cells, increasing B cell IgG production, enhanced induction of cytoxic T
cells, and increased macrophage cytokine production of IL-6 and TNF (in
vitro).1852
II. 2) The hydroalcoholic extract induced Th cells and enhanced
antibody response following use of cyclophosphamide
(IP in mice).599
A partially purified fraction completely reversed
immunosuppression induced by cyclophosphamide (IV in rats).1504
Another fraction of the water extract of the roots
was shown after 6 days to increase proliferation of colony-forming
unit-fibroblast proliferation and improve bone marrow stromal cell survival,
its production of IL-6, and expression of mRNA and bcl-2 protein, which helps
promote blood cell formation after cyclophosphamide myelosuppression (IP in
mice).2212
So, if cyclophosphamide is being used for treatment of lymphomas or leukemias or to prevent graft rejection, concurrent use of astragalus could have an undesirable antagonistic effect to the immunosuppression.
BACOPA new
^ Bacopa monniera =
Herpestis monniera whole plant
(Brahmi; Ind.: Brahmi Patra)
Drug Interactions
II. 1) Both cold aqueous infusion and 95%
alcoholic extract potentiated sleep induced by pentobarbital,
though the water extract was much more active (IP in rats)1291
2) Dried alcoholic extract at 40
mg/kg prevented increased lipid peroxidation and decreased antioxidant enzymes
in liver caused by morphine
when the two were given concurrently (PO in rats).1661 In addition,
prior exposure of intestinal ileum to the alcoholic extract before exposure to
morphine reduced the subsequent naloxone-induced contraction of the ileal
tissue (in vitro), suggesting a possible use in reducing morphine
withdrawal symptoms.1662
3) After using phenytoin for 7 days cognitive deficit demonstrated in
a passive avoidance task was reversed by 40 mg/kg dried alcoholic extract given
concurrently for the next 7 days (PO in mice), suggesting possible use to
prevent this adverse drug effect. Acquisition and retention of memory were also
improved, and phenytoin's anticonvulsant activity was not affected.1663
BARBERRY p.
35
Contraindications
+ 9)
Do not use in nursing mothers without professional advice (speculative), since berberine is passed
through the breast milk to the infant1890 and displacement by
berberine of bilirubin from serum albumen which may lead to kernicterus (IP in
rats).1092
Drug
Interactions
I. + 3)
Berberine 1.2 grams daily, given as tablets to 79 congestive heart failure
patients on ACE inhibitors along with digoxin in 76, nitrates
in 71, and diuretics / spironolactone in 77, significantly increased
left ventricular ejection fraction and exercise capacity, improved
dyspnea-fatigue index, and reduced frequency of ventricular premature complexes
compared with 77 patients using only comparable conventional medications. The
mortality of the berberine group decreased significantly as well, and there
were no apparent side effects (PO in human clinical study).1457 In
56 congestive heart failure patients on loop diuretics and ACE inhibitors,
including 51 using digoxin and 46 on nitrates, the significant increases in
left ventricular ejection fraction and decreases in ventricular premature beats
from baseline from 1.2 grams of berberine daily was also significant better
when plasma berberine concentrations were higher versus lower than 0.11 mg/L
(PO in human clinical study).2639
+ 4)
Berberine at 0.6 grams daily for 3 months increased previously stabilized cyclosporin
A trough blood concentrations by 90% in 52 renal transplant patients,
and when given for 12 days to 6 transplant patients increased the cyclosporine
bioavailability by 35% (PO in human clinical study), likely by inhibition of
CYP 3A4 (speculative).2281
+ 5) The combination of 500 mg berberine 3 times
daily for 3 months in 43 patients with poorly-controlled type 2 diabetes together
with one or more of their regular oral hypoglycemic medications
including sulfonylureas in 28, metformin in 20 acarbose in
15, and/or insulin in 10 resulted in lower fasting and postprandial
blood sugar from week 1 through week 12 (PO in human clinical study). Fasting
plasma insulin was also lowered by 28% and an index of insulin resistance by
45% of those on medications, while total cholesterol and LDL were likewise
reduced. In 31 newly diagnosed type 2 diabetics to whom 15 were given the same
dose of berberine and 16 used 500 mg metformin 3 times daily, berberine’s
hypoglycemic effect was similar to that of metformin on fasting and
postprandial blood glucose, as well as reducing glycosylated hemoglobin and
plasma triglycerides (PO in human clinical study). Transient gastrointestinal
adverse effects were experienced by 35% of the patients, or 20 in total.2315
II. 1) The antitumor constituent berbamine (20 mg/kg once daily
for 7 days) significantly enhanced antitumor activity of cyclophosphamide against Walker tumor (IP in rats).398
When the alkaloid component berberine was given once
or twice at doses of 50, 100, or 200 mg/kg before cyclophosphamide injection,
it significantly reduced the chemotherapy adverse effect of bladder hemorrhage
in a dose-dependent manner (IP in rats).2570
2) Berberine administered prior to pentobarbital increased the induced sleeping time (IP in mice)1032
A single 4 mg/kg dose of berberine prolonged pentobarbital sleeping time and increased strychnine toxicity (PO in rats)1215
+ 3) Pre-treatment with 4 mg/kg berberine prevented a rise in
serum levels of liver enzymes from excessive acetaminophen, suggesting
protection from its toxic effects (PO in rats). Use of this dose three times
every six hours following a toxic dose of acetominophen reduced liver damage.1215
+ 4) Berberine at 100 mg/kg enhanced the anxiolytic
effects of buspirone and ritanserin but did not interact with
diazepine (PO in mice).2668
III. 3) Berberine increased efflux of rhodamine 123 and paclitaxel by inducing P-glycoprotein and thereby reducing the retention and concentration of these drugs in human hepatoma and digestive tract cancer cells, respectively (in vitro)1045,1046
+ 4)
Studies in human liver-derived cells with berberine was found to have an
additive effect with lovastatin by increasing LDL receptor mRNA
expression (in vitro). This statin did not reduce this effect of
berberine, indicating a different mechanism of action (in vitro). In 63
high-cholesterol subjects taking 1.0 grams berberine HCl daily for 3 months,
serum cholesterol was reduced 18%, LDL cholestreol 20%, and triglycerides 28%,
compared to those using placebo (PO in human study). In the 32 who were taking
no other medication or herbs, cholesterol was reduced 29%, LDL cholesterol 25%,
and triglycerides 35%. HDL cholesterol was unaffected, and berberine was well
tolerated. Berberine was found to have a dose-dependent cholesterol-lowering
effect (in hamsters).1656
+ 5)
Do not combine with phenylbutazone or other drugs that displace protein
binding of bilirubin (speculative),1890 since displacement by
berberine of bilirubin from serum albumen which can lead to kernicterus (IP in
rats).1092
BASIL p.
37
Ocimum basilicum plant
Drug Interactions
III. + 1)
Alkaline aqueous extracts of basil were shown to potentiate insulin
activity in glucose metabolism (in vitro).1464
BEEBALM NEW
^ Monarda spp. plant
(Oswego tea, mountain balm/ wild begamot; horsemint;
spotted beebalm)
Contraindications
1) Pregnancy due to the emmenagogue and uterine
stimulant activity (empirical)150
BETH
ROOT NEW
^ Trillium erectum root
(birth root, purple trillium, wakerobin)
Contraindications
1) Pregnancy due to emmenagogue activity
(empirical)150
2) Stomach or intestinal irritation due to its
irritant properties (empirical)150
BILBERRY p.
38
Vaccinium myrtillus
fruit
Drug
Interactions
II. 1) CORRECTION: anti-ulcer activity demonstrated by its 25%
ANTHOCYANIDIN extract was shown by one of its aglycone components (PO in rats).624
III. 1) Warfarin and antiplatelet drugs may be enhanced at
high doses (speculative).777,1890
CORRECTION: The prostaglandin modulation by the
anthocyanosides enhances antiaggregatory processes (in vitro;1084,1086 EX VIVO AFTER PO in rats,684,1086). A daily dose of 480 mg
of an extract containing anthocyanosides (equivalent to 120 mg daily of
anthocyanidins) led to decreased platelet aggregation after 30 days that
decreased further after 60 days (EX VIVO AFTER PO in humans).1085
On the other hand bilberry anthocyanins tended to
reduce retinal hemorrhage due to anticoagulant therapy (in humans) and the
extract reduced post-surgical bleeding complications (empirical).1316
BIRCH p.
38
Betula pendula =
Betula alba leaves or bark
Drug
Interactions
I. + 1)
Warfarin potentiation was determined with 11 patients who concurrently used
ointment containing methyl salicylate, the primary component of birch bark oil.
All of the patients had unusually high INRs after extensive topical use of the
ointment, based on patient history and salicylate blood levels. One had GI
bleeding, 2 were bruising, and 3 had other bleeding events (topically in human
case reports).1392 Several other cases with the same etiology
resulted in significant bleeding problems requiring plasma infusion or
temporary cessation of warfarin intake in 2 cases. A similar case with simply
an elevated INR of 12.2 occurred after applying a low-dose methyl salicylate
gel to both knees for 8 days (topically in human case reports).714,1393,1394
Another case of local application to arthritic knees for two weeks increased
the INR to 6.1 and resulted in multiple bruising.1426 Still another
warfarin case had bleeding and a doubled prothrombin time after using large
amounts of methyl salicylate over arthritic joints (topical in case reports).1427
The methyl salicylate may affect vitamin K metabolism or displace warfarin from
protein binding sites (speculative).1394
BITTER MELON p.
39
Momordica charantia
fruit and its juice
Contraindications
+ 2) Brittle type
1 diabetes (speculative)893
due to hypoglycemic effects in normal and diabetic animals (PO in rats)746-749
and in healthy and diabetic humans when using the cooked fruit, juice or
extract (PO in human studies)34,35,745
Drug
Interactions
II. + 1)
A combination of 500 mg/kg daily each of bitter melon dried juice and an
Ayurvedic preparation of zinc (Jasad Bhasma) reduced fasting blood sugar and
increased the hypoglycemic effect of 250 and 500 mg/kg tolbutamide (PO
in rabbits)1544
However, in a study with
type 2 diabetics using oral hypoglycemic drugs who were given 2 capsules
of fruit and seed extract 3 times daily, no change in glycosylated hemoglobin
or fasting blood sugar was seen after 3 months when compared to placebo (PO in
human clinical study).2275
BITTER ORANGE p.
40
Citrus aurantium fruit, peel, or juice
(Port.: laranja-amarga, laranja-azeda,
laranja-cavalo; Ch.: zhi shi; Jap.: kijitsu; Kor.: chisil)
Contraindications
+ 4)
Avoid juice in severe high blood pressure, rapid heart rate, and
narrow-angle glaucoma due to its content of the adrenergic synephrine
(speculative).1421 A single 900 mg dose of a dried fruit extract standardized
to 6% synephrine significantly
raised systolic and diastolic blood pressures and heart rate (PO in human
study).1867
However, in other tests with
the dried fruit extract standardized to 6% synephrine, a single dose of 450 mg
did not raise blood pressure (PO in human study).1866 Also, 8 oz. did not affect blood
pressure or heart rate in normal subjects (PO in human study)1421
Drug
Interactions
I. 1)
The juice consumed by 11 subjects at a dose of 200 ml increased dextromethorphan bioavailability both
by inhibiting intestinal CYP 3A and affecting an intestinal transport protein
(PO in human study).2666
II. + 1)
Essential oil from the peel at 0.5-1.0 gm/kg increased the sleeping time
induced by pentobarbital (PO in mice).1626
+ 2) In a crossover study 200 ml of decoction
of 20 gm of the fruit increased the maximum concentration of cyclosporine
by 64% and resulted in acute toxicity in 1 of 5 subjects (PO in swine).2028
Enhanced absorption of cyclosporine may occur due to the inhibition of CYP 3A4,
as shown by a 40% reduction following consumption of 8 oz. of the juice (PO in
human study).1031
However, an uncharacterized
bitter orange product lacking the CYP3A4-inducing compound
6,7-dihydroxybergamottin failed to alter bioavailability of 3A4 substrate
midazolam in 12 subjects after 4 weeks (PO in human study).1589
III. + 1) Use of the juice with monoamine
oxidase inhibitors (MAOIs) should be avoided (speculative) due to
its content of the synephrine (speculative), even though 8 oz. did not cause
adrenergic cardiovascular effects in normal subjects (PO in human study)1421
+ 2)
Use of the juice with drug substrates of CYP3A4 may lead to their
enhanced absorption due to the reduction of this isozyme by 40% following
consumption of 8 oz. of the juice (PO in human study).1031
However, an uncharacterized
bitter orange product lacking the CYP 3A4-inducing compound
6,7-dihydroxybergamottin failed to alter bioavailability of 3A4 substrate
midazolam in 12 subjects after 4 weeks (PO in human study).1589
+ 3)
Consumption of the juice with decongestant cold preparations (presumably
containing pseudoephedrine, an alkaloid similar to synephrine in the juice)
should be avoided (speculative).1421
BLACK CHERRY [formerly WILD
CHERRY] p. 198
Ä *Prunus serotina bark
BLACK COHOSH p.
40
*Actaea racemosa = Cimicifuga
racemosa roots/rhizome
Contraindications
1) Avoid in pregnancy
during the first trimester2
due to its emmenagogue possible uterine stimulating
effect (speculative).2141
However, only low-level
evidence is available that indicates the need to use it with caution and
rigorous high-quality studies with humans are needed to better determine its
safety in pregnancy.2141
2) Black cohosh preparations are inappropriate for use
with nursing mothers150,777,1890
due to its possible hormonal effects (speculative).2141
However, only low-level
evidence is available that indicates the need to use it with caution and
rigorous high-quality studies with humans are needed to better determine its
safety in lactation.2141
3) Estrogen-dependent
tumors including some breast cancer
due to potential estrogenic activity (speculative).777
However, black cohosh and its
ethanolic and isopropenolic extracts were found to significantly reduce breast
cancer risk a case-control study involving 949 breast cancer cases and 1524
controls, whether cancers were of estrogen receptor-postitive or -negative
status (PO in human study).2114 In 61 menopausal women taking 80 mg
daily of black cohosh extract containing 2.4% 23-epi-27-deoxyactein, including
45 who used the extract the full 24 weeks, no significant effect on estrogenic
markers in the serum or on cellular mophology in nipple aspirate fluid was
detected (PO in human clinical study).2494 In addition, animals with transplanted
breast cancer and with their ovaries removed were given either synthetic
estrogen (mestranol) positive control, two different doses of an isopropanolic
extract of black cohosh, or the vehicle negative control daily for 6 weeks.
Only those receiving mestranol had enhanced cancer growth at the end of the
study (PO in rats).1383
Also, the isopropanolic extract inhibited cell proliferation in a human breast adenocarcinoma test system (MCF-7) and inhibited estrogen-induced growth of this system (in vitro).1384 The liquid ethanolic extract failed to induce proliferation of the MCF-7 human breast cancer cell line or transactivation of either human alpha- or beta-receptor (in vitro) or increased uterine weight after 4 days (PO in mice).1664 Both the isopropanolic and ethanolic extracts were shown to dose-dependently inhibit growth and induce apoptosis of both estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB231 breast cancer cells (in vitro). The effective concentrations were lower for the isopropanolic extract.1719 Unlike tamoxifen that stimulates estrogen endometrial adenocarcinoma tumor growth, the isopropanolic extract did not increase this growth or metastasis to lymph nodes or lungs in rats when given alone or combined with tamoxifen (PO in rats).1697 Black cohosh as a 40% 2-propanol extract binds to serotonin receptors of the hypothalamus (in vitro), which, rather than any estrogenic activity, may explain its reduction of hot flashes (speculative).2031 The black cohosh 40% isopropanolic extract at 40 mg per day for 12 weeks was shown to have no effect on estrogen concentrations or luteinizing hormone [LH] pulsatility in postmenopausal women (PO in human clinical study). Nonetheless, with naloxone blockade it did suppress LH pulsatility especially during sleep, and its m-opioid receptor binding ranged from 10-61% across brain regions involved with emotional and cognitive functioning.2495
+ 4)
Signs or symptoms indicative of liver dysfunction such as tiredness,
loss of appetite, yellowing of skin or eyes, dark urine, or severe upper
stomach pain with nausea and vomiting after using black cohosh products are
reasons for its discontinuation and avoidance in these individuals (empirical),
due to its association with nearly 3 dozen hepatotoxicity cases in Europe plus 8 published
case reports.1901
Fulminant liver failure in two women in their 50s
followed use of 500-1000 mg/day of black cohosh root for 5-8 months (PO in
human case reports). Both had high bilirubin, aminotransferases, Alk Phos, and
INR, when other probable causes were screened out.1902,1903 One of
the women drank 2 glasses of wine daily as a probable contributing factor; she
had fatigue, weight loss, and upper right abdominal tenderness. Two weeks after
her exam she developed encephalopathy and died from hemorrhage during
transplantation surgery on day 39. Both autoimmune and drug-induced liver
damage were deemed probable after analysis.1902 The other had
jaundice, dark urine and light stools; 1 week after prednisone treatment for
possible autoimmune hepatitis, her aminotransferase levels improved but INR
increased. She developed encephalopathy from the acute hepatitis and underwent
a successful liver transplantation. Temporal association with long-term black
cohosh use prior to this acute episode was the only evidence implicating it as
a causative factor.1903
A 57 year-old woman taking 6 other medications for
over 2 years used black cohosh tablets of unknown brand or dose for 1 week prior to developing
fatigue and lethargy; she saw a doctor 2 weeks later (PO in human case
report).Her anti-nuclear antibody titer and liver biopsy suggested autoimmune
hepatitis. Symptoms resolved in two weeks after withdrawing black cohosh and
tapering steroids. Liver function tests were normal at nine weeks. After 4 months symptoms and signs
recurred, but steroid treatment had rapid success.1909
However, problems with these
reports include a lack of analytical verification of the product contents,
insufficient exclusion of other potential causes, and an implausible proposed
mechanism.1905,1906 An assessment by the European Medicines Agency
concluded that, of 42 patients suspected of severe hepatotoxicity related to
black cohosh use, only 16 were sufficiently documented and in only 4 ot these
was the causality possible or probable.1901 A diagnostic algorithm
applied to these 4 patients that utilized conventional causality assessment
factors allowed an objective analysis of the data to show that 1 patient was
not assessable and the other 3 were unrelated to drug use, including black
cohosh. In 2 cases the steroid therapy possibly augmented the hepatotoxicity
that was finally established as herpetic hepatitis, leading to transplantation
is both cases and the death of one.2490 The steroid therapy employed
in these cases was effective only in one that was finally diagnosed as
autoimmune hepatitis.1909 In a 12-month study of 22 peri- or
postmenopausal women using a 128 mg daily of a dry extract made with a 75%
ethanol solvent and standardized to7.3 mg triterpene glycosides, no elevation
of liver function tests for ALP, ALT, or AST showed significant elevation
compaired to 22 similar women in the placebo group. (PO in human clinical
study).2596
Other cases associated with hepatotoxic effects did
not document such high or prolonged dosage. A 47 year-old woman who used a
black cohosh product for one week developed jaundice and elevated
aminotransferases, but fibrosis from her liver biopsy is indicative of months
of hepatotoxin exposure. She required a liver transplant after two weeks (PO in
human case report). Another hepatotoxicity case with a 43-year-old woman involved use of a
multi-herb preparation (skullcap, valerian, black cohosh, passionflower, dong
quai, hops, oat, chasteberry) with potential adulterants (PO in human case report).1904
Hepatotoxicity associated with black
cohosh fluid extract in a 52-year-old women with jaundice from acute liver
failure showed low serum albumin and high serum bilirubin, Alk Phos, ALT, and
GGT, along with an elevated INR of 3.0. She had taken a mixture of fluid
extracts for 3 months but had ceased their use 4 weeks prior. A week after
examiniation she developed hepatic encephalopathy and herpato-renal failure,
requiring a liver transplantation.1908
However, in the latter case
the 200 ml bottles containing the combination of 1:1 fluid extracts that she
used had 80 ml of ground ivy (Nepeta hederacea) but only 20 ml of black
cohosh.1907 The ground ivy’s pulegone, a well recognized
hepatotoxin, was the most likely cause of liver failure in this case.1908 In a review of the total
69 known distinct hepatotoxicity cases from the European Medicines Agency [36 cases], other
published case reports [11 cases], and others reported in a USP study [22
cases], an updated structured quantitiative scale for causality found that 68
had an excluded, unlikely, unrelated, or unassessable causality for black
cohosh; the only 1 possibly case with causality was complicated by multiple
confounding factors (case series review).2597
5) A
group of infertile women receiving the fertility drug clomiphene citrate were divided into 60 who also recieved 120 mg
per day of black cohosh extract BNO 1055 for 12 days and 59 who did not prior
to HCG injection and timed intercourse (PO in human clinical study). Those
receiving the extract had higher estrodiol and LH concentrations and
significantly higher serum progesterone, endometrial thickness and pregnancy
rate.2704 In a similar study with 134 fertility patients, the half
who received the same dosage of extract had significantly more rapid follicular
maturation, thicker endometrium, and higher estradiol concentration at the time
of the HCG injection, and a higher luteal-phase progesterone level compared the
the half who instead received 100 mcg ethinyl estradiol for 12 days (PO in human clinical study). While clinical
pregnancy rates were not significantly different, the extract group did have a
higher rate [14% versuse 21%].2705
Drug Interactions
I. + 1) Use of 50 mg black cohosh extract daily along with 150 mg of soy
extract containing 40% isoflavones (60 mg daily) and 100 mg dong quai extract
daily for 24 weeks by 49 menstrual migraine patients significantly reduced the
number of doses of triptans and analgesics after 20-24 weeks compared to placebo (PO in human clinical study)1422
+ 2)
Solid black cohosh extract obtained with 58% ethanol (CR BNO 1055),
corresponding to 20 mg of the root, was given by randomization for one year
with 20 mg tamoxifen in daily oral doses with premenopausal breast
cancer survivors (PO in human clinical study). About 74% of those using only
tamoxifen had severe hot flushes, compared with only 24% of those combining it
with the extract. Nearly half of the tamoxifen plus extract group were free of
hot flushes, the most frequent adverse effect of tamoxifen.1655
Alone, both the hydroethanolic and hydropropanolic extracts of the
rhizome inhibited cell proliferation in a human breast adenocarcinoma test
system (MCF-7) and inhibited estrogen-induced growth of this system (in
vitro).1384,1556 The isopropanolic extract alone significantly
inhibited estrogen-deprived cell growth and with tamoxifen further enhanced
inhibition of the breast adenocarcinoma proliferation (in vitro).1384
Unlike tamoxifen that stimulates estrogen endometrial adenocarcinoma tumor
growth, the isopropanolic extract did not increase this growth or metastasis to
lymph nodes or lungs in rats when given alone or combined with tamoxifen (PO in
rats).1697 Black cohosh as a 40%
2-propanol extract binds to serotonin receptors of the hypothalamus (in
vitro), which, rather than any estrogenic activity, may explain its
reduction of hot flashes (speculative).2031
When tested for estrogen-dependent gene
transcription in two types of estrogen alpha-receptor cells, the isopropanolic
extract was shown to be both non-estrogenic and anti-estrogenic (in vitro).
The ethanolic extract activity differed in terms of active extract
concentration, and in one of the alpha-receptor cell assays the ethanolic
extract, though non-estrogenic, was not anti-estrogenic (in vitro).1556
III.
1) [FORMER: See IV. 1) ]
+ Increased
cytotoxicity of doxorubicin was noted only when EMT6
nonestrogen-dependent mouse breast cancer cells were exposed to a concentration
representing 2.5 times or more of the recommended dose of a commercial 50%
ethanolic liquid extract standardized to 3% triterpene glycosides (in vitro).
Two different commercial hydroalcoholic liquid extracts had similar, though
less potent, cytotoxicity-enhancing effects after exposure to the 3 extracts at
100 times the concentration expected from the recommended black cohosh extract
dose (in vitro). At this high concentration a less potent effect of
enhancing doxetaxel cytoxicity was found with the initial extract, while
the same extract and dose reduced the cytoxicity of cisplatin (in vitro).
No interactive effects were found with 4-hydroperoxy-cyclophosphamide or
radiation even at the high extract dose (in vitro).1736
IV. [formerly III. 1) ] 1) Estrogen
replacement therapy may lead to estrogen excess due to phytoestrogen content of
black cohosh (speculative)893
However, when the 40%
isopropanolic extract given to perimenopausal and postmenopausal women in daily
doses derived from 39 mg or 127.3 mg of the dried root were used to assess
estrogenic activity, the lack of changes in vaginal cells indicated a
nonestrogenic effect. Likewise, no significant changes in serum hormone levels
relevant to sexual function were noted (PO in human study).1558 A
dried 58% aqueous/ethanolic extract in daily doses corresponding to 40 mg of
the rhizome was compared to 0.6 mg of conjugated estrogens and placebo in a
study with 62 menopausal women. The extract was as beneficial as the estrogens
for menopausal symptoms and on serum markers of bone metabolism. While the
estrogens and extract increased vaginal cell growth similarly, only the
estrogens increased uterine endometrial thickness. Black cohosh hydroalcoholic
extract therefore has demonstrated selective estrogen receptor modulator (SERM)
activity for bones and the vagina without affecting the uterus (PO in human
study).1559 Black cohosh contains SERM compounds that primarily
interact with the estrogen beta-receptors and affect hypothalamus, bone, liver,
brain, and arteries, but the components did not interact with estrogen
alpha-receptors of the uterus (in rats).1557 The liquid ethanolic
extract failed to induce proliferation of the MCF-7 human breast cancer cell
line or transactivation of either human alpha- or beta-receptor (in vitro)
or increased uterine weight after 4 days (PO in mice).1664 When
tested for estrogen-dependent gene transcription in two types of estrogen
alpha-receptor cells, the isopropanolic extract was shown to be both
non-estrogenic and anti-estrogenic (in vitro). The ethanolic extract
activity differed in terms of active extract concentration, and in one of the
alpha-receptor cell assays the ethanolic extract, though non-estrogenic, was
not anti-estrogenic (in vitro).1556 Black cohosh as a 40%
2-propanol extract binds to serotonin receptors of the hypothalamus (in
vitro), which, rather than any estrogenic activity, may explain its
reduction of hot flashes (speculative).2031 The black cohosh 40%
isopropanolic extract at 40 mg per day for 12 weeks was shown to have no effect
on estrogen concentrations or luteinizing hormone [LH] pulsatility in
postmenopausal women (PO in human clinical study). Nonetheless, with naloxone
blockade it did suppress LH pulsatility especially during sleep, and its m-opioid receptor binding
ranged from 10-61% across brain regions involved with emotional and cognitive
functioning.2495
BLACK
CUMIN NEW
^ Nigella sativa seed
Drug Interactions
I. 1) Chemical war victims from inhalation of mustard gas
reliant on inhaled and oral salbutamol and corticosteroids
required less of these drugs except for the inhaled corticosteroids after 2
months of taking an aqueous extract of black cumin than controls who did not,
yet the respiratory symptoms/wheezing and pulmonary function of those using the
black cumin extract was still significantly better than controls (PO in human
clinical study).2489
II. 1) Nephrotoxicity from cisplatin was ameliorated by
the main active seed oil component thymoquinone when it was given 5 days before
and after the chemotherapy drug at 4 and 8 mg/kg daily (PO in rats and mice,
respectively). The antitumor activity of cisplatin for Ehrlich ascites
carcinoma was enhance by thymoquinone at 8 mg/kg daily (PO in mice).2615
BLACK
CURRANT NEW
^ Ribes nigrum seed oil
[Due to their content of gamma linolenic acid (GLA),
the oil from black currant seeds is similar in activity to borage seed oil and
evening primrose oil. See EVENING PRIMROSE.]
Drug Interactions
I. 1) Rheumatoid arthritis patients using corticosteroids &/or
NSAIDs added 10.5 gm black currant seed oil containing 2 gm GLA (20
subjects) or placebo soybean oil (14 subjects) for 6 months. Those treated at
the end had significantly improved joint tenderness count and tenderness score
with no adverse effects; 2 cases of nausea occurred in the placebo group. Four patients
in the treatment group and 11 receiving placebo were also maintained on steady
doses of second-line anti-rheumatic drugs, particularly methotrexate,
hydroxychloroquine, or gold salts (PO in human clinical study).1399
2) Faster clinical response to tamoxifen was achieved when gamma linolenic acid as found in black
currant seed oil was given to 38 patients with estrogen-dependent breast cancer
(PO in human clinical study).589
III. 1) Due to a decrease in plasma heparin-neutralizing activity
and platelet aggregation inhibition associated with prostaglandin PGE1
that is formed from metabolism of dihomo-gamma-linolenic acid (PO in human
study),681,693 a component formed from GLA in black currant seed
oil, heparin may be potentiated (speculation)
BLACK
PEPPER p.
41
Piper nigrum
fruit
I. 1) Phenytoin was more rapidly
and more completely absorbed and eliminated more slowly in 5 males when taken
with 20 mg of the component piperine (PO in human study).205
A single 20 mg dose of piperine in 2
groups of 10 men receiving 300 mg or 400 mg daily of phenytoin increased mean
plasma drug concentration and bioavailability (PO in human study).1943
+ 4)
Piperine dose of 20 mg increased serum concentrations of curcumin after
0.25-1.0 hours and increased bioavailability by 2000% (PO in human study).1533
Piperine content of black pepper
ranges from about 5-7%.1586
II. + 5)
Increased anti-nociceptive and anti-inflammatory activity from nimesulide
was achieved when 100 mg was combined with 60 mg piperine from black pepper (PO
in mice). This was apparently due to reduced metabolic breakdown of nimesulide.1821
+ 6)
Decreased absorption and anti-inflammatory effect of diclofenac sodium
was observed when it was combined with trikatu, a 1:1:1 mixture of black pepper, long
pepper and ginger (PO in rabbits and rats).2003 Since the drug was
mixed with the herbs in solution prior to administration, the interaction may
have been chemical in nature, rather than biological (speculative).
+ 7)
Reduced absorption, peak concentration, and bioavailability of isoniazid
resulted for 4 hours when it was given together with 500 mg/kg trikatu, a 1:1:1
mixture of dried fruits of black pepper, long pepper and dried rhizomes of
ginger providing 10 mg/kg of the alkaloid piperine (PO in rabbits). This may be
due to a decrease in gastric emptying time (speculative).2005
+ 8)
Increased absorption and peak concentration of indomethicin after 4
hours was achieved when it was given together with 500 mg/kg trikatu, a 1:1:1
mixture of dried fruits of black pepper, long pepper and dried rhizomes of
ginger (PO in rabbits). The pharmacokinetic effect may have been due to an
increased GI blood flow (speculative), but was not due to change in
indomethicin metabolism.2004
III. + 3) Increased membrane transport of the drugs
digoxin and cyclosporine (in vitro) by piperine inhibition
of P-glycoprotein
may lead to increased bioavailability.1820
+ 4) Reduced metabolism of verapamil by piperine inhibition of CYP3A4 (in vitro) may lead to increased bioavailability.1820 Bisalkaloid components called dipiperamides A, B, and C inhibit CYP3A4 metabolism of nifedipine and act much more potently than piperine (in vitro).1822
BLADDER
KELP p.
43
Nereocystis
luetkeana thallus
Contraindications
+ 4)
Large amounts during pregnancy due to potential development of infantile
goiter (empirical)150
BLADDERWRACK p.
43
Fucus vesiculosus
thallus
Drug Interactions
III. 1) Interactions may occur with thyroid replacement medication
like thyroxine or hyperthyroid drugs like carbimazole (speculative) due to its
natural iodine content.1890
2) Do not combine with iodine-containing drugs like amiodarone
or bneziodarone, since there is a greater risk of causing
iodine-induce thyrotoxicosis with these drugs (speculative).1890
BLOODROOT p. 44
*Sanguinaria
canadensis rhizome
Contraindications
+ 3) Hiatal hernia, esophageal varices,
stomach ulcer or peptic ulcer due to aggravation and/or potential
hemorrhage from emetic effect if bloodroot is taken in excessive doses
(speculative)150
Drug Interactions
III. + 1) Do not take large doses after recent
consumption of central nervous system stimulants, due to the emetic
action potentially inducing convulsions (speculative).150
+ 2)
Do not take large doses after recent consumption of central nervous system sedatives,
due to the emetic action potentially inducing aspiration pneumonitis
(speculative).150
BLUE COHOSH
*Caulophyllum
thalictroides root
Contraindications
1) Pregnancy prior
to labor, due to its emmenagogue and abortifacient effects (empirical)2,6,,7,10,74,150
and potential embryotoxic and teratogenic effects
from its extracts and alkaloids (in animals).2,1890
+ 2)
Not to be used by fertile women trying to conceive or nursing mothers
(speculative), due to the potential for teratogenicity in the embryos or
toxicity in the infants, respectively.1890
BLUE FLAG NEW
^ *Iris
versicolor, Iris virginica roots/rhizome
(flag lily, iris liver lily, poison flag, snake
lily, sweet flag, water flag, wild iris; Fr.: fleur-de-lis)
Contraindications
1) Pregnancy
(speculative)150 due to its potential toxicity (empirical)2,150
Drug
Interactions
III. 1) Do not take large doses after recent consumption of central
nervous system stimulants, due to the emetic action potentially inducing
convulsions (speculative).150
2) Do not take large doses after recent consumption of
central nervous system sedatives, due to the emetic action potentially
inducing aspiration pneumonitis (speculative).150
BLUE VERVAIN NEW
^ Verbena
hastata
plant
(American vervain, false vervain, Indian hyssop,
purvain, Simpler’s joy, traveler’s joy, vervain, wild hyssop)
Contraindications
1) Pregnancy
(speculative)2,150 due to its emmenagogue effect in early pregnancy
(empirical)2
BOLDO p.
45
Peumus boldus leaves
Contraindications
+ 8)
Pregnancy or with nursing mothers due to possible toxic effects in
the fetus from boldine (PO in rats) or in infants from the essential oil
components, respectively.1890
+ 9)
Avoid prolonged use (speculative), due to possible toxic effects from
the essential oil components.1890
Drug Interactions
+ 1)
A woman stabilized on warfarin developed an elevated INR after several
weeks of using a capsule of fenugreek before meals and 10 drops of boldo
extract after meals. Her INR returned to the normal range after stopping the
herbal products but became elevated again after resuming their use (PO in human
case study). It may be that warfarin metabolism was reduced or the serum
protein bond of warfarin was modified (speculative).1489
BORAGE p.
46
*Borago officinalis
plant
BORAGE SEED OIL
[Borage seed oil does not contain toxic
pyrrolizidine alkaloids6,150 but has separate effects and
interactions due to its gamma linolenic acid (GLA) content similar to black
currant seed oil and evening primrose oil. See EVENING PRIMROSE.]
Drug Interactions
I. 1) In a 6-month randomized, double-blind,
placebo-controlled (RPCDB) trial with 37 rheumatoid arthritis (RA) patients,
7.2 ml borage seed oil (1.4 gm GLA) or cottonseed oil placebo was given daily
in addition to stable doses of NSAIDs and corticosteroids. Those
receiving GLA had significant reductions in number of tender joints (36%),
tender joint score (45%), swollen joint count (28%), and swollen joint score
(41%). The placebo group was unchanged or grew worse (PO in human clinical
study).1401 In a second RPCDB trial using daily placebo sunflower
seed oil or 2.8 gm GLA derived from borage seed oil, 56 RA patients on stable
amounts of NSAIDs, corticosteroids and second-line anti-rheumatic drugs
received the GLA for the first six months and/or the second six months. After the
first half year, 14 of 22 in the GLA group had at least a 25% improvement in
the four measures, while 4 of 19 using placebo improved this much. When all
received GLA in the second half year, 16 of 21 in the original GLA group had
this degree of response over baseline, while the placebo/GLA group also
improved. Three months after the end of the trial, the GLA group had a smaller
increase in 3 of the 4 measures (PO in human clinical study).1402
III. 1) Due to a decrease in plasma heparin-neutralizing activity
and platelet aggregation inhibition associated with prostaglandin PGE1
that is formed from metabolism of dihomo-gamma-linolenic acid (PO in human
study),681,693 a component formed from GLA in borage seed oil, heparin
may be potentiated (speculation)
BROMELAIN p.
47
Ananas comosus extract
from fruit, stem
Contraindications
1) Allergic
hypersensitivity to bromelain (empirical)17
A worker who handled bromelain for 10 years developed
rhinitis and asthma that could be induced by both 0.03 mg of inhaled bromelain
and 190 grams of ingested pineapple (human case report). Cross-reactivity with
bromelain by skin and RAST tests occurred with 5 of 6 workers sensitized to
airborne papain, and 2 of the 6 had immediate asthmatic reactions (human
clinical study).1275 Cross-sensitivity shown by RAST inhibition
suggested bromelain, papain, wheat flour, rye flour, grass pollen and birch
pollen possess more or less similar or identical antigenically active regions (in
vitro),1276 corresponding to positive skin tests to bromelain in
2 of 60 asthmatics and positive RAST tests to bromelain in 8 of 60 asthmatics
not exposed to airborne sources of this protease (in vitro).1275
2) bile duct obstruction6,17,401,777
due to its choleretic activity as shown with a
single 1.9 gram dose of its 4.5-5:1 strength extract (PO in human study)1270
Drug
Interactions
I. 1) Bromelain at 20 mg/kg increased cerebrospinal fluid
levels of penicillin injected intramuscularly 4 hours later (per
duodenum in rabbits).1111
3) Potentiates bleeding with anticoagulants (PO in case report), [CORRECTION]31
probably due to inhibition of platelet aggregation
shown with 30 mg/kg (IV in rats)1110, increased fibrinolytic activity
shown with 25 mg/kg (enterally in rats),1110 and increased
prothrombin time shown with 5 mg/kg (PO in rabbits)1110
However, following doses of
40 mg four times daily for one week the coagulation and bleeding times were not
changed, and the prothrombin time was only slightly increased (PO in human
study).1253
4) Increases blister fluid concentration of tetracycline in 18 males (PO in human
study)1112
+ 5)
In a randomized, placebo-controlled, double blind trial following episiotomy
for childbirth, 160 patients required aspirin or aspirin with codeine
or propoxyphene HCl for the pain; half received an additional 2
tablets of bromelain (50,000 RU/tablet) 4 times daily for 3 days, beginning 4
hours after delivery. For the bromelain group the responses were considered
good or excellent in 90%, compared to 44% of these responses for the placebo
group, a highly significant difference. While 75%-78% of each group received
asprin or aspirin/propoxyphene, 14% more in the placebo group received the aspirin/codeine
(PO in human clinical study).1405
However, in treating
osteoarthritis of the knee, a randomized, double-blind controlled trial found
that the 14 patients using bromelain as an adjuvant with conventional and/or
alternative medications had not better outcomes based on symptom scores than 17
who used placebo (PO in human clinical trials). Those who recently or currently
used corticosteroids were excluded from this trial.2152 Also, in a
case of combining with NSAID use for rheumatoid arthritis, a 76-year-old woman
developed ecchymosis on her forearms when she used bromelain with naproxen
(PO in human case report).2126
6) In another placebo-controlled, double-blind study
59 patients were given 2 tablets of bromelain 4 times daily for 2 days prior to
cataract surgery, and for the 5 days following. In addition to local cortisone
for all, those on bromelain and the 52 placebo patients also
received oral aspirin and propoxyphene for pain as needed. On the seventh
postoperative day there was significant reduction of lid edema, conjunctival
hyperemia, and conjunctival edema in the bromelain group compared to placebo.
Operative complications included mild hemorrhage in 13 bromelain patients and 6
placebo patients (PO in human clinical trial).1406
II. + 1)
Increased concentration of the antibiotic cefazolin
in bronchial secretions when given at 100 mg/kg (PO in rats)1110
+ 2)
Increases blood and urine levels of the antibiotic ethambutol (in rabbits)1112
+ 3)
Increases duration of sleeping time when given prior to pentobarbital (IP in mice)1112
III. 1) May enhance cholesterol-lowering
agents (speculative).777
Tablets with 450 mg of a 25-35:1 aqueous extract
reduced total cholesterol, LDL cholesterol, and LDL/HDL ratio (PO in human
clinical study)1271
BUCHU p.
48
*Agathosma betulina
= Barosma betulina leaves
Contraindications
4) Nursing mothers (speculative), since the
essential oil may pass through the breast milk to the infant with unforeseen
consequences.1890
BURDOCK p.
50
Arctium lappa
root
Contraindications
1) Allergic
hypersensitivity to the root (human case reports).662
Some even suggest avoiding if there is known
hypersensitivity to other Compositae family plants (speculative).1890
Drug Interactions
II. + 1)
Freeze-dried water extract of burdock root at 300 mg/kg decreased SGOT, SGPT,
and malondialdehyde levels caused by liver damage from acetaminophen.
The decrease in glutathione and cytochrome P450 in the liver caused by
acetaminophen was reduced by burdock extract (PO in mice)1404 The freeze-dried decoction of
burdock at 100 mg/kg reduces edema from injected carrageenan (SC in rats) and
decreases liver toxicity of CCl4 at this dose (IP in rats). This
extract has radical scavenging activity (in vitro).1407
BUTCHER’S BROOM NEW
^ Ruscus
aculeatus roots and rhizome
(box holly)
Contraindications
1) Broken skin or ulcerated skin, due to
the irritant effect of the saponins (speculative).1890
BUTTERNUT NEW
^ *Juglans
cinerea
bark
(lemon walnut, oil nut, white walnut)
Contraindications
1) Pregnancy (speculative) since large doses may
cause a cathartic action150
CAJEPUT NEW
^ Melaleuca
leucodendron = Melaleuca cajeputi leaf oil
(white tea tree, broad-leaved tea tree, paper-barked tea tree, swamp tea tree, white-wood)
Drug
Interactions
I. 1) Component 1,8-cineole (eucalyptol) induces hepatic
microsomal mixed-function oxidase enzyme induction (in rats), resulting in
increased clearance of aminopyrine with
aerosol inhalation of eucalyptol 10 min. daily for 10 days (human study).28
II. 1) Pentobarbital,
zoxazolamine, and amphetamine given
24 hours after an aerosol exposure to 1,8-cineole for 2-10 min/day for 4 days
were effective for a reduced length of time (in rats).28
cALENDULA p.52
Calendula
officinalis flowers
Contraindications
+ 2) Allergic
hypersensitivity to calendula or allergies to other members of the
Asteraceae family (empirical).1890
CALIFORNIA
POPPY p.52
Eschscholtzia californica
herb
Contraindications
+ 2)
Nursing mothers (speculative) without professional advice.1890
CALIFORNIA SPIKENARD NEW
^ Aralia
californica rhizome and roots
Contraindications
1) Pregnancy (speculative)150 probably due to its
similarity to the related species and known emmenagogues Aralia nudicaulis
and A.racemosa, known as small spikenard and spikenard, respectively
(empirical)1125
CAMPHOR
BARK p.
53
Cinnamomum camphora = Laurus camphora bark
oil
Contraindications
5) Epilepsy (empirical), since its rapid
absorption through the skin and mucus membranes in small doses can result in
CNS overstimulation and seizures (empirical).400
6) During fever (empirical),400 due to
potential CNS toxicity (empirical).2
*Cannabis
sativa leaves and tops
Contraindications
2) Avoid in those with a history of schizophrenia, since
psychotic symptoms may be induced with consumption (empirical).2,627,629
Cannabis use increases the risk of incidence of psychosic
symptoms in the young, stronger effects in those predisposed to psychosis, and
a poor prognosis for those with established psychotic disorder (human study).1372,1737
3) Heavy, prolonged
use
may cause psychological dependance and physical withdrawal
(human studies)1198 and increased risk of depressive symptoms
including consideration of suicide and experiencing loss of ordinary pleasure
(human study).1229
+ 6) Daily heavy use due to reversible cognitive deficits detectable for at least 7 days after quitting (PO in human study),1197 as well as impairments in memory and attention (human study)1272 and decrements even after 28 days abstinence in neurocognitive performance (human study)1146
Drug
Interactions
I. 2) Vomiting induced by chemotherapy
including cyclophosphamide, doxorubicin, cisplatin, procarbazine,
methotrexate, dacarbazine and streptozocin
was relieved by cannabis in 78% of the patients (inhaled in human clinical
study).1078
One incident of lethal ischemic stroke was associated
with cisplatin-based chemotherapy and cannabis inhalation (human case report).
Ischemic strokes have occurred at least 15 times with cisplatin use alone and a
few times following cannabis inhalation.1346
CARAWAY NEW
^ Carum
carvi seeds
Contraindications
1)
Allergic hypersensitivity to similar
plants in carrot (Apiaceae) family (speculative)10
CASCARA SAGRADa p.
53
*Frangula purshiana = Rhamnus purshiana aged bark [NOTE: new
scientific name]
CASSIA [formerly
CASSIA CINNAMON] p.
55
Cinnamomum cassia
= Cinnamomum aromaticum bark [See also Cinnamon.]
1) Large doses in pregnancy150,401
due to potential hepatotoxicity of its extremely
high coumarin content (speculative)2231,2248
Drug
Interactions
I. + 1)
In 60 men and women with type 2 diabetes using sulpholylureas such as glibenclamide,
when either 1, 3, or 6 grams of cassia cinnamon or placebos was given daily for
40 days, all three cassia doses reduced fasting glucose along with trigyceride,
LDL cholesterol, and total cholesterol (PO in human clinical study).1592
A 9:1 aqueous extract
at a dose of 336 mg/day for 4 months significantly reduced serum glucose in
type 2 diabetics with poor glycemic control, though 77% were already taking
non-insulin oral hypoglycemics including sulphonylureas, metformin,
glinides, glitazones, and their combinations (PO in human clinical study).1900
One gram daily of cassia powder randomized to type 2 diabetics with blood sugar
poorly controlled by oral hypoglycemics and/or insulin had a significant
reduction in hemoglobin A1C after 90 days compared to controls (PO in human clinical study).2603
However, in a study
involving 25 postmenopausal women with type 2 diabetes, all but 4 of whom were
taking metformin, sulphonylureas and/or thiazolidinediones, 1.5 grams
daily of cassia cinnamon taken for 6 weeks had no effect on fasting blood sugar
or lipids or insulin sensitivity or glucose tolerance (PO in human clinical
study). This disparate result may have been due to use of a different
geographic source of cassia, since the bioactive components have not been
identified to establish an effective profile.2139 Similarly, 60
patients in a randomized, double-blind trial were given 500 mg encapsulated
cassia powder or placebo twice daily for 3 months while ¾ were also taking
metformin and over 1/3 were using thiazoledinedione (PO in human clinical
study). No reduction in fasting glucose, insulin levels or glycosylated
hemoglobin were found.2237
Cassia cinnamon powder given to 7 healthy males at a
dose of 5 grams, either with or 12 hours prior to an oral glucose tolerance
test, resulted in a reduction of total plasma glucose and improved insulin
sensitivity (PO in human study).2567 Taken with a meal, 6 grams of cassia cinnamon
lowered postprandial glucose and slowed gastric emptying in 14 healthy subjects
(PO in human study).2294
However, in 15 healthy
subjects, a single dose of 1 or 3 grams of cassia cinnamon failed to
significantly alter postprandial blood glucose, glucose-dependent insulinotropic
polypeptide or ghrelin response, gastric emptying, or satiety, though 3 grams
did significantly lower changes in glucagon-like peptide 1 response and maximum
concentration, the insulin response at 60 minutes, and total serum insulin for
120 minutes postprandially (PO in human study).2531
III. + 2)
Alkaline aqueous extracts of cassia cinnamon were show to greatly potentiate insulin
activity (in vitro).1464 This is likely due to enhanced
insulin signaling in skeletal muscle as shown with freeze-dried cassia hot
water extract (PO in rats).1762
However, in a
placebo-controlled study with 72 type 1 diabetes adolescents, after consuming a
1-gram dose of cinnamon powder daily for 90 days no differences were found in
total daily insulin intake, number of hypoglycemic episodes, glycated
hemoglobin (A1C), or change in A1C between the cinnamon and placebo groups (PO
in human clinical study). Unfortunately, the authors did not characterize the
type of cinnamon (Cinnamomum spp.) by species name.2108 Giving 3 grams Cassia cinnamon with rice
pudding significantly lowered the insulin response at 60 minutes, and total
serum insulin for 120 minutes postprandially (PO in human study).2531
Cassia bark aqueous extract increased insulin release
from insulin-secreting cells in a dose-dependent manner by 144-182% (in
vitro). The extract and the bark significantly increased plasma insulin in
animals, the bark for 1-2 hours and the extract for 1-4 hours. Cassia cinnamon
bark and extract were more effective than cinnamon (C. zeylanicum)
extract (PO in rats). Only after glucose consumption did the extract reduce
blood glucose (PO in rats).1763 The bark reportedly lowers blood
sugar in normal animals due to cinnamaldehyde effects (PO in animal studies).319 Moreover, water-soluble polyphenol polymers
of A type doubly linked procyanidin oligomers of catechins and/or epicatechins
increased insulin-dependent glucose metabolism 20-fold (in vitro).1659
+ 3)
Essential oil from cassia with its strong antifungal effect against Candida
albicans potentiated amphotericin B by reducing the required
concentration to inhibit candida (in vitro).1856
CAT’S CLAW p. 57
Uncaria tomentosa bark
Contraindications
2) Avoid in pregnancy
(empirical)701,1487,1890 and in women attempting conception
(empirical),1890
due to traditional use as a contraceptive
(empirical)150,1890 and the increased risk of fetal malformation or
damage (PO in mice).1890
5)
Caution is advised for use of the chemotype with tetracyclic oxindole alkaloids
prior to surgery
or by those with bleeding disorders
(speculative) due to the inhibition of platelet aggregation by the alkaloid
rhynchophylline.2667
Drug
Interactions
I. + 1)
Water soluble extract with 8-10% active carboy alkyl esters but free of
oxindole alkaloids given in 350 mg tablets twice daily enhanced immune response
to 23 valent pneumococcal vaccine by elevating lymphocyte/neutrophil
ratios in blood and reducing decay in 12 serotype antibody titers at 5 months
with no adverse effects (PO in human study)1240
+ 2)
60 mg aqueous-acid extract of root with pentacyclic oxindole alkaloids (14.7
mg/g)used for a year or 28 weeks with 40 rheumatoid arthritis patients on sulfasalazine
or hydroxychloroquine treatment for at least 6 months previously showed
a reduced number of painful and swollen joints compared to baseline. In the
first 24-week (placebo) phase the extract group had fewer painful joints than
the placebo group. The steroid prednisolone was used by 38% of the participants; use of NSAIDs
was also allowed.1321
II. + 1)
Intestinal ulceration by indomethacin
was reduced by aqueous extract of cat’s claw (PO in rats).597
This same concentration of cat’s claw decoction in
drinking water given for 3 days prior to a toxic dose of indomethacin (20
mg/kg) caused a protective effect that greatly reduced the extent of erosion to
the stomach lining (PO in rats). Anti-inflammatory and anti-oxidant effects of
this cat’s claw bark extract were both demonstrated as well (in vitro).1389
The protective effect against indomethacin-induced stomach damage was due to
its suppression of NF-kB activation (PO in rats).1784
+ 2)
Avoid use with antihypertensives, since its rhynchophylline
alkaloids may lower blood pressure further (speculative)1487
III. + 3) Use of preparations standardized to
pentacyclic oxindole alkaloids concurrently with immunosuppressants
should be avoided to prevent antagonistic effects (speculative).1890
+ 4) Caution is advised for use of the
chemotype with tetracyclic oxindole alkaloids together with warfarin or other anticoagulants (speculative) due to the inhibition of platelet
aggregation by the alkaloid rhynchophylline.2667
CAYENNE p.
57
Drug
Interactions
I. 1) 20 gm of powdered chili (containing 9.56 mg capsaicin, a concentration of 478 ppm) reduced gastric mucosal damage from aspirin (PO in human study).211
At 10-30 mg/kg capsaicin aggravated the damage
caused by aspirin (PO in rats).1120
II. 3) Prevention of ethanol/acid-induced ulcers was shown by giving 3-30 mg/kg of capsaicin (PO in rats).522
Dilute capsaicin at 0.1 mcg/kg protected the stomach
from mucosal damage by ethanol. At 10-30 mg/kg capsaicin aggravated the damage
caused by ethanol (PO in rats).1120
CELANDINE p.
59
*Chelidonium
majus root and plant
Contraindications
+ 9) Idiosyncratic hepatotoxic reaction after using celandine,
since mild to severe acute hepatitis occurred in 10 patients following its
consumption (PO in human case reports).
These cases were independent of dose and commercial preparation (5
different manufacturers of celandine products, including of two herbal
combinations) and had long and variable latent periods (1-9 months). Recovery
was complete 2-6 months after discontinuation of celandine, but hepatitis
recurred in the one patient who re-introduced it after release from the
hospital.1142 These observations implicate celandine involvement in
a case of hepatotoxicity in a patient who used a different herbal combination
containing celandine (PO in human case report).1143
+ 10) Nursing mothers,
and only preparations of the leaves may be used, but after first receiving
professional advice due to the potential for causing liver problems
(speculative)1890
+ 11) Prolonged use (speculative), due
to its potential toxicity (empirical)1890
Drug Interactions
III. + 1)
Chelerythrine, a major alkaloid component, enhanced the retention of rhodamine
123 in human breast cells by inhibiting its efflux mediated by P-glycoprotein
(in vitro)1034
2) May aggravate hepatotoxic reactions to anesthetics, steroids,
estrogen, or chlorpromazine (speculative), due to its own liver stimulant
and toxic effects (empirical)1890
CELERY p.
60
Apium
graveolens seeds (fruit) or stalks
Contraindications
+ 5)
Not to be used by nursing mothers without professional advice
(speculative).1890
Drug Interactions
I. + 2)
Compared to a basal diet with no vegetables, after eating for 6 days a diet
with the umbelliferous vegetables 110 gm (0.75 cup) frozen carrots, 100 gm (1.25 cup)
fresh grated parsnips, 50 gm (0.5 cup) celery, 5 gm (3 Tbs) parsley and 0.5 gm
(1 tsp) dill daily, 36 subjects had a significantly decreased rate of caffeine
metabolism (PO in human study)1634
+ 3)
Use of celery seed reduced serum concentrations of thyroxine in two
patients (PO in human case reports)1890
CHAMOMILE [formerly CHAMOMILE, GERMAN] p. 61
Matricaria recutita =
Matricaria chamomilla plant or flowers
Contraindications
3) Allergic hypersensitivity (human case reports,
human clinical studies)4,663,666
An enema containing an
oily extract of chamomile flowers given during labor resulted in an
anaphylactic response and cesarean delivery with severe asphyxia in the newborn
which died the following day (human case report)1144 In 14 patients
allergic to either chamomile or spices and weeds and with a positive skin-prick
test to chamomile, 10 had a history of immediate-type reaction to chamomile, 11
were sensitized to mugwort and 8 to birch tree pollen based on RAST, while 4
showed IgE binding to high molecular weight chamomile protein allergens (in
vitro).1740 A man developed acute eczema on his forearms and
hands after washing and applying compresses of chamomile and Roman chamomile
tea (topically in human case report). In patch tests he was shown to be
sensitive to both of the teas and their mix, a Roman chamomile extract, yarrow,
tansy, and feverfew extracts, and a sesquiterpene lactone mix. The chamomile
sesquiterpene lactone desacetyl matricarin likely contributed to his reaction.1742
Drug Interactions
I. + 1) Non-heme iron absorption is reduced with consumption of the tea prepared with 3 grams per cup (PO in human study) likely due to its flavonoid content1246
+ 2) From 10-15 drops of a flower extract in 4
oz of water and used as a thorough mouth rinse 3 times daily prevented and/or
effectively treated oral mucositis from systemic chemotherapy in 78
cancer patients treated with L-asparginase, cisplatin, cyclophosphamide,
cytosine arabinoside, daunorubicin, doxorubicin, 5-fluorouracil,
methotrexate, and/or vincristine (TP in human clinical study). It
also prevented oral mucositis in 19 of 20 head and neck cancer patients treated
locally with radiation.2541
Oral ulcers and mucositis from overdose of
methotrexate resolved within 2 weeks following use of 20 ml of a 1:125
chamomile infusion used as a gargle 4 times daily (local in human case report).1803
3) [Formerly IV.1).] One woman on warfarin
had pelvic ecchymoses and increased INR of 7.9 from 3.6 five days earlier,
after drinking several cups daily of chamomile made with a teaspoon of dried
leaves and applying a lotion containing a chamomile preparation (PO in human
case report).1876
However, such a response
could also have occurred if she drank grapefruit juice with here co-medication
amiodarone, though she denied in general any change in her diet in the prior
days.1876
Chamomile has been identified as potentiating
warfarin due to its coumarin content
(speculative)893-895 that consists of the coumarin derivatives
herniarin and umbelliferone.897-899 Though chamomile and herniarin
(7-methoxycoumarin) are reported to have hemostatic activity,691 and
umbelliferone (7-hydroxycoumarin) shows no evidence of anticoagulant effects,690,847,848
both herniarin and umbelliferone strongly inhibit rabbit platelet aggregation
in platelet-rich plasma induced by collagen and arachidonic acid, while
umbelliferone likewise strongly inhibits aggregation induced by ADP and platelet-activating
factor (in vitro).2497 Chamomile contains the flavonoid
apigenin which also has been shown to inhibit platelet aggregation (in vitro).420,1015
II. 2) Chamomile oil reduced the reduction of ACTH by diazepam in normal animals (inhaled in
rats). 625
Apigenin acts as a strong ligand to central
benzodiazepine receptors (in vitro).1554 Unlike diazepam, the
anxiolytic effect of apigenin does not lead to amnesia of learning tasks but
slightly enhances retention (IP in rats)1555
+ 3)
After being consumed for 4 weeks, a 2% tea made from the flowers reduced the
metabolism of the analgesic CYP 1A2 substrate phenacetin by liver
microsomes to 39% of normal (PO in rats)1608
+ 4)
Chamomile extract standardized to apigenin and given with morphine twice
daily for 7 days reduced the morphine dependence as well as its withdrawal
syndrome after naloxone was administered (IP in rats). The effect appeared to
be due to prevention of increased plasma cAMP.2014
CHAMOMILE, ROMAN [now ROMAN CHAMOMILE] p. 62
Chamaemelum nobile =
Anthemis nobilis flowers and plant
CHAPARRAL p.
63
Larrea tridentata leaves
Contraindications
+ 6)
Pregnancy due to its use as an abortifacient and contraceptive agent
(empirical).1890
CHASTE TREE p.
64
Vitex agnus-castus
berries
Contraindications
+ 4)
Depression associated with reduced estrogen levels (PO in human case
report)1503
Drug Interactions
I. + 1)
The essential oil may potentiate the activity of progesterone drugs, resulting in breakthrough bleeding (PO in
clinical study)1503
III. 1) Chaste tree may interfer with the efficacy of progesterone
drugs such as birth control pills (speculative) or disrupt hormone replacement therarpy due to its
additive progesterone effect (speculative), especially of the essential oil
derived from the berries and leaves (PO in clinical study).1503
However, some cases
combining the essential oil with estrogen in menopause appeared
successful.1503
2) Dopamine
antagonists may be weakened (speculative) due to its dopaminergic effects (in
vitro,1565 in animals,17,401,777,1565 PO in human
clinical study1770).
3) Neuroleptic medications like thioridazine may
reduce chaste tree activity (speculative),1503 as shown by the
antagonism of haloperidol to the
dopamine-induced prolactin inhibition from chaste tree ethanolic extract (in vitro).700
CHICKWEED NEW
^ Stellaria
media herb
(adder’s mouth, Indian chickweed, satin flower, starwort,
tongue-grass, winterweed)
Contraindications
1) Allergic hypersensitivity to topical use of
this plant (empirical).1890
CHICORY p.
64
Cichorium intybus
root
Drug Interactions
II. + 1) Inulin and its short-chain fructan
obtained by partial enzymatic hydrolysis from chicory inulin given at 15 grams
daily beginning seven days before liver tumor transplantation both potentiated
in an additive or synergistic manner the therapeutic effects of 5-fluorouracil, doxorubicin,
cyclophosphamide, vincristine
sulfate, methotrexate, and cytarabine given IP in subtherapeutic
doses 48 hours after transplantation (PO in mice).1115 This may be
due to their prebiotic effect of enhancing bifidobacterial colon flora,
lowering colon pH, enhancing mineral bioavailability, and/or reducing de
novo hepatic synthesis of fats (speculative).1255
CHINESE CUCUMBER NEW
^ Trichosanthes
kirilowii root
(Chinese snakegourd)
Contraindications
1) Pregnancy due to its abortifacient effects (empirical)150
CHINESE RHUBARB [formerly RHUBARB, CHINESE] p. 168
Ä *Rheum officinale, *Rheum palmatum root
CHINESE SKULLCAP [formerly
Baikal skullcap] NEW
Ä Scutellaria
baicalensis root
(Baikal skullcap; Ch.: huang qin)
Drug Interactions
II. + 1)
A decoction in doses of 1 and 2 gm/kg given just before oral administration of cyclosporine reduced its maximum serum concentration by
63% and 80% and the total absorption by 55% and 82%, respectively, compared to
water. In contrast, the root flavonoid components baicalin and baicalein given
alone at 112 mcmol/kg elevated the cyclosporine peak 408% and 88% and the total
absorption by 685% and 150%, respectively. When the cyclosporine was given IV,
there was no change in bioavailability when the decoction was given orally. So
the decoction reduced cyclosporine absorption and should not be used
concurrently (PO in rats).1572
+ 2)
Its component baicalin reduced weight loss, anorexia, and diarrhea resulting
from intake of irinotecan
(PO in rats). Also, less damage accurred to the intestinal mucosa, and the
damage healed more rapidly. Two Kampo formulas contain Chinese skullcap
produced similar effects (PO in rats).1828 One of these formulas,
Hangeshasin-To, was also shown to alleviate diarrhea from irinotecan given for
non-small-cell lung cancer when compared to placebo, given to 18 subjects at
7.5 grams daily (PO in human clinical study).1829 Both methanol
eluate fractions III (68 mg/kg) and IV (63 mg/kg) of Hangeshasin-To helped
reduce diarrhea induced by castor oil
(PO in human study). The main component of fraction III was baicalin in Chinese
skullcap.1830
+ 3)
Liver damage from acetaminophen
as indicated by transaminase leverls and hepatic necrosis was significantly
prevented by 300 mg/kg of the flavone component baicalin (PO in mice).
Acetaminophen-induced mortality was reduced from 43% to 0%, apparently due to
inhibition of acetaminophen bioactivation by CYP 2E1.1891
+ 4)
an extract ameliorated the myelotoxicity of the cytostatic chemotherapy drugs cyclophosphamide and 5-fluorouracil,
as well as helping to decrease tumor cell viability (in mice and rats).2207
III.
+ 1) Absorption of rhodamine 123 was reduced across both the jejunum and
ileum from rats by the root decoction (in vitro)1572
CHOKEBERRY NEW
Aronina melanocarpa fruit
(aronia, black chokeberry, wild chokeberry)
Drug Interactions
I. 1) An
extract of the fruit with about 25% anthocyanins, 9% phenolic acids, and 50% monomeric
and oligomeric procyanidins was given at 255 mg daily to 22 myocardial
infarction patients who had been on the statin
drugs simvastatin and atorvastatin for at least 6 months,
while an equal number of similar patients were given placebo in a double-blind
trial (PO in human clinical study). In addition, 77% of those in the study were
taking aspirin and 52% were using ACE inhibitors. Compared to those given
placebo with their medications, those receiving the extract had significantly
lowered diastolic and systolic blood pressure, C-reactive protein, IL-6,
adhesion molecules, oxidized LDL, and F2-isoprostane measurements
and higher adiponectin. These changes indicate reduced oxidative stress and
inflammatory response and a lower risk for further ischemic heart disease.2675
A total of 250 ml daily of the fruit juice high in polymeric procyanidins,
phenolic acids, and glycosides of quercetin and cyanidin were taken for 6
weeks, stopped for 6 weeks, then taken again for another 6 weeks by 35
hypercholesterolemic men who were not taking medications for their condition;
after the second 6-week juice intake there were significant decreases in mean
serum total cholesterol, LDL cholesterol, and triglycerides and increases in
mean changes in brachial artery diameter, flow mediated dilatation, and serum
nitric oxide levels (PO in human clinical study).2708
II. 1) When given before indomethacin subcutaneous
injections, the fruit juice reduced the number and area of damage to the
stomach lining compared to controls, due to an increase in gastric mucus
production and reduced oxidative stress (PO in rats).1983 Likewise,
the methanol extract of the fruit at 2 gm/kg protected the gastric mucosa from
damage by ethanol by reducing the damaged area to >30% of that in the
control group (PO in rats). The red pigment fraction with 3 main components
including cyaniding 3-O-beta-glucoside demonstrated radical-scavenging
activity (in vitro).1984
CINCHONA p.
65
*Cinchona spp.
bark
Drug Interactions
III. + 5)
Inhibition of glutatithione S-transferase conjugation of ethacrynic acid
and 1,3-gis(2-chloroethyl)-1-nitrosurea (BCNU) by quinine and/or
quinidine (in vitro) could lead greater tumor cell retention and
increased efficacy of BCNU as an anticancer agent1547
CINNAMON p.
66
*Cinnamomum verum =
Cinnamomum zeylanicum bark
[See also Cassia.]
Drug Interactions
III. + 1)
Alkaline aqueous extracts of cinnamon and a concentrated fraction were shown to
greatly potentiate insulin activity (in vitro).1462-1465
A methylhydroxychalcone polymer from this cinnamon
fraction stimulates glucose uptake and glycogen synthesis similar to insulin.
When combined with insulin, together these compounds had greater than additive
activity (in vitro).1466 Water-soluble polyphenol polymers of
A type doubly linked procyanidin oligomers of catechins and/or epicatechins
increased insulin-dependent glucose metabolism 20-fold (in vitro).1659
Cinnamon bark aqueous extract significantly increased plasma insulin in animals
after 1 hour. Cassia bark (C. cassia) and extract were more effective
than cinnamon extract (PO in rats). The extract did not reduce normal blood
glucose.1763
However, in a
placebo-controlled study with 72 type 1 diabetes adolescents, after consuming a
1-gram dose of cinnamon powder daily for 90 days no differences were found in
total daily insulin intake, number of hypoglycemic episodes, glycated
hemoglobin (A1C), or change in A1C between the cinnamon and placebo groups (PO
in human clinical study).2108 When 6 grams of cinnamon were given with 300 grams
of rice to healthy subjects, it delayed gastric emptying and reduced
postprandial blood glucose (PO in human study).2294 Unfortunately,
in these studies the authors did not characterize the type of cinnamon (Cinnamomum
spp.) by species name.2108,2294 A water extract had no effect on
blood sugar in normal or streptozotocin-induced diabetes (PO in rats).1467
CLOVE
p.
66
Syzygium aromaticum
buds
Contraindications
+ 1)
Allergic hypersensitivity to
eugenol (speculative)10
Drug Interactions
III. 1) Anticoagulants
(speculative),777
including warfarin and heparin may be
potentiated, as well as aspirin (speculative)400
+ 3)
Alkaline aqueous extracts of clove were shown to potentiate insulin activity
in glucose metabolism (in vitro).1462,1464 Cloves have been
shown to reduce blood sugar in streptozotocin-diabetic animals, but not in
those that have normal function (PO in animal studies).319
+ 4)
Essential oil should not be used with acetaminophen [paracetamol]
(speculative), due to the potential hepatotoxicity of its eugenol content400
COCOA p.
67
Theobroma cacao
seed
Drug Interactions
I. + 2)
Non-heme iron absorption is diminished by 5 grams of cocoa in a cup of hot
water due to the polyphenol content (PO in human study)1246
3) When cocoa that supplied 963 mg flavanols daily was
given to 41 fully medicated type 2 diabetics with 76% on oral hypoglycemic
drugs, 24% on insulin, 81% on antiplatelet drugs, 76% on statins,
71% on beta blockers, and 67% on ACE inhibitors, flow-mediated
dilation increased initially as after 30 days was 30% over baseline (PO in
human clinical study). Though this appears to reverse vascular dysfunction by
increasing nitric oxide synthesis, the glycemic control, heart rate, and blood
pressure were unaffected.2600
COFFEE p.
67
*Coffea arabica
seeds
Contraindications
3) Consumption of large amount daily should be
avoided in pregnancy (speculative).150,401
A study of 2,714 women who delivered live infants in
which coffee was the main source of caffeine in the first month (38% of all
women) and seventh month (35%) found that > 300 mg caffeine daily was not
associated with growth retardation (PO in human study).1966 However,
a prospective study of 18,478 singleton pregnancies found the risk of
stillbirth is increased by those who drink 8 cups of coffee or more daily
during pregnancy, compaired to those who drink none (PO in human study).1486
In an evaluation of 2,291 mothers caffeine consumption
was found to reduce average birth weight. This was considered significant for
those who consumed more than 600 mg of caffeine daily, approximately equivalent
to six 10-ounce cups of coffee (PO in human study).1568
However, a prospective study
of 873 women found no association between caffeine consumption, primarily from
coffee, at any amount and birth weight, gestational age at delivery, or birth
weight standardized for gestational age (PO in human study).1672
5) Heart disorders
and cardiovascular disease due
to caffeine increasing heart rate and arrhythmias (empirical)8,10
In a study of risk of nonfatal myocardial infarction
(heart attack) based on coffee consumption and CYP1A2 genotype, it was shown
that those with only the allele *1A for rapid caffeine metabolism have a
somewhat reduced risk of heart attack with coffee consumption, while those
carriers of the allele *1F for slow caffeine metabolism have an increasingly
greater risk of myocardial infarction with coffee consumption greater than 11
cup/day (PO in human clinical study).1925
Caffeine at a dose of 250 mg acutely increased
aortic stiffness in 20 healthy subjects, leading to increased blood pressure
centrally and to a lesser extent peripherally (PO in human study). These effects
may impact cardiovascular risk (speculative).1569 However, a study
of 155,594 women over 12 years found no linear association with coffee or
caffeine consumption and hypertension (PO in human study).1859
6) Psychological
disorders (speculative) since caffeine can aggravate depression or induce
anxiety neurosis.8
In a dose-dependent manner coffe consumption
increased state anxiety in men but not in women (PO in human study).1494
7) Glaucoma
(speculative),150
since it increases intraocular pressure in glaucoma
patients 60-90 minutes after drinking caffeinated coffee, as compared to
decaffeinated coffee (PO in human clinical study)1359
Drug
Interactions
I. 2) Increased weight loss occurs due to a reduction of
body fat along with side effects of agitation, tremors, and insomnia, when
caffeine is combined with ephedrine (PO
in human clinical study).19
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interaction was found.1665
+ 14)
Methotrexate efficacy for reducing the joint pain and morning stiffness
of rheumatoid arthritis was diminished for those consuming 260 mg of caffeine
daily on average, compared to those who consumed an average of only 90 mg daily
(PO in human clinical study), probably due to methylxanthines like caffeine
acting as adenosine receptor antagonists while methotrexate increases
adenosine.1495
+ 15) A study over 13.6 years of 26,556
Finnish men with no history of strokes who smoked 5 or more tobacco
cigarettes daily showed the consumption of 8 or more cups of coffee daily
significantly reduced the risk of strokes by cerebral infarction (PO in human
study).2300
COLA p.
71
Cola nitida, Cola acuminata seed
Contraindications
3) High blood pressure (speculative), since caffeine increases the secretion
of epinephrine and norepinephrine.150
However, a study of 155,594 women over 12
years found no linear association with coffee or caffeine consumption and
hypertension, but consumption of sugared or diet cola was associated with high
blood pressure (PO in human study).1859
5) Pregnancy (speculative),
since caffeine crosses the placenta and has been weakly associated with fetal
loss, low birth weight and premature deliveries in humans.8
However, a study of 2,714
women who delivered live infants in which soda was consumed in the first month
by 30% of the women found that > 300 mg caffeine daily from all sources was
not associated with growth retardation (PO in human study).1966
Drug Interactions
I. 2) Increased
weight loss due to a reduction of body fat as well as side effects of
agitation, tremors, and insomnia when caffeine is combined with ephedrine (PO in human clinical study)19
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interaction was found. Oral
contraceptives prolonged caffeine elimination.1665
Similar results occur when cola nut and ephedra are used
together to provide 90 mg of ephedrine alkaloids and 192 mg of caffeine daily
(PO in human study).1307
+ 13)
Methotrexate efficacy for reducing the joint pain and morning stiffness
of rheumatoid arthritis was diminished for those consuming 260 mg of caffeine
daily on average, compared to those who consumed an average of only 90 mg daily
(PO in human clinical study), probably due to methylxanthines like caffeine
acting as adenosine receptor antagonists while methotrexate increases
adenosine.1495
COMFREY p.
75
*Symphytum
officinale root/leaves
Contraindications
1) Internal use due to development of
hepatic veno-occlusive disease (human case reports)17,150,236,237,590
The belief that all internal comfrey use poses an
inappropriate risk has been challenged on the basis of empirical experience and
inadequate scientific investigation (speculative).1355
3) Avoid any use during pregnancy (speculative)150,401
due to fetal hepatotoxicity resulting from
transferral from mother of toxic pyrrolizidine alkaloids similar to those in
comfrey (injected in rats38 and PO in human case report144)
4) Avoid any use by nursing
mothers (speculative)150,401
due to infant hepatotoxicity resulting from
transferral from mother of toxic pyrrolizidine alkaloids similar to those in
comfrey (PO in rats)38
+ 7)
In infants due to their increased susceptibility to the toxicity of
pyrrolizidine alkaloids for even less than a week, whereas older children are
affected after several months (empirical),1311 such as a 13 year old
boy suffering veno-occlusive disease of the liver from consuming unknown
quantities of comfrey root and then a tea made from its leaves for several
years (PO in human case report)237
COPAIBA NEW
^ *Copaiba
langsdorffii, Copaiba spp. oleoresin
(capivi, balsam of copaiba, balsam capivi)
Contraindications
1) Internal use with inflamed urinary tract,
especially in acute gonorrhea, due to its irritate volatiles excreted
in the urine (empirical)2,5
COPTIS NEW
^ Coptis
chinensis and Coptis groenlandica rhizomes
(Chinese goldthread; Ch: huang lian) and (goldthread,
canker root)
Contraindications
1) Pregnancy due to emmenogogue effect of the herb2,150
and uterine stimulant activity of the alkaloid berberine (empirical)74,150
2) Jaundice in newborns from (speculative)
due to the displacement by berberine of bilirubin from serum albumen which may
lead to kernicterus (IP in rats)1092
Drug Interactions
I. 1) 0.2% berberine effectively eliminated inclusion bodies
of Chlamydia trachomatis when used as
eye drops to treat trachoma patients in conjunction with local sulphacetamide solution which
alleviated clinical symptoms alone but did not eliminate this organism (locally
in human clinical study)577
+ 2)
Berberine 1.2 grams daily, given as tablets to 79 congestive heart failure
patients on ACE inhibitors along with digoxin in 76, nitrates
in 71, and diuretics / spironolactone in 77, significantly increased
left ventricular ejection fraction and exercise capacity, improved
dyspnea-fatigue index, and reduced frequency of ventricular premature complexes
compared with 77 patients using only comparable conventional medications. The
mortality of the berberine group decreased significantly as well, and there
were no apparent side effects (PO in human clinical study).1457 In
56 congestive heart failure patients on loop diuretics and ACE inhibitors,
including 51 using digoxin and 46 on nitrates, the significant increases in
left ventricular ejection fraction and decreases in ventricular premature beats
from baseline from 1.2 grams of berberine daily was also significant better
when plasma berberine concentrations were higher versus lower than 0.11 mg/L
(PO in human clinical study).2639
+ 3)
Berberine at 0.6 grams daily for 3 months increased previously stabilized cyclosporin
A trough blood concentrations by 90% in 52 renal transplant patients, and
when given for 12 days to 6 transplant patients increased the cyclosporine
bioavailability by 35% (PO in human clinical study), likely by inhibition of
CYP 3A4 (speculative).2281
+ 4)
The combination of 500 mg berberine 3 times daily for 3 months in 43 patients
with poorly-controlled type 2 diabetes together with one or more of their
regular oral hypoglycemic medications including sulfonylureas in
28, metformin in 20 acarbose in 15, and/or insulin in 10
resulted in lower fasting and postprandial blood sugar from week 1 through week
12 (PO in human clinical study). Fasting plasma insulin was also lowered by 28%
and an index of insulin resistance by 45% of those on medications, while total
cholesterol and LDL were likewise reduced. In 31 newly diagnosed type 2
diabetics to whom 15 were given the same dose of berberine and 16 used 500 mg
metformin 3 times daily, berberine’s hypoglycemic effect was similar to that of
metformin on fasting and postprandial blood glucose, as well as reducing
glycosylated hemoglobin and plasma triglycerides (PO in human clinical study).
Transient gastrointestinal adverse effects were experienced by 35% of the
patients, or 20 in total.2315
II. 1) Berberine administered prior to pentobarbital increased the induced sleeping time (IP in mice)1032
A single 4 mg/kg dose of berberine prolonged
pentobarbital sleeping time and increased strychnine toxicity (PO in
rats)1215
2) pre-treatment with 4 mg/kg berberine prevented a rise
in serum levels of liver enzymes from excessive acetaminophen,
suggesting protection from its toxic effects (PO in rats). Use of this dose
three times every six hours following a toxic dose of acetominophen reduced
liver damage.1215
+ 3)
When the alkaloid component berberine was given once or twice at doses of 50,
100, or 200 mg/kg before cyclophosphamide injection, it significantly
reduced the chemotherapy adverse effect of bladder hemorrhage in a
dose-dependent manner (IP in rats).2570
+ 4) Berberine at 100 mg/kg enhanced the anxiolytic effects
of buspirone and ritanserin but did not interact with
diazepine (PO in mice).2668
III. 1) An aqueous solution of berberine induced susceptibility of
three strains of enteric bacteria to penicillin
and 13 strains to chloromycetin
which had previously been unaffected by these antibiotics (in vitro).578
+ 2)
Berberine increased efflux of rhodamine 123 and paclitaxel by
inducing P-glycoprotein and thereby reducing the retention and concentration of
these drugs in human hepatoma and digestive tract cancer cells, respectively (in
vitro)1045,1046
+ 3)
It may have an additive effect with statins (speculative), since studies
in human liver-derived cells with berberine extracted from coptis was found to
increase LDL receptor mRNA expression (in vitro). Lovastatin did
not reduce the effects of berberine that stabilized mRNA of the LDL receptor
after transcription (in vitro), indicating a different mechanism of
action (in vitro). In 63 high-cholesterol subjects taking 1.0 grams
berberine HCl daily for 3 months, serum cholesterol was reduced 18%, LDL
cholestreol 20%, and triglycerides 28%, compared to those using placebo (PO in
human study). In the 32 who were taking no other medication or herbs,
cholesterol was reduced 29%, LDL cholesterol 25%, and triglycerides 35%. HDL
cholesterol was unaffected, and berberine was well tolerated. Berberine was
found to have a dose-dependent cholesterol-lowering effect (in hamsters).1656
CORDYCEPS p.
76
Cordyceps sinensis
mycelium
Drug Interactions
I. 2) Fermented mycelial product improved clinical outcomes
following cyclosporin A use in 30
kidney transplants (PO in human clinical study).598
In 69 kidney transplant patients receiving cyclosporin,
those 30 given 3 grams cordyceps concurrently had less nephrotoxicity compared
to the 39 receiving placebo, based on serum creatinine and urea levels (PO in
human clinical study).1804
CORYDALIS NEW
^ Corydalis
yanhusuo = Corydalis
ambigua rhizome
(Ch.: yan hu suo)
Contraindications
1) Pregnancy due to its emmenagogue and uterine
stimulant effects (empirical)150,404 due to its emmenagogue and
uterine stimulant effects (empirical)150 and embryotoxicity (PO in
rats)404
COTTON p.
76
Gossypium
herbaceum = Gossypium indicum and Gossypium hirsutum fresh root bark
(Levant cotton, Indian cotton; Ger.: Indische
baumwollstaude; Fr.: cotonnier de l’Inde; Sp.: algodon) and (American Upland
cotton)
Contraindications
3) Self-prescribing since medical supervision is required (empirical)7
and Upland cotton root bark contains 1.2% gossypol1168 with its
potential for adverse effects6 including hypokalemia with use of
20-50 mg gossypol daily for up to twelve months (PO in human studies)1169,1170
that is not controlled by potassium supplementation or use of a potassium
blocker (PO in human studies)1170,1171
+ 4)
Prolonged use in men may cause sterility150 since Upland
cotton root bark contains 1.2% gossypol1168 and gossypol has been
shown to be an effective male antifertility drug (PO in human study).1169
Also, hypokalemia occurs with use of 20-50 mg gossypol daily for 12 months (PO
in human study).1169
Drug
Interactions
III.
+ 1) Accelerated coagulation was shown
with 0.5 ml/kg of an acetone-alcohol root extract (IV in dogs), which also increased
prothrombin in the blood of rats,1172 so use with anticoagulants such as warfarin
should be avoided (speculative)
+ 2) Since upland cotton root bark contains 1.2% gossypol1168 with its potential for hypokalemia with use of 20-50 mg gossypol daily for up to twelve months (PO in human studies)1169,1170 that is not controlled by potassium supplementation or use of the potassium blocker triamterene (PO in human studies),1170,1171 it may potentiate the activity of antiarrhythmic drugs and cardiac glycosides such as those in Adonis, Convallaria, Urginea, Helleborus, Strophanthusand Digitalis (speculative)
COUCH
GRASS [now TRITICUM] p.
77
Elymus repens = Agropyron repens roots, rhizomes and short stems
CRANBERRY NEW
^ Vaccinium
macrocarpon fruit
(craneberry)
Contraindications
II. + 1)
One liter of cranberry juice given daily for 7 days to 12 normal subjects and
12 formers of calcium oxalate stones to assess the risk of developing
urinary stones (PO in human study). There were not differences between the two
groups, but an increased urinary saturation of calcium oxalate of 18% and
reduced pH was found in the combined groups. The risk of calcium oxalate stone
formation is increased (speculative), whereas the risk of brushite stones is
decreased. By comparison, cranberry cocktail contains only 27% juice.1997
Drug
Interactions
I. 1) Initially, a brief report on5 individuals suggested
cranberry juice may increase the effects of warfarin.1764
These included a case of fatal internal hemorrhage in a man in his 70s with an
INR (International Normalized Ratio) initially reported to be >50.1483,1764 This elderly man had been taking a stable
warfarin dosage for 4 years along with digoxin and phenytoin but suffered a
deadly hemorrhage marked by melena after he consumed about 300-400 ml of
cranberry juice daily for 6 weeks (PO in human case report). He had eaten
almost no solid food for 2 weeks prior to his death, but continued his
medication and the juice. On admission to a hospital just hours before dying
his status included: INR >15, hemoglobin 5 g/dl, an immeasurable prothrombin
time, and blood pressure 70/40 mmHG. Autopsy revealed 950 ml of fluid with
blood in his pericardial sac, extensive bruising on his limbs, and blood
throughout his gut from erosive pan-gastritis.2508
However, the fatal case was
dismissed by some as due to an almost complete lack of other nutrition
including competing vitamin K as well as prior 7-day use of the antibiotic
cephalexin which can alter the intestinal flora and vitamin K biosynthesis.1765,2510
In brief anecdotes about another 6 potential interactions of warfarin with
cranberry juice, 4 had INR increases, 2 had unstable INRs, and in 1 the INR
decreased (PO in human case reports).1483,1764 After a 2-week lead-in
for patients with stable warfarin INRs of 1.7-3.3 over the prior 8 weeks, a
randomized double-blind trial with 16 subjects taking placebo and 14 using 9 oz cranberry juice
daily for 2 weeks found no differences in INR or R- or S-warfarin peak levels during
the lead-in or treatment phases. Plasma levels of warfarin were the same for
both enantiomers in both groups at corresponding times. The mean INR was
identical for both groups on day 15 at the end of the intervention. Only on day
11 was the INR of the cranberry group significantly higher. For the 14 subjects
taking cranberry juice, 4 developed slightly higher INRs and 1 had a low INR,
while 4 of 16 in the placebo groups had slightly higher INRs.2512 At
least 30% of patients using warfarin are commonly outside of the normal
therapeutic range.1765
Nonetheless, a 71-year-old man taking warfarin
sustained an INR of 2-3 for 3 months prior to using 24 oz cranberry juice daily
for 2 weeks; he developed blood in his sputum and stools, low hemoglobin, a
prothrombin time >120 seconds, and an INR of >18 (PO in human case
report). After a blood transfusion and stopping warfarin and cranberry juice,
bleeding was controlled in 1 day. His INR was 7 the next day and 2.6 in another
3 days.2505 A 78-year-old man taking a stable warfarin dose for
about 6 years had never had an INR >3.0 before drinking a half gallon of
cranberry/apple juice in the week prior to registering an INR of 6.45, but no
bleeding was reported (PO in human case report). After adjusting warfarin dosage
and refraining from cranberry juice, the INR decreased to 3.39 and normalized
after 2 weeks.2506 A 75-year-old man taking a stable dose of
warfarin for 10 months with INRs from 2-3 registered an INR of 4.8 a week after
Thanksgiving, but no bruising or bleeding had occurred (PO in human case
report). He reported consuming about 113 gm of cranberry sauce over the prior
week. After discontinuing the cranberry sauce and stopping warfarin for 2 days,
the INR returned to 2.2 within a week.2507
However,
cranberry juice does not inhibit the CYP 2C9 isozyme involved in metabolism of
the more potent S-warfarin, since the 2C9 substrate flurbiprofen was not
affected by exposure to cranberry juice (in vitro) or after 8 oz
cranberry juice was consumed twice, the evening before and morning of the
flubiprofen dose (PO in human study).1947 R-warfarin may be
metabolized by CYPs 1A2 or 3A4, but 10 healthy subjects consuming 200 ml of
cranberry juice or water three times daily for 5 days before and 5 days after
taking 10 mg R,S-warfarin caused no changes in bioavailability for either
warfarin isomer (PO in human study). Other CYP 1A2 and 3A4 substrates were also
unaffected. The combination with the juice did not alter hemodynamics, but the
low warfarin dose makes this observation tentative.2316
Taking 25 mg warfarin alone once as a baseline,
following a 2-week washout 12 healthy males of ages 18-34 years took 1 gm of
cranberry extract 3 times daily for 2 weeks; the same dose of warfarin was
given again and the cranberry extract continued for a third week (PO in human
study). The daily extract dose was derived from 57 gm of dried fruit. No
changes in baseline INR or platelet aggregation were found after 2 weeks of
cranberry extract alone. The protein binding and pharmacokinetics of the S- and
R-warfarin enantiomers were not affected by use of the extract, neither for
subjects with wild nor with variant CYP2C9 genotypes. On the other hand, the
pharmacodynamic effect of warfarin combined with the extract, shown by a 30%
increased area under the INR-time curve, was significant both statistically and
clinically. A mean decrease in the estimated S-warfarin effective dose was
shown when the extract was taken compared to control. This decrease was
significant for the 8 subjects with a vitamin K epoxide reductase subunit 1
gene [VKORC1] variant, but not for the 4 subjects with the wild-type VKORC1. No
bleeding or INR readings above 4 resulted. The strength of these findings is
limited by the small sample sizes for the genotypes.2509
The United Kingdom’s Committee on Safety of Medicines has alerted clinicians of a potential interaction and advised patients to avoid concurrent use of warfarin with cranberry juice. It appears that ingestion of large volumes of juice destabilize the therapy, whereas small amounts are not expected to cause a serious interaction, though patients should be counseled and monitored.2510 An earlier pharmacodynamic investigation of 7 subjects on warfarin for 3 months did not find prothrombin time or INR changes when 250 ml of cranberry juice cocktail or placebo was given for 7 days, followed by a crossover after a 7-day washout, though the short time and small sample size limits the findings (PO in human study). The authors suggest that elimination of up to 250 ml [1 cup] cranberry juice cocktail daily should not be required if INRs are closely followed.2511 In a systematic review of the 9 unpublished and 6 published cases of potential interactions of cranberry juice with warfarin, 2 were found to be "probable" and 4 "possible" interactions on the Naranjo validation scale.2698
2)
In 16 subjects consuming 3 glasses of 240 ml double-strength cranberry juice
prior to a single dose of midazolam,
its bioavailability was significantly reduced but not its half-life (PO in human
study). This was indicative of inhibition of intestinal, but not hepatic,
first-pass metabolism. The juice used was the only 1 of 5 commercial cranberry
juice samples tested at 0.05% that showed significant inhibitory effects on
metabolism of midazolam by CYP3A (in
vitro).2699
However, in prior trials no
inhibition was shown in 10
subjects by 200 ml cranberry juice 3 times daily for 10 days with midazolam given on day 5 (PO in human
study)2316 or when a single 240 ml glass of juice was taken with one
dose of the CYP3A substrate cyclosporine by 12 health subjects (PO in
human study). 2021
2)
When 16 healthy volunteers consumed 3 glasses with 240 ml of
double-strength cranberry juice prior
to a single dose of midazolam, its bioavailability,
but not its half-life, was significantly increased (PO in human study). This
was indicative of inhibition of intestinal, but not hepatic, first-pass
metabolism. The juice used was the only 1 of 5 commercial cranberry juice
samples tested at 0.05% that showed significant inhibitory effects on
metabolism of midazolam by CYP3A (in
vitro).2699
However, in
prior studies no inhibition was shown by cranberry juice with midazolam (PO in
humans) 2316 or with CYP3A substrate cyclosporine (PO in humans).
2021
III. 1) In human multiple myeloma cells the triterpenoid component
ursolic acid increased the apoptotic effects of thalidomide from 20% to
70% and enhanced this activity of bortezomib from 25% to 80% (in
vitro).2428
CRANESBILL NEW
^ Geranium
maculatum root
(American cranesbill, spotted cranesbill, spotted
geranium, alum root, crowfoot, wild cranesbill, wild geranium)
Contraindications
II. 1) GI inflammation and ulceration
(speculative),1890 due to its tannin content.232,1890
However, cranesbill has been traditionally used as part of a formula with
demulcents for treating gastric ulcers, especially when bleeding (empirical).1
2)
Iron deficiency anemia and malnutrition (speculative) due to
tannin content that binds metal ions and thiamine1890 and reduces
iron absorption when taken concurrently (PO in human study).1246
3)
Constipation (speculative) due to the high tannin content that produces
an astringent effect.1890
4) Prolonged use
(speculative) due to its tannin content.1890
Drug
Interactions
III. 1) Due to its tannin content, it should not be taken
concurrently with oral thiamine, metal ions like iron and zinc,
or alkaloids because of probable precipitation in the gut leading to
reduced absorption (speculative) as is suggested by studies combining tea with
metal ions or thiamine (in humans), tannins with thiamine (in animals), and
tannins with alkaloids (in vitro).1890
CRATAEVA NEW
^ Crataeva
nurvala and Crataeva religiosa bark
Contraindications
II. 1) Pregnancy (speculative) without professional
advice, due to its known antifertility and fetotoxic effects (in animals) and
potential mutagenic and goitrogenic activity from its glucosinolate content.1890
CRUCIFERs p. 77
Brassica spp
heads or leaves
Drug Interactions
1) Anticoagulant effect of warfarin may be inhibited or rendered ineffective by regular
consumption of broccoli, brussels sprouts (PO in human case reports)32,33,303,304
However, the glucosinolate metabolite indole-3-carbinol formed
after maceration of cabbage, broccoli and Brussels sprouts, etc., also has both
antiplatelet activity associated with inhibiting both fibrinogen binding to
platelet surface glycoprotein receptor and the formation of TXB2 and
PGE2 (in vitro) and has shown antithrombotic effects (PO in
mice).2224
3) Increased caffeine
metabolic rate was shown after consuming 500-600 gm daily of cruciferous
vegetables (PO in human studies).620,801
Compared to a basal diet with no vegetables, 36
subjects after eating for 6 days a diet containing 16 gm (0.5 cup) fresh radish
sprouts, 150 gm (1 cup) frozen cauliflower, 200 gm (2 cups) frozen broccoli,
and 70 gm (1 cup) fresh cabbage daily, had a significantly greater rate of
caffeine metabolism by CYP 1A2 (PO in human study).1634 The juice of
2 cultivars of both Brussels sprouts and red cabbage both induced CYP 1A2 and
UGT when raw or cooked, but Brussels sprouts had greater activity associated
with its 2-3-fold greater glucosinolate content (PO in rats).1987
4) Consuming 500 gm/day of broccoli, healthy subjects had
increased estrone metabolism, due to
increased CYP1A2 and other cytochrome P450 enzymes (PO in human study).620
With every 10 gm/day increase in crucifer
consumption by 34 postmenopausal women, the 2-hydroxyestrone:16alpha-hydroxyestrone [2:16]
ratio increases 0.08 (PO in human study). Increasing the 2:16 ratio is
associated with reducing breast cancer risk.2516 400 mg daily for 2
months of I3C by 5 obese premenopausal women also increased the 2-hydroxyestrone:estratriol
ratio, another indicator of lowered breast cancer risk (PO in human study).2517 Consumption of the cruciferous derivative
indole-3-carbinol increased the detoxifying 2-hydroxylation of estradiol by over 50% (PO in rats, PO
in human study).798,803
Indole-3-carbinol also reduces estrogen
receptor-alpha expression by 50% a 100 mcM concentration in MCF-7 human breast
cancer cells, while its metabolic dimmer has a comparable effect at 5 mcM (in
vitro).1979
CUMIN NEW
^ Cuminum
cyminum seeds
Drug Interactions
II. 1) An aqueous
extract, its concentrated fraction and an isolated flavonoid glycoside
designated CC-I were all capable of increasing the oral bioavailability of the
anti-turberculosis drug rifampicin (PO in rats). In gut sac studies CC-I increased the
rate of mucosal-to-serosal transfer of rifampicin (in vitro). This can
serve a therapeutic advantage since rifampicin has notoriously poor oral
bioavailability.2296
DAN SHEN p.
78
Salvia miltiorrhiza
roots
Drug Interactions
I. 1) Anticoagulants404
are enhanced due to reduced coagulation with extended use of the decoction (PO
in human case reports);202,444,715
antithrombin III-like effects could augment the
action of heparin (speculative).1238
II. + 1)
The chemotherapeutic drug doxorubicin (adriamycin) given
intraperitoneally over a 2-week period caused less heart and liver damage when
a freeze-dried powder of decoction of the roots was given along with it for 30
days (PO in rats). The extract was more effective at 100 mg/kg than 20 mg/kg,
especially in preventing cardiotoxicity.2256
III. + 2) Dan shen extract added to digoxin
pools from patients resulted in false elevations (positive interference) for
digoxin in the fluorescence polarization immunoassay (in vitro)1353,1386
and false reductions (negative interference) in the microparticle enzyme
immunoassay (in vitro).1353 Unlike eleuthero and Asian
ginseng interference, false positives and/or negatives can be avoided by
monitoring free digoxin concentration.1352,1353,1386 The amount of
interference varied with different brands of danshen products (in vitro).1386
DANDELION p.
79
Taraxacum
officinale = Taraxacum dens-leonis roots and leaves
Drug Interactions
II. + 1)
After being consumed for 4 weeks, a 2% tea made from the roots reduced the
metabolism of the
CYP 1A2 substrate phenacetin by liver microsomes to 15% of normal (PO in
rats). It also reduced the activity of CYP 2E to 48% that of controls, while
increasing phase II UDP-glucuronosul transferase activity by 244%.1608
DEVIL’S CLAW p.
80
Harpagophytum
procumbens roots and tubers
Contraindications
3) Avoid use except with caution in hyperacidity
and esophageal reflux (speculative), due the the gastric stimulation
effect of bitters (empirical).1890
Drug Interactions
I. 1) Purpura developed with the use of devil’s claw in
combination with warfarin in one
case (PO in human case report).614
However, this report has
been described as unevaluable based upon report inadequacies.1239
+ 2) In 227 patients with hip, knee, or back
pain associated with osteoarthritis, the use of nonsteroidal anti-inflammatory
drugs (NSAIDs) including diclofenac, metamizol, aspirin, ibuprofen,
naproxen, propyphenazon, clecoxib, acemetacin, ketoprofen, indomethacin,
piroxicam, and rofecoxib was reduced with concurrent use of a
standardized extract containing a daily dose of 60 mg harpagoside in this open
trial (PO in human clinical study). Those with back pain required more
medication, but their requirement decreased more than the other groups over 8
weeks of extract use.1368
Devil’s claw extract with harpagoside has a
dose-dependent analgesic effect (PO in human clinical study)1413 but
lacks the biochemical effect on arachidonic acid metabolism typical of NSAIDs
(PO in human study).1414
A dose of 2 gm/kg of an uncharacterized devil’s claw
preparation lacked both anti-inflammatory and prostaglandin synthetase
inhibiting activity (PO in rats),1415 even though 50-800 mg/kg of an
aqueous extract of the secondary root produced significant analgesic and
anti-inflammatory effects (IP in mice and rats, respectively).1743
Likewise, a 60% ethanolic 4:1 extract in water produced analgesic and anti-inflammatory
effects in acute and chronic treatment with 25, 50 and/or 100 mg/kg (injected
in rats).2001
+ 3)
A randomized, double-blind comparative study with 100 mg daily of the analgesic
diacerhein and 2.6 gm cryoground devil’s claw powder was carried out for 4
months with 122 patients with osteoarthritis of the knee and hip. Both
diclofenac and the analgesic acetaminophen with caffeine were also
allowed and their intake monitored. Pain reduction was equivalent for the two
treatments, but those taking the devil’s claw had less adverse effects
(diarrhea in 8% vs. 27%) and were using significantly less NSAID and analgesic
at the end (PO in human clinical study).1411
A 4-week RPCDB study of 118 chronic low back pain
patients used 2.4 gm daily of a 2.5:1 devil’s claw tuber extract (with 50 mg
harpagoside total) along with the analgesic tramadol. The use of tramadol by
the extract and placebo groups was same, but at the end 9 of 51 in the extract
group were pain-free compared to 1 of 54 in the placebo group. No adverse
effects were noted (PO in human clinical study).1412
In an 8-week single-group open-label study with 259 general rheumatic disorder patients 960 mg of extract tablets from dried tincture was used daily, along with concomitant medications by 94% including analgesics by 154 of these subjects or 69% at baseline. Along with improved quality of life scores, significant reductions in pain scores were found for the hand, wrist, elbow, shoulder, hip, knee and back. Of those using the analgesics, after 8 weeks 26% had stopped taking them and 45% had decreased their dosage, while 17% used the same dosage and 9% increased the analgesic dosage. Tolerability was rated good by 87%; possible or probable adverse events were reported by 17%, most of which were gastrointestinal complaints, though no serious side effects were reported.2259
However,
some are of the opinion that use with powerful prescription analagesics should
be approached with caution (speculative).1890
DILL p.
81
Anethum graveolens fruit
Contraindications
+ 3)
Allergic hypersensitivity to similar
plants in carrot (Apiaceae) family (empirical)10
DOG
ROSE
Rosa canina fruit, petals
(rose hip, brier hip, brier rose, dogberry, eglantine
gall, hip rose, hip tree, hogseed, sweet brier, wild brier, witches’ brier)
Drug Interactions
I. 1) Five grams daily of standardized rose hip powder given
randomly for 4 months to 48 osteoarthritis patients, of whom 23 were taking NSAIDs
and 14 used acetaminophen, resulted in signicantly decreased joint pain
compared to 48 taking placebo and comparable medications, and signicantly
reduced NSAID use compared to baseline (PO in human clinical study). Reduction
of acetaminophen was not significant.2564 In another randomized
double-blind study in which 80 osteoarthritis patients used 5 grams of the same
powder for 3 months in a crossover study design, 36 on prescription NSAIDs were
told to maintain their use and dose; those who took placebo first had
significantly reduced joint pain and use of analgesic rescue medications
including acetaminophen and tramadol compared to baseline (PO in
human clinical trial). Those who used the rose hop powder first showed no
significant changes in pain, stiffness or rescue medications from baseline,
presumably due to a strong carryover effect from the rose hip powder. Overall,
there was a significant decrease in rescue medication from the first 2 weeks of
active treatment compared to the last 2 weeks of the 3-month treatment.2565
In a very similar crossover study with 80 osteoarthritis patients using the
same treatment and duration and advising those 28 on NSAIDS to maintain their
dosage but encouraging all to reduce acetaminophen [n=39] and tramadol or
codeine [n=16] analgesic rescue medications after 3 weeks of blinded active or
placebo treatment in each crossover phase, joint pain was significantly reduced
by rose hip powder after 3 weeks and rescue medication use was significantly
reduced during the active treatment phase, including an acetaminophen reduction
of 40%. After 3 months the stiffness, activities of daily living, and patient’s
global assessment of disease severity were all significantly improved.2566
III. 1) The ethyl acetate extract of the petals increased the
efficacy of b-lactam antibiotics including oxacillin, ampicillin, benzylpenicillin,
or tetracycline against multi-drug resistant/methicillin-resistant Staph.
aureus (in vitro). This was at least partially due to the component
tellimagrandin I that increased oxacillin and tetracycline inhibition of
methicillin-sensitive and multi-drug resistant Staph. aureus (in
vitro). The extract and its isolate both inhibited protein binding of the
antibiotics by these Staph. aureus strains.2351
However, the extract did not
enhance the anti-Staph. effects of fosfomycin, erythromycin, or
kanamycin with multi-drug resistant Staph. aureus strains or with
ofloxacin and methicillin-resistant Staph. aureus (in vitro).2351
DONG QUAI p.
81
Angelica sinensis root
Drug
Interactions
I. 1)
Use concurrently
with warfarin increased prothrombin time and
doubled international normalized ratio (INR) (PO in human case report).616
Another patient who used warfarin for 10 years began having
widespread bruising along with an INR of 10 after one month of using dong quai
(PO in human case report). After six days she was discharged as well.1230
2) Use of 100 mg dong quai
extract daily along with 150 mg of soy extract containing 40% isoflavones (60
mg daily) and 50 mg black cohosh extract daily for 24 weeks by 49 menstrual
migraine patients significantly reduced the number of doses of triptans and analgesics after
20-24 weeks compared to placebo (PO in human clinical study)1422
II.
+ 1) An extract with 95%
polysaccharides precipitated with 75% ethanol from a dong quai decoction
dose-dependently prevented gastric mucosal damage from ethanol and indomethacin. The effective dose was 10 mg/kg; 30 mg/kg had
a protective effect that lasted at least 12 hours (IP in rats).1101
+ 2) Giving a water extract of the root at 15
g/kg daily for 4 weeks, prior to IV doxorubicin
15 mg/kg weekly, reduced the cardiotoxicity by improving heart
performance, preventing loss of
myofibrils, and improving arrhythmias and conduction abnormalities, compared
with water placebo (PO in mice). Mortality was also reduced. The antitumor
activity of doxorubicin was not compromised by the root extract (in vitro).2672
+ 3) A polysaccharide fraction was shown to
offset the leukopenia and gastroduodenal mucosal cytotoxicity induced by cyclophosphamide by promoting white
blood cell recovery and increasing blood vessel number and cell proliferation
in the gut tissues and by reversing the down-regulation of vascular endothelial
growth factor in the stomach mucosa (SC in mice).2677
IV. [1) It has been suggested that use with estrogen
replacement therapy be avoided due to the supposed phytoestrogen content of
dong quai (speculative).893
However, dong quai has shown
no estrogenic activity in tests (in vitro,
in rats, PO in mice, PO in human study).846,923,924,1664
Nonetheless, its alcoholic extract was shown to
stimulate growth in the MCF-7 human breast cancer cell line independent of
estrogenic activity (in vitro)1664]
DULSE p.
82
Rhodymenia palmetta
= Palmaria palmata thallus
Contraindications
+ 3)
Large amounts during pregnancy due to potential development of infantile
goiter (empirical)150
DYER’S BROOM p.
83
Genista tinctoria plant
and flower
Contraindications
+ 3)
Hiatal hernia, esophageal varices, stomach ulcer or peptic
ulcer due to aggravation and/or potential hemorrhage from emetic effect if
bloodroot is taken in excessive doses (speculative)150
Drug Interactions
III. + 1) Do not take large doses after recent
consumption of central nervous system stimulants, due to the emetic
action potentially inducing convulsions (speculative).150
+ 2)
Do not take large doses after recent consumption of central nervous system sedatives,
due to the emetic action potentially inducing aspiration pneumonitis
(speculative).150
EASTERN RED CEDAR NEW
^ *Juniperus
virginiana berries and leaves
Contraindications
1) Pregnancy (speculative)2,150 due
to potential for adverse effects (empirical)2
ECHINACEA p.
83
Echinacea angustifolia, Echinacea
pallida, Echinacea purpurea roots
Echinacea purpurea herb juice
Contraindications
2) “In principle,” avoid in progressive systemic
conditions such as leukosis4,17
(speculative).
Arabinogalactan-proteins from E. pallida
roots increased murine spleen cell proliferation (in vitro).2150
5) For E.
pallida and E. angustifolia herbs
and roots, autoimmune disorders (speculative).4
E. angustifolia hydroalcoholic root extract was shown to
increase antigen-specific IgG production but not IgM during weeks 2-4 of 6-week
use (PO in rats).1176 Arabinogalactan-proteins from E. pallida
roots increased IgM production of mouse lymphocytes (in vitro).2150
However, high doses (250
mg/kg) of high-alcohol
root extracts of a combination of E. purpurea, E. angustifolia, and E.
pallida failed to raise antibody levels to the same KLH antigen in female
rats after two weeks. High and low (50 mg/kg) doses of a commercial 1:4 echinacea
(unspecified “dried herb”) glycerin/water extract likewise had no effect on
antibody production in male rats, but high doses decreased antibody production
in females.1750
A
32-year-old man suffered a severe case of thrombotic thrombocytopenic purpura
following a week of E. pallida
hydroalcoholic extract use (PO in human case report). After transfusions and
plasmapheresis for over a month, along with a variety of medications, the
patient recovered completely.2694
A single case of sudden onset
of Sjogren’s syndrome was associated with two weeks prior use of echinacea and
other herbs. However, no causal evidence and no characterization or positive
identification of the echinacea product were provided, so the association in
this case is entirely speculative (PO in human case report). 1430
A case of pemphigus vulgaris controlled for 3 years
(completely for 1 year) with prednisone, azathioprine, and/or dapsone had a
severe acute exacerbation within a week after beginning daily supplementation
with an uncharacterized echinacea product for an upper respiratory infection
for the first time. He developed blisters on his trunk, head and oral mucosa,
the latter an entirely new location. After discontinuing the echinacea, only
partial control was achieved with the 3-drug combination (PO in human case
report).1682
A 45-year-old male developed acute cholestatic
autoimmune hepatitis with positive IgG levels after taking 1.5 gm/day of
uncharacterized echinacea root tablets for about a month (PO in human case
report). After stopping the echinacea consumption upon admission, the
transaminases and cholestatic enzyme levels spontaneously decreased, and within
a month all lab values were normal except for anti-smooth muscle antibodies.2147
However, though a temporal association existed, no
causal evidence and no characterization or positive identification of the
echinacea product were provided in these cases.1430,1682,2147,2694
6) HIV infection or AIDS (speculative)
for E. angustifolia and E. pallida roots or herbs.4,17
Tumor necrosis factor-alpha (TNF-a) and other cytokines were
not significantly altered after mitogenic stimulation in leukocytes taken from
23 tumor patients after a 4-week oral exposure to 3 ml daily of a combination
extract made with 40% Echinacea angustifolia, 40% Eupatorium perfoliatum,
and 20% Thuja occidentalis (PO in human study). However, this dose of Echinacea is well below
typical therapeutic exposure. Plant parts utilized were not specified, though
the product is described as a spagyric extract combining three mother tinctures.1147
While extracts of E. purpurea herb, root, and
E. angustifolia root all increased production of the cytokines IL-1, IL-8,
IL-10, and TNF-alpha in cell cultures after 6 hours (in vitro),
giving a combination of these extracts at
1.5 grams/day for 2.3 days decreased IL-1, IL-8, and TNF-alpha while increasing
the antiviral cytokine interferon-alpha (PO in human study).1521
7) Allergic
hypersensitivity,777,1244 to aerial parts777,1244,1890
including to plants in the Asteraceae family, (empirical),777,1890 resulting mainly in contact dermatitis,1890
but anaphylaxis can follow internal exposure (PO in human case report).265,1244
Anaphylaxis, two acute asthma attacks, and a severe general rash in another patient has occurred from using internally either echinacea tablets, tea, or tincture (PO in human case reports). Of 26 other adverse reactions reported using one of six brands of these three forms, 26 suggested allergic responses, and half of these were in atopic disease patients. Four were anaphylactic, 12 had acute asthma, and 10 suffered urticaria/angioedema. Of 100 other atopic patients tested, only 3 had used echinacea, but 20% reacted to skin prick testing with aqueous or glycerinated extracts of echinacea, while 90% reacted strongly to grass pollens (topically human study).1244
Using dried E. purpurea juice in 200 children
ages 2-11 years, 7.1% developed rashed compared to 2.7% of the 207 who used
placebo (PO in human clinical study).1684
One individual suffering 4 episodes of erythema
nodosum had used an echinacea product each time for flu-like prodromal symptoms
(PO in human case report). Though a temporal association existed, no causal
evidence was provided and no characterization or positive identification of the
echinacea product was provided.1683
+ 8)
Patients with organ transplants should avoid prolonged use echinacea
preparations (speculative).1890
E. angustifolia hydroalcoholic root extract was shown to
increase antigen-specific IgG production but not IgM during weeks 2-4 of 6-week
use (PO in rats).1176 At doses of 0.4 and 0.8 ml/kg, daily use of a
1:4 extract of E. purpurea leaves, stem and flowers in 50% glycerin amd
water enhanced IgM antibody-forming cell response (PO in mice). At 0.6 mg/kg
the effect was significant at day 4 but not at day 8.2149
Arabinogalactan-proteins from E. pallida roots increased murine spleen
cell proliferation and IgM production of mouse lymphocytes (in vitro).2150
However, though extracts of E.
purpurea herb, root, and E. angustifolia root all increased
production of the cytokines IL-1, IL-8, IL-10, and TNF-alpha in cell cultures
after 6 hours (in vitro), giving
a combination of these extracts at 1.5 grams/day for 2.3 days decreased
IL-1, IL-8, and TNF-alpha while increasing only the antiviral cytokine
interferon-alpha (PO in human study).1521 Also, high doses (250
mg/kg) of high-alcohol root extracts of either E. purpurea or a
combination of E. purpurea, E. angustifolia, and E. pallida
failed to raise antibody levels to the same KLH antigen in female rats after
two weeks. High and low (50 mg/kg) doses of a commercial 1:4 echinacea “dried
herb” glycerin/water extract likewise had no effect on antibody production in
male rats, but high doses decreased antibody production in females.1750
Drug
Interactions
I. + 2)
E. purpurea root at 1.6 gm/day for 8 days both increased the clearance
and reduced bioavailability of midazolam (IV in human study) but did not
alter its clearance when the drug was given to 12 subjects (PO in human study).
These results may suggest that the root extract components in the gut inhibit
intestinal CYP3A while those absorbed induce liver CYP3A.1588
Likewise, when an E. purpurea whole plant extract was given in a 1.6
gram daily dose to 12 healthy subjects for 28 days, no significant effect on
oral midazolam was detected (PO in human study).1589
However, tincture of E. purpurea roots was a strong CYP3A4 inhibitor, moreso than a tincture of the tops, but a E. angustifolia root tincture was the most potent (in vitro).840 A tea made from a mixture of E. purpurea and E. angustifolia tops, E. purpurea root extract, and spearmint and lemon grass leaves also inhibited CYP3A4 (in vitro).1577 The inhibition of CYP3A4 by different Echinacea species and types of preparations corresponded to their relative alkamide content, but CYP1A2 inhibition found with E. purpurea whole fresh plant extract did not (in vitro).2610 Alkamides from root extracts of E. purpurea and E. angustifolia are well absorbed, whereas caffeic acid conjugates are not (PO in human study).1968 Alkamides in E. pallida roots are in minute amounts and are isobutylamides of the type found in E. purpurea.2293 The enteric versus hepatic effects may be due to the fact that phytochemical exposure is different for each; this could help explain why the in-vitro studies of the entire phytochemical complex mimics the enteric rather than the hepatic in-vivo results.
+ 3)
Echinacea purpurea root extract at 1.6 gm/day for 8 days reduced oral
clearance of caffeine and tolbutamide when the drugs were given
orally to 12 subjects, suggesting the root inhibits CYP1A2 and 2C9,
respectively (PO in human study).1588
However, the clearance of
the CYP 2C9 substrate tolbutamide was not considered clinically relevant
because the 90% confidence interval for the geometric mean ratio of treatment
over control phases was between 0.8-1.25 (PO in human study).1588
Also, when an E. purpurea whole plant extract was given in a 1.6 gram
daily dose to 12 healthy subjects for 28 days, no significant effect on
caffeine was detected (PO in human study),1589 suggesting that the
active phytochemical content of the root differs from that of the whole plant
in its effect on CYP 1A2. Isolated
alkamides inhibited CYPs 2C19, 2D6, and 3A4, but not CYP 1A2 (in vitro).2610
+ 4)
The use of 150 mg twice daily of an E. purpurea extract together for 9
months with desamethazone for 21 patients with anterior uveitis and oral
prednisone for 11 patients with intermediate uveitis was compared with
10 and 9 patients, respectively, treated with these steroids alone (PO in human
clinical study). The primary difference
in outcomes was that the patients initially using the echinacea extract with
steroids were able to successfully remain off steroids for an average of 209
and 146 days, respectively, at the end of the test period, compared to 121 and
87 days, respectively, for those initially on steroids alone.2199
II. + 1)
Placebo, 10 mg/kg levamisole, or 360 mg/kg of a 70% ethanolic extract of E.
purpurea dried aerial parts was given on the 10th day of
gestation with phenytoin and 12 hours later (IP in mice). The
teratogenic incidense of phenytoin-induced cleft palate in fetal mice by the 19th
day of gestation was reduced from 16% with placebo to 5.3% by levamisole and
3.2% by the echinacea extract due to their immune-enhancing properties. The
mean weight and length of fetuses were also enhanced by levamisole and the
extract.2202
III. 1) Echinacea may offset or minimize the effects of immunosuppressive drugs (speculative).777,893
Transplant patients who use these drugs should take
echinacea preparations only for short-term use (speculative).1890
However, at doses of 0.4 and 0.8 ml/kg, daily use of a
1:4 extract of E. purpurea leaves, stem and flowers in 50% glycerin amd
water enhanced IgM antibody-forming cell response, and at 0.6 mg/kg the effect
was significant at day 4 but not at day 8 (PO in mice).2149
E. angustifolia hydroalcoholic root extract was shown to
increase antigen-specific IgG production but not IgM during weeks 2-4 of 6-week
use (PO in rats).1176
While extracts of E. purpurea, E. angustifolia,
and E. pallida all increased production
of the cytokines IL-1, IL-8, IL-10, and TNF-alpha in cell cultures after 6
hours (in vitro), giving a
combination of these extracts at 1.5 grams/day for 2.3 days actually decreased
IL-1, IL-8, and TNF-alpha while increasing the antiviral cytokine
interferon-alpha (PO in human study).1521 Also, high doses (250
mg/kg) of high-alcohol root extracts of either E. purpurea or a
combination of E. purpurea, E. angustifolia, and E. pallida
failed to raise antibody levels to the same KLH antigen in female rats after
two weeks. High and low (50 mg/kg) doses of a commercial 1:4 echinacea “dried
herb” glycerin/water extract likewise had no effect on antibody production in
male rats, but high doses decreased antibody production in females.1750
IV. [1) Supposed hepatotoxic effects suggested that echinacea
should not be used with known hepatotoxic drugs (speculation)893,896]
There have been seven cases of hepatitis anonymously
reported in Australia that were suspected to be due to echinacea, though these
reports were not confirmed.1244
ELECAMPANE p.
85
Inula helenium root
Contraindications
+ 2)
Nursing mothers (speculative)150
due to potential toxicity (empirical)2
+ 3)
Pregnancy (speculative)2,150
due to potential toxicity (empirical)2
ELEUTHERO p.
86
Eleutherococcus
senticosus = Acanthopanax senticosus root
Contraindications
2) Prolonged use without
periodic breaks every one to three months (speculative)150
Suspending use is likely based on the need to assess the
response and health status and to determine the value of continuing as before,
adjusting the dose, or stopping its use (empirical). It also may help avoid
developing tolerance to the beneficial influences of the herb (speculative).
Drug Interactions
II. 1) Eleuthero increased
the effect of hexobarbital (IP in
mice), possibly due to inhibition of its metabolic breakdown (in vitro).111 Hexobarbital is
typically metabolized by CYP 2C19.
III. + 1) Due to hypoglycemic effects of the
aqueous extract (IP in mice)116 insulin
dosage may need adjusting when consuming the tea (speculative).
However, 3 gram of root in 12 healthy subjects actually raised plasma glucose in a 75-gram oral glucose tolerance test after 90 minutes (PO in human study).1713
2) [Formerly IV. 1)] It was reported that
eleutherosides were associated with falsely elevated digoxin levels in
the absence of toxic effects, presumably due to a digoxin assay interaction (ex
vivo with human). Though the capsules were analysed and found negative for digitoid
content, the identity of the contents was not established as eleuthero,
referred to as Siberian ginseng.907
Using 5 digoxin immunoassays on 1 liquid eleuthero
extract and 2 eleuthero extract capsules, the liquid and one of the capsules
increased the digoxin concentration test results only for the fluorescence
polarization immunoassay (in vitro, ex vivo with rats, ex vivo with
humans).1352,1995 This increase occurred at at concentrations from
10-50 mcl/ml for the liquid extract, while the microparticle enzyme immunoassay
showed reduced results, but only at 50 mcl/ml, and no change occurred with the
Tina-quant (in vitro).1995
However, the modest
interference does not account for the great elevation noted in the prior case
report, which may have been due to adulteration.1352 Also, and most
importantly, 10 digitalized patients in a double-blind study who were given 300
mg daily of a dry eleuthero extract for 8 weeks did not show an alteration in
blood digoxin levels compared to 10 given placebo, and no adverse effects were
seen in either group (PO in human clinical study).2086
ENGLISH LAVENDER
[formerly LAVENDER] p.
129
Ä Lavandula angustifolia
= Lavandula officinalis = Lavandula vera flowers
Contraindications
+ 2)
Cross-reactivity in those who have allergic hypersensitivity to other
members of the mint family (Labiatae) such as oregano (Origanum vulgare)
or thyme (Thymus vulgaris) may result in contact allergy to lavender
(speculative), especially its oil.1890
+ 3) Skin exposure in prepubertal boys to cosmetic products with lavender essential oil scent including
lotions, soap, shampoo and hair gel was associated with gynecomastia in 3 cases
(TP in human case reports). Cell culture tests showed the oil has both
estrogenic and antiandrogenic activity (in vitro).2025
However,
neither the product names employed in the reported cases nor a listing of their
ingredients with potential chemical hormone disrupters were disclosed, nor were
the products tested for positive botanical identity or adulteration. A lack of
empirical observation of estrogenic type effects for this traditional herb also
challenges conclusions based on isolated cases and in vitro results
(speculative). Since the condition in such boys is uncommon and 3 cases were
reported in a short period of time from the same clinic, factors such as
environmental influences should also be ruled out (speculative).2143 In at least one of the cases that noted only
the use of lavender-scented soap and lotions,2025 it is possible the product
may have not have contained true essential oil of lavender but only a cheaper
lavender fragrance
with synthetic aromatic chemicals, as is typical in some cosmetic products.
Drug Interactions
I. + 1)
In a 4-week randomized, double-blind trial with 45 patients with mild to
moderate depression, 100 mg/day of imipramine combined with 60 drops
daily of a 1:5 strength English lavender tincture (50% alcohol) was more
effective and faster acting than when imipramine was used alone (PO in human
clinical study).1387
ENGLISH PLANTAIN [formerly included with PLANTAIN] p. 162
Ä Plantago lanceolata leaves
(lance-leaf plantain,
ribwort, buckhorn, chimney-sweeps, headsman, snake plantain, ribgrass, ripple
grass, soldier’s herb)
Contraindications
1) Avoid use in profuse catarrh or congestion of
mucous membranes in respiratory conditions (empirical),777 since its
mucilage may exaggerate the effect of the mucosal discharge.
EPHEDRA p.
87
*Ephedra sinica =
Ephedra vulgaris, Ephedra equisetina, Ephedra intermedia;
(Chinese ephedra, Chinese jointfir;
Ch.: ma huang)
Ephedra distachya;
Ephedra gerardiana stems
(European jointfir; Indian
jointfir)
[NOTE: American ephedra, such as Ephedra
nevadensis, contains little or no alkaloids, so the Contraindications and
Drug Interactions for Ephedra are not relevant for American species.150]
Contraindications
+ 21) At least 24 hours prior to surgery due to cardiovascular risks (speculative)1309
+ 22)
Pre-existing psychiatric conditions
due to the occurrence of 57 serious adverse psychiatric events including
psychosis, severe depression, mania, hallucination, sleep disturbance, and
suicidal ideation following ephedra supplement use, in which 2/3 involved
patients who had preexisting conditions and/or were using medications or
illicit substances (PO in human case reports).1863
Drug Interactions
I. 1) Weight loss and
agitation, tremors, and insomnia, may occur when ephedrine is combined with caffeine (PO in mice, PO in human
clinical study)18,19,20,305
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interactions were found.1665
Similar results occur when ephedra with 24 mg
ephedrine alkaloids is taken 3 times daily with a herbal caffeine source such
as guarana containing 80 mg caffeine (PO in human clinical study)1173
or kola nut and ephedra are used together to provide 90 mg of ephedrine
alkaloids and 192 mg of caffeine daily (PO in human study).1307
8 healthy subjects
given a single dose (2 capsules) of a formula with guarana (200 mg caffeine)
and ephedra (20 mg alkaloids) had a significantly increased systolic blood
pressure after 90 minutes and increased heart rate after 6 hours. Though the
kinetics of the caffeine and ephedrine alkaloids were comparable to similar
drugs formulations, one subject with a high urine pH had longer ephedra
alkaloid half-lives, and two subjects on oral contraceptives had longer
caffeine half-lives (PO in human study).1356
In a double-blind, randomized, crossover trial 15
healthy subjects were given a single dose of the commercial product Metabolife
356, a proprietary blend of 728 mg that contained 12 mg of ephedra extract, 40
mg of guarana seed with caffeine, and unspecified amounts of 8 other herbs and
2 bee products, along with vitamin E, magnesium, zinc, and chromium. After
taking the product subjects had significantly higher systemic blood pressure
and extended QT intervals on their ECGs than after taking placebo. All reported
nonspecific adverse events including jitteriness and queasiness after using the
product but not after taking placebo. There were one case each of tachycardia,
hand tremor and premature ventricular complexes after taking the product (PO in
human study).1610
A case of congestive heart failure (CHF) and a case
of myopericarditis were assessed as possibly related to ephedra after the young
male subjects had used one or two products containing ephedra extract combined
with caffeine over the course of 2 years (PO in human case reports). The doses
and frequency of the products used were undetermined. Both smoked tobacco, and
the CHF patient smoked marijuana and drank beer several times per week. The CHF
patient died after 6 weeks, but the myopericarditis patient was stabilized with
medication.1611
+ 11) Psychogenic drugs
due to the occurrence of 57 serious
adverse psychiatric events including psychosis, severe depression, mania,
hallucination, sleep disturbance, and suicidal ideation following ephedra
supplement use, in which 2/3 involved patients who had preexisting conditions
and/or were using medications or illicit substances (PO in human case reports).1863
III. + 4) Pargyline, isoniazid,
and furazolidone (speculative) since they reduce inactivation of
norepinephrine and dopamine, while ephedrine promotes the release of these
neurotransmitters1493
EUCALYPTUS p.
91
Eucalyptus spp.
leaves
Drug Interactions
II. 2) Mixed-function oxidase induction by the leaves increased
the toxicity of plants containing pyrrolizidine
alkaloids such as Senecio jacobaea (PO
in rats).36
The pyrrolizidine alkaloid senecionine from Senecio
jacobaea, tansy ragwort, has been shown to be both bioactivated to its
toxic form and detoxified to its N-oxide form by cytochrome P450 isozyme 3A4 (in
vitro).1183 However, S. jacobaea chronic toxicity was not
increased when fed together with St. John's wort, a known CYP 3A4 inducer (PO
in rats).1653
eUROPEAN GOLDENROD
[formerly GOLDENROD] p. 109
Ä Solidago virgaurea plant
Contraindications
1) Allergic
hypersensitivity to goldenrod or similar plants in the
Asteracea [Compositae] family (empirical). Contact dermatitis after either oral
or topical exposure has occurred.1890
One man had 5 days of generalized
itchy eczema that began 6 days after use of a goldenrod fluid extract (PO in
human case report). Patch tests were postitive for the fluid extract and the
stronger goldenrod dilutions, and mildly positive for the Compositae plants
tansy and yarrow.1976
EUROPEAN PENNYROYAL NEW
^ Mentha
pulegium plant
(pennyroyal)
Contraindications
1) Pregnancy
due to its emmenagogue and uterine stimulant effects (empirical)7,150
and abortifacient activity secondary to the hepatotoxicity of its volatile oil
component pulegone (empirical)2
2) Nursing mothers, due to the
toxicity of its component pulegone (empirical).1890
3) Essential oil for internal use, due to its
hepatotoxicity (empirical).1890
eUROPEAN VERVAIN NEW
^ Verbena
officinalis
plant
(Enchanter’s plant, herb of the cross, holy herb, Juno’s
tears, pigeon’s grass, pigeonweed, simpler’s joy, vervain; Ger.: eisenkraut;
Fr.: verveine)
Contraindications
1) Pregnancy
(speculative)2,150 due to its emmenagogue effect in early pregnancy
(empirical)7,74
EVENING
PRIMROSE p.
92
Oenothera biennis seed oil
I. + 3)
When eight multiple sclerosis patients were given 2.4 ml of evening primrose
oil (EPO) daily, only three showed improvement on their disability score, while
four of six given the same amount of oil with 0.5 mg colchicine twice daily improved the disability score.
Manual dexterity was enhanced overall in both groups (PO in human clinical
study).1148
+ 4)
6-month
double-blind trial involving 40 rheumatoid arthritis (RA) patients with upper
GI lesions due to NSAIDs used 6 gm daily of EPO (540 mg of gamma
linolenic acid, or GLA) or equal amount of “placebo” olive oil. NSAIDs were not
stopped, but 3 in each group reduced their dose. EPO subjects had reduced
morning stiffness after 3 months, while the olive oil group had reduced pain
scores after 6 months (PO in human clinical study).1400 A study of
49 rheumatoid arthritis patients who used only NSAIDs to control symptoms
determined the effects of EPO alone (GLA 540 mg/day) and combined with fish oil
GLA 450 mg/day with EPA 240 mg/day) in comparison to placebo. After a year EPO
improved symptoms in at least 93% with and without the fish oil versus 30% on
placebo. In addition, 73% and 80% using EPO or EPO/fish oil, respectively,
lowered or stopped NSAID use, compared to 30% on placebo (PO in human clinical
study).1537 In a 3-month trial with 18 RA patients not using NSAIDs,
20 ml daily of EPO or olive oil daily reduced prostaglandin E2 and
increased thromboxane B2 in both groups. These results were
associated with a good therapeutic response, but no significant clinical
improvement was found (PO in human clinical study). Acetaminophen was allowed
for pain when necessary, and the antirheumatic drugs such as hydroxychloroquine
and IM gold were continued at unchanged doses.1403
FALSE
UNICORN ROOT NEW
^ Chamaelirium luteum rhizome
(helonias)
Contraindications
1) Pregnancy due to emmenagogue activity and GI
irritant properties (empirical)150
2) Stomach or intestinal irritation due to its irritant
properties (empirical)150,1890 caused by its rich 9.5% saponin
content including chamaelirin.1890
3) Caution is urged when used by patients with
pre-existing cholestasis (speculative).1890
FENNEL p.
93
Foeniculum vulgare
fruit
Contraindications
1) Pregnancy due to the emmenagogue effect (empirical),2,4,14,17,74,401
due to the phytoestrogenic activity as shown by the
acetone extract of its seeds (in rats)1313
+ 6)
CNS toxicity following consumption the tea, especially in nursing
mothers and/or their breast fed infants (PO in human case reports)1141
FENUGREEK p.
93
Trigonella
foenum-graecum seed
2) Brittle diabetes (speculative),893
100 grams of defatted seed
powder daily for 10 days lowered blood sugar and reduced by 54% the urinary
glucose excretion in type 1 diabetics (PO in human clinical study).1646
A hypoglycemic effect is
likewise found in type 2 diabetics (PO in human studies).1360,1645
Both aqueous and
methanolic extracts of the seeds have hypoglycemic activity (PO in mice),
suggesting that the active compounds are polar in nature.2253 A single-dose of dialysed
aqueous extract at 15 mg/kg body weight reduced glucose in diabetics after 90
minutes and increased hepatic glucokinase and hexokinase, similar to insulin
(IP in mice). Glucose tolerance increased while insulin levels were reduced in
normal subjects (IP in mice).2525
Drug
Interactions
I. + 1)
In a double-blind study 2 capsules twice daily of a fenugreek seed
hydroalcoholic extract taken by 12 newly diagnosed type 2 diabetes patients (10
using the oral hypoglycemic drugs sulfonylurea, biguanides, or both)
resulted after 2 months in significantly decreased HbA1c levels,
lower fasting and 2-hour postprandial insulin levels, and increased insulin
sensitivity compared to 13 patients receivng placebo, of which 10 used the oral
hypoglycemic drugs, also (PO in human clinical study).1360
Hypoglycemic activity was also shown in non-insulin dependent diabetes melitus
type 2 with 100 grams defatted seed powder for 10 days with 10-15 patients (PO
in human clinical studies),1645,1646
2) [Formerly IV. 1) ]A woman stabilized on warfarin
developed an elevated INR after several weeks of using a capsule of fenugreek
before meals and 10 drops of boldo extract after meals. Her INR returned to the
normal range after stopping the herbal products but became elevated again after
resuming their use (PO in human case study). It may be that warfarin metabolism
was reduced or the serum protein bond of warfarin was modified (speculative).1489
Boldine, an alkaloid in boldo (Peumos boldus), inhibits platelet
aggregation by arachidonic acid and collagen, probably due to inhibition of
thromboxane A2 (in vitro).1532
3) [Formerly II. 1] In 10
type 1 diabetics on insulin, 100 grams of defatted seed
powder daily for 10 days lowered blood sugar and reduced by 54% the urinary
glucose excretion (PO in human clinical study),1646 suggesting that
it could lead to hypoglycemia in some who do not adjust insulin dosage (speculative).
A dialysed aqueous extract at 15 mg/kg body weight
for 5 days reduced hyperglycemia in diabetics from days 5-15 (IP in mice). A
single-dose of this extract also reduced glucose in diabetics after 90 minutes
and increased hepatic glucokinase and hexokinase similar to insulin (IP in
mice). Glucose tolerance increased while insulin levels were reduced in normal
subjects (IP in mice).2525 The components coumarin and trigonelline have
been shown to be partially responsible for hypoglycemic effects (PO in rats).128
Both aqueous and methanolic extracts of
the seeds have hypoglycemic activity (PO in mice), suggesting that the active
compounds are polar in nature.2253 The fenugreek
component 4-hydroxyisoleucine has been shown to increase glucose-induced
insulin release without interacting with other agonists of insulin secretion
such as tolbutamide and glyceraldehydes, thus demonstrating a novel
insulinotropic activity (in vitro).1507
II. 1) [See I. 3)]
+ 2)
Consumption of 4 ml of a 1% aqueous extract of fenugreek seeds concurrently
with ethanol for 60 days reduced liver and brain damage compared with
use of alcohol alone, as indicated by serum enzymes and histopathological
examinations (PO in rats). The aqueous extract has antioxidant potential
inliver cells comparable to vitamin E and glutathione (in vitro).1484
III. 2) It may enhance cholesterol-lowering
agents due to additive effects (speculative).777
100 grams of defatted seed powder for 10 days
reduced total, LDL, and VLDL cholesterol and triglyceride levels in 10-15
patients (PO in human clinical studies).1645,1646
In a double-blind study 2 capsules twice daily for 2
months of a fenugreek seed hydroalcoholic extract by 12 type 2 diabetes
patients, of which 10 used the oral hypoglycemic drugs, resulted in lower
triglyceride levels compared to baseline, but not in the placebo group (PO in
human clinical study).1360
3) When human chronic myelogenous leukemia [KBM-5] cells
were exposed to the saponin component diosgenin at 10 mM together with paclitaxel
or doxorubicin, the cytotoxic effect of these agents were
synergistically increased (in vitro). Diosgensin alone was equivalent in
cytotoxicity to each of there chemotherapeutic agents in this cell culture (in
vitro).2429
FEVERFEW p.
95
Tanacetum parthenium =
Chrysanthemum partheniumplant
Contraindications
3) Allergic
hypersensitivity to feverfew or other Asteraceae plants428,777
In 300 subjects chewing fresh feverfew leaves, 11.3%
experienced mouth ulcers. This has also been experienced following systemic
exposure from consuming tablets. Some had swollen lips and inflammation
throughout their mouths, possibly due to the local effects of the sesquiterpene
lactones (empirical).1351
Drug Interactions
III. + 2) The combination of feverfew
component parthenolide with the NSAID sulindac inhibited the cell
growth in pancreatic cancer cells synergistically in two lines and additively
in one line (in vitro). The combination lowered the threshold for
apoptosis, increased IkB-a protein, and decreased NF-kB DNA binding and transcriptional activities
compared to their use as single agents.1844
+ 3)
The feverfew component parthenolide and its combinaton with the antiestrogen fulvestrant both inhibited antiestrogen-resistant breast
cancer cell growth (in vitro). The combination resulted in a 4-fold
synergistic growth reduction and restored fulvestrant-induced apoptosis, apparently
due to NFkB inhibition in the drug-resistant cells.1845
+ 4)
The combination of feverfew component parthenolide with the anticancer agent paclitaxel increased the paclitaxel-induced apoptosis
of MDA-MB-231 breast cancer cells by inhibiting NF-kB, thus mimicking IkBa.(in
vitro).1846 The growth of MCF-7 breast cancer cells was
inhibited by parthenolide, which also enhaced paclitaxel effectiveness against
these cells (in vitro). It was observed that parthenolide stimulated
tubulin assembly activity and altered the microtubule network and nuclear
morphology when combined with paclitaxel (in vitro).1847
FLAX p.
96
Linum
usitatissimum = Linum humile seeds
Contraindications
+ 7) Manic or hypomanic
responses to high doses (75-120 ml daily) of flax seed oil used in open-label
in management of schizophrenia and to lower doses effective for depressive
expressions of bipolar disorder (PO in case report series)1496,1497
suggest that it should be avoided in mania patients (speculative).
Drug Interactions
II. + 1)
The combination of 10% flaxseed in the diet for 6 weeks with tamoxifen,
given to groups with estrogen-dependent human breast cancer cell MCF-7 implants
along with high estrogen and low estradiol supplementation, caused a greater reduction
in tumor regression than tamoxifen alone by 50% vs 41% with high estrogen and
by >53% compared to only tamoxifen with low estrogen (PO in mice).2240
When either 5%, or 10% flaxseed in the diet for 8 weeks was given to those with
MCF-7 tumors, high estrogen, and tamoxifen, the tumor growth inhibition
compared to the tamoxifen-only control was 48% and 43%, respectively (PO in
mice). Flaxseed 10% diet with no tamoxifen gave 38% tumor inhibition and was
similar to tamoxifen alone. The reduced tumor growth was caused by decreased
cell proliferation and increased cell apoptosis.2241 Under the same
conditions except without estrogen supplementation, the 5% and 10% flaxseed
diets for 16 weeks reduced tumor size by over 90% compared to controls, while
with tamoxifen alone only a 6% reduction was achieved. Tamoxifen with 10%
flaxseed diet decreased tumor growth by 55%, along with decreased expression of
cyclin D1, estrogen receptor a, insulin-like growth factor 1 receptor and human epidermal growth
factor receptor 2 in both flaxseed groups (PO in mice).2242 In
addition a 10% flaxseed diet with a 20% soy protein diet reduced MCF-7 tumor
growth to size of controls, whereas the soy diet alone caused an increase in
turmor size (PO in mice).2243
The effect of flaxseed may be due at least partially
to the inhibition of the estrogen-generating enzyme aromatase by metabolites of
its lignin secoisolariciresinol diglycoside (in vitro).913,914
This enzyme inhibition may explain the reduction in serum concentration of 17 b-estradiol and estrone compared to controls following flaxseed feeding
of 5 or 10 grams to 28 postmenopausal women for 7 weeks in a crossover trial,
compared to the basal diet with no flaxseed (PO in human study).2244
The flaxseed lignin metabolites enterodiol and
enterolactone also reduced the breast cancer cell adhesion, migration, and
invasion of 2 estrogen-negative cell lines, MDA-MB-435 and MDA-MB-231,
dose-dependently alone and in combination with tamoxifen (in vitro).2245
III. + 1) When consuming significant
quantities of the seeds with medications, the seed mucilage coats GI mucosa and retards absorption of oral drugs (speculative)4,6,17,150,344,401
such as aspirin, digitalis and other cardiac
glycosides, antibiotics,
and anticoagulants if administered
concurrently (speculative),150 and may inhibit iron absorption
(speculative).1890
FORSYTHIA NEW
^ Forsythia
suspense fruit
(golden bells; Ch.: lian qiao)
Contraindications
1) Pregnancy due to its emmenagogue and uterine stimulant effects
(empirical)150
FRAGRANT
ANGELICA NEW
^ Angelica
dahurica root
(Ch.: bai zhi)
Drug Interactions
II. 1) At 1 gm/kg dose of the root extract
the CYP450 metabolism of tolbutamide
(2C9), bufuralol (2D6), nifedipine (3A4) and diazepam
(2C11, 2D1, 3A2) was inhibited. Likewise, the hydroxylation of testosterone by 3 separate enzymes was inhibited.
Diazepam availability was not affected when it was administered IV, but
increased 4 times when diazepam was administered orally (PO in rats).1632
Furanocoumarins from fragrant angelica, Angelica japonica (hamaudo)
root, and other umbelliferous medicinals were shown to inhibit CYP 3A (in
vitro).1637
FRANKINCENSE NEW
^ Boswellia
serrata resin
(Indian frankincense, Indian olibanum, Salai guggal)
Contraindications
1) Allergic hypersensitivity to Boswellia
species, since contact dermatitis may result (empirical).1890
Drug Interactions
I. 1) In 3 groups with osteoarthritis of the knee, the number
of those taking placebo who used ibuprofen as a rescue medication was
16.7% more than subjects using 100 mg/day of extract with 30%
3-O-acetyl-11-keto-beta-boswellic acid, but outcomes were still significantly
better in the extract group; the placebo users of ibuprofen were 72.2% more
than those taking 250 mg extract daily, yet the higher extract dose group had
the greatest efficacy in relieving pain and improving physical function (PO in human clinical
study).2483 In a review of 11 published trials using a standardized
extract of the gum resin to treat rheumatoid arthritis, a considerable
reduction of NSAID [nonsteroidal anti-inflammatory drug] intake was
often shown during the course of treatment (PO in clinical studies).1534
II. 1)
The gum resin extract H15 at 34.2 mg/kg and its component acetyl-11-keto-b-boswellic acid at 3.4 or 5.1 mg/kg reduced tissue injury, inflammatory
features, and leukocyte adhesion to epithelial cells in ileitis induced by SC indomethacin (PO in rats).2662
FRENCH
MARITIME PINE NEW
Pinus
pinaster = Pinus maritima bark fraction
(Pycnogenol®)
Drug Interactions
I.
1) The polyphenol fraction used
by 28 hypertensive subjects at 100 mg daily for 12 weeks allowed for
significant reduction of nifedipine
dosage for treating hypertension compared to subjects receiving placebo (PO in
human clinical study). Heart rate, lab findings, and the rate of adverse
effects (all mild and transient) did not differ significantly between the two
groups.1623
In addition, early evidence of reduced renal function and
blood flow associated with hypertension and leading to the development of
kidney damage was diminished when 150 mg of Pycnogenol daily was combined with
the ACE inhibitor drug ramipril in 29 pateints with high blood
pressure, moreso than used of ramipril alone by 26 hypertesive patients (PO in
human clinical study).2683
2) The use of 50 mg of the special
standardized extract Pycnogenol 3 times daily with meals for 3 months by
patients with osteoarthritis of the knee using concurrent NSAIDs and/or analgesics
led to a significant reduction in inflammation and pain scores over time and
less use of these drugs, compared to baseline and placebo (PO in human clinical
study).2324 A dose of 100 mg Pycnogenol daily in 77 patients with
osteoarthritis of the knee recused NSAID us by 58%, compared to a 1% reduction
by 77 patients taking placebo (PO in human clinical study). Gastrointestinal
complications were thereby reduced by 63% versus 3% for placebo. There was also
a 54% reduction in non-NSAID medications with Pycnogenol, compared to 11% for
placebo. After 3 months the number and duration of hospitalizations and the
symptoms scores, walking distance, and foot edema were significantly improved
in the Pycnogenol group over the control group.2526
3) Pycnogenol given at 150 mg daily
for 2 months beginning the day after the first cycle of chemotherapy for solid tumors with 5-fluorouracil, cisplatin with gemicitabine or 5-fluorouracil, or CCNU with vinblastine,
led to a reduction in adverse effects, especially nausea, vomiting, diarrhea,
and weight loss, compared to controls (PO in human clinical trial). Other
improvements in those taking Pycnogenol were seen with cognitive impairment,
cardiotoxicity, neutropenia, and thrombotic episodes induced by chemotherapy.
Less days of hospitalization were required, and less medications to treat the
adverse effects of chemotherapy were consumed by those given Pycnogenol.
Equivalent results were found with Pycnogenol given to patients receiving only radiotherapy for similar solid tumors.2523
Pycnogenol
given for 13 days at 50-200 mg/kg with injection of the chemotherapy drug cyclophosphamide on days 8, 9, and 10 significantly decreased
the reduction in hemoglobin and red blood cells and the inhibition of DNA
synthesis in the thymus induced by drug (PO in mice). When doxorubicin was given every other day during 13 days of
Pycnogenol daily doses of 50-150 mg/kg, the Pycnogenol significantly reduced
the elevation in creatine phosphokinase and decreased heart rate induced by
doxorubicin (PO in mice). No effect was found with Pycnogenol on the antitumor
effect of doxorubicin or cyclophosphamide against S180 tumors (PO in mice).2522
4) The use of 100 mg daily of Pycnogenol by 30
subjects with allergic rhinitis to birch pollen for at least 3 weeks prior to
seasonal exposure to this allergen led to only 36.7% relying on antihistamines
as a rescue medication through the allergy season, compared to 50% of the 30
taking a matching placebo (PO in human clinical study). For those 8 taking
Pycnogenol >7 weeks, only 1 required this additional drug use, as opposed to
5 of the 10 taking placebo over the same time period. Compared to placebo, hay fever
nasal and eye symptoms were lower in those taking the extract for 5 weeks or
more. The birch specific IgE titer was increased only 19.4% in the Pycnogenol
group but 31.9% in the placebo group.2706
III. 1) 150 mg of the polyphenol fraction
taken 3 times daily for 4 weeks improved microcirculation, myocardial ischemia,
and reduced platelet adhesion and aggregation in 26 coronary arterey disease
patients not using anticoagulants or aspirin, compared to 25 patients taking
placebo (PO in human clinical study).1570 After single doses of
100-120 mg of the bark polyphenol fraction, the enhanced platelet reactivity of
22 heavy German smokers and 19 American smokers who were not using
anticoagulants or aspirin was normalized, similar to 500 mg of aspirin for the
control group. Aspirin significantly increased bleeding time, though the
polyphenol fraction did not (PO in human studies).1571 Though these
platelet effects may safely reduce the risk of cardiovascular disease,
especially coronary thrombosis for smokers, they may increase the risk of
hemorrhage for patients who simultaneously use anticoagulants
like warfarin or antiplatelet drugs like aspirin (speculative).
However,
a study compared the effect on platelet aggregation and TxB2 levels
following daily use of 200 mg of the extracted polyphenol fraction in 19
smokers with non-smokers using the extract. The study found the extract lowered
these factors from hyperactive pretreatment levels in smokers to the normal
level of non-smokers after 8 weeks of treatment (PO in human study). There was
no change in platelet aggregation or TxB2 levels in non-smokers
using the extract.2022 These results together indicate a low risk of
increasing hemorrhage in either smokers or non-smokers (speculative).
GARLIC p.
99
*Allium
sativum bulbs
Contraindications
2) Excessive use should be avoided in early pregnancy
(speculative).2
Prolonged and high doses of fresh garlic or products
high in allicin should not be taken during pregnancy (speculative),1890
since a single dose of aqueous garlic extract at 25 mg/kg inhibits
thrombin-induced platelet synthesis of the pro-aggregating thromboxane-A2
breakdown product, thromboxane-B2, with maximum effect after 6 hours
of 64% inhibition (IV in rabbits).1108 A clove of garlic of about 3
grams daily for 16 weeks lowers serum thromboxane B2 by 90% (PO in
human study).1707
3) Low
thyroid function (speculative)2
since both fresh garlic homogenate and vinyldithiin
components decrease T3 and T4 levels after 6-12 hours,
serum TSH levels are lowered, and pituitary and thyroidial secretions are
reduced (PO in rats).1224, 1234
4) Heavy consumption prior
to surgery (PO in human case
reports)131,738
[CORRECTION] This results from increased fibrinolytic
activity and DECREASED human platelet aggregation after oral consumption of
garlic oil (ex vivo).279,280,286
For this reason garlic use should be discontinued at
least 7 days before surgery, particularly if a person is at risk for excessive
bleeding (speculative).1309,1310
A single dose of aqueous garlic extract at 25 mg/kg inhibits thrombin-induced platelet synthesis of the pro-aggregating thromboxane-A2 breakdown product, thromboxane-B2, with maximum effect after 6 hours of 64% inhibition. This led to a significant recovery after 24 hours to 14% inhibition which was more complete after 72 hours at 11% inhibition (IV in rabbits).1108 About 3 grams of fresh garlic daily for 4 weeks lowers serum thromboxane B2 by 20%, but after 16 weeks it was reduced by 90% (PO in human study).1707 Antiplatelet activity has been shown for aged garlic extract (in vitro).1879 An aqueous extract of raw garlic is more potent than boiled garlic for inhibiting platelet aggregation (in vitro),1708 but boiling or oven-heating at 200oC for only 3 minutes did not affect platelet inhibition (in vitro).2038
However, compared to raw
garlic activity, 6 minutes of boiling or oven-heating at 200oC
suppressed antiaggregation activity with uncrushed garlic, and 10 minutes completely
suppressed this effect for crushed garlic (in vitro).2038
Also, inhibition of platelet cyclooxygenase is achieved with aqueous extract of
raw but not boiled garlic (in vitro).1709 In addition, 10 adults
taking a proprietary garlic product at the manufacturer’s recommended dose for
2 weeks had no increase in coagulation time in ADP and epinephrine assays of
intrinsic and extrinsic platelet function, respectively (ex vivo), but
the product was not analyzed for its phytochemical content.2262
+ 6)
Brittle type
1 diabetes (speculative)893
due to the hypoglycemic effects of garlic, its juice or ether extract (PO in rats
and rabbits)133,538,539 and
its activity shown in healthy humans with 800 mg daily of garlic powder
for over 4 weeks reducing blood glucose by 11.6% (PO in human study)956
+ 7)
Allergic hypersensitivity in rare cases with frequent contact
(empirical),17,401 typically in the form of contact dermatitis from
the juice leading to blistering (empirical)10
+ 8)
Prolonged application externally on unprotected skin may lead to
chemical burn as occurred on the dorsum of the feet of a 17-month-old infant
when no oil was applied and a >50% fresh garlic poultice was used on the
feet for 8 hours (human case report). The child later patch-tested negative for
allergic sensitivity to garlic.1746
Drug Interactions
I. 1) Taking garlic pearls or tablets reported doubled the INR
of two patients stabilized on warfarin (PO
in human case reports),451
though these events have been described as unevaluable
based upon report inadequacies.1239
About 3 grams of fresh garlic daily for 4 weeks
lowers serum thromboxane B2 by 20%, but after 16 weeks it was
reduced by 90% (PO in human study).1707 Compared to raw garlic
activity, boiling or oven-heating at 200oC for 3 minutes did not
affect platelet inhibition (in vitro).2038
However, 6 minutes of either suppressed antiaggregation activity with uncrushed garlic, and 10 minutes completely suppressed this effect for crushed garlic (in vitro).2038
Also, 10 ml daily for 12 weeks of aged garlic extract found no evidence of hemorrhage in 22 patients using warfarin (PO in human clinical study),1878 even though antiplatelet activity has been shown for aged garlic extract (in vitro).1879 Aged garlic extract is active in reducing adherence to fibrinogen at 2.4-7.2 grams per day but only at the 7.2 gm/day in tests employing ADP, collagen, and von Willebrand factor (ex vivo).2037
Likewise,
an enteric-coated garlic tablet derived from 2 gm of fresh garlic with 3.7 mg
allicin per tablet was given twice daily for 3 weeks to 12 healthy subjects;
when a single 25 mg dose of racemic warfarin was given after 2 weeks, no change
in INR was detected over the next week (PO in human study). Also, no effect on platelet aggregation was
found, nor was the bioavailability of warfarin isomers affected as reflected by
the plasma concentration-time profiles, indicating a lack of effect on CYP 2C9.2509
+ 2)
Ten healthy people taking a caplet of garlic twice daily for three weeks had a
reduction in plasma content of the CYP 3A4 substrate and HIV protease inhibitor
saquinavir of just over 50% (PO in human study). After a 10-day washout
period the saquinavir levels were still about 35% less than baseline.1210
However, subsequent testing
in 14 healthy volunteers showed that 1.8 grams of a standardized garlic extract
twice daily for 14 days did not impact the metabolism of the 3A4 substrate
alprazolam or the 2D6 substrate dextromethorphan (PO in human study).1456
CYP 3A4 substrate midazolam was also unaffected by garlic oil (PO in human
study).1328 These results implicate the possible induction of
P-glycoprotein by garlic (speculative).
However, fresh and aged garlic
extracts had a moderate effect on inhibiting P-glycoprotein (in vitro).1594
+ 3)
Chlorzoxazone metabolism by CYP 2E1 was inhibited with consumption of
500 mg of garlic oil 3 times daily for 28 days in 12 healthy subjects; enhanced
sedation from the drug was noted after garlic oil use.
However, CYP isozymes 1A2, 2D6, and 3A4 were unaffected by the garlic oil (PO in human study).1328,1808 A component of garlic oil, diallyl sulphide, given at 0.2 mg/kg was shown to reduce CYP2E1 activity by inhibiting chorzoxazone metabolism (PO in human study). The dose was roughly equivalent to the diallyl sulphide found in 15 cloves of garlic, though it was not equivalent to 15 cloves due to the many other active components in garlic.1717
+ 4)
Aged garlic extract at 4 ml daily for 1 year inhibited the rate of coronary
calcification of plaques in patients with coronary artery disease using
maintenance doses of statins and aspirin (PO in human
clinical trial).1772 In a randomized, placebo-controlled crossover
study, the flow mediated endothelium-dependent dilation in the brachial artery,
following two weeks of 2.4 grams aged garlic extract daily, improved in men
with coronary artery disease who were using statins and aspirin concurrently
(PO in human clinical study).1857
+ 5) A topical garlic gel applied twice daily
for 3 months by 12 men and 8 women, along with a topical corticosteroid cream containing 0.1% betamethasone
valerate for local treatment of
balding areas of scalp, resulted in good results for 95% (TP in human clinical
study). Size of patches and the number of total and terminal hairs in the areas
were monitored. The response to the drug with garlic was significantly better
than for 10 men and 10 women who used only the topical drug.2260
II. 1) Fresh garlic at 5 gm/kg prevented hepatotoxicity from acetaminophen and was partially
protective at 0.5 gm/kg (PO in mice). 540
A single 500 mg/kg dose of
diallyl sulfide depresses hepatic cytochrome P450 and aminopyrine N-demethylase
activities (IP in rats), but 50 mg/kg for 5 days increased these activities (IP
in rats).1362 Diallyl
sulfone, a metabolite of diallyl sulfide, given in doses as low as 5 mg/kg
prevented acetaminophen depletion of glutathione in the liver (PO in mice). At
25 mg/kg it completely protected from hepatotoxicity.1816
However,
16 subjects given 10 ml of aged garlic extract daily for 12 weeks caused no
effect on CYP 2E1 metabolism of acetaminophen (PO in human study). The extract
used minced garlic incubated in 15-20% alcohol for 8-12 months and had as its
major constituent S-allyl-L-cyseine, but very little diallyl sulfide.1815
+ 3)
Aged garlic extract as 2% of the diet for 4-5 days when giving methotrexate
or 5-fluorouracil protected the intestines from damage (PO in rats).1262
Severity of jejunal damage by methotrexate was reduced,
as were increases in tissue MDA and plasma lactate by 250 mg/kg of the aged
extract given to 40 subjects for 7 days (PO in rats).1865
Epithelial cells from the rat ileum were protected from
methotrexate-induced apoptosis by 0.5% aged garlic extract (in vitro).1881
+ 4)
Raw garlic extracts and derivatives allicin and diallyl disulfide protected the
gastric mucosa of rats from damage by 100% ethanol (PO in animal study)1263
+ 5) Aged garlic extract WG-1 given in doses of 0.05 ml six times weekly helped protect animals from doxorubicin toxicity to the heart muscle when it was given 3 times weekly for 40 days (IP in mice)1273
+ 6) Dried powedered leaves of garlic as 2% of
the diet for 7 days,1911 or its components diallyl disulfide1912
or diallyl sulfide1913 at 50 mg/kg/day for 4 days, all reduced the
kidney toxicity from injections of the antibiotic gentamicin, based on
preventing the decrease the manganese superoxide dismutase and glutathione
peroxidase and thereby preventing necrosis and oxidative changes in the kidney
(PO in rats).1911-3 Aged garlic extract at 2.4 ml/kg/day for 6 days1914
and its component S-allylcysteine at 250 mg/kg/day for 5 days1915
likewise prevented kidney toxicity by gentamicin in the same manner (IP in
rats).1914-5 Neither garlic powder extract or its components diallyl
sulfide and diallyl disulfide nor aged garlic extract or its component S-allylcysteine
interfered with the antibiotic activity of gentamicin against E. coli (in
vitro).1910
III. 1) Insulin dose may require adjusting (speculative)
due to 800 mg daily of garlic powder reducing blood
glucose by 11.6% (PO in human study).956
2) Prolonged and high doses of fresh garlic or
products high in allicin should not be taken with antiplatelet drugs
(speculative).1890 About 3 grams of fresh garlic daily for 4 weeks
lowers serum thromboxane B2 by 20%, but after 16 weeks it was
reduced by 90% (PO in human study).1707 Antithrombotic activity of
garlic aqueous extract appears to be due in part to the inhibition of
thromboxane B2 synthesis (IV in rabbits).1108 An aqueous
extract of raw garlic is more potent than boiled garlic for inhibiting platelet
aggregation ( in vitro).1708 Compared to raw garlic activity,
boiling or oven-heating at 200oC for 3 minutes did not affect
platelet inhibition, but 6 minutes of either suppressed antiaggregation
activity with uncrushed garlic, and 10 minutes completely suppressed this
effect for crushed garlic (in vitro).2038
+ 3)
Mashed and freeze-dried fresh garlic, in concentrations corresponding to one
clove in an empty stomach, and its major antibacterial derivative, allicin,
both synergistically lowered the minimum inhibitory concentration of vancomycin
against vancomycin-resistant Enterococcus spp. from 32-256 mcg/ml to
0.5-16 mcg/ml (in vitro)1560
+ 4)
The essential oil and its isolate allicin enhanced the effectiveness of the
antifungal drug ketoconazole against Trichophyton rubrum, T.
erinacei, and T. soudanense (in vitro).2364
IV. [Formerly
III. 2). 1). may enhance the effects of cholesterol-lowering agents due to
additive effects (speculative).777
However, a 6-month study with 192 adults that used doses of fresh garlic, powdered garlic, and an aged garlic extract that were approximately equivalent to 4 grams of garlic for 6 days weekly found no significant effects on LDL-cholesterol, HDL-cholesterol, triglyceride levels or the ratio of total cholesterol to HDL-cholesterol compared to placebo (PO in human study).2034 ]
GINGER p.
101
Zingiber officinale rhizome
Contraindications
1) pregnancy150
due to its emmenagogue344 and abortifacient effects (empirical)74
and increased embryonic loss when consumed regularly as a tea (PO in rats).1157
It has therefore been stated that ginger should not
be used for morning sickness401 when taken in large amounts.2
However, 250 mg four times
daily of the powder root significantly reduced the number of vomiting episodes
and the severity of nausea in 28 of 32 compared to 10 of 35 taking the placebo
with no adverse outcome detected with the pregnancy (PO in human clinical
study).1158
A placebo-controlled study with 26 subjects in the
first trimester using ginger syrup representative of 1 gm ginger daily showed a
reduction of nausea and vomiting with no apparent adverse effects (PO in human
clinical study)1369
3) large doses prior to surgery to avoid risk of hemorrhage (speculative),428 possibly
at least one week before elective surgery (speculative)1310
However, a ginger product dose equivalent to 3.6 grams of the
rhizome daily was given for one week and no change was detected in INR or
platelet aggregation (PO in ex vivo human study).1774 At 100
mg/kg for 4 days an ethanolic extract of the dried rhizomes had no impact on
whole blood clotting time, prothrombin time, or activated partial
thromboplastin time (PO in rats).1174
4) occupational allergic contact dermatitis due to regular, repeated exposure (empirical)777
as well as topical application in patients with allergic
hypersensitivity (empirical)777
+ 5)
Use only with expert advice in the case of peptic ulcers (speculative).1890
However, 500 mg/kg of ginger spray dried extract
significantly reduced gastric mucosal damage from 70% ethanol by inhibiting
reduction of deep corpus mucin content (PO in rats).498 The
protection against hydrochloric acid and/or ethanol is due in part to
6-gingesulfonic acid, zingiberene, 6-gingerol and 6-shagaol (PO in rats).504,505,507
Ginger ethanolic extract at 500 mg/kg likewise inhibited ulcer formation
induced by 80% ethanol, indomethacin, and aspirin (PO in rats).506
I. + 3)
Six Danish rheumatoid arthritis patients using NSAIDs with little or no
benefit found symptomatic relief from pain, swelling, morning stiffness, and
restricted joint movement after adding 5 grams fresh or 0.5-1 gram powdered
ginger daily. They stopped taking the NSAIDs yet remained improved with no side
effects after 3 months (PO in human cases).1408 An open study of 28 patients with rheumatoid
arthritis, 18 with osteoarthritis, and 10 with muscular discomfort using
powdered ginger (from 0.5-1 to 2-4 gm per day, ave. 1-2 gm) from 3 months to
2.5 years found marked relief of pain and swelling was produced in 74% and 59%
of rheumatoid patients, respectively. Good pain relief occurred for 55% of
osteoarthritis patients, while 50% had marked reduction of swelling (PO in human study).1410 In subjects with knee
osteoarthritis of whom 34% were using oral analgesics and 38% were using
oral NSAIDs [nonsteroidal anti-inflammatory drugs], lower extremity massage 6
times within 3 weeks with 1% ginger oil and 0.5% orange oi in olive oil had
significantly improvement in pain, stiffness, and function from baseline,
whereas those receiving only olive oil massage or no massage showed no
improvement (TP in human clinical study).2484
+ 4)
A RPCDB 6-week study with 261 osteoarthritis patients used 2 capsules of
extract EV.EXT77 (each containing 255 mg representing 2.5-4.0 gm dried ginger
and 0.5-1.5 gm dried Alpinia galanga [galangal] ). In addition, acetaminophen
was allowed for pain and was equal for the two groups. Reduced pain on standing
after using the extract was significantly better than for placebo, and
stiffness and pain after walking were also improved by the extract. Withdrawal
rate due to adverse events was 13% in the extract group and 5% for placebo (PO
in human clinical study).1409
However, in a RPCDB
crossover study a 510 mg standardized Chinese ginger extract EV.ext-33 was
compared with 1.2 gm ibuprofen daily when used for 3 weeks each by 56
osteoarthritis patients. As a rescue drug, acetaminophen was allowed up
to 3 gm daily. For visual analogue scale of pain and Lequesne-index, as well as
limiting acetaminophen use, the efficacy ranking was ibuprofen > ginger
extract > placebo. While ibuprofen was significantly better than the other
two using these criteria, the ginger extract was not significantly better than
placebo. The frequency of adverse effects, mainly GI complaints, diminished in
the same listed order (PO in human clinical study).1420
+ 5) One gram of ginger prior to chemotherapy
and repeated six hours after completely controlled nausea and vomiting in
patients receiving cyclophosphamide by 62% and 68%, respectively (PO in
human clinical study). This was equivalent to injections of the antiemetic drug
metoclopramide but significantly less effective than ondnasetron injections.
The percentage of subjects obtaining partial or complete control of nausea and
vomiting was equivalent for all three.1598
When combined with a high-protein meal 1 gram of
ginger twice daily beginning a day after chemotherapy and continuing for
3 days helped reduce delayed nausea, its frequency, and the use of antiemetic
medications compared to controls (PO in human clinical study). Chemotherapy in
this group consisted single drugs or 2-drug combinations of cyclophosphamide,
doxorubicin, epirubicin, etoposide, gemcitabine, navalbine,
and/or paclitaxel. There was no benefit from ginger when used with
regular protein meal under the same circumstances.2513
+ 6)
Regular intake of dried ginger and tea made from ginger powder was associated
with nosebleed and an increase in international normalized ration [INR] to >
10 in a woman who was on long-term phenprocoumon therapy (PO in human
case report). She previously had a stable INR in the therapeutic range of
2.0-3.0. Partial prothrombine time [PPT] was also prolonged to 84.4 seconds,
well beyond the normal range < 35 seconds. After giving vitamin K to
counteract the phenprocoumon, both INR and PPT normalized, and the patient was
stabilized on the same drug dose and advised to refrain from ginger intake.2087
+ 7) In a prospective longitudinal 16-week study
of 171 adults prescribed warfarin for anticoagulation who recorded
bleeding events and risk factor exposures in a diary, garlic was identified as
independently associated with an increased risk of self-reported bleeding,
especially bruising beyond what is considered typical with warfarin (PO in
human study). Seven bleeds associated with ginger during 25 weeks of total use
among all patients were recorded.2206
However, no elevation of
increased INR with was documented when ginger use was combined with warfarin,
and no ginger doses were reported (PO in human study).2206 A ginger
product dose equivalent to 3.6 grams of the rhizome daily was given for one week
after and prior to single doses of warfarin, and no change in warfarin
pharmacokinetics or protein binding was found 12 healthy males (PO in human
study), nor was there detected any alteration in INR or platelet aggregation (ex
vivo).1774 At 100 mg/kg
for 4 days an ethanolic extract of the dried rhizomes given before 1 dose of
warfarin had no impact on whole blood clotting time, prothrombin time, or
activated partial thromboplastin time, when compared to warfarin alone (PO in
rats).1174
+ 8) With 10 healthy subjects taking ginger 1 gram
daily for a week, it reduced platelet aggrevation by 35-38% depending on
whether the inducing agent was collagen, ADP, or epinephrine (ex vivo in
PO human study). Combined with 10 mg of nifedipine for a week in these
healthy subjects, the same ginger dose increased inhibition of platelet
aggregation to 69-80% from the 20-23% inhibition when nifedipine was given
alone (ex vivo in PO human study). Combined with nifedipine for a week
in hypertensive subjects with higher baselin platelet aggregation, the platelet
inhibition was 61-64%, compared to 19-22% with nifedipine alone (ex vivo in
PO human study). The effects of ginger were equivalent to those of 75 mg
aspirin given daily for a week (ex vivo in PO human study). The
synergistic effect on platelets could be useful as a prophylactic measure in
hypertensive patients at high risk for cardiovascular and cerebrovascular
complications (speculative).2312
+ 9)
In a randomized crossover study with 48 gynecologic cancer patients receiving cisplatin
therapy along with metoclpramide 8 times the first day, 1 gram daily of
ginger for the first 5 days after chemotherapy was as effective in
controlling nausea and vomiting as was continuing for 5 days the standard drug
metoclopramide which was more associated with restlessness (PO in human
clinical study).2534
Vomiting induced by cisplatin was prevented by acetone
and 50% ethanolic extracts at doses of 25-200 mg/kg (PO in dogs).1162
Delayed gastric emptying caused by cisplatin was reversed by 50% ethanolic
extract at 500 mg/kg, acetone extract at 200-500 mg/kg, and juice of ginger at
2-4 ml/kg given 30 minutes before cisplatin (PO in rats).1156
+ 10)
Patients consuming methoxsalen (8-methoxypsoralen) for photopheresis
treatment of cutaneous T-cell lymphoma experienced on average 1/3 as much
nausea after taking 1.59 grams of ginger 30 minutes prior than without using it
(PO in human clinical study). Ten of 11 patients maintained therapeutic
methoxsalen levels after using ginger; connective tissue disease may account
for poor methoxsalen absorption by the one patient.2535
+ 7)
When given 3 days before and 3 days after chemotherapy together with 5HT3
receptor antagonist antiemetics (ondansetron or granisetron) on the
day of chemotherapy, 0.5-1.5 grams of ginger significantly reduced nausea
greater than the antiemetic drug alone (PO in human clinical study).2585
III. 1) See IV. 2).
IV. [Formerly,
III. 1) ] [2)
An ethanol extract of dried ginger rhizomes had no effect on coagulation
parameters or changes in coagulation induced by warfarin when given in
doses of 100 mg/kg (PO in rats).1174
Ginger extract tablet derived from 0.4 grams of
rhizome powder were given in doses of 3 tablets three times daily for a week,
followed by a single dose of warfarin (PO in human study). No changes were
observed in R- or S-warfarin kinetics including protein binding, nor was any
alteration of INR detected following ginger extract use.1774 One
week is unlikely to be sufficient for cytochrome P450 induction that might
reduce warfarin bioavailability. Continuing ginger extract use for another
week, no change in INR or platelet aggregation ex vivo were detected
from using the daily extractive of 3.6 gram of ginger alone (PO in human
study).1774
Only extremely large doses
of ginger beyond its normal therapeutic use of 2-4 gm daily appear to increase
the risk of further reducing coagulation when taken with anticoagulants, and no
such incidences have been documented in animals or humans.]
GINKGO p.
103
Ginkgo biloba leaves
Contraindications
1) Allergic
hypersensitivity of the skin or gastrointesitinal tract to ginkgo or its
preparations which are rare (empirical).17,344,401
What has been described as fruit ginkgolic acid cross-reactions in ivy-sensitive individuals may actually be irritative and/or allergic reactions to cardanols, decarboxylation products of ginkgolic acids that may be produced in solution (topically in guinea-pigs).1266 Injection of 2 mg of a 60% hydro-alcoholic extract and a concentrated fraction with 24.6% ginkgolic acids produced a significant lymphoproliferative reaction in the local lymph node (subplantar in mice). A heptane fraction that contained no ginkgolic acids or cardanols and one that had 49.1% ginkgolic acids also produced significant reactions.1267
2) Bleeding
disorders428 due to potential association with hemorrhage as
reported after chronic (6-month or 2-year) daily use of 120-160 mg ginkgo
extract (human case reports).195,525,1190,1191,1449
A systematic review of 12 case reports of ginkgo products associated with hemorrhage found that the likelihood of causality were in 10 case possible, while one case was unevaluable and only one case involving a drug interaction was likely caused by ginkgo extract.1727 Another case and a systematic review of 15 published cases associated ginkgo with bleeding episodes. Other risk factors were identified in 13 of the cases, but in 6 reports the bleeding did not recur after the ginkgo was stopped. This incident involved a 73-year-old man with multiple spontaneous bleeds that stopped when he discontinued his 6-month, 75 mg/day dose of ginkgo extract standardized to 27% flavone glycosides and 10% terpene lactones (PO in human case report). After a 6-week washout lab tests for bleeding parameters were normal, e.g., bleeding time 5.5 minutes. After 10 weeks back on the same dose he had occasional ecchymoses and a bleeding time elevated to >15 minutes.1916
A couple of
poorly-documented cases illustrate the uncertainty in a number adverse
incidences in which ginkgo is suspected of contributing to bleeding events. A
78-year-old woman with age-related macular disease took an unspecified amount
of ginkgo with fish oil and other supplements for 4 months and developed
preretinal and subretinal hemorrhage, and in the following month a dense
vitreous hemorrhage appeared (PO in human case report). After stopping ginkgo
use, the vitreous hemorrhage gradually resolved.2320 A 59-year-old
man also suffered a vitreous hemorrhage during ginkgo use of undocumented
amount and duration, subsequent to a subphrenic hematoma following a liver
transplant (PO in human case report). Though ginkgo use began before the
transplantation, no bleeding problems occurred during the procedure; also, 81
mg of aspirin were given daily after the transplant. No bleeding episodes were
noted after ginkgo cessation.2321
While ginkgolide B can prevent and embolize
PAF-induced thrombi (in vitro), several ginkgo extracts and ginkgolide B
reduce PAF-induced thrombus formation (IV in guinea pigs).1380
However, a PAF-induced
aggregation of human platelets requires a concentration of 100 times or more
greater than is achieved in the plasma by normal therapeutic doses of 120-240
mg of a 50:1 concentrated ginkgo extract (in vitro).1747
A database of bleeding
episodes among 320,644 German patients indicated that EGb 761 does not increase
the risk of bleeding episodes when taken with or without anticoagulant or
antiplatelet drugs (PO in human study).2117 Also, 10 adults taking a
proprietary ginkgo product at the manufacturer’s recommended dose for 2 weeks
had no increase in coagulation time in ADP and epinephrine assays of intrinsic
and extrinsic platelet function, respectively (ex vivo), but the product
was not analyzed for its phytochemical content.2262
In 21 of 28 healthy midage (ave. 43) subjects and 16
of 19 midage (ave. 54) patients with type 2 diabetes mellitus, taking 120 mg of
standardized ginkgo extract for 3 months significantly reduced collagen-mediated,
but not PAF-mediated, platelet aggregation (PO in human study).1381
A randomized,
placebo-controlled, double blind crossover trial used 120 mg daily of the
extract EGb 761 with 12 healthy subjects for 3 months, with the result of COX-1
inhibition decreasing production of thromboxane B2, a promoter of
platelet aggregation, after taking the extract (ex vivo). When the
extract was added to platelet-rich plasma, platelet aggregation and thromboxane
B2 were both inhibited (in vitro).1848
However, in 32 healthy young
males, taking ginkgo extract EGb761 for 2 weeks at 120, 240 or 480 mg daily
hemostasis, coagulation and fibrinolysis were not significantly altered (PO in
human study).1455 Furthermore, 40 subjects aged 65-79 years taking 120 mg Egb-761 daily
for 7 days had no change in bleeding or coagulation parameters (PO in human
study).1833
Type 2 diabetics using 240 mg EGb 761 daily for 3
months had significantly decreased fibrinogen levels and blood viscosity
compared to baseline values (PO in human study).1759 Also, 25
subjects from age 60-70 taking 80 mg daily of a standardized dry extract had
reduced blood viscosity compared to 23 men of the same age taking placebo (PO
in human study).1526 Blood viscosity decreased after 6 months in 25 men
when taking EGb761 at 80 mg/day, compared to placebo (PO in human study). The
decrease was progressive for the first 90 days, but not during the second 90
days.2297
3) Use before elective surgery (speculative)428,703
for at least 36 hours1309 or up to one week.1310,1782
A rare retrobulbar hemorrhage following injection of
local anesthetic prior to cataract surgery was associated with daily use of 120
mg ginkgo extract for two years (PO in human case report).1488
On the first night after an unspecified ambulatory
surgery, disseminated bleeding in the operative field occurred in a 75-year-old
woman who had taken 80 mg daily for 2 years of a 35-67:1 ginkgo concentrated
extract (PO in human case report). Platelet count, coagulation factors, and
prothrombin time were normal, but platelet aggregation to collagen was
decreased, though normal with ADP, epinephrine, and ristocetin (in vitro).
Bleeding times, also known as closure times, were prolonged with ADP and
epinephrine (in vitro). After being advised and stopping extract use, 10
days later the platelet aggregation and closure times were normal.2322
Following a total hip arthroplasty in a 77-year-old
woman, persistent bloody/serous discharge 3 weeks after aspirin was stopped was
connected with the ongoing use of 120 mg daily of ginkgo extract, though no
clotting cascade abnormalities were identified (PO in human case report).
Following the ginkgo extract withdrawal, the oozing gradually reduced until it
was dry 5.5 weeks later.2318 In another total hip arthroplasty, a
65-year-old man had acute postoperative wound hemorrhage associated with
preoperative use of 2 tablespoons daily of a liquid herbal extract from ginkgo
and 4 other herbs: Piper longum, Tylophora indica, Marrubium vulgare,
Cetraria islandica (PO in human case report). After a 4-unit transfusion
the bleeding stopped after 8 hours, and the patient was discharged on the fifth
postoperative day.2319
A 59-year-old man suffered a subphrenic hematoma
with ginkgo use of undocumented amount and duration, following a liver
transplant (PO in human case report). Though ginkgo use began before the
transplantation, no bleeding problems occurred during the procedure; also, 81
mg of aspirin were given daily after the transplant. This was followed by a
vitreous hemorrhage 3 weeks later. No bleeding episodes were noted after ginkgo
cessation.2321
Recently, two incidences of bilateral hematomas
following a rhytidoplasty or blepharoplasty occurred after chronic use of 160
mg ginkgo extract daily (PO in human case reports).1782
A case report of spontaneous bleeding and a systematic review of 15 published cases associated ginkgo with bleeding episodes. Other risk factors were identified in 13 of the cases, but in 6 reports the bleeding did not recur after the ginkgo was stopped.1916
A systematic review of 12 case reports of ginkgo products associated with hemorrhage found that the likelihood of causality were in 10 case possible, while one case was unevaluable and only one case involving a drug interaction was likely caused by ginkgo extract.1727 A database of bleeding episodes among 320,644 German patients indicated that EGb 761 does not increase the risk of bleeding episodes when taken with or without anticoagulant or antiplatelet drugs (PO in human study).2117
25 subjects from age 60-70 taking 80 mg daily of a standardized dry extract had reduced blood viscosity compared to 23 men of the same age taking placebo (PO in human study).1526
A randomized, placebo-controlled, double blind
crossover trial used 120 mg daily of the extract Egb 761 with 12 healthy
subjects for 3 months, with the result of COX-1 inhibition decreasing
production of thromboxane B2, a promoter of platelet aggregation,
after taking the extract (ex vivo). When the extract was added to
platelet-rich plasma, platelet aggregation and thromboxane B2 were
both inhibited (in vitro).1848
However, in 32 healthy young
males taking ginkgo extract EGb761 for 2 weeks at 120, 240 or 480 mg daily
hemostasis, coagulation, and fibrinolysis were not significantly altered (PO in
human study).1455 In
addition, 40 subjects aged 65-79 years taking 120 mg Egb-761 daily for 7 days
had no change in bleeding or coagulation parameters (PO in human study).1833
Type 2 diabetics using 240 mg Egb 761 daily for 3 months had significantly
decreased fibrinogen levels and blood viscosity compared to baseline values (PO
in human study).1759 Also, 10 adults taking a proprietary ginkgo product
at the manufacturer’s recommended dose for 2 weeks had no increase in
coagulation time in ADP and epinephrine assays of intrinsic and extrinsic
platelet function, respectively (ex vivo), but the product was not
analyzed for its phytochemical content.2262
While ginkgolide B can prevent and embolize
PAF-induced thrombi (in vitro), several ginkgo extracts and ginkgolide B
reduce PAF-induced thrombus formation (IV in guinea pigs).1380
However, a PAF-induced
aggregation of human platelets requires a concentration of 100 times or more
greater than is achieved in the plasma by normal therapeutic doses of 120-240
mg of a 50:1 concentrated ginkgo extract (in vitro).1747
In 21 of 28 healthy
midage (ave. 43) subjects and 16 of 19 midage (ave. 54) patients with type 2
diabetes mellitus, taking 120 mg of standardized ginkgo extract for 3 months
significantly reduced collagen-mediated, but not PAF-mediated, platelet
aggregation (PO in human study).1381
+ 4)
Patients possibly predisposed to seizures should be avoided or done
cautiously (speculative). At least seven anecdotal reports have been submitted
to the FDA’s Special Nutritionals Adverse Event Monitoring System by the
general public concerning claims of ginkgo-linked seizures, though most follow
use of multi-ingredient products.
Apparently, no follow-up medical reports have documented these or other
such claims appearing on several other online forums; neither has ginkgo
identity nor plant part been confirmed in these cases. 1105
Drug Interactions
I. 1) A A50:1 concentrated extract induced bleeding following chronic use of aspirin (PO in human case report).194
Following a total hip arthroplasty in a 77-year-old woman, persistent bloody/serous discharge continued for 10 days, at which time aspirin use was stopped (PO in human case report). Then 3 weeks later, the continued oozing was associated with the continuing use of 120 mg daily of ginkgo extract, though no clotting cascade abnormalities were identified. Following the ginkgo extract withdrawal, the oozing gradually reduced until it was dry 5.5 weeks later.2318 A 59-year-old man suffered a subphrenic hematoma with ginkgo use of undocumented amount and duration following a liver transplant; 81 mg of aspirin were given daily after the transplant, and though ginkgo use began before the transplantation, no bleeding problems occurred during the procedure (PO in human case report). This was followed by a vitreous hemorrhage 3 weeks later. No bleeding episodes were noted after ginkgo cessation.2321
However, in a randomized
double-blind study of 67 peripheral arterial disease patients taking 325 mg of
aspirin daily, compared to placebo the addition of 300 mg/day for 4 weeks of
EGb 761 made no difference in platelet function analysis or platelet aggregation
induced by the agonists epinephrine, collagen or ristocetin (ex vivo).2229
Use should be avoided with anticoagulants.401,415,416,777,893 including heparin, and antiplatelet
drugs including NSAIDs (speculative).893
[For warfarin, see IV. 1).]
However,
a database of bleeding episodes among 320,644 German patients indicated that
EGb 761 does not increase the risk of bleeding episodes when taken with or
without anticoagulant or antiplatelet drugs (PO in human study).2117
A systematic review of 12 case reports of ginkgo products associated with
hemorrhage found that only the case involving the ibuprofen interaction was
likely caused by ginkgo extract.1727 This case involved 2.5 years
use of 80 mg daily of a 50:1 ginkgo extract and resulted in a fatal intracerebral
hemorrhage when 600 mg of the NSAID ibuprofen daily was introduced for 4
weeks (PO in human case report).1432
A randomized, placebo-controlled, double blind
crossover trial used 120 mg daily of the extract EGb 761 with 12 healthy
subjects for 3 months, with the result of COX-1 inhibition decreasing
production of thromboxane B2, a promoter of platelet aggregation,
after taking the extract (ex vivo). When the extract was added to
platelet-rich plasma, platelet aggregation and thromboxane B2 were
both inhibited (in vitro).1848 While ginkgolide B can prevent
and embolize PAF-induced thrombi (in vitro), several ginkgo extracts and
ginkgolide B reduce PAF-induced thrombus formation (IV in guinea pigs).1380
Type 2 diabetics using 240 mg EGb 761 daily for 3 months
had significantly decreased fibrinogen levels and blood viscosity compared to
baseline values (PO in human study).1759 Also, 23 subjects from age 60-70 taking 80 mg of a standardized dry
ginkgo extract daily for 8 months had reduced blood viscosity compared to 25
men of the same age taking placebo (PO in human study).1526 In 21 of 28 healthy midage
(ave. 43) subjects and 16 of 19 midage (ave. 54) patients with type 2 diabetes
mellitus, taking 120 mg of standardized ginkgo extract for 3 months significantly
reduced collagen-mediated, but not PAF-mediated, platelet aggregation (PO in
human study).1381
However, in 32 healthy young males taking ginkgo extract EGb761 for 2 weeks at 120, 240 or 480 mg daily, hemostasis, coagulation and fibrinolysis were not significantly altered (PO in human study).1455 Furthermore, 40 subjects aged 65-79 years taking 120 mg EGb-761 daily for 7 days had no change in bleeding or coagulation parameters (PO in human study).1833 A PAF-induced aggregation of human platelets requires a concentration of 100 times or more greater than is achieved in the plasma by normal therapeutic doses of 120-240 mg of a 50:1 concentrated ginkgo extract (in vitro).1747
2) ginkgo leaf extract offset sexual dysfunction
following antidepressant use.
A placebo-controlled double blind study with 37 patients involved 36 using SSRIs; half were given 120 mg ginkgo extract EGb 761 daily fo 2 weeks, 160 mg for the next 2 weeks, and finally 240 mg daily for 4 weeks. The ginkgo and placebo both showed significant improvement over baseline performance at some point. Comparing the two showed placebo to be better in one of 9 categories with no significant difference in the others (PO in human clinical study).1318
4) Ginkgolide B helped prevent rejection of kidney
transplants when used with cyclosporine (IV
in human clinical study).527
A ginkgo product given at 240 mg daily did not alter
digoxin pharmacokinetics in 8 healthy subjects (PO in human study),1477
so an effect on cyclosporine absorption is unlikely, since both digoxin and
cyclosporin are P-glycoprotein substrates.
5) Ginkgo extract taken with trazodone resulted in a coma (PO in human case report).1058
Trazodone is metabolized by CYP 3A4, but
standardized ginkgo extract given at 240 mg daily for 4 weeks did not alter
midazolam metabolism by 3A4. Likewise, isozymes 1A2, 2D6, and 3E1 were not
affected by ginkgo extract (PO in human study),1328 though the extract
as 0.5% of the
diet caused induction of CYPs 1A1, 1A2, 2B, 2C9, 2E1, 3A4, and GST (PO in
rats). The induced isozymes had all returned to normal levels within 2 weeks,
including the increased CYP 3A4 metabolism of testosterone after 1 week.1952
Likewise, ginkgo extract at 90 mg/day for 30 days in
14 subjects did not alter the metabolism of CYP3A4 substrate donepezil after
prolonged therapeutic use (PO in human clinical study).1824
6) Patient taking a thiazide diuretic had an increase in blood pressure after she took
ginkgo for a week (PO in human case report).614 This report has been
described as unevaluable based upon report inadequacies.1239
A clinical survey identified a 66-year-old man whose
hypertension was exacerbated when the hydrochlorothiazide that he was
taking was combined with a ginkgo product (PO in human case report).2126
+ 7)
[previously considered as part of Drug Interactions IV. 1)] Two elderly
epilepsy patients who had been stabilized on anticonvulsant therapy with
sodium valproate without a seizure for 1.5 and 2.0 years experienced 3
to 4 seizures within two weeks of beginning use of 120 mg daily of ginkgo
extract (PO in human case reports). After two days of being off the ginkgo
extract, no more seizures occurred over the next 18 and 4 months, respectively.
The mechanism of this interaction has not been established, nor have the
responsible components.1247
+ 8)
Ginkgo standardized extract LI 1370 given at 240 mg/day with trimipramine
to 8 patients with major depression for 4 weeks improved sleep patterns by
reducing awakenings and increasing sleep efficiency compared with trimipramine
given alone to 8 patients (PO in human clinical study). Discontinuation of the
ginkgo extract reversed the effects.1317
+ 9)
Ginkgo leaf extract EGb 761 given to 56 refractory schizophrenia patients at a
dose of 360 mg/day together with haloperidol increased the effectiveness
and reduced the extrapyramidal side effects of the medication compared to 53
given placebo, probably due to the free radical scavenging effects provided by
the complex spectrum of active substances in the ginkgo extract (PO in human
clinical study)1281 A group of 109 schizophrenic subjects given
haloperidol with either 360 mg ginkgo extract daily or placebo had low CD3+,
CD4+, and IL-2-secreting T cell subsets and a low CD4/CD8 ratio at baseline,
but those receiving ginkgo for 12 weeks increased these subsets and ratio and
lowered SOD compared to baseline and placebo (PO in human clinical study).
There was also a significant correlation with a lower score on the Brief
Psychiatric Ratio Scale and use of ginkgo but not placebo, indicating that
ginkgo both improved immune function and psychiatric outcome when used with
haloperidol.2113
+ 10)
120 mg daily of ginkgo extract EGb 761 taken by type II (non-insulin-dependent)
diabetics reduced oral glucose tolerance test plasma insulin and increased the
blood glucose levels during this test in patients who were taking the oral
hypoglycemic agents metformin, troglitazone, glipizide, and glyburide
(glibenclamide) (PO in human clinical study)1323
However, a single 120 mg/day
dose for 3 months of a ginkgo extract standardized to appear similar to EGb 761
decreased glycated hemoglobin concentrations in 20 type II diabetics using 500
mg/day metformin, though it did not affect glucose or insulin concentrations
(PO in human clinical study). Metformin pharmacokinetics were not affected at a
dose of 500 mg or less, though its excretion was decreased by the ginkgo
extract combined with 850 mg metformin.1978
In addition, when 360 mg/day of ginkgo extract EGb
761 was taken for 28 days by 10 healthy males, it reduced the bioavailability
of CYP 2C9 substrate tolbutamide by 16% and attenuated its effect on
lowering blood glucose (PO in human study).2015
Tolbutamide and CYP 2C9 substrate diclofenac were
not affected by 240 mg ginkgo extract for 8 days (PO in human study),2011
not did it alter metabolism of CYP 2C9 substrates S-warfarin after 7 days (PO
in human study)1774 or flurbiprofen after 2 days (PO in human
study),1842 but these studies were not sufficiently long to
determine potential induction of this isozyme to reduce the availability of
these drugs. Glipizide and glyburide are also CYP 2C9 substrates.
+ 11)
Ginkgo extract EGb761 given in doses of 280 mg/day to 12 Chinese subjects
significantly decreased omeprazole bioavailability by inducing its
metabolism by CYP 2C19, and it also reduced the urinary excretion of its major
metabolite (PO in human study).1617,2301 Among this ethnic group
with CYP 2C19 genetic polymorphism, the 7 poor metabolizers had a significantly
greater increase in hydroxylation of the drug than the 5 heterozygous and 6
homozygous extensive metabolizers, though all three genotypes showed
significant induction of this isozyme. The conversion of omeprazole by CYP 3A4
to omeprazole sulfone was not affected, nor was the conversion by this isozyme
of cortisol to 6b-hydroxycortisol enhanced by ginkgo extract.2301
+ 12)
Following treatment of colorectal cancer patients with 5-fluorouracil,
32 with advanced cases were treated every 3 weeks with 350 mg EGb 761 followed
by 5-fluorouracil for 6 days for each course (IV in human clinical study).
After two courses the disease progressed in 22, was stable in 8, and responded
partially in 2. Of the 22, the disease progressed further in 17 after two
courses, in 2 after three courses, and in the other 3 after four courses,
similar to other second line treatments. EGb761 was well tolerated, and median
survial was 9.5 months. Good benefit-risk ratio with improvement in some,
despite 5-fluorouracil failure, suggests application as a first-line treatment.1669
+ 13)
120 mg/day of uncharacterized ginkgo for 18 days inhibited metabolism of CYP
3A4 substrate nifedipine as indicated by an increase in peak plasma
concentrations of 53% (PO in humans).1728
+ 14)
A dose of 360 mg/day of EGb 761 increased bioavailability of CYP 3A4 substrate midazolam
by 25% and decreased its oral clearance by 26% (PO in humans study).2015
However, daily doses for 28
days of 240 mg ginkgo standardized to 24% flavone glycosides and 6% terpene
lactones failed to alter the metabolism of CYP 3A4 substrate midazolam (PO in
humans).1328 In addition, 240 mg daily for 14 days of ginkgo extract
slightly decrease alprazolam availability, suggesting CYP 3A4 induction (PO in
human study).1840
15)
While consumption of a single standardized extract
dose had no effect on talinolol
pharmacokinetics, taking 360 mg extract
daily for 14 days significantly increased the drug bioavailability, likely due
to inhibition of P-glycoprotein or another efflux protein (PO in human study).2680
+ 16) EGb761 at 280 mg twice daily for 12 days in 12 healthy Chinese subjects significantly increased metabolism of a single dose of CYP 2C19 substrate mephenytoin by a mean of 8.6%, though it ranged from 0.6% to 30.4% (PO in human study). In the same study the CYP 2E1 substrate chlorzoxazone showed a mean change of 15.0%.2302 Ginkgo extract as 0.5% of the diet was shown to induce this isozyme. Recovery from CYP2E1 induction occurs within 2 weeks (PO in rats).1952
However, in other studies normal
therapeutic doses did not produce this effect with chlorzoxazone (PO in
humans).1328,1808
II. + 2) EGb 761 96 mg/kg for 8 days increased social contact in animals given an injection of diazepam more than diazepam alone, even though EGb 761 by itself had diminished social contact (PO in rats)1268
+ 3)
The antiplatelet drug ticlopidine
was as effective inhibiting platelet aggregation ex vivo in a small dose of 50 mg/kg/day combined with ginkgo
extract EGb761 at 40 mg/kg/day as with a large dose of 200 mg/kg/day alone (PO
in rats and mice). The combination increased bleeding time by 150% and improved
recovery in acute thrombosis.1090
It has been suggested that caution be used when
combining ginkgo products with antiplatelet drugs (speculative).1890
A daily dose of 80 mg of a 50:1 concentrated extract was associated with
spontaneous bleeding, following chronic (3-year) use by a 70-year-old man of aspirin as an antiplatelet drug (PO in human case report).194
+ 4)
Compared to controls, administering the extract at 100 mg/kg daily for 5 days
decreased the bioavailability of the CYP 1A2 substrate theophylline by
38% when the drug was given intravenously and by 40% when it was given orally
(PO in rats). The only significant effect with 10 mg/kg extract dose was an
increase in total theophylline clearance, independent of route. The normal
human dose is less than 5 mg/kg daily.2278
5)
Compared to animals given 600 mg/kg of amikacin
daily for 2 weeks, those also given EGb761 at 100 mg/kg/day over the same
period plus an additional week had increased ototoxicity (PO in rats). Those
receiving only the EGb761 had no change in auditory measurements. Other aminoglycoside antibiotics may have a
similar interaction with ginkgo extract (speculative).2654 The
normal human dose is less than 5 mg/kg daily.2278
III. 2) [Formerly IV. 1)] Ginkgo may diminish the effectiveness of anticonvulsants
[See I. 7) above.] or potentiate seizures with medications like tricyclic
antidepressants that reduce the seizure threshold (speculative).893
At least seven anecdotal reports submitted to the
FDA’s Special Nutritionals Adverse Event Monitoring System by the general
public concerning claims of ginkgo-linked seizures, though most follow use of
multi-ingredient products. Similar claims appear on several other online
forums; but ginkgo identity and plant part have not been confirmed in these
cases. Still, the recommendation is made that ginkgo (leaf? leaf extract?
seeds?) use with medicines known to incite seizures should be avoided or done
cautiously (speculative).1105 Convulsions occurred twice in a 36-year-old woman
after eating 70-80 ginkgo nuts/seeds (PO in human case report).1106
However, no convulsions
occurred after administration of the anticonvulsants phenobarbital and later
carbamazepine. The convulsive effect
seems to be due to high ginkgotoxin content in the nuts interfering with
vitamin B6 activity as a cofactor of glutamate decarboxylase,
resulting in decreased GABA levels in the brain and loss of GABAergic
inhibition of convulsions.1106 In contrast the bilobalide in the
leaves has been shown to suppress glutamatergic toxic convulsions (IP in rats).1107
IV. + [1) [Previously in I.1).] Warfarin use stabilized for 5
years with a 78-year-old woman resulted in intracerebral hemorrhage with the
addition of ginkgo for 2 months (human case report).524
A Danish randomized,
placebo-controlled, double-blind cross-over trial with 24 patients found that
100 mg of a ginkgo product used for 4 weeks did not alter the effective
warfarin dosage required to maintain an INR between 2.0-4.0 (PO in human
study). Unfortunately, the report failed to identify the type of ginkgo product
as to whether it was the leaf, a native leaf extract, or a concentrated
standardized extract.1433 In addition, ginkgo standardized extract
EGb761 tablets derived from 2 grams of leaf powder were given in doses of 2
tablets three times daily for a week, followed by a single dose of warfarin (PO
in human study). No changes were observed in R- or S-warfarin metabolism by
CYPs 1A2 or 2C9, respectively, or alterations in warfarin protein binding, nor
was any alteration of INR detected following ginkgo extract use. Continuing
ginkgo extract use for another week, no change in INR or platelet aggregation (ex
vivo) were detected from using the daily extractive of 12 gram of ginkgo
alone (PO in human study).1774 Likewise, no effect was found in the
pharmacokinetics of other CYP 2C9 drug substrates including flurbiprofen, diclofenac
and tolbutamide (PO in human studies).1842,2011 While a lab study
did show ginkgo extract inhibited warfarin metabolism (in vitro),2011
the extract as 0.5% of the diet caused induction of CYP 2C9 metabolism of
S-warfarin (PO in rats). The isozyme level returned to normal within a week.1952
CYP 2C9 induction would increase the tendency to clot, not bleed.
A systematic review of 12 case reports of ginkgo
products associated with hemorrhage found that the likelihood of causality were
in 10 cases possible, while one case was unevaluable and only the case
involving the ibuprofen interaction was likely caused by ginkgo extract.1727
Also, a database of bleeding episodes among 320,644 German patients indicated
that EGb 761 does not increase the risk of bleeding episodes when taken with or
without anticoagulant or antiplatelet drugs (PO in human study).2117
Furthermore, 40 subjects aged 65-79 years taking 120 mg EGb-761 daily for 7
days had no change in bleeding or coagulation parameters (PO in human study).1833
GINSENG [Now
ASIAN GINSENG.] p.
107
Panax ginseng
root
GOAT’S
RUE NEW
Galega officinalis herb
(French lilac)
Drug
Interactions
III. 1) Blood glucose may be reduced in those
stabilized on insulin or hypoglycemic drugs (speculative),1890
based on the hypoglycemic effect of its seeds (PO in animals).127,954,1868
and a decoction of the herb equivalent to the 12.5
grams dry weight of the herb per kg body weight (PO in mice).2252
GOLDENROD [now eUROPEAN GOLDENROD] p.
109
Solidago virgaurea plant
GOLDENROD
^ Solidago
canadensis and Solidago gigantean herb NEW
(Fr.: gerbe d’or) and (Ger.:
riesengoldrute)
Contraindications
1) Chronic kidney
disorder unless a medical practitioner has been consulted
(speculative)6,150 to assess the nature and seriousness of the
condition
GOLDENSEAL p.
110
*Hydrastis
canadensis roots/rhizome
Contraindications
4) High blood
pressure (speculative)777
However, a 0.2 mg/kg/min
rate of berberine infusion caused a significant decrease in peripheral vascular
resistance and systemic arterial pressure (IV in human clinical study).1367
Drug
Interactions
I. + 2)
Berberine 1.2 grams daily, given as tablets to 79 congestive heart failure
patients on ACE inhibitors along with digoxin in 76, nitrates
in 71, and diuretics / spironolactone in 77, significantly
increased left ventricular ejection fraction and exercise capacity, improved
dyspnea-fatigue index, and reduced frequency of ventricular premature complexes
compared with 77 patients using only comparable conventional medications. The
mortality of the berberine group decreased significantly as well, and there
were no apparent side effects (PO in human clinical study).1457 In
56 congestive heart failure patients on loop diuretics and ACE inhibitors,
including 51 using digoxin and 46 on nitrates, the significant increases in
left ventricular ejection fraction and decreases in ventricular premature beats
from baseline from 1.2 grams of berberine daily was also significant better
when plasma berberine concentrations were higher versus lower than 0.11 mg/L (PO
in human clinical study).2639
+ 3)
2.7 gram daily of goldenseal extract given for 28 days inhibited metabolism of
CYP3A4 substrate midazolam by 40% in 12 healthy subjects (PO in human
study).1807 Also, 3.97 gram of the root extract delivering 132 mg
hydrastine and 77 mg berberine per day for 14 days significantly reduced
midazolam bioavailability in 16 healthy subjects (PO in human study).2501
Goldenseal tincture and its herb tea were the
strongest CYP 3A4 inhibitors tested in vitro of the 21 herb extracts840
and 20 herb and black teas.1577
However, 2.28 grams of the
root given daily to 10 healthy volunteers for 14 days failed to affect the
pharmacokinetics of CYP 3A4 substrate indinavir (PO in human study).1700
+ 4)
Berberine at 0.6 grams daily for 3 months increased previously stabilized cyclosporin
A trough blood concentrations by 90% in 52 renal transplant patients,
and when given for 12 days to 6 transplant patients increased the cyclosporine
bioavailability by 35% (PO in human clinical study), likely by inhibition of
CYP 3A4 (speculative).2281
However, 2.28 grams of the
root given daily to 10 healthy volunteers for 14 days failed to affect the
pharmacokinetics of CYP 3A4 substrate indinavir (PO in human study).1700
+ 5)
The combination of 500 mg berberine 3 times daily for 3 months in 43 patients
with poorly-controlled type 2 diabetes together with one or more of their
regular oral hypoglycemic medications including sulfonylureas in
28, metformin in 20 acarbose in 15, and/or insulin in 10
resulted in lower fasting and postprandial blood sugar from week 1 through week
12 (PO in human clinical study). Fasting plasma insulin was also lowered by 28%
and an index of insulin resistance by 45% of those on medications, while total
cholesterol and LDL were likewise reduced. In 31 newly diagnosed type 2
diabetics to whom 15 were given the same dose of berberine and 16 used 500 mg
metformin 3 times daily, berberine’s hypoglycemic effect was similar to that of
metformin on fasting and postprandial blood glucose, as well as reducing
glycosylated hemoglobin and plasma triglycerides (PO in human clinical study).
Transient gastrointestinal adverse effects were experienced by 35% of the
patients, or 20 in total.2315
+ 6)
The use of 900 mg goldenseal root extract 3 times/day for 28 days in 12
volunteers resulted in about a 40% inhibition of CYP 2D6 metabolism of debrisoquin
(PO in human study).1807 With 18 volunteers taking 1.1 gm of the
root extract containing 44 mg hydrastine and 25.6 mg berberine 3 times daily
for 14 days, the debrisoquin metabolism was inhibited by about 50%, as
determined by 8-hour debrisoquine urinary recovery ratios (PO in human study).2502
II. + 1)
Pre-treatment with 4 mg/kg berberine prevented a rise in serum levels of liver
enzymes from excessive acetaminophen, suggesting protection from its
toxic effects (PO in rats). Use of this dose three times every six hours
following a toxic dose of acetominophen reduced liver damage.1215
2) Berberine administered prior to pentobarbital increased the induced sleeping time (IP in mice).1032
A single 4 mg/kg dose of berberine prolonged
pentobarbital sleeping time and increased strychnine toxicity (PO in
rats).1215
+ 3)
When the alkaloid component berberine was given once or twice at doses of 50,
100, or 200 mg/kg before cyclophosphamide injection, it significantly
reduced the chemotherapy adverse effect of bladder hemorrhage in a
dose-dependent manner (IP in rats).2570
+ 4) Berberine at 100 mg/kg enhanced the anxiolytic
effects of buspirone and ritanserin but did not interact with
diazepine (PO in mice).2668
III. + 4) Studies in human liver-derived cells with
berberine was found to have an additive effect with lovastatin by
increasing LDL receptor mRNA expression (in vitro). This statin did not
reduce this effect of berberine, indicating a different mechanism of action (in
vitro). In 63 high-cholesterol subjects taking 1.0 grams berberine HCl
daily for 3 months, serum cholesterol was reduced 18%, LDL cholestreol 20%, and
triglycerides 28%, compared to those using placebo (PO in human study). In the
32 who were taking no other medication or herbs, cholesterol was reduced 29%,
LDL cholesterol 25%, and triglycerides 35%. HDL cholesterol was unaffected, and
berberine was well tolerated. Berberine was found to have a dose-dependent
cholesterol-lowering effect (in hamsters).1656
+ 5)
It could have an additive effects with drugs like phenylbutazone that
displace protein binding of bilirubin (speculative),1890 since the
displacement by berberine of bilirubin from serum albumen has been demonstrated
(IP in rats).1092
+ 6)
Berberine increased efflux of paclitaxel (taxol) by inducing
P-glycoprotein1046 and thereby potentially reduces its retention and
concentration in human hepatoma or digestive tract cancer cells (in vitro).1045,1046
Goldenseal extract components, berberine and hydrastine, were shown to act as
substrates for P-glycoprotein (in vitro).2145
However, a study with the P-glycoprotein probe drug digoxin in 20 subjects found that 3.2 grams daily for 14 days of an extract of goldenseal containing 3.25% isoquinoline alkaloids failed to alter the bioavailability of digoxin (PO in human study).2082
GOTU KOLA p.
111
Centella asiatica =
Hydrocotyle asiatica plant
Contraindications
2) Allergic hypersensitivity resulting in contact
dermatitis by using topical medications containing the extract (human case
reports)1185,1186
Drug Interactions
II. + 1)
Aqueous extract at a 50 mg/kg dose increased the sleeping time induced by pentobarbital
(IP in mice),1201 so barbiturates may be enhanced
(speculative)
GRAPES NEW
^ Vitis
spp. seeds
Drug Interactions
II. 1) Pica induced by the chemotherapy agent cisplatin was significantly reduced by 3 different grape seed extracts made from different varieties or species of grapes at a dose of 10 mg/kg, but the percentage reduction correlated dose-dependently with the variable polyphenol content of the 3 products (IP in rats).1877
GRAPEFRUIT p.
111
Citrus paradisi fruit/juice;
seed extract
Drug Interactions
I. 1) Juice consumed concurrently increases
bioavailability of many calcium
antagonists777
Use with verapamil also resulted in prolongation of the PR intervals in subjects (PO in
human study).1304 Several studies noted that the small inhibition of
verapamil metabolism by grapefruit juice did not appear to be clinically
significant (PO in human studies).1161,1333 Nonetheless, when a
42-year-old woman accidentally took 2 additional verapamil tablets in addition
to her 120 mg tablet daily after having consumed 3-4 liters of grapefruit juice
during the prior 7 days, she presented with palpitations, a complete heart
block with ventricular escape rhythm of 34 beats/minute, systolic blood
pressure of 56 mm/Hg, hypoxic respiratory failure, and metabolic acidosis (PO
in human case report).2584
The absorption of other calcium channel blockers is
also increased. Six
healthy men drinking 300 ml grapefruit juice 30 minutes before taking nicardipine
increased the average oral drug bioavailability and increased their heart rates
1-2 hours after dosing, compared to taking the drug after consuming 300 ml
water (PO in human study).2099 When 10 healthy males took diltiazem
with 250 ml of grapefruit juice or water, the juice increased the drug
bioavailability but did not affect blood pressure or heart rate (PO in human
study).2100
However, furanocoumarin-free
juice did not alter felodipine pharmacokinetics compared with grapefruit
juice that did not have the furanocoumarins removed (PO in human study). Other
CYP 3A4 substrates will likely also not have altered metabolism if the
furanocoumarins are removed from the juice (speculative).1862
2) When 240
ml of grapefruit juice is consumed with terfenadine,
or in some individuals even two hours after its consumption, it increases the
bioavailability of the drug (PO in human study).1980
+ 3)
After using simvastatin for more than two years with no problems, a
40-year-old woman over 10 days gradually developed muscle weakness in her lower
extremities secondary to statin-associated rhabdomyolysis for which she was
hospitalized. Fourteen days prior she had begun eating one grapefruit daily (PO
in human case report).1575 When 200 ml of water or juice were taken for 3.3
days before simvastatin, the juice increased bioavailability 3.6-fold and
simvastatin acid 3.3-fold, while the peak concentrations were increased 3.9-
and 4.3-fold, respectively (PO in human study).2046 In an animal
study, 200 mg/kg of simvastatin resulted in 50% survival after 10 days, but
when 20 mg/kg were given with 5 ml/kg grapefruit juice no signs of toxicity
were observed after 4 weeks (PO in rats). This suggests that the
pharmacokinetic changes following a single dose of simvastatin do not
necessarily carry over to pharmacodynamic changes with repeated doses,2255
but the interspecies differences may have contributed to the lack of effect.
When 16 healthy subjects were given 8 oz grapefruit
juice or water for breakfast for 3 days and then given lovastatin on the
last evening, the bioavailability and maximum concentration of the statins was
increased 30-40% (PO in human study).2049
In two groups of studies with 12 and 10 subjects
that compared the effects of water and grapefruit juice, given at 200 ml
[double-strength] or 250 ml, respectively, 3 times daily for 2.3 days, on both atorvastatin
and pravastatin, the bioavailability of atorvastatin acid was increased
2.5- or 1.4-fold, respectively, but no change was found in pravastatin
pharmacokinetics (PO in human studies).2047,2048
Another statin drug whose bioavailability is
increased by grapefruit or its juice is cerivastain.1161
4) increased plasma concentration of cyclosporine (PO in human studies),320,483
probably due in part to inhibition of P-glycoprotien efflux (PO in human
study).1031
When 8 oz of grapefruit juice were given to 10 renal
transplant patients on steady state cyclosporine A dosing and results compared
to the effects of 8 oz of water, the grapefruit juice was shown to increase
drug exposure and delay absorption without changing the peak concentration (PO
in human clinical study).1988
However, increased excretion, due to enhancement of P-gp efflux of cyclosporine in kidney cells (in vitro), may offset increased absorption somewhat.1036 Pharmacokinetic studies with a single dose of digoxin showed no significant change of serum levels from P-glycoprotein inhibition from 0-48 hours with 4 doses of 220 ml grapefruit juice consumed before and during the first 12 hours. Though a 9% increase in digoxin occurred from 0-4 and 0-24 hours, no change in digoxin clearance from the kidneys occurred during these intervals (PO in human study).1216
5) CORRECTION - Caffeine metabolism is inhibited
when 300 ml of [CORRECTION] GRAPEFRUIT JUICE was drunk one half hour before and
every six hours following 167 mg caffeine ingestion in 5 gram instant coffee by
12 subjects (PO in human study). Area under curve and caffeine half-life were
increased while oral caffeine clearance was decreased. Caffeine metabolites
were not identified. [CORRECTION] NARINGENIN inhibits CYP1A2 conversion of
caffeine to paraxanthine (in vitro).852
7) Fexofenadine
bioavailability was reduced two thirds when taken with grapefruit juice (PO
in human study).1097
While
300 ml juice reduced the bioavailability and peak plasma concentration to 58%
and 53% of control values, respectively, 1.2 liters of juice reduced these
parameters to 36% and 33%.1757 When 240 ml of double-strength grapefruit juice
was taken three times daily for 2 2/3 days, and fexofenadine dose was taken
with, and then followed by, the last final two doses, the total absorption and
maximum serum concentration were reduced by 30% (PO in human sudy).1919
Even a single 300 ml dose of grapefruit juice taken with oral fexafenadine or 2
hours before, but not 4 hours before, reduced its oral bioavailability in 12
healthy subjects by 52% and 38%, respectively (PO in human study).2304
The reduced uptake is due to
inhibiting intestinal organic anion transporting polypeptide (OATP) 1A2,1097,1757
not to inducing P-glycoprotein efflux (in
vitro).1097 The grapefruit flavonoid naringin inhibits the
OATP1A2 transport of fexofenadine (in vitro). Based on comparative
testing in 12 subjects of 300 ml juice, an equivalent amount of naringin in
water, and a low-naringin furanocoumarin fraction of the juice, the reduced
bioavailability of fexofenadine by 55-57%, 75%, and 96%, respectively, appears
to be due largely to naringin (PO in humans).2305
+ 8)
A man maintained on HIV protease inhibitors indinavir, stavudine and lamivudine
(CYP 3A substrates and inhibitors) and co-medicated for depression with fluoxetine
and trazodone began to experience serotonin syndrome after increasing
grapefruit consumption from one to three grapefruit daily (PO in human case
report). Advised to discontinue the grapefruit, his symptoms resolved within
one month.1231
+ 9)
Conversion of sildenafil to N-desmethylsildenafil by CYP3A4 was reduced
when 500 ml grapefruit juice was taken in the hour before the drug by 24 men,
resulting in a 23% increase in plasma sildenafil and a 15 minute delay in
reaching the maximum plasma concentration (PO in human study)1274
+ 10)
250 ml of grapefruit juice also increases bioavailability of other oral drugs320
including praziquantel,1300 amiodarone,
carbamazepine, clomipramine, and tacrolimus (PO in human
studies)1161,1333 due mostly to inhibition of metabolism by cytochrome P450 3A4 enzymes
in the gastrointestinal tract by furanocoumarins like dihydroxybegamottin as
shown with midazolam (in vitro).476
Inhibited metabolism of calcium
antagonists such as nifedipine and felodipine by
dihydroxybegamottin and grapefruit flavonoids, respectively, has also been show
in liver microsomes (in vitro).475,1454
The CYP3A4 inhibition from a single dose of 300 ml of juice is complete withing
3 days, with a recovery half-life of 23 hours (PO in human study).1454
+ 11)
100 ml of grapefruit juice decreases the bioavailability of oral etoposide
by 26% when given to 6 subjects and compared to its oral consumption without
grapefruit juice (PO in human study). No certain mechanistic explanation was
offered.1329
+ 12) Comparing the consumption of 240 mg of
water or reconstituted grapefruit juice three times daily for 5 days on the
absorption of a single 1.0 mg oral dose of digoxin significantly
increased absorption lag time with the juice but no differences were found in
digoxin maximum concentration, area under the curve (AUC), elimination
half-life, or renal clearance.1434
However, the juice reduced
the maximum digoxin concentration, absorption rate, and AUC among subjects with
a T allele compared to CC homozygotes. Since digoxin is a P-glycoprotein
substrate, but not a CYP 3A4 substrate, the inhibition of P-glycoprotein by
grapefruit juice appears to be not generally important but may impact
individuals (PO in human study).1434
+ 13)
Combining large amounts of grapefruit juice with the quinine from
excessive tonic water intake was suspected as the cause of torsad de pointes,
resulting in convulsive syncope in a diabetic woman with polydipsia (PO in
human case report). This combination was proposed as a probable cause of
increasing her QT interval since quinine’s optical isomer quinidine prolongs
the QT interval, and other research shows the grapefruit flavonoid naringen
increases quinine availability (PO in rats).1452
However, grapefruit juice
failed in research with10 subjects to significantly alter the bioavailability
of oral quinine which is metabolized by liver CYP 3A4 (PO in human study),1453
and naringin failed to inhibit CYP3A activity in rat liver microsomes (in
vitro).1450 The inhibition of CYP3A4 occurs in the intestines,
but not in the liver (PO in human study), and in human liver microsomes CYP3A4
inhibition is due largely to the juice component dihroxybergamottin (in
vitro).1454
+ 14)
350 ml of fresh frozen grapefruit juice taken by six healthy male subjects
increased the total absorption and maximum serum concentration of artemether,
while reducing the time required to reach this peak, but this did not influence
ECG results (PO in human study).1506 Another antimalarial drug, primaquine,
has increased bioavailability in 10 male and 10 female subjects when taken orally with 300 ml of
grapefruit juice made from concentrate (PO in human study).1917
However, taking this
medication with bread and butter caused a similar increase, as shown by the
maximum serum concentration and total absorption.1917
A third antimalarial drug, halofantrine, was
given to 6 men and 6 women with either 250 ml of water, orange juice, or
grapefruit juice after use for 4 days at 250 ml/day (PO in human study). Besides
grapefruit juice increasing halofantrine peak plasma concentration and the
total absorption in comparison to water or orange juice, it also increased the
halofantrine-induced QT interval prolongation, increasing the risk of fatal
ventricular arrhythmia. Therefore, grapefruit juice is contraindicated while
using halfantine.1918
15)
Consumption by 25 subjects of a single 300 ml glass of regular grapefruit juice
2 hours before midazolam led to a significant increase in the drug's
bioavailability and peak plasma concentration. A single glass could increase
bioavailability of midazolam if taken 1-2 days, but not 3 days, prior (PO in
human study).1624 When 16 healthy subjects were given 8 oz
grapefruit juice or water for breakfast for 3 days and then given midazolam on
the last evening, the bioavailability of midazolam increased 2.4-fold (PO in
human study).2049
A single 200 ml dose of juice increased
bioavailability and peak plasma concentration of triazolam in a random
crossover trial, while 3 doses of juice daily for three days increased
bioavailability even more along with increasing the drug half-life and its
pharmacodynamic effects in 12 subjects (PO in human study).2051
However,
in separate single-dose studies with either 10 mg of midazolam or 0.25 mg of
triazolom in 12-15
healthy students given water or 300 ml grapefruit juice or 750 mg erythromycin in 6
subjects as a positive
control of CYP3A inhibition, post-treatment psychomotor
function tests showed the addition of grapefruit only with midazolam
significantly increased only digit symbol substitution [DSS] impairment
compared to water (PO in human study). On the other hand erythromycin use led
to greater impairment in both DSS and letter substitution than water or
grapefruit, and much higher plasma values of midazolam, whereas grapefruit led
to only slightly higher plasma midazolam values than water. The single oral
dose of grapefruit juice therefore had no important interactions with either doses
of midazolam or triazolam in healthy young subjects.2697
Another benzodiazepine drup increased after
grapefruit juice consumption is diazepam.1333
+ 16) A dose of 200 ml of juce 3 times daily for
2.3 days, followed by two more doses after consuming buspirone, led to a
4.3-fold increase in peak plasma concentration and a 9.2-fold increase in
bioavailability compared to water in the randomized, crossover design, along
with an increase in subjective drug activity among the 10 subjects (PO in human
study).2052
+ 17)
Compaed to water, after 3 doses daily of 200 ml of juice in 10 healthy subjects
for 2.3 days followed by a cisapride dose and 2 more juice doses, the
peak drug concentration and its bioavailability were increased by 81 % and
144%, respectively (PO in human study). The time of peak concentration and
elimination half-life were also delayed, though no differences in QTc interval
could be found by ECG.2053 After a single 250 ml dose of juice in 12
healthy men, the peak cisapride concentration and bioavailability were
increased168% and 151%, respectively, but the time for maximum concentration
and the apparent elimination half-life was not affected (PO in human study).1731
+ 18)
Ineffective results with clomipramine in children and adolescents with
obsessive-compulsive disorder and excessive CYP3A demethylation led to use of
250 ml grapefruit juice with each dose of the drug to lower the ratio of blood levels of metabolite to drug (PO
in case studies). While this combination was effective in raising trough levels
of clomipramine and reducing the ratio, the clinical effect was variable,
apparently depending upon individual metabolic differences.2589
+ 19)
Taking 250 ml of grapefruit juice 3 hours before and with a dose of sildenafil
led to increased bioavailability by 23% and somewhat delayed absorption in 24
healthy white males (PO in human study). The maximum plasma concentration was
delayed by 15 minutes on average, but this peak plasma concentration was not
increased. Even though grapefruit juice used concurrently will not usually
increase the risk of sildenafil adverse
effects, due to interindividual variability it appears advisable to avoid this
combination.2590
+ 20)
Use of 200 ml grapefruit juice a half hour before and then with a dose of methadone
in 8 patients led to an average 17% increased bioavailability for both
enantiomers of the drug during the next 24 hours (PO in human clinical study).
The peak level increased similarly and the apparent clearance decreased, but no
symptoms of overmedication were detected by clinicians or patients.
Nonetheless, due to variability among patients, grapefruit juice intake is not
recommended with methadone, especially when beginning this treatment.2591
+ 21) Taking 250 ml of grapefruit juice 3 time
daily for 5 days and then with sertraline on day 6 led to significant
increases in average peak concentration and bioavailability of the drug (PO in
humans study).2592
+ 22)
While one 300 ml glass of grapefruit juice significantly reduced nonmetabolized
single-dose talinolol bioavailability, peak concentration, and urinary
excretion 56-57% in 24 healthy subjects, 900 ml/day for 6 days also reduced
these parameters 44-65% (PO in human study). MDR1 RNA and P-glycoprotein levels
in duodenal biopsies of 3 subjects showed no changes, and 3 MDR1 genotypes did
not alter the pharmacokinetics.2619
+ 23) The juice consumed by 11 subjects at a dose of 200 ml increased dextromethorphan bioavailability both by inhibiting intestinal CYP 3A and affecting an intestinal transport protein (PO in human study).2666
III. + 1) grapefruit juice increased the efflux of
P-glycoprotein substrates losartan and vinblastine from kidney
cells, thus speeding their elimination from these cells (in vitro),1036
but inhibited the P-glycoprotein efflux of digoxin,2029
saquinavir and vinblastine from colon
and/or intestinal cells, thus enhancing their retention (in vitro).1029,1030,2026
The inhibition of vinblastine efflux from colon
cells was due to furanocoumarins including dihydroxybergamottin, begamottin,
bergaptol, and bergapten (in vitro). Of these furanocoumarins, only
bergaptol did not also inhibit human liver CYP3A4 (in vitro).1358
P-glycoprotein efflux of vincristine, rhodamine-123, and fexofenadine
was also inhibited by an ethyl acetate extract of grapefruit juice (in vitro)1627,2026
and its components dihydroxybergamottin and begamottin (in vitro). This
resulted in a 3-fold increase of vincristine in some leukemia cells (in
vitro).1627
+ 2) The conversion of testosterone to 6beta-hydroxytestosterone by CYP 3A activity was inhibited by fresh-squeezed juice and a juice extract with no naringin, but was not inhibited by a solution of naringin of the same concentration as it occurs in the fresh juice (in vitro)1450
+ 3)
The OATP transporter protein substrates estrone and glibenclamide
have reduced uptake in kidney cells via OATP-B in the presence of 5% grapefruit
juice and at 10 mM concentrations of several of its flavonoids and furanocoumarins (in
vitro).1922
IV. + [1) The consumption of grapefruit seeds extracts as an
antimicrobial agent for 3 days was associated with an incidence of increased
INR in 2 patients stabilized on warfarin, one of whom experienced a
subcutaneous hematoma (PO in human case reports). When this product and 2 other
European “grapefruit seed extract” products were compared to an actual seed
extract for content and CYP influence, none of the 3 were found to contain seed
components, but all yielded the undeclared synthetic preservative benzethonium
chloride. The 3 commercial “extract” products and benzethonium chloride all
were shown to inhibit CYP 2C9 (in vitro), thus accounting for the
increased INR values associated with probable inhibition of warfarin
metabolism.2225]
Benzethonium chloride was identified in both liquid
and solid commercial American grapefruit seed extracts.2226 Several
batches of another commercial extract revealed a content of 22% of the
synthetic antimicrobial preservative agent benzalkonium chloride.2227
In another assay of 1 powdered and 8 liquid commercial grapefruit seed
extracts, 4 contained benzethonium chloride and 3 contained benzalkonium
chloride along with smaller amounts of other preservatives including
4-hydroxybenzoic acid esters, benzoic acid, and salicylic acid.2228
The benzalkonium chloride was shown to inhibit CYP 2C9 similar to benzethonium
chloride (in vitro).2225 So, while common adulterants of
grapefruit seed extract likely inhibit warfarin metabolism and increase risk of
hemorrhage, this effect has not been demonstrated for authentic grapefruit seed
extract.]
GUAR GUM p.
113
Cyamopsis tetragonolobus seeds
Drug
Interactions
I. 1) Insulin doses
for 3 of 6 diabetic patients required reduction after using 25 grams of guar
gum daily for 5-7 days lowered urinary glucose excretion (PO in human clinical study)730
Also, in 3 subjects with type 1 diabetes 16 grams of
guar gum plus 10 grams of pectin reduced the rise in blood glucose between 1-2
hours after the test meal. Likewise, in and 8 subjects with type 2 diabetes
blood glucsose decreased after 30-90 minutes and insulin levels were reduced
from 30-120 minutes (PO in human clinical study).958
A hot water extract of the
seeds and green fruit was also hypoglycemic at 20 mg/kg in normal subjects as
well as at 40 mg/kg in diabetic subjects that were resistant to tolubutamide,
indicating a extra-pancreatic action for the guar (PO in rabbits).957
2) Guar gum may inhibit
absorption of oral drugs
such as aspirin, digitalis
and other cardiac glycosides, antibiotics, and anticoagulants
if administered concurrently (speculative).150
+ 7) When 10 healthy women were given at weekly
intervals glyburide with either 5 grams of guar gum in 200 ml of tap
water or with tap water only, after receiving the guar the effects of glyburide
were increased (PO in human study). The enhanced effects were increases in
serum insulin and C-peptide after 0.75-1.0 hours and decreases in serum glucose
after 0.75-1.5 hours. Hypoglycemic sensations were reported by some subjects
after 3 hours, but these were reversed with sweetened beverages.2148
GUARANA p.
114
Paullinia cupana
seeds
Contraindications
3) Heart disorders
(speculative) due to caffeine increasing heart rate or exacerbating arrhythmias
(empirical).8
Caffeine at a dose of 250 mg acutely increased aortic stiffness in 20 healthy subjects, leading to increased blood pressure centrally and to a lesser extent peripherally (PO in human study). These effects may impact cardiovascular risk (speculative).1569 Guarana extract with 150 mg of caffeine plus black tea extract yielding 120 mg raised systolic blood pressure and resting metabolic rate 2 hours after a single dose in 16 healthy male subjects (PO in human study).1973
However, a study of 155,594
women over 12 years found no linear association with caffeine consumption and
hypertension (PO in human study).1859
6) Pregnancy (speculative)
since caffeine has been associated with fetal loss, low birth weight and
premature deliveries.8
In an evaluation of 2,291 mothers caffeine
consumption was found to reduce average birth weight. This was considered significant
for those who consumed more than 600 mg of caffeine daily (PO in human study).1568
However, a prospective study
of 873 women found no association between caffeine consumption at any amount
and birth weight, gestational age at delivery, or birth weight standardized for
gestational age (PO in human study).1672
Drug Interactions
I. 1) Guarana as a source of 40 mg of caffeine per
tablet containing an herbal mixture including ephedra having 12 mg of ephedrine-like
alkaloids per tablet was shown to promote short-term fat loss and weight loss
when two tablets were taken before meals three times daily (PO in human
clinical trial).1173 8 healthy subjects given a single dose (2
capsules) of a formula with guarana (200 mg caffeine) and ephedra (20 mg alkaloids)
had a significantly increased systolic blood pressure after 90 minutes and
increased heart rate after 6 hours. Though the kinetics of the caffeine and
ephedrine alkaloids were comparable to similar drugs formulations, one subject
with a high urine pH had longer ephedra alkaloid half-lives, and two subjects
on oral contraceptives had longer caffeine half-lives (PO in human study).1356
In a double-blind, randomized, crossover trial 15
healthy subjects were given a single dose of the commercial product Metabolife
356, a proprietary blend of 728 mg that contained 40 mg of guarana seed with
caffeine, 12 mg of ephedra extract, and unspecified amounts of 8 other herbs
and 2 bee products, along with vitamin E, magnesium, zinc, and chromium. After
taking the product subjects had significantly higher systemic blood pressure
and extended QT intervals on their ECGs than after taking placebo. All reported
nonspecific adverse events including jitteriness and queasiness after using the
product but not after taking placebo. There were one case each of tachycardia,
hand tremor and premature ventricular complexes after taking the product (PO in
human study).1610
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interaction was found. Oral
contraceptives prolonged caffeine elimination.1665
+ 12) Methotrexate efficacy for reducing the joint pain and
morning stiffness of rheumatoid arthritis was diminished for those consuming
260 mg of caffeine daily on average, compared to those who consumed an average
of only 90 mg daily (PO in human clinical study), probably due to
methylxanthines like caffeine acting as adenosine receptor antagonists while
methotrexate increases adenosine.1495
GUGGUL NEW
^ Commiphora
mukul gum resin
Contraindications
1) Pregnancy due to its emmenagogue and uterine stimulant effects
(empirical)74,150 and its use as an abortifacient (empirical)74
2)
Nursing mothers (speculative) unless following professional advice, due
to its allergic potential.1890
3) Hyperthyroidism may be adversely affected
(speculative),1890 due to
increase in T3 found with 0.2 gm/kg guggul extract daily for 15 days (PO in
mice).1981
When 750 mg guggul extract daily was given as part of a formula in a
double-blind randomized study on obesity, the serum throid hormone status of
the 3 subjects tested showed no clear trends of change for T3, T4,
or TSH from baseline to week 6, though 2 of 3 had an 8-10% increase in T3
(PO in human clinical study).2109
The antihyperthyroid drug
effect of carbimazole was counteracted by guggulsterones (in chickens).1890
Likewise, the hypothyroid effect of propylthiourasil was counteracted when
guggul extract with 3.8% guggulsterones was given in doses of 200 mg/kg daily
for 14 days (PO in mice). The extract also decreased liver lipid-peroxidation
induced by the drug.2110
4) Caution in coagulation
disorders, due to increase fibrinolytic activity and reduced platelet
adhesiveness associated with its nonpolar fraction (PO in human study).1890
I. 1)
A single dose of 1 gram guggulipid in 10 volunteers in a randomized crossover
study reduced
the bioavailability of single dose of propranolol
and of diltiazem in 7 subjects (PO
in human study). This may result in clinically reduced efficacy or no response for
these CYP 3A4 substrates (speculative).1701 The probable mechanism
of induction of CYP 3A4 is the activation of the pregnane X receptor by
guggulsterone (in vitro).1636 However, it is improbable that
a single dose would immediately induce a CYP isozyme, so binding of the drugs
in the intestinal lumen to reduce absorption seems more likely (speculative).
II.
1) The antihyperthyroid drug
effects of carbimazole
involving decreased iodine uptake were counteracted by guggulsterones (in
chickens).1890
Likewise, the hypothyroid effect of propylthiourasil was counteracted when guggul extract with
3.8% guggulsterones was given in doses of 200 mg/kg daily for 14 days (PO in
mice). The extract also decreased liver lipid-peroxidation induced by the drug.2110
When 750 mg guggul extract daily was given as part of a
formula in a double-blind randomized study on obesity, the serum throid hormone
status of the 3 subjects tested showed no clear trends of change for T3,
T4, or TSH from baseline to week 6, though 2 of 3 had an 8-10%
increase in T3 (PO in human clinical study).2109 In addition 0.2 gm/kg guggul extract
daily for 15 days increased T3 (PO in mice).1981
GURMAR
[now GYMNEMA] p. 117
Gymnema sylvestre leaves
GYMNEMA [formerly GURMAR] p. 117
Ä Gymnema
sylvestre
leaves
Contraindications
+ 1)
Brittle type
1 diabetes (speculative)893
due to reduced insulin requirements in
insulin-dependent diabetics when given 400 mg/day of a water-soluble acidic
fraction of the ethanol extract (PO in human clinical study)357
resulting in part from increased insulin levels (PO in human clinical studies).359
This correlates with the hypoglycemic effect produced by the dried leaf powder
(PO in rabbits and rats).355,356
HAWTHORN p.
118
Crataegus spp.
leaves/flowers/fruit
Drug Interactions
I. 1) Crataegus extract
enhanced cardiac glycoside drug digoxin
in cardiac and coronary insufficiencies (perlingual in human clinical
trial).395
When compared by matched pairs technique to NYHA class II
patients on chemical-synthetic drugs only, those class II using only hawthorn
extract WS 1442 or the extract in addition to cardiac glycosides such as
digoxin had significantly less fatigue, stress dyspnea, and palpitations (PO in
human clinical study). The hawthorn extract cohort required significantly fewer
cardiac glycosides [18% vs. 37%].2238
Concurrent use with cardiac glycosides theoretically
might potentiate their toxicity (speculative).895 In a randomize, double-blind placebo controlled trial
with 120 ampulatory patients 18 years of age or older with NYHA class II-III
chronic heart failure, no symptomatic or functional benefits were found by
adding 900 mg of hawthorn exract WS 1442 daily to standard medications
(angiotensin II receptor blockers, ACE inhibitors, diuretics, beta-blockers, and/or digoxin) for
6 months, though left ventricular ejection fraction was better with the extract
than placebo (PO in human clinical trial). There were not more cardiac adverse
events in the hawthorn group, though there was a significantly greater number
of patients with any adverse events.2669
However, the so-called SPICE
trial, in which 2681 congestive heart failure patients were randomised to
either WS 1442 or placebo, included 56% of subjects taking digitalis and
nitrites, and 22% on antiarrhythmics [mostly amiodarone]. No drug
interaction adverse effects or adjuvant effects were detected (PO in human
clinical study).2493 In a pharmacokinetic test to assess whether
hawthorn flavonoids affect P-glycoprotein and digoxin uptake, no interference
was found during 3 weeks of digoxin use with hawthorn (C. oxyacantha)
leaf and flower extract WS 1442. Also, ECG PR interval, heart rate, and blood
pressure were not affected (PO in human study).1442
+ 2)
Concentrated extract WS 1442 at a daily dose of 1800 mg combined with diuretic
drugs triamterene and hydrochlorothiazide increased exercise
tolerance and reduced adverse effects compared with using the diuretics alone
for NYHA class III heart failure (PO in human clinical study).1303
In a similar study patients with NYHA class II heart failure also increased
exercise tolerance from using the extract LI 132, compared to placebo, while
some were allowed to continue established diuretic therapy unchanged (PO in
human clinical study).1095 When compared by matched pairs technique
to NYHA class II patients on chemcal-synthetic drugs only, those class II using
only hawthorn extract WS 1442 or the extract in addition to cardiac glycosides
such as digoxin had significantly less fatigue, stress dyspnea, and
palpitations (PO in human clinical study). The hawthorn extract cohort used
significantly fewer cardiac glycosides [18% vs. 37%], as well as significantly
less ACE-inhibitors [36% vs. 54%], beta-blockers [22% vs. 33%],
and diuretics [49% vs. 61%].2238
HOWEVER,
the so-called SPICE trial, in which 2681 congestive heart failure patients were
randomised to either WS 1442 or placebo, included 85% of subjects taking
diuretics [39% spironolactone]
and 83% receiving ACE-inhibitors, as well as 64% of subjects taking
beta-blockers, 56% of subjects taking digitalis and nitrites, and 22% on
antiarrhythmics, but no adjuvant effects were detected (PO in human clinical
study).2493 Also, in a randomize, double-blind placebo controlled
trial with 120 ampulatory patients 18 years of age or older with NYHA class
II-III chronic heart failure, no symptomatic or functional benefits were found
by adding 900 mg of hawthorn exract WS 1442 daily to standard medications
(angiotensin II receptor blockers, ACE inhibitors, diuretics, beta-blockers, and/or digoxin) for
6 months, though left ventricular ejection fraction was better with the extract
than placebo (PO in human clinical trial). There were not more cardiac adverse
events in the hawthorn group, though there was a significantly greater number
of patients with any adverse events.2669
3) [Formerly III.2).] May have additive effects with
antihypertensives (speculative)777
Of hypertensive diabetics taking antihypertensive
medications, the 39 given 1.2 grams daily of the 3:1 hawthorn flower extract LI
132 twice daily, of which 19 used ACE inhibitors, 10 took diuretics, 6 were on beta-blockers,
and 8 consumed calcium channel blockers, had a significant reduction in
mean diastolic blood pressure compared to 40 patients on placebo using these
drugs in equivalent proportion (PO in human clinical study). No adverse
herb-drug reactions were found.2239 When compared by matched pairs
technique to NYHA class II patients on chemical-synthetic drugs only, those
class II using hawthorn extract WS 1442 required significantly fewer
beta-blockers [22% vs. 33%] (PO in human
clinical study).2238
However, the so-called SPICE
trial, in which 2681 congestive heart failure patients were randomised to
either WS 1442 or placebo, included 64% of subjects taking beta-blockers [about
one half carvedilol and almost one third metoprolol] as well as
85% on diuretics, 83% receiving ACE-inhibitors, 56% of subjects taking
digitalis and nitrites, and 22% on antiarrhythmics. No drug interactions were
detected (PO in human clinical study).2493
III. + 3) Additive effects with the coronary
vasodilators theophylline, caffeine, papaverine, sodium nitrate, adenosine,
epinephrine (in vitro)156
IV. + [1) sedative activity of hawthorn was presumed on the basis of
its oligomeric procyanidins increasing sleep induced by hexobarbital (IP
in mice).1102 This supposed
observed sedative hypnotic effect suggested that hawthorn may potentiate CNS
depressant effects of anesthetic agents such as barbiturates, benzodiazepines
and opioids (speculative).1103 However, the pain induced by
intraperitoneal injection or injection of nonsedative tannins results in
similar sedated behavior as observed for phenolic fractions of hawthorn. This
modified behavior can be abolished by simultaneous administration of aspirin
for relief of the consequent pain (IP in mice).1104]
HENNA NEW
^ Lawsonia
inermis leaves
(alcanna, Egyptian privet, Jamaica mignonette, migonette
tree, reseda)
Contraindications
1) Pregnancy due to its internal use as an abortifacient (empirical)150
2) Internal use (speculative)150
probably due to most henna products being combinations intended for external
use only as hair coloring agents (speculative).
However, 2-week before and
during exposure by procarcinogens, use of 200 mg and 400 mg doses of an 80%
ethanolic extract of the fresh leaf led to increase in antioxidant and phase II
metabolic enzymes and reduction in LDH and of skin and forestomach tumors
induced by procarcinogens (topically and PO in mice). When used alone, these
internal doses did not cause any visible changes attributed to liver, lung or
kidney toxicity or alteration in liver phase I enzyme activity.1960
HOPS p.
119
(Humulus lupulus) strobiles
Contraindications
+ 3)
Nursing mothers should not use hops without professional advice, since
the infant may experience a sedating effect (speculative).1890
Drug Interactions
I. 3) Prepared as a 5:1 45% methanolic valerian
extract in combination with a 6:1 hops extract, 2 and 6 tablets of this mixture
reduced or inhibited, respectively, the stimulant effect of a single 200 mg
dose of caffeine (PO in human study)1658
II. 1) Sedative activity of a hop extract (100-500 mg/kg)
dose-dependently increases the sleeping time induced by the barbiturate drug pentobarbital (IP
in mice).57
This dose-dependent effect was confirmed with a CO2
extract and with the alpha-acid fraction of this extract, each beginning at a
dose of 10 mg/kg (PO in rats).2198
+ 2)
Increased sleeping time with the narcotic ketamine was induced by hops
extracts and fractions at different doses depending on the component contents
(PO in mice). The full CO2 extract from a “Perle” variety harvested
in 1999 was effective at 200 mg/kg, whereas when this extract was enriched by
about 1/3 with the pure oil the effective dose was 100 mg/kg. Equivalent doses
for this extract’s oil fraction with small amounts of bitter acids was 50
mg/kg, while the pure oil required 100 mg/kg. The equivalent doses of humulone
fraction with alpha-bitter acids andlupulone fraction with beta-bitter acids
were 25 and 200 mg/kg, respectively. A soft resin fraction was inactive, but a
combination of the hop oil and alpha- and beta-bitter acid fractions was
similar to the oil-enriched CO2 extract.2197
To test whether the combination effects were due to
an impact on ketamine metabolism pharmacokinetics, increases in sleeping time
with ether by the “Perle 99” CO2 extract, the pure oil, and
the lupulone showed the results were due instead to pharmacodynamic sedative
effects (PO in mice).2197
III. + 2) The beta-acid lupulone and xanthohumol
enhanced the antibacterial activity of polymyxin B, tobramycin, and ciprofloxacin
against all Gram-positive and some Gram-negative bacteria tested (in vitro).2274
HORSE CHESTNUT p.
120
*Aesculus
hippocastanum bark or seeds
Contraindications
+ 3)
Kidney insufficiency or liver dysfunction due to inadequate
clearance of escin (speculative)1371
+ 4)
Children due to the potential for toxicity, based on 2 cases of renal
failure in children and 2 cases of tubulonephrosis in adults following escin
therapy (speculative)1370
+ 5)
Pregnancy or with nursing mothers without professional advice
(speculative), reportedly due to lack of fetal weight gain when very high doses
of extract were given (PO in rabbits).1890
Drug Interactions
III. + 2) Hypoglycemic drugs
such as sulfonylureas, insulin or metformin may have an additive effect
with horse chestnut seed extract (speculative)1370 since 200 mg/kg
has hypoglycemic effects in a glucose tolerance test and 100 mg/kg of escins
Ia, Ib, IIa, and IIb have significant hypoglycemic activity (PO in rats)338
+ 3)
Protein-bound drugs1370,1371 such as phenytoin, warfarin
or amiodarone (speculative)1370 since escin binds to plasma
protein (speculative)1371
HORSERADISH p.
120
Armoracia rusticana
= Cochlearia armoracia fresh root
Contraindications
+ 1) Stomach
ulcers or intestinal ulcers (empirical)
6,17,401,777 or stomach inflammation due to the membrane
irritating effect on the mucosa150
HORSETAIL p.
121
*Equisetum spp.
plant
Contraindications
+ 4)
The species E. hyemale in pregnancy (empirical)150
IBOGA p.
122
*Tabernanthe iboga
root bark
Drug
Interactions
I. 1) Acute decreases in intravenous self-administered morphine
intake were dose-dependent (2.5-80 mg/kg) with the iboga alkaloids ibogaine,
tabernanthine, R-coronaridine, R-ibogamine, and desethylcoronaridine and lasted
for at least a day, and for several days for some alkaloids, especially
R-ibogamine (IP in rats). Tremors
induced by ibogaine and other alkaloids were inconsequential with
R-coronaridine and R-ibogamine, both of which also decreased dopamine in the
striatum and nucleus accumbaens (NA).1126 An alkaloidal analogue of
ibogaine, 18-methoxycoronaridine, reduced IV morphine self-administration and
attenuated signs of opioid withdrawal with no apparent toxicity (IV in rats).
This compound is a potent antagonist at 3a4beta nicotinic receptors.1459
Decreased dopamine in the striatum, NA, and frontal
cortex and decreased serotonin in the striatum followed 40 mg/kg ibogaine (IP
in rats).1127 This dose reduced morphine stimulatory effects1127
and signs of morphine withdrawal (IP in rats).1128 The reduced
morphine-induced locomotor stimulation was greater when there had been prior
morphine exposure (in rats).1129 Ibogaine is an agonist for the mu
opioid receptor (in vitro).1130
Noribogaine, an ibogaine metabolite, also reduces
dopamine levels, morphine self-administration, and morphine’s locomotor
stimulant effect but did not induce tremors (in rats).1131
II. + 1)
Acute decreases in intravenous self-administered cocaine intake were
dose-dependent (2.5-80 mg/kg) with the iboga alkaloids ibogaine, tabernanthine,
R-coronaridine, R-ibogamine, and desethylcoronaridine and lasted for at least a
day, and for several days for some alkaloids, especially R-ibogamine which also
decreased dopamine in the striatum and nucleus accumbaens (IP in rats).1126
An alkaloidal analogue of ibogaine, 18-methoxycoronaridine, reduced IV cocaine,
methamphetamine, and nicotine self-administration with no apparent toxicity (IV
in rats). This compound is a potent antagonist at 3alpha4beta nicotinic
receptors.1459 In addition to decreased dopamine in the striatum and
frontal cortex, decreased serotonin in the striatum followed 50 mg/kg ibogaine
(IP in rats).1132 Ibogaine blocks cocaine-induced serotonin transmission
which is modulated by kappa-opiod receptors; serotonin transmission in turn
modulates dopamine release (in vitro).1133 Administration of
40 mg/kg of ibogaine once or twice reduced self-administered cocaine
consumption for at least 2-5 days (IP in mice and rats).1134,1135 A
greater reduction of cocaine intake followed administration of 40 mg/kg
ibogaine once weekly for 3 weeks (IP in rats).1135
Noribogaine, an ibogaine metabolite, also reduces
dopamine levels and cocaine self-administration but did not induce tremors (in
rats).1131
Ibogaine involves 5-hydroxytryptamine(2) agonist
activity (in rats)1136 and improves memory retrieval (in rats) that
may be of importance in combating addictions (speculative).1137
Purkinje cell degeneration in the cerebellum from a toxic dose of 100 mg/kg
ibogaine does not occur with therapeutic doses of 40 mg/kg (in rats) and so is
not responsible for anti-addictive effects.1138
+ 2)
Ibogaine at single doses of 10, 30, or 60 mg/kg reduced alcohol (ethanol)
intake (IP in rats), as did subchronic dosing with 60 mg/kg (PO in rats),
though it was ineffective subcutaneously.1139 Ibogaine has
N-methyl-D-aspartate (NMDA) antagonistic actions (in vitro) associated
with attenuation of multiple addictions.1140 An alkaloidal analogue
of ibogaine, 18-methoxycoronaridine, reduced oral alcohol self-administration
with no apparent toxicity (IV in rats). This compound is a potent antagonist at
3alpha4beta nicotinic receptors.1459
+ 3)
Ibogaine increases brain levels of amphetamine when given prior to the
drug, possibly due to a hepatic drug-drug interaction (IP in rats).1471
Pretreatment with ibogaine increases the stimulatory motor effects of
amphetamine at various doses of the drug (IP in rats).1472 Locomotor stimulation by
amphetamine was decreased by 40 mg/kg ibogaine given 18 hours prior, likely due
to its decrease in striatal dopamine levels that are increased by amphetamine
(IP in mice). The interspecies differences were confirmed when the same dose
and timing of ibogaine again resulted in a further increase in locomotor
stimulation from amphetamine (IP in rats).1551
INMORTAL NEW
^ Asclepias
asperula = Asclepias capricornu root
Contraindications
1) Pregnancy (empirical)150
due to its emmenagogue, oxytocic, and abortifacient effects (empirical)75
IPECAC p.
123
*Cephaelis
ipecacuanha root/rhizome
Contraindications
2) Petroleum
distillate poisoning777 due to aspirational pneumonitis
(empirical)2
[CORRECTION] though the risk appears less with emesis
than with gastric lavage, especially if emesis is done under medical
supervision (empirical)150
6) Extended use as an emetic for over 3-4 days
[CORRECTION: not PROLONGED USE for more than a month] can produce dehydration
and severe electrolyte imbalances, and muscular cramping (empirical)150
12) Drowsiness or
reduced conciousness (empirical)2
or sedation due to risk of aspiration of stomach contents (empirical)150
+ 14)
Hiatal hernia, esophageal varices, stomach ulcer or peptic ulcer
due to aggravation and/or potential hemorrhage from emetic effect if bloodroot
is taken in excessive doses (speculative)150
+ 15)
High blood pressure150 due to the muscular exertion produced
by inducing vomiting with ipecac (speculation)
Drug Interactions
III. + 1) Do not take large doses after recent
consumption of central nervous system stimulants, due to the emetic
action potentially inducing convulsions (speculative).150
+ 2)
Do not take large doses after recent consumption of central nervous system sedatives,
due to the emetic action potentially inducing aspiration pneumonitis
(speculative).150
JAMAICA DOGWOOD p. 124
*Piscidia erythrina
= Piscidia piscipula bark
Contraindications
+ 3)
Avoid in pregnancy (speculative), due to fetal malformation or
irreversible damage from its rotenone content (PO in rats).1890
+ 4)
Do not use in bradycardia (low heart rate) or cardiac insufficiency
(speculative), due to rotenone impairing heart contractile force and lowering
blood pressure (in animals).1890
+ 5)
Avoid use by nursing mothers without professional advice, due to
potential toxicity for infant (speculative).1890
Drug Interactions
III. 1) Do not use concurrently with powerful analgesics
(speculative), due to potential additive effects.1890
JOB’S TEARS NEW
^ Coix
lacryma-jobi seeds
(Ch.: yi yi ren)
Contraindications
1) Pregnancy (empirical)150 due to uterine stimulant
component palmitic acid as shown in lab studies74
JUJUBE SEEDS NEW
^ Ziziphus
spinosa seeds
(Ch.: suan zao ren)
Contraindications
1) Pregnancy due to its
emmenagogue and uterine stimulant effects (empirical)150
KAVA p.
125
*Piper methysticum root and rhizomes
(kava pepper, kawa pepper, maori kava; S. Pacific: ava,
gea, gi, kao, kawa, kew, malohu, maluk, meruk, milik, sakau, tonga, yagona,
yangona, yaqona, yongona; Ger.: kawapfeffer, wurzelstock)
[FOR MORE INFORMATION ON
KAVA, KAVALACTONES (PYRONES), AND POTENTIAL ADVERSE EFFECTS ON THE LIVER, SEE www.eclecticherb.com/kava]
Contraindications
3) Do not use in endogenous
depression to avoid potentiating
suicidal tendencies (speculative).6,17,401,777
However, an aqueous extract of peeled roots was shown to acutely decrease scores on a depression rating scale after 1 week, while also reducing scores on 2 anxiety assessments in a placebo-controlled crossover study (PO in human clinical study).2575 With professional supervision, its use may be considered in this condition with caution (speculative).1890
4) Avoid operating a motor vehicle following excessive use due to impaired driving
ability (PO in news reports).244,728
A study of kava drinkers compared 11 who had
consumed kava beverage in the previous 24 hours made on average from 205 grams
of powder to a group of 17 who had not drank the beverage for at least one
week. The intoxicated group was found to have ataxia, tremors, sedation, eyelid
spasm, and elevated GGT and ALP liver enzymes. They also had problems
performing complex visual search tasks, but complex cognitive functions were
normal. Saccade impairment indicates disrupted GABAerbic and cerebellar
functions (PO in human study).1480
5) Regular prolonged use is suspected of
contributing to the risk of adverse effects on the liver. One proposal is to
limit daily use to no more than four weeks (speculative).1232
+ 6)
Parkinson’s disease due to its aggravation by the dopamine antagonist
properties of kavalactone-containing extract (PO in human case report) 316
and since concentrated kava concentrated extracts including WS1490 led to
involuntary muscle movements in three people as bingeing on its traditional
water extract did in another (PO in human case reports).316,1149
Another case of sudden, severe, and persistent Parkinsonism associated with 65
mg/day kava concentrated extract for 10 days appeared related to a genetic
predisposition due to the presence of essential tremor in other family members
(PO in human case report).1264
+ 7)
Consumption of kava products should be avoided in individuals with jaundice
or past liver disorders (speculative). A total of 24 cases of liver
toxicity associated with kavalactone-concentrated extracts have been reported
in Germany, including five in Switzerland. In 18 cases drugs with known or
potential liver toxicity were also used.1232 A review of
pre-clinical hepatotoxicity studies on kava and the 19 suspected German cases
revealed that in only one was a probable causal relationship established.1476
In hepatotoxicity cases after kavalactone extract use, one patient has died and
three required liver transplants. No association with liver damage has been
reported in South Pacific islands where consumption of kava as a beverage is an
important aspect of the traditional culture.1232 An aqueous extract
of peeled roots was shown to acutely decrease scores on anxiety assessments in
a placebo-controlled crossover study with no clinical signs of hepatotoxicity
in 37 subjects (PO in human clinical study).2575
However, a critical analysis
of 26 reported hepatotoxicity cases associated with kava ethanolic and acetonic
extracts concluded that the clinical patterns indicated idiosyncratic reactions
of the metabolic type, rather than predictable hepatotoxicity (PO in human case
series).2327 Another possible cause of liver damage associated with
use of concentrated kava preparation is an immunologically mediated
idiosyncratic mechanism (speculative).1445,1607
Consumption of 3-4 capsules daily for two months of
an acetone extract standardized to total kavalactones (WS1490 with 70 mg
lactones per capsule) led to fulminant toxic hepatitis that required a liver
transplant in a person who had not previously taken drugs or consumed alcohol
(PO in human case report). Three capsules daily is the maximum recommended dose
for this product.1150 One patient used the maximum recommended dose
of WS1490 for three weeks followed by consumption of 60 grams of alcohol,
resulting in acute toxic hepatitis. Use of the concentrated extract was
stopped, and liver enzyme levels returned to normal within 8 weeks.
T-lymphocyte reactivity to the extract suggested an immune-mediated reaction.
In addition, like 9% of the local Swiss population, the patient showed poor
metabolism by cytochrome P450 (CYP) 2D6 (PO in human case study).1211
German medical literature also reports overuse of an
ethanolic concentrated extract of kava standardized to 120 mg total kava
lactones (intake 480 mg lactones/day for over a year) was the probable cause of
toxic hepatitis in another woman who required a liver transplant (PO in human
case report).1159 Use of an ethanolic extract with 60 mg total kava
lactones consumed daily induced hepatitis in a woman who had previously
experienced acute hepatitis with elevated GPT while using the extract, but she
recovered fully within four months when the kava extract was withdrawn (PO in
human case report).1151 At high concentrations of 50 mcg/ml and
above both acetonic and methanolic extracts of the dried root with 81.4-81.6%
kavalactones, respectively, showed lactate dehydrogenase (LDH) leakage from
hepatocytes after only 1.0-5.5 hours of exposure (in vitro).2222
However, estimates of
hepatocyte exposure to extract concentration from normal dosing is only about
2-10 mcg/g tissue (speculation).2222 Also, giving an ethanolic root
extract with 47.4% kavalactones at a dose of 73 mg/kg kavalactones daily
for 3-6 months
produced no signs of liver toxicity (PO in rats).1957 Piperidine
alkaloids present in the basal stem peelings, including pipermethystine, may be
hepatotoxic based on cytotoxicity demonstrated in hepatic cells unaffected by
several kavalactones (in vitro). These peelings were formerly waste
products but may have been used prior to hepatoxicity cases in manufacturing
extracts.1500,1787
Two women in their 50s from Oceania consuming kava
tea prepared from the dried root (one used 4 cups daily with approximately 18
grams of kavalactones/week) developed jaundice after 4-5 weeks. They had highly
elevated levels of transaminases and total bilirubin. They did not consume
alcohol, were negative for acute viral hepatitis, and were not poor CYP 2D6
metabolizers. Symptoms and lab results returned to normal after 3 months of
eliminating kava tea consumption. The
assessment was possible kava allergenic idiosyncrasy (PO in human case
reports). Further assessment of regular heavy kava tea consumers (about 32
grams of kavalactones/week) found most had elevated GGT and dry skin but no
liver disease. Four who reduced their kava consumption had normal skin and GGT
levels after one month (PO in human study).1445
However, on the island of
Pohnpei it is estimated that the dose of kavalactones per sitting (drinking
about 8 cups over 5 hours) was 2.4 grams, with no obvious liver damage
occurring as a result (PO in field study).1499 With abusive kava tea
consumption equivalent to using an average of 310-440 grams of dried root
weekly for years, only gamma-glutamyl transferase (GGT) plasma enzyme levels
indicative of liver damage were greatly elevated in an Australian aborigine
population (PO in human study). Prior to this group being introduced to using
the water extract of kava, they had previously abused alcohol.1160
Water extracts given at daily doses of 200 or 500 mg/kg for 2 or 4 weeks failed
to cause elevations of 3 enzymes (ALT, ALP, LDH) that indicate liver damage,
but instead reduced these enzyme levels. Malondialdehyde levels were increased
but not significantly, when compared to placebo (in rats).1528
Inhibition of CYP isozymes 1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11 by kava extract, largely involving inhibition of CYP 2C9, 2C19, 2D6, and 3A4 by the kavalactones desmethoxyyangonin, dihydromethysticin. and methysticin but not kavain (in vitro), may contribute to increased circulating levels of hepatotoxins when cultivars such as “tudei” that are high in these two kavalactones are used (speculative).1327 The tudei cultivar is traditionally only used in mixtures, due to its potent effect that causes intoxication for “two days." HPLC assays on lots of the commercial acetonic extract from the period of 1999/2000 reveal that the kavalactone profile of one of the three lots tested was “a typical ‘tudey’ quality, a ‘no-drink’ kava type.”2286 Also, extracts made with acetone, ethanol or methanol inhibit CYPs 1A2, 2C9, 2C19, and 3A4 much more than a water extract (in vitro).1733
Another studied confirmed kavalactone inhibition of
CYP 3A4 (in vitro).1475 Metabolites of kavalactones do not appear to have
enhanced toxicity, since cells transfected with human CYP 1A1,1A2, 2A6, 2E1,
and 3A4 and epoxide hydrolase were not more affected than cells without these
enzymes when exposed to dried kava root ethanolic extract or the kavalactones
methysticin, yangonin, and desmethoxyyangonin (in vitro).1643
However, 6-phenylhexenone (6-PHO),
a highly reactive metabolite of kavain and dihydrokavain has been identified in
the urine of 2 subjects given dried kava root (PO in human study). Such
metabolites are not necessarily hepatotoxic themselves and usually require an
adjuvant. This 6-PHO may also be formed during the processing of the root
(speculative). 1781
Pipermethystine, an alkaloid present in the formerly
discarded basal stem peelings, may be hepatotoxic based on cytotoxicity
demonstrated in hepatic cells that were unaffected by several kavalactones (in
vitro).1787 A methanolic extract of the leaves with 1.34%
pipermethystine was shown in concentrations as low as 10 mcg/ml to increase the
concentration of oxidized glutathione and decrease the ratio of reduced to
oxidized glutathione in hepatic cells, while methanolic and acetonic extracts
of the roots did not do so even at concentrations up to 150 mcg/ml (in vitro).
The pipermethistine content of the root extracts was around 0.01%.2222
Piperidine alkaloids
including pipermethystine are present in the basal stem peelings. These
peelings were formerly waste products but may have been used prior to
hepatoxicity cases in manufacturing extracts.1500,1787
A combination product with 60 mg kavalactones along
with 50 mg Passiflora incarnata and 100 mg Scutellaria lateriflora
taken three times daily was associated with acute liver failure and death in a
56-year-old Australian woman (PO in human case report). While analysis
confirmed the kava and passionflower content, the Scutellaria (skullcap)
ingredient could not be identified. Rather, a third unknown component was
detected.1513
However, hepatotoxicity has
been reported in a number of cases where patients in Great Britain supposedly
used products containing skullcap that may have been misidentified (PO in human
case reports).1514 Some wholesale suppliers in Great Britain had
provided Teucrium species in place of skullcap.1515 Teucrium
chaemaedrys (germander) has been shown to cause hepatotoxicity in at least
seven instances in France (PO in human case reports)1516 and two in
Canada (PO in human case reports),1517 in addition to a case of
fatal hepatitis (PO in human case report).1518 The American Scutellariea
lateriflora is sometimes known as “blue skullcap” to distinguish it from “pink
skullcap,” the American species Teucrium canadense (wild germander).
This spurious skullcap Teucrium spp. may responsible for some cases of
hepatitis based on misidentification as Scutellaria, due to similar
common names of American “skullcap” species.1519 Teucrium and
Scutellaria spp. can be readily distinguished based on their HPLC
phytochemical profiles.1520
8) at least 24 hours and possibly one week prior
to surgery (speculative)1309,1310 due to the potential for
interaction with intra- and postoperative medications (speculative)1310
including the sedative effects of anesthetics (speculative)1309,1715
Drug Interactions
I. 2) Alprazolam, a
benzodiazepine, may have been enhanced by the use of a kava product (human case
report).137
This report has been described as unevaluable based
upon report inadequacies.1239
However, the man in
the case report was taking cimetidine along with the alprazolam,137
and cimetidine is a known CYP3A4 inhibitor of alprazolam metabolism,2501
while kava does not inhibit CYP3A4 metabolism of midazolam (PO in human
studies).1807,2501
Also,
concurrent use of kava extract with 240 mg kavalactones daily and bromazepam
at 9 mg/day reportedly did not cause adverse effects on mental performance
and well-being more than the benzodiazepine alone (PO in human study).1890
Kavalactone-concentrated
extract WS 1490, gradually increased from 50 mg to 300 mg over one week as
benzodiazepine doses were tapered off over two weeks, was given as a
monotherapy for three weeks to 40 non-psychotic anxiety patients. Following the
pretreatment with alprazolam or lorazepam, bromazepam or oxazepam, WS 1490
efficacy was better than placebo and tolerance was as good (PO in human
clinical study).1212
Inhibition of cytochrome P450 (CYP) isozyme 3A4 by kava
extract involving the kavalactones desmethoxyyangonin, dihydromethysticin, and
methysticin (in vitro) may contribute to increased circulating levels of
benzodiazepines (speculative).1327
However,
in human hepatocytes kava
was shown to induce CYP 3A4 mRNA via pregnane X receptor (in vitro).1696
3) Sedation, cogntion, co-ordination, and intoxication increased when kava was taken with alcohol (PO in human study).1025
Kava products should be avoided in individuals who
consume alcohol on a regular basis (speculative).1232 It is also recommended that
alcohol should be avoided with long-term kava beverage intake, especially in
high doses, to minimize the risk of hepatic damage (speculative).2140
With abusive kava tea consumption equivalent to
using an average of 310-440 grams of dried root weekly for years,
gamma-glutamyl transferase plasma enzyme levels indicative of liver damage were
greatly elevated in an Australian aborigine population (PO in human study).
However, prior to this group being introduced to beverage kava, they had
previously abused alcohol.1160
One patient used the maximum recommended dose of the
kavalactone-concentrated extract WS1490 for three weeks with no incident. Two
months later another three-week course of WS1490 use was followed by
consumption of 60 grams of alcohol, resulting in acute toxic hepatitis. Use of
the concentrated extract was stopped, and liver enzyme levels returned to
normal within 8 weeks (PO in human case study).1211
+ 4)
1 gram root extract twice daily for 28 days inhibited metabolism of the CYP2E1
substrate chlorzoxazone by 40%, but not substrates for CYP 1A2, 2D6 or
3A4 (PO in human study).1807 Kava root preparations and its various
isolated kavalactones 1733 have been shown to be in vitro inhibitors
of CYP 1A2, 2C9, 2C19, 2D6, and 3A4 substrate metabolism,1327,1475,1577
but 2E1 was unaffected.1327
II. 1) Extract and lactones increased sleeping time from pentobarbital
(in mice).510
Inhibition of cytochrome P450 isozyme 2C9 by kava extract
involving the kavalactones desmethoxyyangonin, dihydromethysticin, and
methysticin (in vitro) may contribute to increased circulating levels of
barbiturates in general (speculative).1327
+ 3)
Hypermotility induced by amphetamine was reduced by both kava resin and
a lactone-free aqueous fraction of kava extract (IP in mice)1152
III. 1) Psychopharmacological agents such as sedatives may be enhanced by the extract (speculative),6,17,401
Prolonged sedation may result when combined with
intra- and postoperative medications (speculative)1310,1715
including the sedative effects of anesthetics (speculative)1309,1715
and anesthetic induction drugs like benzodiazepines or opioids
(speculative)1715
2) Kavalactone products equivalent to those
associated with adverse effects on the liver should be avoided in individuals
taking any liver-toxic drugs (speculative). A total of 24 cases of liver
toxicity associated with kavalactone-concentrated extracts have been reported
in Germany and 5 in Switzerland. In 18 cases drugs with known or potential
liver toxicity were also used. No association with liver damage has been
reported in South Pacific islands where consumption of kava as a beverage is an
important aspect of the traditional culture.1232
However, a critical analysis
of 26 reported hepatotoxicity cases associated with kava ethanolic and acetonic
extracts concluded that the clinical patterns indicated idiosyncratic reactions
of the metabolic type, rather than predictable hepatotoxicity (PO in human case
series).2327
One patient used the maximum recommended dose of
WS1490 for three weeks followed by consumption of 60 grams of alcohol,
resulting in acute toxic hepatitis. Use of the concentrated extract was
stopped, and liver enzyme levels returned to normal within 8 weeks.
T-lymphocyte reactivity to the extract suggested an immune-mediated reaction.
In addition, the patient showed poor metabolism by cytochrome P450 2D6 (PO in
human case study).1211
Two women in their 50s from Oceania consuming kava
tea prepared from the dried root (one used about 18 grams of kavalactones/week)
developed jaundice after 4-5 weeks. They had highly elevated levels of
transaminases and total bilirubin. One woman had taken phenobarbital,
lisinopril, and fenofibrate for months or years which she then discontinued.
They did not consume alcohol, were not poor CYP 2D6 metabolizers, and returned
to normal after 3 months of eliminating kava tea consumption. The 3 drugs were
restarted without incident. The
assessment was possible kava allergenic idiosyncrasy (PO in human case
reports). Further assessment of regular heavy kava tea consumers (about 32
grams of kavalactones/week) found most had elevated GGT and dry skin but no
liver disease. Four who reduced their kava consumption had normal skin and GGT
levels after one month (PO in human study).1445 It is recommended
that medications with hepatotoxic potential should be avoided with long-term
kava beverage intake in high doses to minimize the risk of hepatic damage
(speculative), even though elevated GGT is the only associated significant lab
deviation from normal (PO in human study).2140
Co-medication with kava preparations and other herbs
and/or synthetic drugs is considered a risk factor for hepatotoxicity
(speculative).2594 A 14-year-old female developed hepatic failure
and required a liver transplant after using a combination product with 100 mg
kava extract, 100 mg chamomile (Matricaria chamomilla) extract, and 50
mg St. John’s wort (Hypericum perforatum) extract twice daily for 4
months, as well as ibuprofen (PO in human case report). She developed nausea
and vomiting for 8 days prior to becoming jaundiced. When he was admitted to
the hospital 2 days later, she had elevated bilirubin and transaminases, and 8
days later her excised liver showed fulminant hepatitis with total hepatocyte
necrosis. Her recovery was complete after liver transplant.2595
In addition, a combination product with 60 mg
kavalactones along with 50 mg Passiflora incarnata and 100 mg Scutellaria
lateriflora taken three times daily was associated with acute liver failure
and death in a 56-year-old Australian woman (PO in human case report). While
analysis confirmed the kava and passionflower content, the Scutellaria
(skullcap) ingredient could not be identified. Rather, a third unknown
component was detected.1513 Hepatotoxicity has been reported in
a number of cases where patients in Great Britain supposedly used products
containing skullcap that may have been misidentified (PO in human case
reports).1514 Some wholesale suppliers in Great Britain had provided
Teucrium species in place of skullcap.1515 Teucrium
chaemaedrys (germander) has been shown to cause hepatotoxicity in at least
seven instances in France (PO in human case reports)1516 and two in
Canada (PO in human case reports),1517 in addition to a case of
fatal hepatitis (PO in human case report).1518 The American Scutellariea
lateriflora is sometimes known as “blue skullcap” to distinguish it from
“pink skullcap,” the American species Teucrium canadense (wild
germander). This spurious skullcap Teucrium spp. may responsible for
some cases of hepatitis based on misidentification as Scutellaria, due
to similar common names of American “skullcap” species.1519 Teucrium
spp and Scutellaria spp can be readily distinguished based on their
HPLC phytochemical profiles.1520
Giving an ethanolic root extract with 47.4%
kavalactones at a dose of 73 mg/kg kavalactones daily for 3-6 months produced
no signs of liver toxicity (PO in rats).1957 Pipermethystine, an
alkaloid present in the formerly discarded basal stem peelings, may be
hepatotoxic based on cytotoxicity demonstrated in hepatic cells that were
unaffected by several kavalactones (in vitro).1787 6-phenylhexenone (6-PHO), a
highly reactive metabolite of kavain and dihydrokavain has been identified in
the urine of 2 subjects given dried kava root (PO in human study). This 6-PHO
may also be formed during the processing of the root (speculative).1781
However, such metabolites
are not necessarily hepatotoxic themselves and usually require an adjuvant.1781
Inhibition of cytochrome P450 (CYP) isozymes 1A2,
2C9, 2C19, 2D6, 3A4, and 4A9/11 by kava extract (in vitro) largely
involved inhibition of CYP 2C9, 2C19, 2D6, and 3A4 by the kavalactones desmethoxyyangonin,
dihydromethysticin. and methysticin but not kavain. This may contribute to
increased circulating levels of hepatotoxins when cultivars such as “tudei”
that are high in these two kavalactones are used (speculative).1327
Another studied confirmed kavalactone inhibition of CYP 3A4 (in vitro).1475
On the other hand, in human hepatocytes kava was shown to induce CYP 3A4 mRNA
via pregnane X receptor (in vitro).1696 Inhibition in-vitro
isozyme studies are notoriously unreliable when compaired to results from human
studies, especially for CYP3A4.
+ 3)
the kavalactone kavain relaxes arterial constrictions caused by phenylephrine
due to its inhibition of calcium channels in the smooth muscles (in vitro)1527
KHELLA p.
128
*Ammi visnaga
fruit
Contraindications
2) Ultraviolet
light or solarium therapy due to photosensitization (empirical)10
KONJAC p.
128
Amorphophallus konjac tuber
Drug
Interactions
I. 2) Diabetics given 3.6-7.2 grams of konjac mannan had insulin or hypoglycemic drugs reduced or withdrawn (PO in human clinical
study)729
In 22 diabetic subjects using insulin (1) or glinbenclamide
(13), metformin (15), glipizide (7), or acarbose (1) as
single and/or combination oral hypoglycemic drugs, 4.5 grams daily of konjac
powder with 80% glucomannan for 28 days lowered fasting glucose and blood lipid
levels including plasma cholesterol, LDL-cholesterol, total/HDL cholesterol
ratio and apolipotrotein B (PO in human clinical study). Without taking
lipid-lowering medication, they also had increased fecal concentrations of
neutral sterol and bile acids. Triglycerides, HDL-cholesterol, and postprandial
glucose were not changed.1666
KUDZU p.
129
Pueraria
lobata root
Drug
Interactions
I. 1) Physicians used kudzu root to treat alcohol abusers; 80%
no longer experienced alcohol craving
(empirical).546
In a placebo-controlled double-blind crossover trial
14 heavy beer drinkers (11 males) given 1 gram three times daily for a week of
kudzu extract with 19% puerarin, 4% daidzin and 2% daidzein significantly
reduced beer intake during a 1.5 hour session (PO in human study). The total
volume and the size of each sip decreased.1726
However, when 2.4 grams of
an uncharacterized kudzu extract was given in a double-blind study of 38
alcoholic patients there appeared to be no reduction in alcohol craving or
sobriety for those who received the extract (PO in human clinical study).1491
An isoflavone from kudzu, puerarin, decreases
alcohol consumption when given chronically, gradually producing greater
suppression of alcohol intake (PO in animals).1470 Puerarin
increased locomotor activity and social interaction that were otherwise reduced by withdrawal
from 7% alcohol used in the diet for 17 days, similar to flumazenil. Puerarin
showed other anxiolytic effects consistent with it being a weak benzodiazepine
site antagonist (IP in rats).1460
II. + 1)
The simulataneous administration of the decoction at 2 gm/kg and higher with
the chemotherapy and antirheumatic drug methotrexate led to its
increased bioavailability and increase in mortality (PO in rats). This may be
due to its interference with multi-drug resistant proteins or organic anion
transporter proteins (speculative).2269
KUTAKI NEW
Ä Picrorhiza kurroa root
(picrorhiza; Ind.: kutki, katuka)
Contraindications
1) Due to the emmenogogue and
abortifacient effects (empirical),74 picrorrhiza should be avoided
in large amounts in pregnancy
Drug Interactions
II. 1) The ethanol extract at 80 mg/kg for 15 days protected
against myocardial infarction induced by isoproterenol (PO in rats).1214
2) The ethanol extract at 100 mg/kg for 10 days
protected against stomach ulceration induced by a mixture of hydrochloric
acid (HCl) and ethanol (PO in rats).1213
3) The freeze-dried methanolic extract
given at 20 mg/kg for 3 days reduced ulcer indices by 45% in ulcerations
induced by indomethacin, compared to no treatment (PO in mice). After 3
days the extract reduced levels of thiobarbituric acid reactive substances by
33% and increased mucin by 42%, epidermal growth factor by 149%, mucosal PGE2
by 21%, and COX-1 and –2 expression by 27% and 19%, respectively.2276
LAVENDER [now ENGLISH LAVENDER] p.
129
Lavandula angustifolia =
Lavandula officinalis = Lavandula vera flowers
LEMONGRASS p.
130
Cymbopogon citratus plant
Contraindications
+ 3)
Pregnancy due to its emmenagogue and/or uterine stimulant effects
(empirical)150
LESSER PERIWINKLE [formerly PERIWINKLE] p. 161
Ä Vinca minor plant
LICORICE p.
131
+ *
Glycyrrhiza
glabra or Glycyrrhiza uralensis root/rhizome
(G. uralensis =
Chinese licorice; Ch: gan cao)
Contraindications
1) High blood pressure344,401 due to hypertension caused by
its overuse (PO in human case report)1379,2578
Increase in blood pressure after 1 week from 500
mg/day of glycyrrhizic acid is greatest in salt-sensitive individuals (PO in
human study)1667
Eating 100 grams of licorice candy daily led to
increased systolic blood pressure in a normotensive population of 30 subjects
(PO in human study). The 13 women had increased systolic and diastolic blood
pressure after consuming only 50 grams of licorice daily.2120
2) Low blood
potassium4,150,401 due
to diminished serum potassium associated with over-consumption of licorice (PO
in human case reports) 1379,2578
Eating 100 grams of licorice candy daily led to
decreased plasma potassium in 30 subjects (PO in human study).2120
Eating 250-500 grams of licorice candy daily for
several years led to hypokalemia with ventricular fibrillation and hypertension
(PO in human case report).2578
Eating 750 grams/day for 2 weeks led to progressive
tetraparesis, flaccid paresis in all limbs, with a massive hypokalemia of 1.13
mmol/L in a 54-year-old woman who had just stopped smoking (PO in human case
report).2279
3) Prolonged
use150 for more than
4-6 weeks due to resulting hypertension, hypokalemia, and edema (empirical)4,6
A woman with a history of chronic hypokalemia
developed a 5-month progressive weakness of her neck, so holding up her head
became difficult. Supplementing potassium raised her serum level and gradually
improved her condition. She had used to Chinese herbal medications containing
licorice for over 10 years, and potassium levels did not normalize until the
licorice ingestion was discontinued. Potassium supplementation was stopped, and
full neck extension was regained in about 2 months (PO in human case report).1468
4) Pregnancy2,4,6,17,401
Women consuming more than 500 mg of glycyrrhizin per week
were more likely to give birth earlier (PO in human study),1163
though not necessarily (PO in human study).2616 This heavy
glycerrhizin exposure is associated with preterm (<37 weeks gestation) and
especially early preterm (<34 weeks) delivery (PO in human study).1385
The inhibition of placental 11-beta-hydroxysteroid
dehydrogenase by glycerrhizin following dose-related consumption of licorice in
pregnancy in amounts >500 mg/week causes significant diminishment of
verbal and visuospatial skills and narrative memory in the children by age 8
years (PO in human study). Also, these children show significant increases in
problems with attention, aggression, and rule-breaking, apprarently due to
overexposure to glucocorticoids in the womb.2616
5) Chronic
hepatitis (empirical)6,401
However, limited success is
claimed in treating chronic hepatitis B with a combination therapy involving
glycyrrhizin withdrawal and interferon-beta (PO in human clinical study)1989
and in preventing liver carcinogenesis in those with chronic hepatitis C with
glycyrrhizin combined with cysteine and glycine (IV in human clinical study).1990
Those 72 of 115 chronic hepatitis C patients receiving 40 mg glycyrrhizin in
the combination therapy 6 times weekly for 4 weeks that showed ALT lowering
continued on an additional 22 weeks to see if results were sustained at
different dosing frequencies (IV in human clinical study). 60% of those who had
continued the 6 times weekly injections maintained lower ALT, compared to only
24% and 9% of those who had 3 times and once weekly injections, respectively.
Those treated for 26 weeks had improvement of the physical functioning scale of
the quality of life assessment and higher overall scores compared to those who
stopped at 4 weeks.2121
10) men with decreased
libido or other sexual dysfunction since
licorice extract given to 7 men in doses containing 0.5 gram glycyrrhizin
significantly reduced serum testosterone (PO in human study).888
However, a follow-up study
repeating the same daily 0.5 gram dose of glycyrrhizin with 20 men found the
salivary testosterone reduction to be an insignificant 9.5%. Using another
source of licorice but the same glycyrrhizin dose again in 11 men and 10 women
showed the salivary testosterone was not decreased significantly in either,
though the salivary cortisol increased significantly in both (PO in human
study).1261
+ 11)
Nursing mothers (speculative)150 due to potential influence
of hormone metabolism in infant (speculative)
Drug Interactions
I. 4) Licorice extract given to men at 7 grams daily (0.5 gram glycyrrhizin) reduced their serum testosterone (PO in human study).888
Licorice root extract at 3.1 or 6.3 gm/kg or glycyrrhizin
at 240 or 480 mg/kg significantly induced the activity of 5-6 types of
testosterone hydroxylase (PO in mice).1630,1650
7) Additive increase of potassium loss can occur even
with small amounts when taken along with laxatives
(human case report).541
Myoclonus due to metabolic alkalosis occured with an
antacid powder with licorice was used with sennoside (PO in human case
report).1690
II. + 4)
Glycyrrhizin inhibits the metabolic conversion of dexamethasone (PO in
rats). This is likely due to its inhibition of the catalytic enzyme 11b-hydroxysteroid
dehydrogenase.983
+ 5)
Enhanced metabolis breakdown of S-warfarin was induced by 500 mg/kg of
an aqueous extract equivalent to 3 gm/kg dried root (PO in rats) evidently
through activation of pregnane X receptor as shown by an ethanolic extract of G.
uralensis (in vitro).1926
III. + 3) [Prior III. 3) added to I. 2).] Glycyrrhizin inhibited Herpes varicella-zoster virus replication in an additive or synergistic manner with anti-herpes drugs acyclovir, adenine arabinoside, bromovinyldeoxyuridine, phosphonoformate, and beta-interferon (in vitro).1826
+ 4)
Avoid use with antihypertensives due
to antagonism (speculative),777 due to hypertension caused by its
overuse (PO in human case reports)215,275,344,401,573,1379 and the
sodium and fluid retention caused by its saponin glycyrrhizin, also called
glycyrrhizic acid.4,6,150 Increase in blood pressure after 1 week
from 500mg/day of glycyrrhizic acid is greatest in salt-sensitive individuals
(PO in human study).1667
+ 5)
Hepatotoxicity induced by clinically relevant micromolar concentrations of azathioprine,
as indicated by reduced cell viability and GSH depletion, was reduced by an
aqueous extract of licorice and its component glycyrrhizic acid (in vitro).1953
LIFE ROOT p.
136
*Senecio aureus plant
Contraindications
5) Avoid internal
use, since pyrrolizidine alkaloid content (speculative),2
including senecionine,24,333 can lead to fatality (PO in human case
report).144
The pyrrolizidine alkaloid senecionine from Senecio
jabobaea has been shown to be both bioactivated to its toxic form and
detoxified to its N-oxide form by cytochrome P450 isozyme 3A4 (in vitro).1183
LINDEN
FLOWER NEW
^ Tilia
cordata flowers
(lime blossom, tilia)
Contraindications
1) Avoid in allergic hypersensitivity for those
rare individuals who are reactive to this plant (empirical).1890
Drug Interactions
I. 1) The absorption of iron was reduced by 52% when an
infusion of 3 grams in 300 ml was given concurrently with ferric chloride (PO in
human study). This was likely due to the content of monomeric flavonoids in the
preparation that bind iron in the gut lumen.1246
LOBELIA p.
136
*Lobelia inflata
plant or seeds
Contraindications
+ 12)
Hiatal hernia, esophageal varices, stomach ulcer or peptic ulcer due
to aggravation and/or potential hemorrhage from emetic effect if bloodroot is
taken in excessive doses (speculative)150
Drug Interactions
II. + 1)
Lobeline alkaloid reduces hyperactivity due to amphetamine, while it
inhibits this and drug discrimination and self-administration of methamphetamine
(in rats). Lobeline reduces amphetamine-induced relase of dopamine (in vitro),
while lacking its own addiction liability from self-adminstration (in rats).1602
III. + 1) Do not take large doses after recent
consumption of central nervous system stimulants, due to the emetic
action potentially inducing convulsions (speculative).150
+ 2)
Do not take large doses after recent consumption of central nervous system sedatives,
due to the emetic action potentially inducing aspiration pneumonitis
(speculative).150
LOMATIUM NEW
^ Lomatium
dissectum root
(Indian balsam, cough root, lace-leaved leptotaenia; Am.
Ind: doza (Washoe), toh-sah-ah (Paiute), toh-sup (Shoshone) )
Contraindications
1) Pregnancy (speculative)150
possibly due to the uterine relaxant effects of its coumarin component
columbianin (in vitro) or the toxic effects of its oil fraction (IP and
SC in mice)3
2) Due to content of potentially phototoxic
furocoumarins3 and skin rash that can occur with internal use,150
ultraviolet light and solarium therapy should be avoided
(speculative)
LONG PEPPER p.
138
Piper longum
fruit
Drug Interactions
A single 20 mg dose of piperine in 2 groups of 10 men
receiving 300 mg or 400 mg daily of phenytoin increase mean plasma drug
concentration and bioavailability (PO in human study).1943
+ 4)
Piperine dose of 20 mg increased serum concentrations of curcumin after
0.25-1.0 hours and increased bioavailability by 2000% (PO in human study).1533
II. + 5)
Increased anti-nociceptive and anti-inflammatory activity from nimesulide
was achieved when 100 mg was combined with 60 mg piperine from long pepper (PO
in mice). This was apparently due to reduced metabolic breakdown of nimesulide.1821
+ 6)
Decreased absorption and anti-inflammatory effect of diclofenac sodium
was observed when it was combined with the trikatu combination of long pepper,
black pepper and ginger (PO in rabbits and rats).2003 Since the drug
was mixed with the herbs in solution prior to administration, the interaction
may have been chemical in nature, rather than biological (speculative).
+ 7)
Reduced absorption, peak concentration, and bioavailability of isoniazid
resulted for 4 hours when it was given together with 500 mg/kg trikatu, a 1:1:1
mixture of dried fruits of black pepper, long pepper and dried rhizomes of
ginger providing 10 mg/kg of the alkaloid piperine (PO in rabbits). This may be
due to a decrease in gastric emptying time (speculative).2005
+ 8)
Increased absorption and peak concentration of indomethicin after 4
hours was achieved when it was given together with 500 mg/kg trikatu, a 1:1:1
mixture of dried fruits of black pepper, long pepper and dried rhizomes of
ginger (PO in rabbits). The pharmacokinetic effect may have been due to an
increased GI blood flow (speculative), but was not due to change in
indomethicin metabolism.2004
LYCIUM NEW
^ Lycium
barbarum, Lycium chinense berry and root bark
(matrimony vine, wolfberry; Ch.: gou
qi zi (berry), di gu pi (root bark) )
Contraindications
1) Pregnancy (empirical)150 due to its abortifacient
activity and the emmenagogue effect associated with the fruit (empirical)74
MACA NEW
^ Lepidium meyenii root
(Peruvian ginseng)
Drug Interactions
I. 1) In a randomized double-blind dose-finding 12-week trial
involving 14 women and 2 men with sexual dysfunction resulting from use of SSRIs
[selective serotonin re-uptake inhibitors: escitalopram, citalopram,
sertraline, venlafaxine, fluoxetine, paroxetine, duloxetine, or
fluvoxamine] to treat depression, 9 taking 3 gr/day of maca had increased
sexual function scores, whereas the 7 on 1.5 gr/day did not (PO in human
clinical trial). The 16 in both dosing groups combined showed an increase
scores for libido.2486
MAITAKE p.
140
Grifola
frondosa
mushroom fruiting bodies
Drug
Interactions
I. + 1)
Six type II diabetes mellitus patients using the oral hypoglycemic
agents glyburide, glipizide, or metformin further lowered
their fasting blood glucose 30-63% after 2-4 weeks by taking 500 mg of whole
maitake mushroom powder in caplets three time daily in an open-label trial
(PO in human clinical
trial)1609
III. + 1)
Maitake beta-glucan fraction potentiates the cytotoxicity of carmustine
(BCNU) against prostate cancer cells, apparently by enhancing inhibition
of the detoxifying enzyme glyoxalase I (in vitro)1511
MAKANDI p.
141
Coleus forskohlii root
Drug Interactions
III. 1) An additive effect could occur with epinephrine
and/or theophylline (speculative), since these drugs are like forskohlin
in that it has positive inotropic action (in vitro),1991,1992
increases heart rate (in vitro), and induces vasodilation
(intraarterially in dogs). Yet, unlike epinephrine, forskohlin has neither
direct nor indirect sympathomimetic activity (in vitro, IV in dogs), nor
does it block phosphodiesterase significantly (in vitro) like
theophylline.1991
2) Disruption of predictable effects from digoxin
could occur (speculative), since it shares positive inotropic activity with
forskohlin, but the effect on potassium-sodium-ATPase is different. In
addition, forskohlin increases heart rate (in vitro, IV in dogs), while
digoxin reduces it.1991
MANGOSTEEN NEW
^ Garcinia
mangostana stem bark
Drug Interactions
III. 1) The component a-mangostin is synergistic with gentamicin
for inhibiting vancomycin resistant Enterococci and with vancomycin
for inhibiting methicillin resistant Staphylococcus aureus (in vitro).
The a-mangostin
inhibits 5 strains of the resistant Enterococci and 9 strains of the
resistant S. aureus (in vitro).1771
MARIJUANA [now CANNABIS.] p.
142
Cannabis sativa leaves and
tops
MARJORAM [now SWEET MARJORAM] p. 143
Majorana
hortensis leaves
MARSHMALLOW p. 143
Althaea officinalis
root
Drug
Interactions
I. 1) Giving 20 drops of an extract from 40 mg of marshmallow
3 times daily for 4 weeks reduced the incidence of coughs induced by ACE
inhibitors compared to placebo in a group of 60 hypertensives (PO in human
clinical study).2273
II. 1) Aqueous extract of roots potentiates andi-inflammatory
activity of dexamethasone when skin is exposed to tetrahydofurfurylic
alcohol or ultraviolet radition (topically in rabbits)1258
MATE p.
144
Ilex paraguayensis
leaves
Contraindications
3) Heart disorders
(speculative) due to caffeine increasing heart rate or exacerbating arrhythmias
(empirical).8
Caffeine at a dose of 250 mg acutely increased aortic
stiffness in 20 healthy subjects, leading to increased blood pressure centrally
and to a lesser extent peripherally (PO in human study). These effects may
impact cardiovascular risk (speculative).1569 However, a study of
155,594 women over 12 years found no linear association with caffeine
consumption and hypertension (PO in human study).1859
6) Pregnancy (speculative)
since caffeine has been associated with fetal loss, low birth weight and
premature deliveries.8
In an evaluation of 2,291 mothers caffeine
consumption was found to reduce average birth weight. This was considered
significant for those who consumed more than 600 mg of caffeine daily (PO in
human study).1568
However, a prospective study
of 873 women found no association between caffeine consumption at any amount
and birth weight, gestational age at delivery, or birth weight standardized for
gestational age (PO in human study).1672 In addition, though those
consuming mate daily during the entire pregnancy appeared to have a 30%
increase in the risk of small for gestational age births, after controlling for
confounders there was no significant association of this risk with daily mate
drinking (PO in human study).1827
+ 8)
Daily use of very hot mate tea and/or consumption of one liter or more
daily leads to a 2 to 3-fold increased risk of developing esophageal cancer (PO
in human study)1443
Drug Interactions
I. 1) Increased
weight loss due to a reduction of body fat as well as side effects of
agitation, tremors, and insomnia when caffeine is combined with ephedrine (PO in human clinical study)19
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interaction was found. Oral
contraceptives prolonged caffeine elimination.1665
In tests using various anti-obesity herbs including
mate, guarana, tea, and ephedra, only mate extract reduced the respiratory
quotient, indicative of a rise in fat oxidation (PO in human study)1423
+ 12)
Methotrexate efficacy for reducing the joint pain and morning stiffness
of rheumatoid arthritis was diminished for those consuming 260 mg of caffeine
daily on average, compared to those who consumed an average of only 90 mg daily
(PO in human clinical study), probably due to methylxanthines like caffeine
acting as adenosine receptor antagonists while methotrexate increases
adenosine.1495
+ 13)
Consumption of 330 ml of infusions made with 16.5 g green or 6.6 g roasted mate
3 times daily for 40 days significantly enhanced the reduction of LDL
cholesterol by statins (simvastatin, atorvastatin, lovastatin) 10%
after 20 days and 13.1% after 40 days in 30 hypercholesterolemic subjects (PO
in human clinical study). Significant LDL-cholesterol reductions without
statins after 40 days were 8.7% for 15 normolipemics and 8.6% for 57
dyslipemics.2605
MAYAPPLE [now PODOPHYLLUM] p. 147
MEADOWSWEET p.
148
Filipendula ulmaria
= Spiraea ulmaria flowers
Contraindications
2) Avoid in pregnancy (speculative), due to
aqueous infusion increasing force and tone of uterine muscle from animals (in
vitro) and also because of fetal toxicity from 400mg/kg salicylaldehyde (SC
in pregnant rats), though this dose exceeds normal therapeutic use. Do not use
during pregnancy without professional advice.1890
3) Do not use in constipation (speculative), due
to its high tannin content that has an astringent effect on fluid secretions in
bowels (empirical).1890
4) Avoid in iron-deficiency anemia and malnutrition
(speculative), due to its tannin content that can reduce absorption
(empirical).1890
Drug Interactions
I. 1) Do not take concurrently with iron or other metal
ion supplements, with thiamine, or with alkaloid medications, due
to the tannin content than can bind these compounds (empirical). There should be
at least a 2-hour separation between their consumption.1890
MILK
THISTLE p.
149
Silybum marianum seeds
Contraindications
+ 1)
Avoid in pregnancy (speculative)2
due to the emmenagogue effect of its seeds and root (empirical).74
However, the milk thistle
seed extract silymarin was safely used as a dose of 210 mg three times daily by
6 women with cholestasis of pregnancy for 15
days (PO in human clinical study).190
+ 2)
A woman in Australia who suffered nausea, vomiting, colicky pain, diarrhea,
weakness and collapse over a two-month period while using a commercial milk
thistle preparation. She recovered completely after she stopped taking the
product, but suffered a violent reaction a few weeks later after taking another
capsule (PO in human case report). This resembled one other report of a woman
who had nausea, abdominal pains, listlessness, and insomnia after taking a milk
thistle product. These were considered probable idiosyncratic reactions.752
They may be due to allergic hypersensitivity (speculative).
Drug Interactions
I. 2) Silymarin given to alcohol
cirrhosis patients reduced the mortality rate compared to controls (PO in human
clinical studies)495,1256 and use following ethanol liver damage helps normalize lab indices for transaminases
(human clinical studies).119,1257
+ 4) Given with tacrine, 420 mg/day of silymarin reduced the gastrointestinal and cholinergic side effects of the drug compared with placebo, without interfering with tacrine’s effect on cognitive performance (PO in human clinical study)1260
+ 5) When used concurrently
with insulin in alcoholic cirrhotis patients with noninsulin-dependent
diabetes mellitus, 600 mg silymarin daily for 4 months significantly decreased
fasting and mean glucose levels, daily glucosuria and glucosinated hemoglobin
levels, fasting insulin and average insulin requirements. The control group had
increased fasting insulin and stable insulin requirements (PO in human clinical
study).1438
+ 6) After 800 mg silymarin was given with methotrexate and 6-mercaptopurine chemotherapy, liver aminotransferase levels normalized in 34-year-old woman with promyelocytic leukemia with no therapy interruptions and no reported adverse effects. During prior 18-month period of chemotherapy, treatment course had been interrupted repeatedly by dose modifications for hepatotoxicity.1795 The reduction of hepatotoxicity appears to be due to antioxidant and free radical scavenging properties1123 and includes replenishing mitochondrial glutathione (in vitro).1124
Silymarin abolishes the enhanced hepatotoxicity of
CYP 2E1 substrate methotrexate after the toxicity is increased 2 to 3 times by
2E1 inducers acetaminophen and ethanol, respectively (in vitro).1124
Silymarin seemed to induce carbon tetrachloride metabolism by CYP 2E1 in one
study (in vitro).1082
However, an uncharacterized
milk thistle product failed to alter metabolism of 2E1 substrate chlorzoxazone
in 12 subjects after 4 weeks (PO in human study).1589 Another study
found no evidence of an interaction of silymarin or silybin with CYP 2E1
substrates carbon tetrachloride, acetaminophen, or NDMA (in vitro).1123
While CYP 2E1 hydroxylation of p-nitrophenol
was inhibited by silybin, silydianin, and silychristin at 10 mcm concentrations
or greater (in vitro), this was not considered therapeutically relevant
because concentrations of these flavonolignans in the body do not exceed 0.5
mcm.1398
+ 7)
When tested with Pgp and CYP 2C9/3A4 substrate metronidazole in 12
healthy subjects, 140 mg silymarin daily for 9 days increased drug substrate
clearance, while reducing the half-life, bioavailability, and urinary excretion
of the drug and its active metabolite (PO in human study).1948
However, when given to treat
giardia infections alone or with 3.5 mg/kg silymarin once daily, the drug was
at least as effective with silymarin after 7-14 days but side effects were less
(PO in dogs). With silymarin, metronidazole did not cause poor appetite or
vomiting and the body weight was not reduced, compared to the drug alone. Also,
serum GOT, GPT, and ammonia were increased while total protein, albumin, and
the number of red and white blood cells were decreased with the drug alone but
not the combination.2267
In spite of silymarin inhibiting Pgp efflux of substrates daunomycin, doxorubicin, digoxin, and vinblastine in vitro,1562,1837 Pgp induction is the probable cause, since silymarin does not modulate CYP 3A4 in humans1374,1431,1718,1589 and has an inhibitory effect on CYP 2C9 in vitro.1297 The Pgp substrate digoxin in 16 healthy humans together with 440 mg silymarin in 900 mg standardized extract daily for 14 days did not significantly alter the drug bioavailability, but there was a tendency toward reducing digoxin levels, suggesting potential Pgp induction.1806
+ 8)
Silymarin 200 mg tablets given 3 times daily to 25 type II diabetic patients
taking the oral hypoglycemic drugs metformin and glibenclamide
significantly decreased glycosylated hemoglobin, fasting blood sugar, total
cholesterol, LDL, triglycerides, and SGOT and SGPT levels, compared to 26 type
II diabetics taking the drugs with a placebo (PO in human clinical study).2041
+ 9) A standardized extract with
phosphatidylcholine in 240 mg capsules with 80 mg of silibinin or placebo was
given to 50 children with acute lymphoblastic leukemia for 28 days,, at doses
of silibinin ranging from 80 mg to 320 mg daily based on weight and concurrent
with the chemotherapy drugs dexamethasone,
6-mercaptopurine, methotrexate, prednisone,
thioguanine, vincristine; the liver toxicity from the drugs with the
extract had lower levels of aminotransferases that was significant for AST and
trending lower for ALT after 56 days compared to placebo (PO in human clinical
study). [When the capsules were independently measured there weight was 282 mg
with 97 mg silibinin.]2650
+ 10)
In a study with 59 b-thalassemia major patients
treated with the iron chelator desferrioxamine,
29 who also received 140 mg of silymarin t.i.d. for 3 months had lower liver
alkaline phosphatase and higher red blood cell glutathione levels than those
who received placebo (PO in human clinical study). There was no significant
difference between transferrin levels in the 2 groups.2702
II. 2)
Prevention by silybin of hepatotoxicity from acetaminophen was associated with protection from glutathione
depletion and lipid peroxidation (IV in rats).117
Exposing kidney cells to silybin before or after acetaminophen (paracetamol) prevented or lessened cell damage (in vitro).1621
4) Silybin helps prevent kidney damage from the nephrotoxic anti-tumor agent cisplatin when given at doses of 200 mg/kg (IV in rats)186,187 Exposing kidney cells to silybin before or after cisplatin prevented or lessened cell damage (in vitro).1621
The use of silybin proved synergistic at 1.0 mcM with
cisplatin in human ovarian cancer cells and cisplatin-resistant ovarian cancer
cells (in vitro) 1619,1620 and at 100 mcM in
estrogen-dependent MCF-7 and estrogen–independent MDA-MB468 breast cancer cells
with either cisplatin or carboplatin (in vitro).1796 This anti-tumor enhancement trend with human
ovarian cancer cells was similar when using a silybin phospholipid complex IdB 1016
(silipide) at 450 mg/kg for 4 days with cisplatin. The derivative silipide was
found to be antiangiogenic when given by itself (PO in mice).1620
5) Silybin protects the exocrine secretions of the
pancreas from the toxicity of cyclosporin
A (IP in rats).496
This is probably not associated with reducing
bioavailability due to induction of P-glycoprotein or CYP 3A4, since in two
separate studies, milk thistle extract was given at doses of 153 mg or 173 mg
silymarin 3 times daily for 2 or 3 weeks, respectively, did not inhibit 3A4
metabolism of substrate indinavir which is a substrate of both P-glycoprotein
and CYP 3A4 (PO in human trial),1374,1431 and an uncharacterized
milk thistle product failed to alter bioavailability of 3A4 substrate midazolam
after 4 weeks (PO in human study).1589
+ 6)
Milk thistle seed infusion reduces liver damage from methoxsalen when
given 24 hours and 2 hours before the drug, as indicated by SGOT serum levels
(PO in mice)1334
+ 7)
Silybin suppresses human non-small-cell lung cancer xenographs in mice and
enhances doxorubicin effects against this carcinomoma, while reducing
this drug’s adverse effects (PO in mice). Both decreased cell proliferation and
vasculature and increased apoptosis, while further enhancing these effects when
combined (in vivo, in vitro). These effects involved NFkB signaling.1835
Silybin at 0.1 mcM proved synergistic with doxorubicin in doxorubicin-resistant
breast cancer cells (in vitro) 1619 and at 100 mcM in
estrogen-dependent MCF-7 and estrogen–independent MDA-MB468 breast cancer cells
sensitive to doxorubicin (in vitro).1796 In addition, silybin
at 100 mcM synergized with doxorubicin to induce apoptosis and inhibit prostate
cancer cell growth for hormone-insensitive cells and inhibit growth in
androgen-dependent human prostate cancer cells (in vitro).1834
Silymarin was found to inhibit P-glycoprotein removal of the chemotherapeutic
agent doxorubicin from breast cancer cell lines (in vitro).1562
Silymarin and its flavonolignan components, especially silydianin, protected
rat heart muscle cells from doxorubicin-induced damage (in vitro).1836
III. + 1)
Silymarin inhibits P-glycoprotein removal of daunomycin in breast cancer
cell lines (in vitro).1562
+ 2)
While metabolism of erythromycin by CYP 3A4 was not siginificantly inhibited by
silybin, 3A4 oxidation of denitronifedipine was clearly inhibited in a
mostly non-competitive fashion (in vitro).1297 The conversion
of testosterone by CYP 3A4 was also inhbited by silymarin (in vitro).1293
While 3A4 oxidation of
nifedipine was inhibited by silybin, silydianin, and silychristin at 10
mcm concentrations or greater (in vitro), this was not considered
therapeutically relevant because concentrations of these flavonolignans in the
plasma do not exceed 0.5 mcm.1398 Iron-binding activity of silybin (in
vitro)1761 may be responsible for isozyme inhibition in vitro.1639
+ 3) S(-)-warfarin 7-hydroxilation by CYP 2C9 was competitively inhibited by silybin (in vitro)1297
+ 4)
Exposing kidney cells to silybin before or after vincristine prevented
or lessened cell damage (in vitro).1621
+ 5)
Silymarin with the toxic antiarrhythmic agent amiodarone increased the
splenocyte proliferation, compared to amiodarone alone reducing it (in vitro).
The conjugated dienes in liver tissue raised by amiodarone were lowered when
silymarin was combined with the drug (in vitro).1817 Since
silymarin does not attenuate the antiarrhythmic cardiac effect of amiodarone
after daily use for 4 weeks (PO in mice), the combination may be useful to
ameliorate its toxicity.1818
MUIRAPUAMA NEW
^ Ptychopetalum olacoides roots
Drug Interactions
II. 1) Hydroalcoholic extract at 200 mg/kg potentiated the
lethal effects of yohimbine (IP in
mice).1116
2) Hydroalcoholic extract at 50 mg/kg reversed the ptosis
induced by reserpine (IP in mice).1116
3) Hydroalcoholic extract at 60 mg/kg attenuated the
stereotypy induced by apomorphine
(IP in mice).1116
MUSTARD p.
151
Brassica alba, Brassica juncea and Brassica
nigra (sometimes Sinapis spp.) seed
[CORRECTION] (white mustard, Chinese mustard and black
mustard, RESPECTIVELY)
MYRRH p. 152
Commiphora myrrha,
Commiphora molmol gum-resin
Contraindications
3) Arterial excitement, since large doses can
accelerate the pulse (empirical).5
However, 4 mg/kg of an
aqueous extract reportedly reduced the heart rate by 14% in anesthetized
subjects (IV in rats). Likewise, the systemic arterial blood pressure was
acutely lowered by 20%. Both effects were blocked by atropine, indicative of a
cholinergic mechanism.1890
+ 6)
Allergic hypersensitivity, since contact allergy has been reported (TP
in humans)1890
+ 7) Nursing mothers
without professional advice (speculative).1890
+ 8)
Prolonged use (speculative), due to reported increase in contact allergy
with continued exposure in atopic subjects (TP in human study).1890
NARD NEW
^ Nardostachys
jatamansi roots/rhizome
(spikenard, jatamansi)
Contraindications
1) Pregnancy due to its emmenagogue and uterine stimulant effects
(empirical)150
Drug Interactions
II. 1) Its component valeranone prolongs sleep induced by 100
mg/kg of the barbiturate hexobarbital
(PO in animals).1061
NEEM NEW
^ Azadirachta indica leaves
Drug Interactions
2) Pretreatment with 2.5 or 24 mg/kg aqueous extracts of the bark or
leaves, respectively, reduced gastric lesions induced by indomethacin by
75-85% (IP in rats). This is due in part to free-radical scavenging by the
extracts preventing oxidative damage to gastric mucous membrane and to their
antisecretory effects by which gastric acid secretion was reduced by 50% at
2.0-2.7 mg/kg for the bark extract and 3.7 mg/kg for the leaf extract (IP in
rats).2518,2519 The extracts not only prevented mucosal DNA damage (in
vitro),2518,2519 but the bark extract also blocked
indomethacin-induced apoptosis of gastric mucosa by inhibiting the decrease in
cytochrome-c release and caspase-3 activation. 2521 Freeze-dried
powder of the bark aqueous extract at 30 mg twice daily for 10 days decreased
gastric acid secretion by 77%, and at 30-60 mg twice daily healed cases of
esophageal and gastric ulcers after 6 weeks and almost completely healed 6
cases of duodenal ulcers after 10 weeks (PO in human clinical study).2520
NONI
NEW
^ Morinda citrifolia fruit
Drug Interactions
II. + 1) Precipitates collected after adding ethanol to the juice, when given with suboptimal doses of adriamycin, cisplatin, 5-fluorouracil, or vincristine for Lewis lung peritoneal carcinomatosis, increased the number of survivors and life span significantly (IP in mice).1758
NUTMEG p.
153
*Myristica fragrans seeds
Drug Interactions
III. + 2)
Alkaline aqueous extracts of nutmeg were shown to potentiate insulin
activity in glucose metabolism (in vitro).1464
OAT p.
154
Avena sativa fresh
plant/seeds or bran
Drug Interactions
I. + 3)
Consumption of 50-100 grams daily of oat bran by two patients taking lovastatin
resulted in elevated LDL that decreased again after oat bran was withdrawn (PO in
human case reports). Similar results were found with 3 patients using 15 grams
of pectin daily (PO in case reports).1841
OCOTILLO NEW
^ Fouquieria
splendens stem
(candle flower, coach whip,
slimwood, flaming sword, wolf’s candles, desert candlewood, Joseph’s staff; Am.
Ind.: moelhok (Pima); Mex.: albarda)
Contraindications
1) Pregnancy (speculative)150 due to its emmenagogue
effects (empirical)1314
OLIVE p.
155
Olea europaea
fruit oil
Drug Interactions
I. + 1)
Consumption of 3-4 spoonsful of extra virgin olive oil daily for 6 months
compared to safflower oil in a crossover study led to significant reductions in
the use of antihypertensive medicines like atenolol, nifedipine,
lisinopril, doxazosin, and hydrochlorothiazide (PO in human
clinical study).1773
ORANGE NEW
^ Citrus
sinensis fruit
(sweet orange)
Drug Interactions
Ia. 1) The reductions in fexofenadine
bioavailability and maximum concentration were 69% and 67%, respectively, when
taken with orange juice by 10 healthy subjects, compared to consuming it with
water (PO in human study). Consumption of 1.2 liters of orange juice in a
3-hour period should be avoided with concurrent fexofenadine use. The reduced
uptake is due to inhibiting intestinal organic anion transporting polypeptide
(OATP) 1A2, not to inducing P-glycoprotein efflux (in vitro).1097 The flavonoid hesperdin is one orange
component that appears to be at least partially responsible for this inhibition
of OATP1A2 (in vitro).2305
2) After 10 healthy subjected ingested 200 ml juice or
water 3 times daily for 2.7 days in a randomized crossover format, celiprolol
maximum concentration, bioavailability, and excretion were reduced by 89%, 83%,
and 77%, respectively, following consumption of the juice (PO in human study).1582
However, no blood pressure
and heart rate changes were detected when drinking the juice, compared to
consuming water, before taking celiprolol (PO in human study).1582
3) When 8 male and 8 female subjects ingested 750 ml of juice
over 4 hours, the maximum concentration and bioavailability of ivermectin
was reduced compared to consuming water, and no differences were noted between
P-glycoprotein genotypes (PO in human study).1628
4) When 200 ml of water or orange juice made from
concentrate were consumed 3 times daily for 3.7 days in a randomized crossover
design, the juice led to decreased peak concentration and bioavailability of atenolol
by 49% and 40%, respectively (PO in human study).2045
OREGANO [formerly wild marjoram] p.
200
Origanum vulgare
plant
Contraindications
1) Excessive use should be
avoided in pregnancy2 due
to its emmenagogue and abortifacient effects (empirical)74
+ 2)
Avoid topical use on hypersensitive, diseased or damaged skin
(empirical)400
+ 3)
Topically for children under age 2 (empirical)400
+ 4)
Over 1% concentration on mucous membranes (empirical)400
OREGON GRAPE p.
155
Mahonia spp. root bark
Contraindications
+ 8)
Avoid use by nursing mothers without professional advice (speculative),1890
due to displacement by berberine of bilirubin from serum albumen which may lead
to kernicterus (IP in rats).1092,1890
Drug
Interactions
I. + 3)
Berberine 1.2 grams daily, given as tablets to 79 congestive heart failure
patients on ACE inhibitors along with digoxin in 76, nitrates
in 71, and diuretics / spironolactone in 77, significantly
increased left ventricular ejection fraction and exercise capacity, improved
dyspnea-fatigue index, and reduced frequency of ventricular premature complexes
compared with 77 patients using only comparable conventional medications. The
mortality of the berberine group decreased significantly as well, and there
were no apparent side effects (PO in human clinical study).1457 In
56 congestive heart failure patients on loop diuretics and ACE inhibitors,
including 51 using digoxin and 46 on nitrates, the significant increases in
left ventricular ejection fraction and decreases in ventricular premature beats
from baseline from 1.2 grams of berberine daily was also significant better
when plasma berberine concentrations were higher versus lower than 0.11 mg/L
(PO in human clinical study).2639
+ 4)
Berberine at 0.6 grams daily for 3 months increased previously stabilized cyclosporin
A trough blood concentrations by 90% in 52 renal transplant patients,
and when given for 12 days to 6 transplant patients increased the cyclosporine
bioavailability by 35% (PO in human clinical study), likely by inhibition of
CYP 3A4 (speculative).2281
+ 5) The combination of 500 mg berberine 3
times daily for 3 months in 43 patients with poorly-controlled type 2 diabetes
together with one or more of their regular oral hypoglycemic medications
including sulfonylureas in 28, metformin in 20 acarbose in
15, and/or insulin in 10 resulted in lower fasting and postprandial
blood sugar from week 1 through week 12 (PO in human clinical study). Fasting
plasma insulin was also lowered by 28% and an index of insulin resistance by
45% of those on medications, while total cholesterol and LDL were likewise
reduced. In 31 newly diagnosed type 2 diabetics to whom 15 were given the same
dose of berberine and 16 used 500 mg metformin 3 times daily, berberine’s
hypoglycemic effect was similar to that of metformin on fasting and
postprandial blood glucose, as well as reducing glycosylated hemoglobin and
plasma triglycerides (PO in human clinical study). Transient gastrointestinal
adverse effects were experienced by 35% of the patients, or 20 in total.2315
II. 1) The antitumor constituent berbamine (20 mg/kg once daily
for 7 days) significantly enhanced antitumor activity of cyclophosphamide against Walker tumor (IP in rats).398
When the alkaloid component berberine was given once
or twice at doses of 50, 100, or 200 mg/kg before cyclophosphamide injection,
it significantly reduced the chemotherapy adverse effect of bladder hemorrhage
in a dose-dependent manner (IP in rats).2570
+ 2) Berberine administered prior to pentobarbital increased the induced sleeping time (IP in mice)1032
A single 4 mg/kg dose of berberine prolonged
pentobarbital sleeping time and increased strychnine toxicity (PO in
rats)1215
+ 3)
Pre-treatment with 4 mg/kg berberine prevented a rise in serum levels of liver
enzymes from excessive acetaminophen, suggesting protection from its
toxic effects (PO in rats). Use of this dose three times every six hours
following a toxic dose of acetominophen reduced liver damage.1215
+ 4) Berberine at 100 mg/kg enhanced the anxiolytic
effects of buspirone and ritanserin but did not interact with
diazepine (PO in mice).2668
III. 3) Berberine increased efflux of rhodamine 123 and paclitaxel by inducing P-glycoprotein and thereby reducing the retention and concentration of these drugs in human hepatoma and digestive tract cancer cells, respectively (in vitro)1045,1046
+ 4)
Studies in human liver-derived cells with berberine was found to have an
additive effect with lovastatin by increasing LDL receptor mRNA expression
(in vitro). This statin did not reduce this effect of berberine,
indicating a different mechanism of action (in vitro). In 63
high-cholesterol subjects taking 1.0 grams berberine HCl daily for 3 months,
serum cholesterol was reduced 18%, LDL cholestreol 20%, and triglycerides 28%,
compared to those using placebo (PO in human study). In the 32 who were taking
no other medication or herbs, cholesterol was reduced 29%, LDL cholesterol 25%,
and triglycerides 35%. HDL cholesterol was unaffected, and berberine was well
tolerated. Berberine was found to have a dose-dependent cholesterol-lowering
effect (in hamsters).1656
+ 5)
Avoid use with drugs that displace the protein binding of bilirubin such as phenylbutazone
(speculative).1890
OSHA NEW
^ Ligusticum porterii root
(Porter’s lovage, Colorado cough
root, Indian parsley, bear medicine; Mex.: chuchupate)
Contraindications
1) pregnancy150 due to its emmenagogue and abortifacient effects (empirical)75
PAPAIN p.
156
Carica papaya extract from unripe fruit
Contraindications
1) Allergic hypersensitivity401 to chymopapain can lead to
anaphylaxis (empirical).24
Cross-reactivity with bromelain by skin and RAST
tests occurred with 5 of 6 workers sensitized to airborne papain, and 2 of the
6 had immediate asthmatic reactions (human clinical study).1275
Cross-sensitivity shown by RAST inhibition suggested bromelain, papain, wheat
flour, rye flour, grass pollen and birch pollen possess more or less similar or
identical antigenically active regions (in vitro).1276
Drug
Interactions
I. 1) Papain increases warfarin anticoagulation effects if
used concurrently (PO in human case report).143,614
However, this report has been described as
unevaluable based upon report inadequacies.1239
PASSION FLOWER p.
158
Passiflora
incarnata plant
Drug
Interactions
I. + 2)
A dose of 60 drops daily of an undefined extract in combination with clonidine
reduced the mental symptoms and improved total withdrawal scores compared to
using clonidine alone in assisting opiate withdrawal for 65 male opiate
addicts (PO in human clinical trial)1192
A 10 mg/kg dose of the benzoflavone fraction of a
methanol extract delayed tolerance to morphine analgesic effect and
reduced withdrawal symptom after chronic morphine treatment (PO in mice).1541
II. 1) A passion flower methanolic fraction at 100-200 mg/kg (IP
in mice)2299 or hydroethanolic extract at 65-250 mg/kg (IP in mice)516,2196
potentiates pentobarbital sleeping
time.
+ 2)
The benzoflavone fraction of a methanol extract significantly prevented ethanol
(alchohol) withdrawal anxiety when giving with addictive doses twice
daily or as a single dose following ethanol addiction (PO in mice). The
multiple daily doses were more effective than the single dose, and the effect
was dose dependent using 10, 20 or 50 mg/kg benzoflavone.1751
However, in samples of passion flower grown
in India, Italy, and France, the previously described benzoflavone was found only
in the one grown in Italy and only in trace amounts (in vitro), inadequate to serve as an active marker (speculative).2700
+ 3)
The benzoflavone fraction of a passion flower dried aerial parts methanol
extract significantly prevented nicotine withdrawal jumps when given
with addictive nicotine doses four times daily for 14 days or as a single dose
following nicotine addiction (SC in mice). The multiple daily doses were more
effective than the single dose, and the multiple doses inhibiting withdrawal
were 10 or 20 mg/kg benzoflavone while the effective acute dose was 20 mg/kg.
Normal ambulatory behavior and performance in the swimming endurance test and
prevention of weight loss were also observed following benzoflavone use.1752
However, in samples of passion flower grown
in India, Italy, and France, the previously described benzoflavone was found
only in the one grown in Italy and only in trace amounts (in vitro), inadequate to serve as an active marker (speculative).2700
+ 4)
The benzoflavone fraction of a methanol extract of passion flower dried aerial
parts significantly prevented changes in ambulatory behavior following benzodiazepine
withdrawal when given with addictive doses of 20 mg/kg of diazepam daily
for 21 days (PO in mice). The efficacy was dose dependent using 10, 50, or 100
mg/kg benzoflavone, the highest dose being the most effective. These doses
given alone caused no change in normal ambulatory behavior following
withdrawal.1753
However, in samples of passion flower grown in
India, Italy, and France, the previously described benzoflavone was found only
in the one grown in Italy and only in trace amounts (in vitro), inadequate to serve as an active marker (speculative).2700
+ 5)
The benzoflavone fraction of a methanol extract of passion flower dried aerial
parts at 10 or 20 mg/kg doses significantly prevented the cannabinoid THC
tolerance and dependence, as well as withdrawal paw tremors and head shakes after
receiving a cannabinoid-receptor antagonist, when given with addictive THC
doses twice daily (PO in mice). A single dose of 20 mg/kg benzoflavone also
reduced severe paw tremors and head shakes from THC withdrawal after receiving
a cannabinoid-receptor antagonist (PO in mice).1754
However, in samples of passion flower grown
in India, Italy, and France, the previously described benzoflavone was found
only in the one grown in Italy and only in trace amounts (in vitro), inadequate to serve as an active marker (speculative).2700
PENNYROYAl [now AMERICAN PENNYROYAL] p.
159
PEPPERMINT p.
160
Mentha piperita
leaves
Contraindications
+ 6)
Avoid essential oil in nursing mothers without professional advice
(speculative), due to concerns that it may reduce milk secretions.1890
+ 7)
Avoid oral exposure in those with contact sensitivity reactions to
peppermint oil or its component menthol, especially when resulting in mouth
ulcers (empirical)1890
Drug Interactions
I. + 1)
Non-heme iron absorption is reduced with consumption of the tea prepared
with 3 grams per cup (PO in human study) likely due to its flavonoid content1246
+ 2)
Peppermint oil fraction dose of 600 mg increase bioavailability and peak plasma
concentration of oral felodipine by
140% in 9 males and 3 females, all healthy subjects, similar to grapefruit
juice (PO in human study). This was presumably due to inhibition of CYP3A4 (in
vitro).1756
However,
menthol in successive doses of 100, 50, 25 and 25 mg at the beginning and after
2, 5, and 7 hours, respectively, had no affect on pharmacokinetics or
pharmacodynamics of a single oral dose of felodipine in a study with 10 females
and one male (PO human study).2307
+ 3) When 6-10 menthol cough drops were used
daily for 4 days or 3 weeks, beginning 2 or 4 weeks after instituting warfarin therapy, respectively, the
therapeutic INR levels were significantly reduced (PO in human case reports).
In one case the INR returned to normal after stopping the drops and increasing
warfarin, then returning to the original dose,2643 while the other
case was normalized by withdrawing the cough drops, and later lowering warfarin
dosage.2642
However, reduced INR is suggestive of induction of CYPs
2C9, 1A2, and/or 3A4, but menthol has been shown to have no effect on the
CYP1A2 probe caffeine (PO in human study).2308 Though peppermint oil
inhibits metabolism of the 3A4 substrates cyclosporine (PO in rats)1755
and felodipine (PO in human study),1756 menthol has shown no effect
felodipine (PO in human study).2307 Though this suggests that
menthol induces CYP2C9, only these 2 cases exist out of the many of people who
use warfarin and other CYP2C9 substrates simultaneously with mentholated cough
drops, indicating extremely rare and likely idiosyncratic responses, if menthol
is involved at all.
II. + 1)
Cardiotoxicity from doxorubicin, a widely used antitumor agent, was
reduced by luteolin (PO in mice),1282 a component of peppermint also responsible
for the antimutagenic effect of water extracts of this fresh herb (in vitro)
and also fresh thyme (Thymus vulgaris) and sage (Salvia officinalis).1283
+ 2)
After being consumed for 4 weeks, a 2% tea made from the leaves reduced the
metabolism of phenacetin by liver microsomes to 24% of normal (PO in
rats). It also reduced the activity of CYP 2E to 60% that of controls.1608
+ 3)
The peppermint oil fraction at 50 and 100 mg/kg increased 25 mg/kg cyclosporine
peak plasma concentration and bioavailability by 2-3 times (PO in rats). The
amounts given were greater than humans doses of 2-10 mg/kg cyclosporine and 17
mg/kg peppermint oil, but the blood levels of cyclosporine and the ratio of
doses were similar to those found wih humans.1755
III. + 1) Peppermint
oil fraction and its components menthol and menthyl acetate caused reversible
but nonmechanism-based inhibition of the CYP3A4 metabolism of nifedipine in
human liver microsomes (in vitro).1756
2) Due to its tannin content, it may reduce absorption of
metal ions, thiamine or alkaloids when taken concurrently
(speculative).1890
PERIWINKLE
[now LESSER PERIWINKLE] p. 161
Ä Vinca minor plant
PETASITES p.
162
Petasites hybridus =
Petasites officinalis root
Drug Interactions
I. + 1) A standardized CO2 extract with a minimum of 15% petasins was given for 2 months in doses from 50-150 mg daily, depending on age, to children and adults with asthma concurrently treated with inhaled corticosteroids (28%), short-acting beta-agonists (53%), and other medications (69%) and found to decrease number, duration, and severity of asthma attacks (PO in human clinical study). More than 40% of those using asthma medications reduced their intake, including 43% of those using steroids (avg. 16% reduction) and 48% using beta-agonists (avg. 13% reduction).1660
PLANTAIN [Plantago lanceolata now ENGLISH PLANTAIN] p. 162
Plantago major leaves
Drug Interactions
II. + 1)
An official Russian preparation of the sap reduced the acute toxic effect on the
gut mucosa from 5-fluorouracil used to treat Ehrlich ascites tumors. The
DNA of the tumore cells also declined more drastically when the plantain sap
was used with 5-fluorouracil than by using the chemotherapy alone (PO in mice).1525
PLEURISY ROOT p.
163
*Asclepias tuberosa
root
Contraindications
+ 2)
Hiatal hernia, esophageal varices, stomach ulcer or peptic ulcer
due to aggravation and/or potential hemorrhage from emetic effect if bloodroot
is taken in excessive doses (speculative)150
Drug Interactions
II. + 2)
Do not take large doses after recent consumption of central nervous system stimulants,
due to the emetic action potentially inducing convulsions (speculative).150
+ 3)
Do not take large doses after recent consumption of central nervous system sedatives,
due to the emetic action potentially inducing aspiration pneumonitis
(speculative).150
POKE NEW
^ *Phytolacca
decandra = Phytolacca americana root
(pokeweed, coakum, garget, inkberry, pigeon berry, red weed,
scoke)
Contraindications
I. 1) Pregnancy, due to its uterine stimulant activity
(in animals)74 and abortifacient and toxic effects (empirical).2,1890
2) Stomach irritation or intestinal irritation,
due to its saponins’ irritant and purgative effects,1890 especially
when fresh (empirical).2,5,7,1890
3) Broken skin or skin ulcers, due to its
irritant properties of its saponins, especially when fresh (empirical).1890
However, the hydroalcoholic
extract of the root has been applied locally in glycerin to fissures and
varicose or ulcerations of the legs (empirical). A poultice of the bruised
fresh leaves or their dried juice has also been used as a local treatment for
indolent ulcers (empirical).5
4) Contact with eyes, due to
the local irritant effects of its saponins (empirical).1890
II. 1) Nursing mothers, due to its potential toxicity
(speculative). Since it is used for the topical treatment of mastitis, local
application to the nipple should be avoided if nursing.1890
2) Lymphocytic leukemia (speculative), due to
mitogenic effects, especially of the fresh plant parts or liquid extracts
(empirical).1890
3) Exceeding recommended dose or extended use over
6 months (speculative), due to its potential of causing emesis, purgation, or
other toxic effects (empirical).1890
Drug
Interactions
III. 1) Avoid use with immunosuppressant drugs (speculative), due to
poke’s mitogenic effects (empirical).1890
POMEGRANATE p.
163
Punica granatum fruit juice
Drug
Interactions
I. + 1)
Ten carotid artery stenosis patients, 6 on ACE inhibitors, 2 on beta-blockers
and 2 on calcium channel blockers, had significant reductions in
systolic blood pressure after consuming 50 ml/day of pomegranate juice with
about 124 mg polyphenols, reconstituted from frozen concentrate (PO in human
clinical study). Systolic blood pressure measurements were lowered by 7% after
1 month, and 10-12% after 3-12 months of daily use compaired to baseline
values. No dialstolic blood pressure lowering found, and five who continued the
juice for 3 years had no further systolic reduction. Nine placebo control
patients with the same drug use pattern had no significant blood pressure
changes in one year.1693 In a prior study with ten hypertensive
patients, 8 on the ACE inhibitors enalapril or ramipril and 2 on
calcium channel blockers, 50 ml of pomegranate juice with 1.5 mmol polyphenols
daily resulted in a reduction of serum angiotensin converting enzyme (ACE)
activity by 36% and a 5% reduction in systolic blood pressure (PO in human
clinical study). This is probably not due to increased serum levels of ACE
inhibitors because CYP 3A4 is only minimally inhibited by pomegranate juice.1694
2) A man using ezetimibe daily and rosuvastatin
every other day for 17 months to control familial hypercholesterolemia
developed rhabdomyolysis 3 weeks after beginning to drink 200 ml of pomegranate
juice twice weekly (PO in human case report). He had greatly elevated creatine
kinase levels that returned to normal 10 days after stopping the drugs and the
juice. However, prior to statin treatment he had elevated creatinine kinase,
and taking atorvastatin and simvastatin previously caused myalgia. All 3
statins additionally increased the creatine kinase levels. Unlike atorvastatin
and simvastatin that are metabolized by CYP 3A4, rosuvastatin is metabolized by
CYP 2C9 and 2C19.1982
Though pomegranate juice has been shown to inhibit
CYP 3A (PO in rats,1920 in vitro1920,1923), there
is no data concerning its effect on other isozymes or P-glycoprotein or on CYP
3A4 in humans.
II. + 1) After 2 ml of pomegranate fruit juice was administered, carbamazepine
was given by gastric intubation after 1 hour and its total absorption and
maximum concentration were increased by 1.45 times, the same extent as when an
equivalent dose of grapefruit juice is given (PO in rats). Pomegranate juice at
25 ml or
5% v.v was shown to inhibit CYP 3A almost completely, reducing the metabolism
of carbamazepine to only 1.8% (in vitro).1920
III.+ 1) Pomegranate juice strongly inhibited the metabolism of the
CYP 3A substrate midazolam (in vitro).1923
+ 2)
A methanol extract of the fruit in combination with chloramphenicol, gentamicin,
ampicillin, tetracycline, or oxacillin increased the efficacy
of the antibiotics against methicillin-resistant and methicillin-sensitive Staph.
aureus (in vitro). This was apparently due to inhibition of the NorA
efflux transporter protein, since the extract likewise increased the efficacy
of nalidixic acid (in vitro).2355
IV. [2) A woman was
stabilized on warfarin dosage for 5 months while consuming pomegranate
juice 2-3 times/week (PO in human case report) . She began to have
subtherapeutic INRs for 4 months after skipping a couple of doses, but returned
to normal dosing and INRs. After referral to an anticoagulation clinic, she
stopped the juice and had 2 normal INRs, but then 2 subnormal INRs though any
potential CYP inhibition by the juice would have been eliminated. Another dose
increase resulted in normal INRs. 2602 Pomegranate juice does
inhibit CYP3A (in vitro,1920,1923,2123,2213 in rats1920).
However, 2 doses of 8 oz juice each given about 12 hrs and 1
hr prior to CYP3A substrate midazolam had no effect on IV or oral midazolam
clearance (PO in human study).2213 ]
PRICKLY ASH p.
164
Zanthoxylum
americanum = Xanthoxylum americanum
^ and Zanthoxylum
clava-herculis
= Xanthoxylum clava-herculis bark
(northern prickly ash) and (southern prickly ash,
Hercule’s club)
PRICKLY PEAR p.
164
Opuntia spp.
stems
Drug Interactions
I. 1) Blood sugar for a diabetic using chlorpropamide improved with prickly pear sap of Opuntia
streptacantha (PO in human case report).952
A unidentified species of prickly pear also lowered
blood sugar when 100 gm were given before meals to diabetics receiving tolbutamide
at stable doses (PO in human study).945
Opuntia lindheimeri aqueous protein extract when
given with feed had a time- and dose-dependent hypoglycemic effect in diabetics
but not in non-diabetics (PO in pigs).1451
The ethanolic extract of O. megacantha leaf
lowered plasma glucose concentrations in both streptozotocin-diabetic and
non-diabetic animals, but those
receiving the extract had higher plasma urea and creatinine concentrations and
reduced plasma sodium, possibly indicative of kidney toxicity (PO in rats).1228
In a clinical survey in which 17 patients reported
using uncharacterized prickly pear pads [nopal] with metformin and 10
with glyburide, 5 were reported to have mild hypoglycemic symptoms when
the nopal was used with a combination of metformin and glyburide, while 2
others had hypoglycemic symptoms when it was taken only with metformin (PO in
human case series).2126
II. 1)
After 7 weeks of an off-white powder of a proprietary purified extract of O. fuliginosa stems being given daily to
streptozotocin-induced diabetic rats at a dose of 1 mg/kg body weight 8 hours
after insulin treatment, normal
glycemic and glycated hemoglobin levels resulted (PO in rats). At week 8 the insulin was suspended
but the extract was continued for 7 more weeks, and normoglycemia was
maintained.2695
2) The freeze-dried powder from pads with epidermis and glochids removed was prepared by mixing 20 grams in 100 ml water and given in doses of 1 gram per kilogram before or after the 90% ethanol (PO in rats). Ethanol given alone caused widespread gastric hyperemia and thickened lesions with an ulcer index (UI) of 8.24, but the pad pre-treatment significantly reduced hyperemia and lesions to near-normal with a UI of 1.48, while post-ethanolic treatment also significantly decreased the UI to 3.25.2696
PSORALEA NEW
^ Cullen
corylifolia = Psoralea corylifolia seed
(scurfy pea; Ch.: bu gu zhi)
Contraindications
1) Pregnancy due
to its potential purgative and abortifacient effects (empirical)150
2) Excessive sunlight and ultraviolet light
or solarium therapy due to its
phototoxic furocoumarin component (empirical)150
PSYLLIUM p.
165
Plantago psyllium =
Plantago afra and Plantago ovata = Plantago
ispaghula seed or seed husk
Contraindications
+ 4)
Allergic hypersensitivity following psyllium use, due to the risk of
anaphylaxis (empirical)1890
Drug
Interactions
I. + 3)
Taking 6.0 grams of psyllium husk in water three times daily with orlistat
reduced the percentage of patients experiencing gastrointestinal side effects
from 71% to 29%, including the most troubling symptoms of flatulence and fecal
incontinence associated with the increased intestinal fat load from the lipase
inhibitor drug that were 2-6 times more common without psyllium use (PO in
human clinical study)1193
+ 4)
Psyllium reduced glucose absorption 12.2% and maximum glucose concentration in
the blood by 10% while taken with sulfonylurea medication glibenclamide
compared to using the medication alone. In addition, significant decreases in
total and LDL cholesterol and uric acid also occurred (PO in human clinical
study).1448
+ 5)
When 68 patients with high cholesterol used 10 mg or 20 mg of simvastatin
with placebo or 10 mg with 15 gm psyllium daily for 12 weeks, after 8 weeks LDL
cholesterol was lowered by the psyllium and drug combination more than the 10
mg and as much as 20 mg of the drug (PO in human clinical study). Similar
results were found for total cholesterol and apolipoprotein B, but no changes
in HDL cholesterol or triglycerides occurred.1735
III. + 1)
Psyllium may inhibit absorption of oral drugs
(speculative)4,6,17,401
such as aspirin, digitalis and other cardiac
glycosides, antibiotics,
and anticoagulants if administered
concurrently (speculative).150
PULSATILLA p.166
Anemone pulsatilla, Anemone pratensis herb
Drug Interactions
III. + 1) Avoid combining with powerful analgesics
(speculative), especially long-term, due to possible additive effects.1890
PUNCTURE
VINE NEW
^ Tribulus
terrestris herb
(goat’s head, bullhead, burnut, little caltrop, terror of
the earth; Sp. torrito)
Contraindications
1) Pregnancy except under professional advice
(speculative), due to reported fetotoxic effects (PO and IV in animals).1890
2) Nursing mothers except under professional
advice (speculative).1890
PURSLANE NEW
^ Portulaca
oleracea plant
(Arab.: humdeh)
Contraindications
1) Pregnancy (empirical)150
due in part to uterine stimulation shown with an extract of 6 gm dry plant
(injected in humans)1315
2) History of kidney
stones (speculative) due to
its content of up to 1.7% oxalic acid150
QUASSIA (JAMAICAN) NEW
^ Picrasma
excelsa bark, wood, root
(bitter ash, bitter wood)
Contraindications
1) Pregnancy due to its
stomach mucosal irritation that can lead to vomiting (empirical)150
QUASSIA (SURINAM) NEW
^ Quassia
amara bark, wood, root
Contraindications
1) Pregnancy due to its
stomach mucosal irritation that can lead to vomiting (empirical)150
QUEEN
ANN’S LACE (See WILD CARROT.)
RASPBERRY p.
167
Rubus idaeus
leaves
Contraindications
+ 2)
Iron-deficiency anemia, malnutrition and constipation
(speculative), due to the high tannin content that produces an astringent
effect.1890
Drug
Interactions
III. + 1) Due to its tannin content, it may reduce
absorption of metal ions, thiamine or alkaloids when taken
concurrently (speculative).1890
RED
CLOVER p.167
Trifolium pratense
Drug
Interactions
III. + 2) The major isoflavone component biochanin A was found to inhibit P-glycoprotein removal of daunomycin and the chemotherapeutic agent doxorubicin from breast cancer cell lines (in vitro)1562
IV. [1) It
has been suggested that anticoagulant drugs such as warfarin may be potentiated due to the anticoagulant effects
of the coumarin content of red clover (speculative).894,895
The prodrug coumarin is also present in red clover,
along with the derivative umbelliferone (7-hydroxycoumarin).1769
However, in a preliminary
report on using “approximately 400 mg/d” of a standardized extract with 29.4%
total isoflavones, none of 17 potential coumarins were detected at levels
greater than 0.3% by weight. Only 5 including coumestrol and scopoletin were
detected in even trace amounts. Prothrombin time levels in 6 women taking this
extract for one month showed no changes from baseline in any of the women (PO
in human clinical study).1769 The final report on the 378 mg/day
dose of an ethanolic extract of the aerial parts standardized to 117 mg
isoflavones given to 22 peri- or postmenopausal women showed no significant
change in prothrombin time after 1 month compared to 22 similar subjects given
placebo (PO in human clinical study).2596]
REHMANNIA p.168
Rehmannia glutinosa
root
Contraindications
2) Uncured rehmania in pregnancy in
traditional Chinese medicine patterns of deficient blood, deficient spleen or
deficient stomach (empirical). It should not be used in pregnancy without
professional advice (speculative).1890
REISHI p.
168
Ganoderma lucidum fruiting body
Contraindications
+ 1)
Organ transplants in which patients
must use immunosuppressive agents due to potential immune enhancement
(speculative)1122
+ 2)
Autoimmune disorders due to potential immune enhancement
(speculative)1122
Drug
Interactions
I. + 1)
Potentiates the sedative effects of reserpine and chlorpromazine
(empirical)1122
+ 2)
Antagonizes the stimulant effect of amphetamines (empirical)1122
+ 3)
Increased the sleeping time induced by barbital and pentobarbital
(human clinical studies)1122 [However, see II. 2).]
III. + 1)
If anticoagulants are used, consult with health care provider before
taking reishi (speculative)1122 due to potential anti-platelet
activity of its adenosisn-containing water extract (in vitro)418
+ 2)
Lovastatin and other cholesterol-lowering medications may be potentiated
(speculative) due to reishi’s inhibitory action on HMG-CoA reductase1122
+ 3)
Immunosuppressants due to potential immune enhancement
(speculative) and because reishi polysaccharides have been shown to antagonize
the immunosuppression caused by morphine
(in vitro, in animals)1122
RHATANY NEW
^ Krameria
triandra root
(Ratanhia)
Drug
Interactions
I. 1) The use of a rhatany extract mouthwash and toothgel 3
times daily for 4 weeks by 32 women while undergoing chemotherapy druing
the first week with carboplatin, cyclophosphamide, epirubicin, and/or taxol
resulted in only 16% developing a mild mucositis (PO in human clinical
study). The oral symptoms that developed during the week of chemotherapy were
markedly improved three weeks later. Plaque and gingival indices were also
reduced, compared to baseline. 2314
RHODIOLA NEW
^ Rhodiola
rosea root
(golden root, Arctic root, roseroot)
Drug
Interactions
II. 1) Cyclophosphamide antitumor and antimetastasis
effects on Ehrlich ascites tumor and Lewis lung carcinoma were enhanced when
combine with 0.5 ml/kg rhodiola extract daily for 7 days, while the
hematotoxicity to leucocytes and myelokariocytes was reduced (PO in mice)1549
2) Antimetastatic activity of adriamycin was
unimpaired and its hepatotoxicity was greatly reduced when combined with
rhodiola extract (in mice).1563
RHUBARB, CHINESE [now CHINESE RHUBARB] p. 168
*Rheum officinale, *Rheum palmatum root
ROMAN CHAMOMILE [formerly
CHAMOMILE, ROMAN] p. 62
Chamaemelum nobile =
Anthemis nobilis flowers and plant
Contraindications
2) Allergic
hypersensitivity skin reactions occur in 20% of those tested(topically in
human study)64
Two women who used a
chamomile ointment on their nipples while breastfeeding developed severe
bilateral eczema on the nipples and areolae (topically in human case reports).
Both had 3+ positive reactions to chamomile oil patch tests.1741 A
man developed acute eczema on his forearms and hands after washing and applying
compresses of chamomile and Roman chamomile tea (topically in human case
report). In patch tests he was shown to be sensitive to both of these teas and
their mix, a Roman chamomile extract, yarrow, tansy, and feverfew extracts, and
a sesquiterpene lactone mix. The Roman chamomile sesquiterpene lactone nobilin
likely contributed to his reaction.1742
ROSEMARY p.
170
Rosmarinus
officinalis leaves
Drug
Interactions
I. 1) A decrease in nonheme iron absorption by 21% was
shown in 14 women after consumption of rosemary extract (PO in human study).
This was likely due to the phenolic components carnosol, carnosic acid and
rosmarinic acid, whose total content in the extract given with test meals was
32.7 mg.1993 Therefore, it is best to avoid concurrent consumption of iron and
rosemary preparations rich in phenolic compounds.1890
III. 2) In human multiple myeloma cells the triterpenoid component
ursolic acid increased the apoptotic effects of thalidomide from 20% to
70% and enhanced this activity of bortezomib from 25% to 80% (in
vitro).2428
ROYAL
SUN AGARICUS NEW
^ Agaricus
blazei mycelia or mushroom
(sun mushroom, Brazilian sun-mushroom; Br.: cogumelo do
sol, cogumelo piedade, cogumelo de deus; Jap.: himematsutake, kawariharatake, agarikusutake;
Ch.: ji song rong)
Drug
Interactions
I. 1) In a study with gynecological cancer patients (61
cervical, 35 ovarian, and 4 endometrial), one dose three times daily of an
uncharacterized royal sun agaricus extract was combined with chemotherapy in 29 using carboplatin
and etoposide and in 10 using carboplatin and taxol and compared
to placebo in 39 and 22 patients using these combinations without the extract,
respectively. Those taking the extract had fewer adverse effects from the
therapy, such as loss of appetite, hair loss, emotional lability, and general
weakness (PO in human clinical study).1850
2) A 500 mg capsule of extract from the mushrooms or placebo was given
3 times daily for 12 weeks to 60 adult Chinese type 2 diabetic patients who had
been taking gliclazide and metformin for at least 6 months (PO in
human clinical study). Those 29 receiving the extract had improved insulin
resistance compared to the placebo group, based on lowered HOMA-IR index and
increased plasma adiponectic concentration.2215
SAGE p.
171
*Salvia officinalis
leaves
Contraindications
+ 3)
Nursing mothers, unless the intent is to help stop milk flow
(empirical).1890
Drug
Interactions
II. + 1) Cardiotoxicity from doxorubicin, a widely used
antitumor agent, was reduced by luteolin (PO in mice),1282 a component of sage also responsible for the
antimutagenic effect of water extracts of this fresh herb and also fresh thyme
and peppermint (in
vitro).1283
SAW
PALMETTO p.
173
Serenoa repens fruit
Contraindications
+ 1) Avoid a few weeks prior to surgery and use with caution for those with hemostatic disorders (speculative), due to a severe intraoperative hemorrhage that occurred in association with use of the hexane extract (PO in human case report).1724
However, 10 adults taking a
proprietary saw palmetto product at the manufacturer’s recommended dose for 2
weeks had no increase in coagulation time in ADP and epinephrine assays of
intrinsic and extrinsic platelet function, respectively (ex vivo), but
the product was not analyzed for its phytochemical content.2262
Drug
Interactions
III. + 3)
Use of a formula with saw palmetto extract, pumpkin seed (Cucurbita pepo)
extract, and 10 mg of vitamin E results in an increase INR of 2.1 in one case
and and INR increase of 1.0 in a man using warfarin (PO in human case
reports). The increases were largely attributed to the vitamin E.1725
Nonetheles, other anticoagulants should also be used with caution
with the extract (speculative),
due to a severe intraoperative hemorrhage that occurred in association with use
of the hexane extract (PO in human case report).1724
SCHISANDRA p.
173
Schisandra chinensis fruit
Contraindications
+ 1)
Pregnancy due to its uterine stimulant effects (empirical),404
except
to assist childbirth such as by inducing labor (empirical).1890
+ 2) Early stages of cough or rash (empirical), based on excessive heat patterns in traditional Chinese medicine energetics.1890
Drug
Interactions
II. 1)
Schizandra given at 50 mg/kg 30 minutes before pentobarbital reduced
sleeping time of this barbiturate by 41% (IP in mice).1236
However, an ethanol fraction of the fruit of
another species, S. sphenanthera, dose-dependently reduced sleep latency
and increased sleeping time induced by pentobarbital (PO in mice).2074
+ 3)
Enhanced metabolic breakdown of S-warfarin was induced by 500 mg/kg of
an aqueous extract equivalent to 3 gm/kg dried fruit (PO in rats), evidently
through activation of pregnane X receptor as shown by an ethanolic extract of
schisandra (in vitro).1926
SCOTCH BROOm p.
174
*Cytisus scoparius =
Sarothamnus scoparius
Contraindications
6) Avoid self-prescribing
since only under the supervision of a qualified expert can its safe use be
expected (empirical).150
From 6-10% of Caucasians down to 1% or less of east
Asians are poor CYP 2D6 metabolizers that have an impaired ability to eliminate
sparteine, leading to a potentially toxic outcome (human studies).1566
Drug Interactions
I. 1) Quinidine and
haloperidol inhibit the CYP 2D6
metabolism of the component sparteine (PO in human studies).657-659
Other clinically relevant CYP 2D6 inhibitors include amiodarone,
chlorpheniramine, cimetidine, clomipramine, fluoxetine,
methadone, paroxetine, and ritonavir (in vitro, animal
and/or human studies).1567
SCOURING
RUSH NEW
^ Equisetum hyemale plant
(rough horsetail; Ch.: mu zei)
Contraindications
1) Prolonged use due
to thiaminase activity of plants (in
vitro; PO in horses).182
2) Pregnancy (empirical)150
Drug Interactions
II. 1) Herb thiaminase content causes breakdown of thiamine (in vitro; PO in horses)2,150,182
III. 1) Digitalis and its cardiac glycosides and others heart tonic
herbs containing similar compounds such as Adonis, Apocynum, Convallaria, Urginea,2,6
Helleborus, and Strophanthus (speculative) since they can become more toxic due
to the loss of potassium2 associated with the diuretic effect of
horsetail (PO in mice)12
SEA
BUCKTHORN NEW
^ Hippophae
rhamnoides fruit
(sea berry, swallow thorn, Siberian
pineapple)
Drug Interactions
SENNA p.
175
*Cassia spp= Senna spp. leaves or pods
Contraindications
II. 1)
Avoid in pregnancy,4,17,150 due to
potentially mutagenic and genotoxic anthraquinones (in vitro).6,844
However,
a case-controlled population-based comparison of 22,843 congenital
abnormalities found 2.2% of mothers had senna treatment with a dose Of 10-30 mg
(mode 20 mg), while of 38,151 controls with no congential abnormalities 2.5% of
mothers had used senna (PO in human study). No association was found with senna
use and a higher risk in the offspring of women using senna for constipation
during pregnancy.2655
Drug Interactions
+ 4)
Laxative effect caused by 7.2 grams of psyllium daily was effective in
increasing stool dry weight and frequency in 48% of 42 constipated adults,
compared to 63% when 6.5 grams of psyllium were combined with 1.5 grams of
senna daily (PO in human clinical study)1473
SESAME NEW
^ Sesamum
indicum seed oil
Drug Interactions
1) When used exclusively in place of
other oils in cooking and salads for 45 days by 40 hypertensive diabetic men
and women taking as medications the beta-blocker atenolol
and oral hypoglycemic drug glibenclamide,
sesame oil reduced systolic and diastolic blood pressures, but these rose when
other oils were substituted (PO in human clinical study). Also reduced by the
sesame oil were body weight and girth, and plasma levels of sodium, glucose,
glycosylated hemoglobin, LDL-cholesterol, and triglycerides. Antioxidant and
potassium levels were increased during the 45 days of using about 35 grams of
sesame oil daily.2050
SHEPHERD’S PURSE p.
177
Capsella
bursa-pastoris herb
Contraindications
+ 2) Nursing
mothers without professional advice, due to its glucosinolates that can
taint the milk, reportedly caused adverse effects in newborns drinking milk
from goats fed glucosinolates (empirical).1890
^ Aloe
arborescens (= Aloe perfoliata)
(tree aloe, Krantz aloe, candelabra
aloe)
Drug Interactions
Ia. 1) A
trial with chemotherapy
drugs given with or without shrub aloe extract at 30 ml/day to treat metastatic
solid tumors, including vinorelbine or
cisplatin and etoposide for lung cancer, oxaliplatin and 5-fluorouracil for colorectal cancer, 5-fluorouracil for
gastric cancer, and gemcitabine
for pancreatic cancer, found the chemotherapy/extract combination significantly
improved tumor regression and increased 3-year survival from 5% to 19% (PO in
human clinical study). Use of the extract also was associated with
significantly greater average lymphocyte counts and significantly less fatigue.
Of those taking vinorelbine alone 71% had constipation, but only 18% of those
also using the extract were constipated.2611
SILK TREE NEW
^ Albizia
julibrissin bark
(mimosa tree; Ch.: he huan pi)
Contraindications
1) Pregnancy due to its emmenagogue and uterine stimulant effects
(speculative)150
SMALL SPIKENARD NEW
^ Aralia
nudicaulis rhizome
(false sarsaparilla, wild sarsaparilla, rabbit’s root,
wild licorice)
Contraindications
1) Pregnancy (speculative)150 due to its emmenagogue effect
(empirical)1125
SOY p.
177
Glycine max
beans
Contraindications
1) Iodine-deficiency thyroid conditions such as nontoxic goiter
(empirical)970
However, the
concentration of thyroxine (T4) and the free thyroxine index were actually
elevated, though not to clinically levels, when 56 mg of isoflavones in 40
grams of soy protein was taken daily for 3-6 months by 73 post-menopausal
women, while thyroid stimulating hormone (TSH) concentration was higher with 90
mg soy protein isoflavones during this time (PO in human clinical study).1251
A study with 38 postmenopausal women not on hormone replacement therapy
supplemented them with 150 mcg of iodine daily. In randomized, double-blind
fashion, 21 received 90 mg of soy isoflavones daily for six months, but this
did not alter TSH, T4, or T3 levels when compared to those on placebo (PO in
human study).1680
2) Allergic hypersensitivity to soy including
soy-based formulas for infants who respond with enterocolitis typified by
diarrhea with fecal blood and vomiting (PO in human clinical study).1546
Young children with cow’s milk allergy in addition to soy allergy have the
greatest clinical response to soy exposure (PO in clinical studies),1546,1548
with immediate reactions elicited by very small doses and late reactions
requiring higher repeated doses.1548
+ 3) Extensive long term continual
use of concentrated isoflavones from soy, since 5 years, though not 3
years, of taking 150 mg soy isoflavones per day was associated with endometrial
hyperplasia in 3.4% of postmenopausal women (PO in human study)1616
Drug
Interactions
I. 1) Oral thyroxine
doses to infants had to be reduced after discontinuation of soy-based formula
(PO in human case reports).934 The isoflavones are absorbed by
infants fed soy protein-based formula (PO in human study).978
In contrast, the
concentration of thyroxine and the free thyroxine index were elevated when 56
mg of isoflavones in 40 grams of soy protein was taken daily for 3-6 months by
73 post-menopausal women, while thyroid stimulating hormone concentration was
higher with 90 mg soy protein isoflavones during this time (PO in human
clinical study).1251
+ 2)
Use of 16 oz. soy milk daily for 4 weeks while taking warfarin led to a
diminished INR value indicating reduced anticoagulation. Withdrawal of soy milk
for 2 weeks led to a return of therapeutic coagulation values (PO in human case
report).1347
However, soy protein that
was either isoflavone-rich or -poor failed to produce an effect on coagulation
and fibrinolytic factors after 24 weeks when each was used by 24 perimenopausal
women, compared to baseline or 21 subjects taking whey protein (PO in human
clinical study).1523
+ 3)
Use of 150 mg of soy extract daily containing 40% isoflavones (60 mg daily)
along with 100 mg dong quai extract and 50 mg black cohosh extract for 24 weeks
by 49 menstrual migraine patients significantly reduced the number of doses of triptans
and analgesics after 20-24 weeks compared to placebo (PO in human
clinical study)1422
II. + 1)
Soybean meal or concentrate as the sole protein source taken 14 days prior and
7 days after methotrexate injection completely alleviated the anorexia
and diarrhea associated with receiving the drug, along with preventing the
intestinal necrosis observed when using a casein-based diet. Soybean fiber and
isolate also provided some positive results. Methotrexate plasma levels were
similar with all diets, as were the resultant depressed white blood cell counts
(PO in rats).1545
+ 2)
Increased apoptosis in prostate cancer tissue with docetaxel or cisplatin
occurred when they combined with genistein, apparently due to an abrogation of
the induction of NF-kB by the genistein (in vitro, PO in mice).1961,1962
Similar effects were found when genistein was combined with docatxel or
cisplatin in cancer cells of the breast, lung, and pancreas (in vitro),1961
and with cisplatin in human malignant melanoma cells, though the mechanism in
the latter appears to be suppression of anit-apoptotic proteins (in vitro).1963
III. + 2) The cytotoxic effect of gemcitabine, a standard drug for pancreatic cancer, on pancreatic cancer cells was inhibited in the presence of genistein even when used at 2.5 times higher concentration (in vitro)1681
+ 3)
Increased apoptosis in
tumor cells, apparently due to an abrogation of the induction of NF-kB by the genistein, were
found when genistein was combined with doxorubicin in cancer cell
cultures of the prostate, breast, lung, and pancreas (in vitro).1961
+ 4)
3 dysplastic and 3 malignant breast cell
lines showed inhibition of cell proliferation that was synergistic and
additive, respectively, when exposed to the combination of tamoxifen
with genistein continuously for 72 hours in comparison with the dose-dependent
inhibition caused by genistein alone (in vitro). The effects were not
modulated by the presence of estrogen receptors.2128
+ 5)
In a culture of colon cancer cells the apoptotic effect induced by 5-fluorouracil
was increased by genistein, while the COX-2 up-regulation and increased
prostaglandin secretion caused by the drug were abolished by the addition of
genistein (in vitro).2129
SPIKENARD NEW
^ Aralia
racemosa rhizome
(American spikenard, Indian root, life-of-man, nard,
spignet)
Contraindications
1) Pregnancy (speculative)150 due to its emmenagogue effect
(empirical)1125 except for prior to labor to facilitate childbirth
(empirical)7
ST.
JOHN’S WORT p. 178
Hypericum
perforatum plant
Contraindications
+ 1)
Pregnancy3 due to its
emmenagogue1125 and abortifacient effects (empirical) and its
uterine stimulant action (in vitro or
in animals).74
In prospective, observational, controlled study of
women in Canada to investigate the teratogenic potential of substances during
pregnancy, 54 women who used St. John’s wort tablets at an average dose of 615
mg/day were compared with 56 women using pharmaceutical antidepressants and 56
women not exposed to any known teratogens (PO in human study). The groups were
matched by gestational age, maternal age, and number of prior pregnancies, and
the St. John’s wort group had more spontaneous abortions, 20.3% versus 12.5%
and 8.9%, and more malformations, 5% versus 4% and 0%, compared to the
pharmaceutical- and non-antidepressant groups, respectively.2622
However, no significant
differences were found between the groups in the number of spontaneous
abortions or malformations, suggesting some evidence of fetal safety. In
addition, the small sample sizes of the groups may exaggerate these percentages,
and the malformation rate for St. John’s wort group is within the 3-5% range
expected in the general population.2622
At least caution is warranted,2115 since
100 mg/kg of the
extract its induction of metabolic isozymes and transporter proteins in the
mother and their reduction in the fetus (PO in rats) may lead to a disruption
of hormonal concentrations and/or toxicity (speculative).1944 A 100
mg/kg dose of the extract during the entire prenatal period caused kidney and
liver damage in the newborn (PO in rats).1945
2) Prior to extensive exposure to sunlight,6
therapeutic ultraviolet light or solarium therapy (speculative)4,6,777
Acute polyneuropathy following consumption of 500
mg/day of powdered whole St. John’s wort occurred on areas exposed to the sun,
though the skin was not burned. Pain resulted from mild mechanical stimulation
only on the exposed areas, but disappeared gradually over two months following
withdrawal of the herb use (PO in human case report).1175
Skin
reactions from radiotherapy in a 65-year-old man recurred as radiation recall
dermatitis with later use of St. John's wort extract (PO in human case report).2656
While St. John’s wort extract and hypericin were
both shown to have dose-dependent phototoxicity, the extract flavonoid
component quercetrin helps reduce the phototoxicity (in vitro),
indicating the extract is probably less phototoxic than an equivalent amount of
hypericin that it contains (speculative).1332
Of special concern is exposure of the eyes to
intense sunlight while using St. John’s wort due to photooxidation of
alpha-crystallin of the lens by hypericin (in vitro) that could lead to
the formation of cataracts (speculative).1378
3) Endogenous
depression24 or as sole therapy for psychotic symptoms or suicidal
risk (speculative)777
A recent study showed 900-1200 mg daily of St.
John’s wort extract was not effective in the treatment of major depression (PO
in human clinical study).1113 The much publishized failure in
treating major depression with St. John’s wort extract by the Hypericum
Depression Trial Study Group in 2002 was complicated by the fact that the
standard medication sertraline also failed to improve the primary outcome
measures in this trial.1337
+ 4)
Prior to surgery due to potential
for interactions with some anesthetic agents (speculative).428,940,941,1309
(See drug interactions I.10 below.)
A woman using tablets of standardized St. John’s
wort for about 3 months in doses of one
gram three times daily had delayed emergence from general anesthesia following
surgery (PO in human case report). It is considered wise to discontinue St.
John’s wort at least five days prior, based on known pharmacokinetics of
hyperforin and hypericin.1289
St. John’s wort should be discontinued at least 5
days prior to surgery (speculative).and should be avoided postoperatively
in organ transplant patients and those requiring oral anticoagulation.1309
(See drug interactions I.6 and I.8 below.)
However, 10 adults taking a proprietary St. John’s wort product at the manufacturer’s recommended dose for 2 weeks had no increase in coagulation time in ADP and epinephrine assays of intrinsic and extrinsic platelet function, respectively (ex vivo), but the product was not analyzed for its phytochemical content.2262
+ 5)
A history of hypomania, mania or bipolar disorder since two cases
of mania have been associated with use of 900 mg daily of standardized St.
John’s wort extract in subjects with prior manic histories (PO in human case
reports)1189 Another two cases of hypomania were associated with its
use for 6 weeks and 3 months, though the dose and form of the products were
unreported (PO in human case reports).1265 In cases of mania induced
by St. John’s wort, one woman with depression stopped her medications and
became over-active after using 900 mg daily for 3 weeks, while a man with
bipolar II disorder self-medicating with 900 mg/day also experienced extreme
manic behavior after two months (PO in human case reports). Reducing the dosage
to 300 mg/day in both cases caused a reversion to depression.1269
+ 6) It should be avoided without professional advice and used with caution by nursing mothers (speculative),1890 since an increased incidence of infant side effects like colic,drowsiness, and lethargy can occur when the mother uses the botanical (PO in human study).1971
However, a prospective,
observational cohort study with 33 breastfeeding women using St. John’s wort
preparations on average 705 mg/day for 1.5 months, starting at 4.2 months postpartum
found no statistical differences in reported decreases in milk production
compared to controls, nor were there differences in infant weight during the
first year (PO in human study). The average duration of infant exposure to the
herbal products was 2.1 months.1946
Drug
Interactions
I. 1)
Incidences of serotonin syndrome from combining St. John’s wort with the
antidepresssants nefazodone1022 and trazodone611
and the selective serotonin reuptake inhibitor (SSRI) sertraline1022
have been reported (human case reports).
The hospitalization for loss of consciousness and an
epileptic fit of a 28-year-old woman who was taking 60 mg/day of the SSRI fluoxetine
for 1 year and uncharacterized St. John’s wort for a month was complicated by
her use of eletriptan for the 3 days prior to treat a recurring migraine
(PO in human case report). On admission myoglobin was elevated. Fluoxetine dose
was reduced to 20 mg/day, eletriptan was continued, and St. John’s wort was
discontinued. Myalgias and serum myoglobin continued to increase for a few
days, so both drugs were also discontinued. When discharged 10 days later, she
had normal blood indices and no myalgias.2626 In a 42-year-old woman
receiving 20 mg b.i.d. fluoxetine with 20 mg b.i.d. buspirone for major
depression, hypomania characterized by anxiety, insomnia, and panic developed
when she began taking uncharacterized
St. John’s wort extract, Ginkgo biloba extract, and melatonin for
several weeks (PO in human case report). After discontinuation of the nonprescription
items, the anxiety diminished and behavior improved over the next several
months.2628
A 19-yea-old man with a cough treated by an unknown
OTC cold medicine, and who was attempting to self-detoxify from ecstasy [MDMA]
use, took 200-250 mg of tryptophan for 2 days along with several St.
John’s wort tablets and developed symptoms typical for serotonin syndrome (PO
in human case report). Tryptophan combined with monoamine oxidase inhibitor
antidepressants was associated with the first reported cases of serotonin
syndrome. Dextromethorphan in some cold products can also increase serotonin
levels. His symptoms included confusion, agitation, anxiety, hypertehermia,
flushing, sweating, rapid breathing and heart rate, restlessness, tremor, and
ataxia, but lab tests were normal. After treatment with fluids, a cooling
blanket and the sedative lorazepam, his symptoms resolved, and he was
discharged.2632
3) Theophylline
dose required increasing when standardized St. John’s wort was used for 2
months by a woman (PO in human case report). Theophylline is metabolized by the
enzyme CYP 1A2.435
However, no change in
theophylline plasma levels were found when 12 healthy Japanese males took 900
mg daily of a St. John’s wort extract standardized to 0.3% hypericin in a 15-day
randomized, open-labeled, crossover study (PO in human study). A tendency for
one of the major metabolites to increase proportionally to the total excreted
in the urine was the only change noted. Duration may be a factor.1585
Likewise, no increased metabolism by CYP 1A2 of caffeine was found in a study
of 12 Chinese men using the same dose (PO in human study).1584
Combining data from both genders resulted in no
inducing effect on caffeine metabolism by CYP 1A2 found with oral use of 900 mg
extract of St. John’s wort standardized to 0.3% hypericin for 14 days in 5
women and 7 men (PO in human study)1217 and either a moderate or no
inducing effect after 28 days with the same dose in 6 men and 6 women (PO in
human studies),1328,1808 as well as no effect by 240 mg of 0.4%
hypericin extract after 10 days (PO in human study).1775
Nonetheless, another study using caffeine found no effect in 8 men but significantly increased metabolic ratios in 8 women, when results were separated by gender (PO in human study).1838 Therefore, CYP 1A2 induction by St. John’s wort preparations may be gender specific (speculative).
Paradoxically, the constituents I3,II8-biapigenin and quercetin inhibit CYP 1A2 (in vitro).1522 The unreliability of inhibitory test tube results using constituents in predicting herb and extract effects in humans is thereby demonstrated.
4) St. John’s wort for 14 days reduced the HIV proteinase
inhibitor indinavir, due in part to
CYP 3A4 induction (PO in human study).436
Hyperforin acts as a potent ligand for activating
the steroid X receptor [pregnane X receptor] (in vitro) that in turn regulates expression of CYP3A4.1002,1288
Indinavir is also a substrate for P-glycoprotein, an
efflux drug transporter induced by St. John’s wort.1969 Hyperforin
daily dosage correlated well with P-glycoprotein induction, hypericins and
total flavonoid dosage did not (PO in human study).1343 Hyperforin
and quercetin in nanomolar concentrations increase transport activity of Pgp (in
vitro).1720
5) Extract after 10 days reduced the peak digoxin AUC by 25% (PO in human study).437
18 subjects were given 300 mg tablets 3 times daily
for 14 days of extract WS 5572, each tablet standardized to contain 9 mg
hyperforin [but assayed as containing 8 mg], that was comparable in
significantly reducing digoxin bioavailability to rifampin, a known
P-glycoprotein inducer (PO in human study).2504
Different St. John’s wort dosages and formulations
used with digoxin for 14 days vary in their influence on its bioavailability
(PO in human study). While 900 mg daily of the extract LI160 (80% methanol extact
of 4-7:1 strength, standardized to 0.3% hypericins) reduced digoxin
bioavailability described as 24-hour-area-under-curve (AUC) by 25% compared to
placebo, 4 grams daily of the encapsulated herb powder reduced digoxin AUC by
27%, and 2 grams encapsulated powder decreased AUC by 18%. Hyperforin dosage
was similar between the extract and 4 grams of powder at 29 and 21 mg/day,
respectively. Using daily either 0.5-1.0
gram of the same powdered herb, or 2 grams of a different powder, 2 cups of the
tea each made with 1.75 grams herb, 1.2 grams of the encapsulated oil 0.075:1
strength extract, 20 ml fresh juice, or 500 mg of Ze117 that is a 5:1 strength
50% ethanolic extract, all with low hyperforin doses from 0-5.3 mg/day, caused
no significant change in AUC or trough levels when compared to placebo. Whereas
hyperforin dosage correlated well with P-glycoprotein induction, hypericins and
total flavonoid dosage did not.1343 Ze 117, with low hyperforin, 0.2% hypericins,
and 0.35% quercetin, has shown year-long safety and efficacy for mild to
moderate depression (PO in human clinical trial).2576 Furthermore, a
240 mg/day dose of a 1.5% hyperforin extract providing a daily hyperforin dose
of 3.5 mg failed to significantly reduce steady state digoxin levels in the
blood after 10 days of concurrent dosing (PO in human study).1775
The extract LI 160 at 1 mcg/ml and its components hyperforin and quercetin in
nanomolar concentrations increase transport activity of Pgp (in vitro).1720
St. John’s wort extract LI 160 given
at 900 mg daily for 14 days decreased AUC of a single dose of digoxin by 18% by
increasing duodenal P-glycoprotein 1.4-fold, duodenal CYP3A4 1.5-fold, and hepatic
CYP 3A4 1.4-fold (PO in human study). The LI 160 extract given at 1000 mg/kg
daily for 14 days increases intestinal P-glycoprotein 3.8-fold and hepatic
CYP3A2 2.5-fold (PO in rat study).1350
6) St. John’s wort extract (0.3% hypericin) 300 mg
three times daily for three weeks resulted in a decrease in the concentration
of the immunosuppressant drug cyclosporine
in a heart transplant patient (PO in human case report). Endomyocardial biopsy indicated acute
transplant rejection.438 Two kidney transplant cases with serum
cyclosporin reduction to subtherapeutic levels, including one case resulting in
organ rejection, were scored as probable interactions since 300-900 mg daily of
standardized St. Johns wort extract had been used for 1-6 months prior (PO in human
case reports).1248,1601 Dozens of other cases reportedly had a
lowering of serum cyclosporine while using St. John’s wort (PO in human case
reports),602,612,1187,1249 although several of these reports have
been described as unevaluable based upon report inadequacies.1239 A
model of interaction based on rate of induction and elimination half-life of
cyclosporine detoxicating proteins indicates that dosage regimens need to be
carefully monitored for 2 weeks at the beginning of St. John’s wort
introduction and for 2 weeks after its cessation.1924
Eleven renal transplant patients receiving
cyclopsonin A were given 600 mg St. John’s wort extract for 14 days. After 2
weeks the bioavailability of cyclosporin was significantly reduced by over 40%,
and its average dose required increasing from 2.7 mg/day to 4.2 mg/ day to
maintain therapeutic levels (PO in human trial). Potentially nephrotoxic
metabolites of cyclosporin increased with the elevated dosage.1377 A study of 12 days with 21 healthy subjects using 900 mg daily of the
extract LI 160 standardized to 0.3% total hypericins found a greater increase
in cyclosporine clearance after oral administration by 1.9-fold (PO in human
study).1590 In a crossover study with 10 renal transplant patients
using cyclosporine, one group received 900 mg/day for 14 days of an extract
with 4.7% hyperforin content and the other group received an extract with less
than 0.1% hyperforin. The high hyperforin extract led to significantly less
cyclosporine bioavailability, peak concentration and plasma concentration at
the end of 12 days requiring an increased daily dose, whereas the low
hyperforin caused no changes in cyclosporine parameters (PO in human clinical
study).1691
7) Breakthrough bleeding occurred in 3 women in Switzerland
using ethinylestradiol and desogestrel with St. John’s wort (PO in
human case reports)602 and in Sweden with women using oral contraceptives with St. John’s
wort for one week in 5 cases (PO in human case reports).603
However, these reports have
been described as unevaluable based upon report inadequacies.1239
In a randomized controlled trial with 18 females
taking low-dose contraceptives with 0.02 mg ethinylestradiol and 0.15 mg
desogestrel, intracyclic bleeding increased significantly, estradiol increased
in those with enlarged follicle-like structures, and the concentration of the
active progestin metabolite 3-ketodesogestrel was significantly reduced (PO in
human study).1505 In addition, 9 reports of unplanned pregnancies
from Sweden and Great Britain have occurred in association with using St.
John’s wort concurrently with oral contraceptives (PO in case reports).1330
However, when LI160 was
taken with ethinylestradiol and desogestrel, no evidence of ovulation or of
altered ethinylestradiol metabolism was found (PO in human study).1505
Likewise, 500 mg/day of the solid ethanolic extract Ze 117, containing 0.13%
hyperforin that provided 0.65 mg daily for 14 days, did not significantly alter
the pharmacokinetics of ethinylestradiol or desogestrel/3-ketodesogestrel in
low-dose contraceptive pills used by 16 healthy females (PO in human study).2569
Ze 117, with 0.2% hypericins and 0.35% quercetin, has shown year-long safety
and efficacy for mild to moderate depression (PO in human clinical trial).2576
A low-dose oral contraceptive with 20 mcg
ethinylestradiol and 1 mg norethindrone (norethisterone) was
given to 16 women for 2 successive 28-day cycles before 900 mg/day of a St.
Johns wort preparation was combined with the contraceptives on the next 2 cycles
(PO in human study). The St. John’s wort was standardized and verified to
contain 0.3% hypericin and 3.7% hyperforin. By the third week of the second
combination cycle the bioavailability of both drugs had been reduced 13-15%
with increased breakthrough bleeding and evidence of follicle growth. Whereas
physical and hormonal indicators showed one probable ovulation during the first
2 weeks, after St. John’s wort introduction there was evidence of 3 probable
and 3 possible ovulations among the 16 women.1802
An open study with 12 healthy females given the oral
contraceptive combination of 0.035 mg ethinylestradiol and 1 mg norethindrone
for three months introduced 900 mg of St. John’s wort during the second and
third months. The half-life of ethinylestradiol was reduced. Clearance of
norethindrone was increased in the third month when 7 of the 12 had
breakthrough bleeding, compared to 2 of 12 in the first month. CYP 3A activity
in the intestines, but not in the liver, also increased from the first to the third
month (PO in human studies).1524,1809 Lower serum 3-ketodesogestrel
and norethindrone are probably due to its enhanced metabolism by induction of
CYP 3A4. This suggests caution when using St. John’s wort products with oral
contraceptives (speculative).1505,1524
8) A total of 7 patients had a lower INR while using
St. John’s wort while on warfarin
(PO in human case reports).603
However, this report has been described as unevaluable based upon report inadequacies.1239
An open-label 3-way crossover randomized trial with
12 healthy subjects showed that St. John's wort standardized extract, daily
providing 37.5 mg hyperforin and 2.5 mg hypericin derived from 3 grams
flowering tops, when given 14 days before and 7 days after a single 25 mg dose
of racemic warfarin significantly increased both R- and S-warfarin apparent
clearance (PO in human study). S-warfarin, the active isomer, is metabolized by
the CYP 2C9. R-warfarin,
the less active
isomer, is metabolized by the CYPs 1A2 and 3A4.1578 In this study the extract increased apparent
clearance by 39%.2016
However, no effect on the
CYP 2C9 metabolism of tolbutamide after 10 or 14 days was found with oral use
of 240 mg or 900 mg of extracts of St. John’s wort standardized to 0.4% or 0.3%
hypericin, respectively (PO in human studies).1217,1775 Likewise, no changes in
metabolism of the CYP 2C9 substrates S(+)- or R(-)-ibuprofen stereoisomers
were found after 21
days use of 0.03% hypericin-standardized St. John’s wort extract at 900 mgs
daily in 8 males (PO in human study).2079
The extract and constituents hyperforin, hypericin,
and I3,II8-biapigenin are potent inhibitors of CYP 2C9, while I3,II8-biapigenin
and quercetin inhibit CYP 1A2 (in vitro).1522 The
unreliability of inhibitory test tube results using constituents in predicting
herb and extract effects in humans is thereby demonstrated.
9) Oral anticoagulant phenprocoumon had a reduced plasma concentration after ingesting
St. John’s wort extract daily (PO in human study).605
Phenprocoumon is metabolized by CYP 2C9,1167 but no effect on metabolism of tolbutamide by 2C9 after 10 or 14 days was found with oral use of 240 mg or 900 mg of extracts of St. John’s wort standardized to 0.4% or 0.3% hypericin, respectively (PO in human studies).1217,1775 Likewise, no changes in metabolism of the CYP 2C9 substrates S(+)- or R(-)-ibuprofen stereoisomers were found after 21 days use of 0.03% hypericin-standardized St. John’s wort extract at 900 mgs daily in 8 males (PO in human study).2079
However, S-warfarin
metabolism, apparently by the CYP 2C9, was shown to be increased by St. John's
wort extract, also (PO in human study).1578 The extract1522 and constituents
hyperforin, hypericin, and I3,II8-biapigenin are potent inhibitors of CYP 2C9 (in
vitro),1522 which would be expected to raise phenprocoumon
levels.
10) 21-year-old woman using 3 grams daily of
standardized St. John’s wort for 3 months was slow to emerge from general
anesthesia induced with fentanyl and propofol and maintained
with sevoflurane and nitrous oxide. Eight hours later she had
recovered (PO in human case report).1289
11) The benzodiazepine drug midazolam blood levels were reduced by
60% when the drug was given orally after 12 days of taking 900 mg/day of St.
John’s wort (PO in human study). Midazolam is a specific substrate for CYP 3A4.1096
A single 900 mg dose of St. John’s wort extract standardized to 0.3% hypericin
had no effect on oral midazolam given to 12 healthy subjects. However, after 2
weeks of 900 mg extract daily, serum levels of midazolam were reduced by
>50% when midazolam was given orally and by 20% when medazolam was given IV
(PO in human study).1217 Another study of 12 days with 21 subjects
using 900 mg daily of the extract LI 160 standardized to 0.3% total hypericins
also found a greater increase in midazolam clearance after administration
orally (2.7-fold) than by IV dosing (1.5-fold) (PO in human study).1590 Other reports
noted St. John’s wort extract 900 mg/day for 50 days increased clearance only
when midazolam was taken orally, not when systemically (PO and IV in human
studies).1524,1809 900 mg daily for 28 days of an extract that
delivered 4.8 mg hyperforin per day induced midazolam metabolism by 141%, when
measured as a single timepoint phenotypic metabolic ratio (PO in human study).1808
In a 10-day study 900 mg of a St. John’s wort preparation significantly reduced
midazolam bioavailability and increased its systemic clearance similarly among
5 subjects in each of 6 ethnic groups: White, Black, Hispanic, Mayla, Indian,
and Chinese. The induction of CYP 3A4 was greater in the intestines than in the
liver (PO in human study).1613
Midazolam metabolism by CYP 3A4 was also induced by
hypericin-standardized St. John’s wort in 12 healthy subjects after using 300
mg 3 times daily for 28 days (PO in human study).1328
However, when 1 gram/day of
St. John’s wort herb providing only 0.06 mg total hyperforins, 0.6 mg total
hypericins, and 17.8 mg total flavonoids was given daily for 14 days to 20
healthy men, the bioavailability of midazolam was significantly but mildly
reduced by 11% and apparent oral clearance increased by 22% compared to
baseline, though other pharmacokinetic factors such as maximum concentration
and half-life were no significantly changed (PO in human study). Since 90%
confidence intervals of all pharmacokinetic parameters were within no-effects
limits, the mild induction of CYP 3A by the low hyperforin content of this herb
was not considered clinically relevant.2598 When 42 men took 1 of 6
other St. John’s wort preparations for 14 days, these also reduced midazolam
bioavailability compared to baseline based on their hyperforin content: e.g.,
79% by 900 mg of LI 160 with 41 mg/day hyperforin, 48% by 2.7 grams of St.
John’s wort powder tablets with 12 mg/day hyperforin, and 21% by 2.7 grams of
powder tablets with 0.13 mg/day hyperforin (PO in human study). The
bioavailability of midazolam correlated with the hyperforin dose and
significantly with flavonoid dose but
not with hypericin dose.2599
The related drug alprazolam is another CYP
3A4 substrate that showed increased clearance and decreased bioavailability
when 900 mg daily St. John’s wort extract LI 160 was given for 2 weeks prior
and concurrently to 12 healthy subjects (PO in human study).1478
However, no effect on
alprazolam metabolism occurred with 240 mg daily of an extract that delivered
only 3.5 mg hyperforin per day for 10 days (PO in human study).1775
This extract, Ze 117 with 0.2% hypericins and 0.35% quercetin, has shown
year-long safety and efficacy for mild to moderate depression (PO in human
clinical trial).2576 So adequate hyperforin dosage and duration are
both necessary factors for inducing CYP 3A4, but hyperforin is not essential
for an antidepressant effect.
The constituents hyperforin, hypericin, and
I3,II8-biapigenin are potent inhibitors of CYP 3A4 (in vitro).1522
The unreliability of inhibitory test tube results using constituents in
predicting herb and extract effects in humans is thereby demonstrated.
In a randomized, placebo-controlled, double-blind,
crossover trial 900 mg daily of an extract standardized to 0.3% hypericin was
given for 14 days to 13 healthy subjects and reduced the bioavailability of a
single dose of the benzodiazepine quazepam (PO in human study). While
reducing drug concentrations, the sedative drug effect was not altered
pharmacodynamically by St. John’s wort with its distinct measurable psychomotor
effect.1819
+ 12)
[previously III. 1)] Oral clearance of the HIV non-nucleoside reverse transcriptase
inhibitor nevirapine, a substrate of
P-glycoprotien, is increased with concurrent use of St.
John’s wort which should therefore be avoided. Five male HIV patients aged 34-53 were treated
with nevirapine while concurrently using SJW for several months. No forms or
doses of St. John’s wort were specified. Nevirapine plasma concentrations were
reduced with St. John’s wort intake compared with prior values. Oral clearance
was increased 35% when taking St. John’s wort preparations (PO in human clinical
study).1188
+ 13)
After safely taking 2 tablets of St. John’s wort with 1 tablet of valerian
daily for six months for her depression and migraines, a woman was hospitalized
with delirium, rapid breathing, rapid heart rate, and mild hypertension
following the additional use of loperamide for diarrhea (PO in human
case report). The patient recovered in two days after naltrexone was given to
counteract the drug. A MAO-inhibitor reaction was theorized, possibly in
conjunction with loperamide-induced delirium.1227
+ 14) 300 mg of LI 160 taken three times daily for two weeks prior to administering single doses of simvastatin and pravastatin to 8 healthy males each resulted in lower plasma levels of simvastatin and its active metabolite, simvastatin hydroxy acid, but pravastatin plasma concentration was not influenced (PO in human study). Simvastatin is a substrate of P-glycoprotein and CYP3A4 in the intestinal wall and liver, but pravastatin is not a substrate for P-glycoprotein or CYP3A4.1250
In a controlled, randomized, crossover trial with a
4-week run-in, 16 hypercholesterolemia patients on a stable dose of atorvastatin
received 600 mg daily of a commercial St. John’s wort product and a multivitamin
control for 4 weeks each (PO in human clinical study). After the botanical use
period, the serum LDL cholesterol level was increased compared to the control.
Atorvastatin is a CYP 3A4 substrate, but its levels were not monitored.2200
+ 15)
A woman with bipolar I disorder experienced psychotic mania after taking St.
John’s wort at an unknown dose for two weeks together with maintainence doses
of lithium, clonazepam and olanzapine (PO in human case
report)1269
+ 16) Chlorzoxazone
metabolism by CYP 2E1 was enhanced by hypericin-standardized St. John’s wort in
12 healthy subjects after using 300 mg 3 times daily for 28 days (PO in human
study).1328 In 12 healthy elderly subjects, the metabolism of
chlorzoxazone was increased by 28% (PO in human study).1808
+ 17) A single 900 mg dose of
St. John’s wort inhibited intestinal P-glycoprotein, increased the maximum
plasma concentration of fexofenadine by 45%, and decreased its oral
clearance by 20%. Compared to a single dose, 2 weeks of using 300 mg St. John’s
wort three times daily reversed this effect and decreased fexofenadine maximum
plasma concentration by 35% and increased its oral clearance by 47%, but there
was no difference from baseline when compared to no St. John’s wort treatment
(PO in human study).1331
However, a study of 12 days
with 21 subjects using 900 mg daily of the extract LI 160 standardized to 0.3%
total hypericins found a greater increase in fexofenadine clearance after oral
administration by 1.6-fold (PO in human study).1590
In a 10-day study 900 mg of a St. John’s wort preparation significantly
increased fexofenadine oral clearance similarly among 5 subjects in each of 6
ethnic groups: White, Black, Hispanic, Malay, Indian, and Chinese (PO in human
study).1613
+ 18)
5 cancer patients receiving 900 mg daily of a St. John’s wort product together
with the CYP 3A4 substrate irinotecan (CPT-11) in a randomized,
unblinded crossover study had a reduction in plasma levels of its active
metabolite SN-38 by 42% and a decrease of its detoxified metabolite APC (PO in
human clinical study).1342
However, the authors suggest
that induction of irinotecan metabolism resulting in lower levels of the active
metabolite SN-38 and inactive APC may be due to prior metabolic induction of
CYP 3A4 by the comedication dexamethasone, leading to other inactive
metabolites (speculative).1342 Otherwise, inducing CYP 3A4 with
either dexamethasone or St. John’s wort would be expected to lead to an
increase of APC (speculative).
St. John’s wort extract LI-160 given at 400 mg/kg
reduced the bioavailability of SN-38 glucuronide after 3 days of pretreatment
and SN-38 after 14 days of pre-treatment, whereas SN-38 glucuronide bioavailability
tended to rise after 2 weeks (PO in rats).2163 Ethanolic extract of
St. John’s wort at a concentration of5 mcg/ml decreased SN-38 glucuronidation
in rat hepatic microsomes but increased its glucuronidation in rat hepatoma
cells (in vitro).2165 Both early and late-onset diarrhea were
reduced when the extract was combined with irinotecan, and decreases in
neutropils, lymphocytes and platelets were also lessened (PO in rats).2163
Besides decreasing intestinal apoptosis from irinotecan on days 5-11, the same
dose of the extract for 8 days led to reduced production of pro-inflammatory
cytokines TNF-alpha mRNA during the same time period (PO in rats).2164
+ 19)
A patient on the immunosuppressant drug tacrolimus after a kidney
transplant had lower blood levels of this drug a month after taking 600 mg
daily of a St. John’s wort extract. Tacrolimus levels returned to the previous
range after stopping use of the herb extract (PO in human case report).1349
Ten renal transplant patients receiving tacrolimus and mycophenolic acid were
subjected to 600 mg St. John’s wort extract for 14 days. After 2 weeks the
bioavailability of tacrolimus was significantly reduced. The average tacrolimus
dose required an increase from 4.5 mg/day to 8.0 mg/ day to maintain
therapeutic levels (PO in human trial). Mycophenolate mofetil kinetics were
unaffected.1376 Ten healthy volunteers
received tacrolimus, a substrate for CYP 3A4 and P-glycoprotien, prior to and
during a course of St. John’s wort 900
mg daily for 18 days. St. John’s wort reduced AUC and increased oral clearance,
probably due to induction of both CYP 3A4 and P-glycoprotein.1552
+ 20)
In 6 strong CYP2C19 metabolizers, but not in 6 poor metabolizers, 900 mg daily
for 14 days of St. John’s wort extract containing 4% hyperforin and 0.3%
hypericin increased metabolism of mephenytoin significantly (PO in human
study).1584
However, when 3 different
St. John’s wort extract products were tested they inhibited CYP2C19 (in
vitro).1593 St. John’s wort appears to inhibit CYP 2C19 in the
first 10 hours but induce this isozyme after 15 days of use (PO in human
study).1839
+ 21)
St. John's wort standardized extract at 900 mg/day given for 14-47 days to 4
patients on methadone resulted in a 19%-60% (median 47%) decrease in
methadone plasma concentration to dose ratios (PO in human clinical trial).
Methadone is a substrate of P-glycoprotein and CYP 3A4. Two patients reported
opioid withdrawal-like symptoms.1641
+ 22)
St. John's wort 900 mg daily for 2 weeks in 10 healthy subjects reduced the
maximum concentration of a single dose of imatinib mesylate by29%, its
half-life by 21%, and its bioavailability by 32% (PO in human study).
Coadministration may compromise the drug's clinical efficacy which is both dose
and concentration dependent.1668 Twelve healthy subjects taking 900
mg/day for two weeks of extract LI160 increased clearance of a single dose of
imatinib by 43% compared to baseline, while its metabolite was increased
significantly. Half-life and maximum concentration were significantly decreased
and bioavailability reduced by 30% (PO in human study). Imatinib is metabolized
by CYP3A4, and metabolite N-desmethyl-imatinib is active in vitro.1692
+ 23)
900 mg of extract with 0.3% hypericins and at least 4% hyperforin given daily
to 12 men for 14 days reduced the peak plasma concentration and bioavailability
of a single dose of omeprazole by 38% (PO in human study). Induction of
isozymes increased both CYP 2C19 metabolite 5-hydroxyomeprazole and CYP 3A4
metabolite omeprazole sulfone.1674
+ 24)
900 mg of extract with 3-6% hyperforin given daily for 14 days to 8 males
reduced the biavailability of the R- and S-enantimers of verapamil by
51% and 63%, respectively, due to first-pass CYP 3A4 metabolism, most likely in
the gut (PO in human study).1675
+ 25)
In 22 healthy subjects 900 mg/day for 18 days reduced nifedipine peak
concentration by 53% 0.5 hour after a single dose (PO in human study).1728
When 10 healthy subjects were given a St. John’s wort preparation standardized
to 0.3% hypericin and 5% hyperforin at a dose of 900 mg/day for 14 days,
followed by a single dose of the calcium channel blocker drug
nifedipine, the drug’s maximum plasma concentration and bioavailability were
significantly reduced (PO in human study). Consequently, the maximum plasma
concentration and bioavailability of the metabolite dehydronifedipine were
significantly increased.2623
+ 26)
When 900 mg LI 160 daily was given 16 men and the CYP 3A4 and 2C19 substrate voriconazole
was taken after 1 day, bioavailability was increased 22% in the first 10 hours,
but after giving the extract LI 160 for 15 days, the voriconazole 10-hour
bioavailability was reduced 43% (PO in human study).1839 Initial
inhibition of metabolism followed by induction could be due to the influence of
different active components (speculative);2621 its components
quercetin,1854 I3,II8-biapigenin, hyperforin,1522 and
hypericin840,1522,1854 all inhibited CYP 3A4 in vitro, while
CYP 3A4 induction occurs primarily through hyperforin activation of pregnane X
receptor (in vitro). 1002,1288,1703
+ 27)
The administration of 900 mg/day of the extract for 12 days to 9 subjects
caused a significant decrease in peak serum concentration and bioavailability
of orally-administered talinolol due to induction of P-glycoprotein (PO
in human study).1972
+ 28)
A 58-year-old woman who had taken 300 mg of a St. John’s wort preparation once
daily for several years began taking bupropion for 4 days when she
developed oro-facial dystonia on the right side of her face (PO in human case
report). These episodic spasms occurred every 3-4 minutes and lasted about 45
seconds, during which her eyes would roll back and she could not communicate.
Between attacks she was normal. She was treated with parenteral
chlorpheniramine, procyclidine and diazepam which lengthened the spasm-free
intervals but otherwise had no effect. She was released after 1 week and later
given solium valproate with little effect; carbamazepine later produced some
response. The dystonia became less frequent over 5 months and completely
resolved, so all medications were gradually withdrawn with no dystonia
recurrence. It was recommended not to combine St. John’s wort and bupropion
use.2280
+ 29)
In a 49-year-old man with recurrent depression and secondary sexual dysfunction
from sertraline treatment that recurred when St. John’s wort was used in its
stead, sildenafil was found to alleviate the impotency (PO in human case
report).2084
+ 30)
St. John’s wort extract LI 160 given at 900 mg daily for 14 days increased
demethylation of erythromycin 1.44-fold, indicating an induction of CYP
3A4 (PO in human study).1350
+ 31)
Use for 2 months of tablets containing an extract derived from 2 grams dry
herb, standardized to 1 mg hypericin and combined with 250 mg typrosine and 25
mg magnesium, by a 27-year-old woman taking buspirone for 4 months
resulted in nervous and hyperactive symptoms associated with serotonin syndrome (PO in
human case report). After tapering off the St. John’s wort product, these
symptoms disappeared within a week.2627 In a 42-year-old woman
receiving 20 mg b.i.d. fluoxetine with 20 mg b.i.d. buspirone for major
depression, hypomania characterized by anxiety, insomnia, and panic developed
when she began taking uncharacterized
St. John’s wort extract, Ginkgo biloba extract, and melatonin for
several weeks (PO in human case report). After discontinuation of the
nonprescription items, the anxiety diminished and behavior improved over the
next several months.2628
+ 32)
In 5 HIV-1 patients taking the non-nucleoside reverse transcriptase inhibitor (NNRTI)
nevirapine and 2 nucleoside analogue reverse transcriptase inhibitors
for over a year, St. John’s wort was also used for several months and was
associated with a significant 35% increase in oral clearance (PO in case
series). Since this could result in antiretroviral resistance and possibly
treatment failure, it is recommended that concurrent use of of St. John’s wort
and nevirapine be avoided.2629
+ 33)
After 12 healthy subjects were given a single dose of ivabradine
followed by 300 mg t.i.d. of a commercial St. John’s wort extract for 14 days,
the subsequent metabolism of another dose of ivabradine and its main active
metabolite after the 2 weeks was increased as indicated by significantly less
bioavailability and lower maximum plasma concentration of the drug and its
active metabolite than at baseline (PO in human study).2630
+ 34)
The ingestion of a single 80 mg dose of gliclazide before and after 15
days of 300 mg t.i.d. LI 160 extract resulted in significantly lower
bioavailability if all but 4 of 21 subjects, independent of their CYP2C9 genotypes
(PO in human study). The gliclazide clearance was increased and its half-life
decreased following 2-week use of the extract, but insulin and glucose levels
were unaffected when 75 grams of glucose was given a half hour after the oral hypoglycemic
drug.2624
However, though gliclazide
is metabolized by CYP 2C9,2624 no effects on the metabolism of the
oral hypoglycemic tolbutamide by CYP 2C9 were found with long-term oral use of
900 mg standardized extract of St. John’s wort daily (PO in human study).1217
Likewise, no changes in metabolism of the CYP 2C9 substrates S(+)- or
R(-)-ibuprofen stereoisomers were found after 21 days use of 0.03% hypericin-standardized St. John’s
wort extract at 900 mgs daily in 8 males (PO in human study).2079
A single dose of the oral hypoglycemic drug and CYP
2C8 substrate rosiglitazone was found in 27 subjects to have
significantly reduced bioavailability and increased clearance after daily use
of 900 mg of an uncharacterized St. John’s wort product, independent of the CYP
2C8 genotype (PO in human study).2635
+ 35)
After two weeks of giving the tricyclic antidepressant drug
amitriptyline to 12 patients with depression, combining it with 900 mg/day
of extract LI160 for two weeks led to a significant decrease in bioavailability,
peak and trough plasma concentrations, and urinary excretion of amitriptyline
and most of its metabolites (PO in human clinical study). The effect seems to
be largely due to induction of P-glycoprotein, though CYP 3A4 and 2C19 may be
involved. Amitriptyline did not significantly affect the metabolism of the
hypericins or hyperforin, nor did individual cytochrome P450 genotypes affect
theses outcomes at the end of the four weeks.1614
+ 36)
A 59-year-old man whose elevated total cholesterol and LDL-cholesterol were
being contolled by rosuvastatin took 300 mg St. John’s wort b.i.d. for 4
months; the lipid levels were re-elevated on a routine test (PO in human case
report). After refraining for 4 months from the herbal product that also
contained 80 mg rosemary (Rosmarinus officinalis) and 40 mg spirulina,
his blood lipids had returned to prior treatment levels.2631
However, rosuvastatin is not
a substrate for CYP 3A4 or P-gp, and only 10% is metabolized hepatically by
CYPs 2C9 and 2C19 that are also induced by St. John’s wort.2631
Other factors may have contributed to this case, since rosuvastatin
bioavailability can be reduced by a several drugs including aluminum and
magnesium antacids or erythromycin, according to its pharmacokinetic profile.
+ 37) Of 20 women undergoing breast cancer
treatment assessment with a photodiagnostic utilizing d-aminolevulinic acid [ALA] to induce
protoporphyrin IX, 19 did not suffer photoxic reactions but the 1 using a St.
John’s wort extract had a burning rash and severe swelling on the face, neck
and hands (PO in case report). Only light-exposed body parts were affected, and
she was not previously photosensitive or allergic. After 3 days of
corticosteroid treatment, her skin peeled and recovery was complete. On testing
the ALA with and without the St. John’s wort preparation on human keratinocyte
cells, a synergistic effect of light sensitization was demonstrated with the 2
photosensitizing agents (in vitro).2633
II. 1) Extract enhanced sleeping time from alcohol and antagonized the effects of reserpine (PO in mice),51 though a secondary source
reports that, in terms of cognitive abilities, no interaction was observed with
alcohol and St. John’s wort in a human trial.1890
A St. John’s wort 0.3% hypericin extract in doses that did not affect general behavior or food intake reduced the amount of ethanol intake in alcohol-preferring rats offered 10% ethanol for 2-10 hours. The extract did not alter the absorption or metabolism of ethanol (PO in rats).1479 St. John’s wort extracts, especially those with high hyperforin content, reduce voluntary alcohol intake when used in chronic treatments (PO in rats)1470 A comparitive study of a St. John’s wort methanolic extract with 0.3% hypericin and 3.8% hyperforin with a carbon dioxide extract with neglible hypericin and 24.3% hyperforin found the higher hyperforin extract reduced the ethanol intake over a 2-hour exposure period about 8 times more. At higher doses of hyperforin the blood-alcohol level was also reduced. The neurochemical mechanism for reducing alcohol appears to be different than the antidepressant effect (PO in rats).1480 Tests using the extract with 3.8% hyperforin found antidepressant-type activity involved alpha-receptors and some serotonergic neurotransmission, but blocking these effects did not alter the reduction in ethanol consumption (PO in rats).1481 Giving GABAA,B receptor blockers likewise did not alter ethanol-intake reduction when using the extract with 24.3% hyperforin, indicating that St. John’s wort GABA agonist effects are not responsible for reducing ethanol cravings in alcohol-preferring rats (PO in rats).1482
+ 2)
Ethanol extract prolonged the time it took for sleep to be induced by pentobarbital
and also reduced muscle relaxant effect of diazepam (IP in mice).1338
+ 3) Combining hypericin with the chemotherapy drug temozolomide enhanced the antiglioma effects (in mice). In human
glioblastoma multiforme cell line the apoptosis-stimulation and
growth-inhibition induced by temozolomide was greatly increased by hypericin (in vitro).2657
III. 1) Due to concern over potentially-enhanced metabolism of drug substrates
of CYP3A4 by St. John’s wort, it should not be used concomitantly with
other crucial drugs that have a potential for interaction due to metabolism by
these pathways (speculative).1330
The component hyperforin acts as a potent ligand for
activating the steroid X receptor or pregnane X receptor (in vitro) that in turn regulates expression of CYP3A4.1288,2127
+ 6) Drugs that have a potential for reduction due to increased metabolism by pathways induced by St. John’s wort include anti-cancer drugs such as etoposide (speculative).1003,1330 Induction of P-glycoprotein is associated with resistance to anthracyclines, vincristine, vinblastine, epipodophyllotoxins, taxanes, and they may be reduced by hypericin (speculative).1498 In addition, hypericin has been shown to antagonize the inhibitory activity of etoposide and amsacrine against topoisomerase II (in vitro)1348 and likewise may inhibit dactinomycin activity (speculative).1498
+ 7)
At clinically relevant, low concentrations both St. John’s wort and hypericin
caused significant induction of P-glycoprotein in intestinal cells and reduced
absorption of rhodamine 123 (in vitro).1366
8) Inducement of exogenous steroid metabolism (speculative) was suggested by enhanced
6-beta-hydroxycortisol urinary excretory rate relative to cortisol
excretion in 48 volunteers given 1800 mg daily for 2 weeks (PO in human study).1595
Hyperforin is the extract component that acts as a potent ligand for activating
the steroid X receptor or pregnane X receptor (in vitro) that in turn regulates expression of CYP3A4.1002,1288,2127
However,
after giving 900 mg daily for 4 weeks of an extract standardized to 0.3%
hypericin and a “minimum” of 4% hyperforin to 8 male adults, the
pharmacokinetics of a single dose of prednisone and its metabolite prednisolone were not
altered compared to baseline values (PO in human study).2216
STEVIA NEW
^ Stevia
rebaudiana leaves
Drug
Interactions
II. 1) Stevioside reduced insulin
resistance in noninsulin-dependent diabetic animals and increased the blood
sugar-lowering effects of tolbutamide (PO
in rats). The component stevioside lowers blood glucose levels in diabetic rats
when given twice daily, reduces the rise in glucose in normal rats during a
glucose tolerance test, and slows gluconeogenesis (PO in rats).1783
STINGING NETTLE p.
184
Urtica dioica leaf
Contraindications
+ 4)
Brittle diabetes (speculative)893,2250 due to the
hypoglycemic effect shown in animals (PO in rabbits)89,319
An increased insulin secretion has been shown with
an active fraction of the leaf decoction (in vitro, IP in rats).2251
However, both the herb
decoction and its 80% ethanolic extract increased blood sugar levels when given
at doses equivalent to 25 grams of dry herb per kg body weight 2 hours prior to
a 5 mg/kg dextrose feeding (PO in mice).2252
Drug Interactions
II. + 1) Pretreatment with 50-200 mg/kg of a freeze-dried water
extract of nettle reduced ulcer formation by 61-72% when 70% ethanol was
given orally (PO in rats).2071
SWEET
ANNIE NEW
^ Artemisia
annua plant
(Chinese wormwood, annual wormwood; Ch.: qing hao)
Contraindications
1) Pregnancy (speculative)150,404 due to potential
teratogenicity of the component artemisinin (speculative)404
Drug Interactions
I. 1) Artimisinin given at 250 mg/day to 14 subjects for for 9
days and 500 mg on day 10 induced N-demethylation of mephenytoin
probably by CYPs 2B6 and 2C19 (PO in human study).1512 Artimisinin
also induced its own metabolism, likely by the same mechanism.1512
2) Artimisinin given at 500 mg/day to 9 subjects for for
7 days increased the metabolism and reduced the bioavailability of omeprazole
by inducing CYP 2C19 (PO in human study).1931
SWEET CLOVER p.
185
*Melilotus
officinalis plant
Drug Interactions
I. 1) With woodruff and tonka beans providing additional
coumarin, added to bromelain, induced a hemorrhagic
diathesis (human case report) probably from conversion of coumarin by mold (speculative).31
Coumarin alone does not influence coagulation,
clotting factors, or fibrinolysis (PO in human study).1738
SZECHUAN LOVAGE NEW
^ Ligusticum
chuanxiong = Ligusticum wallichii rhizome
(Ch.: chuan xiong)
Contraindications
1) Pregnancy (empirical)150
SZECHUAN PEPPER NEW
^ Zanthoxylum
simulans, Zanthoxylum bungeanum, Zanthoxylum schinifolium fruit rind
(Ch.: chuan jiao)
Contraindications
1) Pregnancy (empirical)150
TEA p.
186
Camellia sinensis leaves
Contraindications
2) Duodenal ulcers
(speculative) possibly due to increased gastric acid secretion after large
doses of caffeine,8
though a water extract of black tea at 2 gm/kg body
weight did not significantly increase total gastric acid but reduced acid,
ulcer incidence, and ulcer number induced by aspirin, inodmethacin, ethanol,
reserpine, and cold restraint stress (PO in rats)492
3) Heart disorders
(speculative) due to caffeine increasing heart rate or exacerbating arrhythmias
(empirical).8
Caffeine at a dose of 250 mg acutely increased
aortic stiffness in 20 healthy subjects, leading to increased blood pressure
centrally and to a lesser extent peripherally (PO in human study). These
effects may impact cardiovascular risk (speculative).1569 However, a
study of 155,594 women over 12 years found no linear association with caffeine
consumption and hypertension (PO in human study).1859
5) Prolonged
use of fermented black tea (speculative)150 due partly to
calcium and magnesium loss with potential for osteoporosis (SC in rats, PO in
human studies)150,753, 774,780
Guarana extract with 150 mg of caffeine plus black
tea extract yielding 120 mg raised systolic blood pressure and resting
metabolic rate 2 hours after a single dose in 16 healthy male subjects (PO in
human study).1973
However, an epidemiological
survey of 497 men and 540 women over age 30 found 502 were habitual tea
drinkers (91% consuming oolong or green tea) for 10 years on average. Compared
with the non-habitual tea drinkers, those whose habitual use was from 6-10
years had higher lumbar spine bone mineral density, and habitual tea consumers
over 10 years had the highest bone mineral density in all measured regions (PO
in human study).1469
6) Pregnancy (speculative)
since caffeine has been associated with fetal loss, low birth weight and
premature deliveries.8
In an evaluation of 2,291 mothers caffeine
consumption was found to reduce average birth weight. This was considered
significant for those who consumed more than 600 mg of caffeine daily (PO in
human study).1568 However, a study of 2,714 women who delivered live
infants in which tea was consumed in the first month by 25% of the women found
that > 300 mg caffeine daily from all sources was not associated with growth
retardation (PO in human study).1966
However, a prospective study
of 873 women found no association between caffeine consumption at any amount
and birth weight, gestational age at delivery, or birth weight standardized for
gestational age (PO in human study).1672
+ 9)
A concentrated
aqueous-ethanolic extract of green tea associated with at least 13 cases of
hepatitis in 12 women and 1 man from France and Spain leading to increases in
liver enzymes and total and direct bilirubin, after taking it from 9 days to 5
months (PO in human case reports).1508,1579,1580,2328,2577 Causality
was determined on the Naranjo scale as possible in 11 cases and probable in 2
cases.2577 Viral serologies tested negative in 8 cases, while one
positive rechallenge and 8 positive dechallenges occurred (PO in human case
reports). Resolution occurred after discontinuance in 12 cases; 1 requiring
liver transplantation was complicated by concurrent alcohol and drug use.1508,1951,2577
This 48-year-old woman who drank 30 gm of alcohol daily for 10 years took 4
capsules per day of an a hydroalcoholic extract of green tea leaves for 6 weeks
before developing stomach pain, fatigue, and then jaundice, dark urine and pale
stools (PO in human case report). She stopped taking the extract and other
medication but took 1 gm of acetaminophen on the day the jaundice began. Two
weeks later she was admitted to the hospital for liver insufficiency. After a
biopsy showed necrosis and fatty liver and fibrosis, she was given a liver
transplant. The causative factors were likely additive.1951 In a
clinical study on obesity of this tea extract AR25, an ethanolic dry extract
standardized to 25% catechins, one person in 70 subjects had an increase of
liver enzymes after using four capsules containing a total of 375 mg catechins
daily for three months (PO in human clinical study).1345
Different products with concentrated green tea
extracts, some combined with other ingredients have also been associated with
hepatotoxicity, including at least 4 cases involving an aqueous extract.2577
A 37-year-old woman with
acute liver toxicity for 10 days with jaundice and nausea had used a weight
lost supplement for 4 months containing green tea extract, magnolia extract,
epimedium extract, b-sitosterol, calcium, chromium, and vanadium (PO in case report). She
had greatly elevated liver enzymes but recovered when the product was
withdrawn, but it recurred when it was re-introduced, and she recovered again
after a second withdrawal period.2328 Two men 27 and 30 years of age
developed jaundice, fatigue and elevated liver enzymes after 5 days or 4 weeks
of using 9 tablets daily of a combination weight loss product with green tea
extract along with Garcinia cambogia, Gymnema sylvestre leaf
extract, willow bark extract, guarana extract, and caffeine, glucomannan,
a-lipoic acid, L-carnatine, calcium, chromium, and potassium (PO in human case
reports). Both recovered within 1-2 months after withdrawal, but the evidence
is not definitive nor a causative ingredient certain.2329
However, dilute liquid
infusion of green tea leaves commonly consumed as a beverage are not implicated
in liver toxicity cases.2577 Also, a systematic review on green tea,
extract, and/or catechin consumption and liver disease revealed that of 10
human trials published, 8 found a significant protective effect against various
liver diseases, though 2 only showed a partial tendency (PO in human clinical
studies). Four showed a positive attenuation of liver disease, and these all
were based on intake of aqueous infusions of green tea.2496
+ 10)
Beriberi or any thiamine deficiency, since fermented tea leaves
when chewed by 20 volunteers aged 18-40 years caused thiamine deficiency even
when 10 mg/day of thiamine was supplemented (PO in human study). When black tea
was drunk it also created a thiamine deficiency, but this was counteracted when
10 mg/day of thiamine was supplemented in 20 children aged 15-17 years (PO in
human study).2023 When
3-week-old weanlings were given 1:50 w/v black tea to drink and compared with
others given water, those receiving the tea had a progressive drop in brain
levels of total thiamine after 2 weeks, reaching 60% after 14 weeks (PO in
rats). No further decline in brain thiamine was found from 14 to 24 weeks, but
activities of ketoglutarate and pyruvate dehydrogenase dropped by 65% during
this period.2075
Drug Interactions
I. 1) Reduced absorption of iron (PO in human study).382,434
Nonheme-iron absorption is reduced by 70% with
consumption of only 20 mg of tea polyphenols available in a dilution of black
tea to 5%, while the addition of milk had little effect on tea inhibiting iron
absorption (PO in human study).1246 Iron absorption is only affected by tea when
they are consumed together, probably due to the formation of iron complexes
with tannins in the gut (PO in rats).1145 The green tea catechin
epigallocatechin gallate in a doses of 150 mg and 300 mg taken concurrently
with iron reduced its absorption by !4% and 27%, respectively (PO in human
study). Though the effect of the higher dose was significant, it was
substantially less than the reduced iron absorption associated with concurrent
consumption of black tea.1749
Nonheme iron absorption was also reduced by 28% in
10 women after consumption of green tea extract (PO in human study). This was
likely due to the phenolic components containing epicatechin and galloyl
moieties, whose total content in the extract given with test meals was 37.3 mg.1993
3) Increased weight loss occurs due to a reduction
of body fat, along with side effects of agitation, tremors, and insomnia, when
caffeine is combined with ephedrine (PO
in human clinical study).19
When 25 mg ephedrine was taken with 200 mg caffeine,
systolic blood pressure, heart rate, and glucose, insulin and lactate
concentrations were all raised (PO in human study). Taken alone, ephedrine
increased heart rate, glucose, and insulin, and caffeine increase systolic
blood pressure. No pharmacokinetic interaction was found. Oral
contraceptives prolonged caffeine elimination.1665
An 80% ethanolic dry extract of green tea AR25
standardized to 25% catechins inhibited lipases and stimulated thermogenesis (in
vitro). After 3 months of using AR25 with 375 mg catechines (270 mg EGCG)
daily, body weight and waist circumference decreased about 4.5% in obese
patients in open trial. One of the 70 patients had increased transaminases, a
possible indication of liver insult (PO in human clinical study).1345
However, this ethanolic
green tea extract has been associated with cases of liver disorders in France
and Spain after taking it from 9 days to 5 months. One positive rechallenge and
8 positive dechallenges occurred (PO in human case reports).1508,1579,1580
+ 15) Methotrexate efficacy for reducing the joint pain and
morning stiffness of rheumatoid arthritis was diminished for those consuming
260 mg of caffeine daily on average, compared to those who consumed an average
of only 90 mg daily (PO in human clinical study), probably due to
methylxanthines like caffeine acting as adenosine receptor antagonists while
methotrexate increases adenosine.1495
However, 80% ethanolic
extract of green tea with 5-10% caffeine inhibited multidrug resistance-associated protein 2
(MRP2) removal of methotrexate from kidney cells (in vitro). MRP2
function was not affected by caffeine alone.1776
+ 16)
Fermented tea
leaves when chewed by 20 volunteers aged 18-40 years caused thiamine
deficiency even when 10 mg/day of thiamine was supplemented (PO in human
study). When black tea was drunk it also created a thiamine
deficiency, but this was counteracted when 10 mg/day of thiamine was
supplemented in 20 children aged 15-17 years (PO in human study).2023
Also, when 3-week-old weanlings were given 1:50 w/v
black tea to drink and compared with others given water, those receiving the
tea had a progressive drop in brain levels of total thiamine after 2 weeks,
reaching 60% after 14 weeks (PO in rats). No further decline in brain thiamine
was found from 14 to 24 weeks, but activities of ketoglutarate and pyruvate
dehydrogenase dropped by 65% during this period.2075
+ 17)
A study over 13.6 years of 26,556 Finnish men with no history of strokes who
smoked 5 or more tobacco cigarettes daily showed the consumption of 2 or
more cups of tea daily significantly reduced the risk of strokes by cerebral
infarction (PO in human study).2300
II. 2) In another study theanine also enhanced the
inhibition by doxorubicin of hepatic metastasis of ovarian sarcoma (IP
in mice). The doxorubicin concentration was increased 1.4-fold in ovarian
sarcoma cells because theanine inhibited its efflux (in vitro).1245
In addition to the effect of theanine, doxorubicin
concentration in Ehrlich ascites carcinoma cells was also significantly
enhanced by the green tea components epigallocatechin gallate, cyaniding,
dephinidin, and caffeine (in vitro). The inhibitory ratio in P388
leukemia cells was significantly increased along with a reduction in tumor
weight when theanine at 10 mg/kg/day was combined with doxorubicin (IP in
mice).1604 Theanine at 10 mg/kg/day for 4 days likewise induced the
antitumor activity of idarubicin against P388 even at subtherapeutic
doses (IP in mice) by doubling its concentration in tumor cells (in vitro),
while reducing idarubicin toxicity to leukocytes and bone marrow cells (IP in
mice).1605 In addition theanine inhibited pirarubicin efflux
from M5076 ovarian sarcoma cells while increasing its concentration by 1.3-fold
in the tumor and improved the therapeutic efficacy as determined by tumor
weight (IP in mice).1606
+ 4)
Green tea extract increased apoptosis in estrogen-receptor(ER)-positive breast
tumor tissue when combined with tamoxifen compared to tamoxifen alone;
the combinations also decreased MCF-7 graft tumor size and suppressed
angiogenesis more than either agent alone (PO in mice). The extract decreased
the ER-alpha levels in tumors (in vitro, PO in mice) and increased
inhibitory effect of tamoxifen on
proliferation of the ER-positive human breast cancer cell lines ZR75 and T47D,
while blocking ER-dependent transcripton (in vitro).2039
The induction of apoptosis of human lung cancer
cells by epigallocatechin gallate [EGCG] was synergistically enhanced by
tamoxifen, as well as epicatechin from green tea (in vitro). Epicatechin
also increased the apoptotic effects of epigallocatechin and epicatechin
gallate, indicating that it is more beneficial to consume all of the catechins
in green tea than to use one like EGCG in isolation (speculative).2133
+ 5)
The green tea constituent EGCG [epigallocatechin gallate] was shown to
neutralize the antitumor effects of bortezomib against multiple myeloma
(in vivo). In addition, green tea extract and several of its
polyphenolic components, especially EGCG, blocked the cytotoxic effect of this
proteasome inhibitor in multiple myeloma and glioblastoma cells (in vitro).
The chemical antagonism of EGCG was also demonstrated against other boronic
acid-based proteasome inhibitors including MG-262 and PS-IX (in
vitro), but not MG-132, PS-I, or nelfinavir (in vitro) which lack
the boronic acid moiety.2485
However,
the systemic concentration required to inhibit bortezomib activity can only be
achieve by ingesting concentrated EGCG in a fasting state (PO in humans), not
by drinking brewed green tea (speculative).2690 In addition, another
study showed EGCG and bortezomib are synergistic for inhibiting cell
proliferation and inducing apoptosis in the multiple myeloma cell line KM3 (in vitro).2691
III. + 3)
Freeze-dried water extract of Japanese sencha green tea was found to reverse
resistance to methicillin of a resistant strain of Staphylococcus
aureus and reduce resistance to benzylpenicillin of S. aureua
that produce b-lactamase (in vitro). No synergy was found with the extract and
penicillin-resistant gonococci, pneumococci, or Hemophilus influenza.1439
Green tea extract reduced the minimum inhibitory concentration of all b-lactam antibiotics
(benzylpenicillin, oxacillin, ampicillin, cefmetazole, imipenem), but
not other types of antibiotics, that were tested against four methicillin-resistant
strains of S. aureus, but not a methicillin-sensitive strain (in
vitro). Catechins found in green tea including epigallocatechin,
epigallocatechin gallate, and especially epicatechin gallate reduced the
minimum inhibitory concentration for oxacillin in these four strains (in
vitro).1531
+ 4)
Alkaline aqueous extracts of black and green tea were shown to potentiate insulin
activity in glucose metabolism (in vitro).1464 Tea was also
effective in lowering blood sugar in normal, streptozotocin- and
alloxan-diabetic animals (PO in animal studies).319
+ 5)
Green tea polyphenolic fraction inhibited P-glycoprotein leading to increase
retention of rhodamine-123 in ovary cells, while the isolated phenolic
component epigallocatechin gallate produced this effect with vinblastine
in intestinal cells (in vitro)1561
+ 6)
Induction of apoptosis of human lung cancer cells by epigallocatechin gallate
[EGCG] was synergistically enhanced by sulindac, as well as epicatechin
from green tea (in vitro). Epicatechin also increased the apoptotic
effects of epigallocatechin and epicatechin gallate, indicating that it is more
beneficial to consume all of the catechins in green tea than to use one like
EGCG in isolation (speculative).2133
TEA TREE NEW
^ Melaleuca
alternifolia leaf oil
Contraindications
1) Allergic hypersensitivity to tea tree oil or
its components including limonene, alpha-terpinene, aromadendrene,
terpinene-4-ol, and/or eucalyptol as shown with external application (human
study, human case report),672,673,1424 with internal use (PO in
human case report),673 or by inhalation (human case report)1425
Drug
Interactions
I. 1) Component 1,8-cineole (eucalyptol) induces hepatic
microsomal mixed-function oxidase enzyme induction (in rats), resulting in
increased clearance of aminopyrine with
aerosol inhalation of eucalyptol 10 min. daily for 10 days (human study).28
II. 1) Pentobarbital,
zoxazolamine, and amphetamine given
24 hours after an aerosol exposure to 1,8-cineole for 2-10 min/day for 4 days
were effective for a reduced length of time (in rats).28
THUJA p.
190
Thuja occindentalis leaves
(American arborvitae, eastern white cedar, northern
white cedar; Am. Ind.: hackmatack; Czech.: zerav zapadni; Dan.: livsta; Fr.:
thuya d’occident; Ger.: amerikanischer lebensbaum, heckenthuja,
lebensbaumItal.: thuia; Russ.: tuja; Swed.: livstrad)
Contraindications
+ 4) Nursing mothers
(speculative), due to the potential toxicity of its essential oil (empirical)1890
THUNDER GOD VINE NEW
^ *Tripterygium wilfordii
peeled root
(Ch.: lu fan teng, chi hsueh teng,
koikema, lei gong teng, lei ling ting, lei kung teng, mang cao)
Contraindications
1) Pregnancy
due to severe brain anomalies after use by mother in early pregnancy
(empirical)1416
Drug
Interactions
1) A standardized ethyl acetate extract of the
peeled roots was given at increasing does to 10 rheumatoid arthritis patients
who were using NSAIDs; 8 were also taking prednisone at stable
doses. Six of the 10 had improvement at 180 mg, and 8 of 9 had improved
clinical and laboratory findings at doses over 360 mg. Adverse effects included
8 cases of dyspepsia, 2 with nausea, and 2 with diarrhea, 6 other GI
complaints, plus diastolic hypertension (PO in human clinical study).1417
A PCDB study with 35 rheumatoid arthritis patients used standardized ethanol
ethyl acetate extract in doses of 180 or 360 mg/day for 20 weeks. Thirty of the
subjects were using stable doses of NSAIDs, and 21 were taking prednisone.
After 4 weeks 0% on placebo, 40% on the low dose, and 80% on the high dose met
the criteria for clinical response. Adverse effects were minor and occurred in
4 on placebo and in 11 using extracts, with diarrhea in 7 and nausea in 3 the
most common extract problems (PO in human clinical study).1418 In a third study with 121 rheumatoid
arthritis patients, 60 were randomized to receive 180 mg daily of the extract
while 61 were given sulfasalazine; 17 of each were on stable doses of
prednisone, and others were using stable NSAID doses (PO in human clinical
study). Although only about half finished the trial after 24 weeks, subjects
receiving extracts had a significantly better response than for sulfasalazine
based on American College of Rheumatology criteria, as well as significantly
greater IL-6 decreases and similar adverse event profiles.2606
Glycosides from the
extract inhibit PGE2 production by synovial cells and COX-2 mRNA
expression, similar to dexamethasone, but did not act as glucocorticoid
agonists or directly inhibit COX-2 like NSAIDs (in vitro).1419
THYME p.
191
*Thymus spp.
leaves
Contraindications
+ 2) Allergic
hypersensitivity following thyme or other mint family (Lamiaceae), due to
the risk of anaphylaxis (empirical)1890
Drug
Interactions
II. + 1)
Cardiotoxicity from doxorubicin, a widely used antitumor agent, was
reduced by luteolin (PO in mice),1282 a component of thyme also responsible for the
antimutagenic effect of water extracts of this fresh herb and also fresh sage
and peppermint (in vitro)1283
III. + 1) The essential oil from plants of thymol
chemotype enhanced the antifungal activity of amphotericin B against Candida
albicans (in vitro).2365
TOBACCO
p.
191
*Nicotiana
tabacum leaves
Drug Interactions
(The following are based on
smoking tobacco. Smokers may require a higher initial therapeutic dose of drugs
that are CYP 1A2 substrates; likewise, a 10% daily dosage reduction of these
drugs is recommended until the fourth day after abrupt cessation of smoking,
such as in hospitalized patients. This is independent of nicotine replacement.2211)
I. 2) Smoking speeds the elimination of alprazolam up to 50%,2211 and caffeine2008 that has an increased 56% clearance (in human studies).2211
Smoking lowers blood levels of tricyclic antidepressants such
as antipyrine (in human studies)81,345,2008 but the clinical importance has not been established.2211
3) Bioavailability of chlorpromazine is
reduced by 36%, while its serum concentration decreases 25% (in human study),
possibly resulting in diminished sedation (speculative).2211 Also,
tacrine serum concentrations are
three-fold lower, and its half-life is reduced by half, while haloperidol
clearance increasing by 44% and serum concentrations decrease 70% (in human studies).2211
4) Insulin effect is reduced345
probably due to the vasocontrictive of nicotine (speculative).2211
However,
inhaled insulin has greatly increased systemic exposure in smokers, with
greater maximum concentrations of 3-5 fold and bioavailability 2-3 fold greater
(in human studies).2211
Also, the high blood pressure medication propranolol, a beta-blocker with
an increased clearance of 77%, is less effective (in human clinical studies),
probably due to the vasocontrictive and/or stimulant effects of nicotine
(speculative).2211
6) Smoking increases the risk of clots, strokes and
heart attack in women over age 30 who use oral
contraceptives (human clinical studies).81,345
Use in women over 35 years of age on hormonal
contraceptives of any type is contraindicated due to increased risk of serious
cardiovascular adverse effects (human studies).2211
7) For heparin, besides an pharmacokinetic
increase in clearance and decrease in half-life, there is pharmacodynamic
antagonism since smoking has prothrombotic effects (IH in human studies).
Therefore, an increased dosage is usually desirable (speculative).2211
8) The asthma drug theophylline has an increased clearance of 58%-100% and a decreased
half-life of 36% (human clinical studies).2211
+ 10)
Analgesic effect of opioid drugs propoxyphene and pentazocine are
reduced, due at least in part to their increased metabolism by 15-20% and 40%,
respectively (IH in human studies).2211
+ 11)
Metabolism of verapamil occurs more rapidly leading to lower serum
levels and maximum concentration (PO in human clinical study).1304
+ 12)
Smoking increases the CYP 1A2 metabolism of the selective serotonin reuptake
inhibitor (SSRI) fluvoxamine with a 24% increased clearance, plasma concentrations decreased by
32%, and bioavailability 31% less (IH in human study).2211
+ 13)
Psychotropic olanzapine drug metabolism by CYP 1A2 is increased by
smoking, with a 98% increased clearance and serum concentrations decreased by
12% (IH in human study).2211
+ 14)
Smoking decreases the half-life of the antiarrhythmic drug mexiletine by
36% and increase its clearance by 25% due to enhanced oxidation and
glucuronidation (IH in human studies). Another antiarrhythmic medicine, flecainide,
has 61% increased clearance and 25% decreased trough serum concentration that
may require an increase in dosage for smokers (IH in human study).2211
+ 15)
CYP 1A2 metabolism induced by smoking decreases clozapine plasma
concentrations by 18% (in human study).2211
+ 16)
A study over 13.6 years of 26,556 Finnish men with no history of strokes who
smoked 5 or more tobacco cigarettes daily showed the consumption of 8 or more
cups of coffee or 2 or more cups of tea daily significantly
reduced the risk of strokes by cerebral infarction (PO in human study).2300
+ 17)
Tobacco smokers taking the antiplatelet prodrug clopidogrel had lower
platelet aggregation and glycoprotein IIb/IIIa expression than nonsmokers using
the prodrug (IH in human clinical study). Since clopidogrel is metabolized by
CYP 1A2 to it activate form, induction of this isozyme by tobacco smoke
increases the drug effect.2306
+ 18) Nicotine is more slowly metabolized
when consumed with menthol in mentholated tobacco smoke (IH in human
study).2309 Reservoir formation for the carcinogenic benzo[a]pyrene
and NNK found in tobacco smoke is increased in mucosal (esophageal) cells by
menthol (in vitro),2310 possibly helping to explain the
elevated esophageal squamous cell carcinoma and lung cancer rates in African
Americans, since a greater percentage of cigarette smokers in this ethnic group
use mentholated cigarettes (75%) than in white smokers (10-15%).2309,2310
Also, in a smoking cessation study with 265 African
Americans receiving bupropion, 60.3% non-menthol cigarette smokers were
abstinent after 6 weeks compared with only a 36.2% abstinence rate for
mentholated cigarette smokers (PO in human clinical study).2311
III. + 1) Inhaled corticosteroids may have
reduced efficacy in asthma patients who smoke tobacco (speculative).2211
TRITICUM [formerly COUCH
GRASS] p.
77
Ä Elymus
repens = Agropyron repens roots,
rhizomes and short stems
TURKEY TAIL p.
193
Trametes versicolor
= Coriolus versicolor mycelia extracts
Contraindications
1) Autoimmune
diseases or bone marrow
transplant due to immune enhancing effects (speculative)1375
Drug
Interactions
I. + 6)
137 randomized patients who received 3 grams/day of PSK along with tegafur/uracil
for 2 years or until tumor recurrence, beginning two weeks following surgery
and bolus doses of mitomycin C for Stage II and II colorectal cancer, had
decreased recurrence, especially lung metastases, as well as reduced mortality
and increased 5-year disease-free survival (PO in human clinical studies).2537
They also had reduced
immunosuppressive acidic protein [IAP] and increased natural killer [NK] cells
for the first year, compared to 68 tegafur/uracil chemotherapy-only
controls (PO in human clinical studies). Among those receiving PSK with IAP
values < 500 mcg/ml the 5-year disease-free rate was significantly
better than for controls, as it was for those on PSK with NK cell populations >8%
3 months after surgery. Also, the overall survival rate was significantly
better than controls for those receiving PSK with IAP values < 500
mcg/ml.2536
+ 7)
Of 520 gastric cancer patients treated with mitomycin C on the day of surgical
resection and with futraful for 1 year, PSK at 3 g/day was given to 264
who showed a significant increase in 5-year survival [71.7% for PSK vs. 58.5%
for controls] (PO in human clinical study).2538
However, when only futraful
was given to 406 patients after gastric cancer surgery for 3 months with two
months rest, and PSK was given at 3 g/day to 198 of these during the rest
period, there was no significant difference between the groups though those
taking PSK tended to show increase 5-year survival [71.3% for PSK vs. 63.6% for
controls] (PO in human clinical study).2538
III. 1) Immunosuppressants may be counteracted by turkey
tail decoctions or dried extract due to stimulation of various immunocompetent
cells (speculative)1375 as has been shown with PSP in animals (PO in
rats).1091
TURMERIC p.
194
Curcuma aromatica,
Curcuma longa = Curcuma domestica root
Contraindications
1) Avoid in bile duct obstruction
(empirical).4,6,17,150,1890
This is due to curcumin’s cholagogue activity, since
a 50% contraction of the gall bladder was produced with a 40 mg dose of
curcumin in 12 healthy subjects (PO in human study).2194
2) Do not use in cases of gallstones unless a physician has first been consulted
(speculative).4,17,150,1890
This is because of curcumin’s cholagogue effect,
since a 50% contraction of the gall bladder was produced with a 40 mg dose of
curcumin in 12 healthy subjects (PO in human study).2194
Drug
Interactions
I. 1) Curcumin at a dose of 550 mg twice daily for 1 month and
then 3 times daily for another month was used in 5 ulcerative proctitis
patients receiving 5-aminosalicylic acid locally with sulfasalazine,
prednisone, or azothiopine internally (PO in human clinical
study). All 5 improved as 2 eliminated, 2 reduced, and 1 left unchanged their
conventional medications. One of those who reduced the drugs completely stopped
using prednisone.2195
2) In a group of 5 with Chrohn’s disease, 4 improved from
using 1080 mg curcumin daily for a month
and 1440 mg per day for another month along with 6-methylprednisone in 3
patients or with budesonide in 1 subject (PO in human clinical study).
All four of these improved, whereas the patient with no medication aside from
curcumin withdrew due to worsening fistula.2195
3)
When 43 ulcerative colitis patients received 1 gram curcumin after both
breakfast and supper along with daily sulfasalazine
or mesalamine for 6 months, 4.65%
relapsed compared with a 20.51% relapse in 39 patients receiving only the drugs
(PO in human clinical study). The clinical activity index and endoscopic index
determined at entry and every 2 months were improved significantly with
concurrent curcumin use.2674
II. + 2)
Curcumin at 25-50 mg/kg both prevented and corrected the reduction of bile flow
and biliary bilirubin excretion induced by cyclosporine
due to the choleretic effects of curcumin, but failed to alter the
reduction of cholesterol by the drug (IV in rats). Only at the highest dose did
curcumin temporarily increase cholesterol excretion after 60 or 90 minutes.
Curcumin did not significantly affect the biliary excretion of cyclosporine or
its metabolites.1119
+ 3)
Curcumin at 25 mg/kg following 4 weeks prophylaxis with a melanoma protein immune
preparation resulted in a substantial inhibition of melanoma growth that
was not reduced by either intervention given separately (IP in mice). The
immune response and median survival time were also significantly improved by
the combination in comparison to their individual effects.1635
+ 4)
Curcumin reduced cardiotoxicity of the antitumor antibiotic drug adriamycin
when given at 200 mg/kg doses for 7 days prior and 2 days after a single toxic
drug injection (IP in rats). Curcumin prevented ECG abnormalities and rises in
creatinine and LDH induced by adriamycin, and it reduced the rise in lipid
peroxide and catalase. Glutathione levels and glutathione peroxidase activity
were increased by curcumin.2019
+ 5)
A human breast cancer model showed curcumin as 2.5% of the diet significantly
inhibited tumor regression by cyclophosphamide (PO in mice). This was
due to a reduction in generation of reactive oxygen species and activation of
the JNK pathway. Breast cancer patients receiving chemotherapy should avoid
curcumin supplementation (speculative).2020
III.+ 2) Alkaline aqueous extracts of turmeric were shown to
potentiate insulin activity in glucose metabolism (in vitro).1462,1464
+ 3)
The antitumor apoptosis effects on breast cancer cells MCF-7, MDA-MB-231 and
BT-474 by camptothecin, mechlorethamine and doxorubicin,
respectively, were inhibited by curcumin by upt to 70% (in vitro). This
was due to a reduction in generation of reactive oxygen species and activation
of the JNK pathway.2020
However, curcumin further
inhibited cell growth and increased apoptotic effects in an additive or
sub-additive fashion with doxorubicin on a hepatic cancer cell culture (in
vitro). This appeared to be due in part to generation of free radicals, but
it was mainly dependent on caspase-9 and -3 activation.2134
+ 4)
Curcumin further inhibited cell growth and increased apoptotic effects in a
synergistic manner with the antitumor agent cisplatin on a hepatic
cancer cell culture, compared to the effects of cisplatin alone (in vitro).
This appeared to be due in part to generation of free radicals, but it was
mainly dependent on caspase-9 and -3 activation.2134
+ 5)
Curcumin was shown to enhance the cytotoxic effect of the chemotherapeutic
agent vinorelbine on human squamous cell lung carcinoma H520 cells (in
vitro). Curcumin augmented caspase-9 and -3 activation and induced 24%
apoptosis, while vinorelbine resulted in 38% apoptosis, but together they
induced 61%. By acting as an adjuvant chemothery agent (in vitro),
cucurmin could benefit elderly lung cancer patients with poor response or
adverse effects from standard doses of vinorelbine (speculative).2135
+ 6) Curcumin at a sub-inhibitory
concentration of 500 mcg/disc enhanced the antibacterial activities of cefixime, cephotaxime, tetracycline,
and vancomycin against Staphylococcus
aureus by 52.6%, 24.9%,24.4%, and
26.5%, respectively (in vitro).2673
However,
when combined with nalidixic acid, this same curcumin concentration antagonized
the antibacterial effect against this Staph.
aureus strain (in vitro).2673
TYLOPHORA NEW
^ *Tylophora indica leaves
(Indian lobelia, Indian ipecac)
Contraindications
1) Pregnancy, due to potential abortifacient and
fetotoxic effects from its potent pharmacological activity (empirical)1890
2) Nursing mothers (speculative), due to its
potential toxicity (empirical),1890 and immunosuppressive effects of
its alkaloids on cellular immune responses (in vitro, PO in rats)1994
UVA URSI p.
195
Arctostaphylos
uva-ursi leaves
Contraindications
1) Pregnancy (empirical)17,24,150,401,777,1890
due to the possibility of fetotoxicity (in animals).1890
2) Prolonged use unless consulting with a
physician.6,150 due to its tannin content1890
A woman who consumed uva ursi tea regularly for 3
years developed bull’s-eye maculopathy (PO in human case reports). This was
likely due to the inhibition of melanin synthesis, since the uva ursi component
arbutin is metabolized to hydroquinone which is known to inhibit the enzyme
tyrosine kinase involved in synthesizing melanin.1603
+ 7)
GI ulceration (speculative),1890 since its excessive use can
lead to stomach distress (empirical)7 due to its tannin content232,1890
+ 8)
Iron deficiency anemia and malnutrition (speculative) due to
tannin content that binds metal ions and thiamine1890 and reduces
iron absorption when taken concurrently (PO in human study)1246
+ 9)
Constipation (speculative) due to the high tannin content that produces
an astringent effect1890
Drug
Interactions
II. 1) 50% methanolic extract (100 mg/kg) and its component
arbutin both enhanced the anti-inflammatory effect of subcutaneous prednisolone when administered
simulaneously for picryl chloride-induced contact dermatitis due to additive
therapeutic effects (PO in mice)399 [CORRECTION: CATEGORY II, NOT
III. 2).]
III. + 2) A 60% methanol extract of uva ursi and its component, corilagin, were shown to increase the effectiveness of the b-lactam antibiotics such as oxacillin and cefmetazole against Staphylococcus aureus strains that are resistant to methacillin (in vitro) Corilagin, a glucose conjugation of ellagic acid and gallic acid, also dramatically increased the efficacy of other b-lactams including imipenem, benzylpenicillin, streptomycin, and tetracycline (in vitro).1340
+ 3)
Due to its tannin content, it should not be taken concurrently with oral thiamine,
metal ions like iron and zinc, or alkaloids because of
probable precipitation in the gut leading to reduced absorption (speculative),
as is suggested by studies combining tea with metal ions or thiamine (in
humans), tannins with thiamine (in animals), and tannins with alkaloids (in
vitro).1890
VALERIAN p.
196
*Valeriana officinalis
root/rhizome
Contraindications
1) Nursing
mothers without professional advice or for prolonged
duration (speculative), due to possible reduction of vigilance (empirical)1890
2) Children
under 3 years of age, especially for prolonged
duration (speculative), due to sedative effect on nervous
system (empirical)1890
Drug
Interactions
I. + 2)
After safely taking 2 tablets of St. John’s wort with 1 tablet of valerian
daily for six months for her depression and migraines, a woman was hospitalized
with delirium, rapid breathing, rapid heart rate, and mild hypertension
following the additional use of loperamide for diarrhea (PO in human
case report). The patient recovered in two days after naltrexone was given to
counteract the opioid drug. A MAO-inhibitor reaction was theorized, possibly in
conjunction with loperamide-induced delirium.1227
+ 3)
Prepared as a 5:1 45% methanolic valerian extract in combination with a 6:1
hops extract, 2 and 6 tablets of this mixture reduced or inhibited, respectively,
the stimulant effect of a single 200 mg dose of caffeine (PO in human
study)1658
+ 4) A solid extract, made using 70% ethanol as a solvent and yielding 1.1% valerenic acids including 0.54% valerenic acid, given at night in 1 gram doses for 14 days to12 healthy subjects increased the maximum concentration of a single dose of the CYP3A4 substrate alprazolam compared to baseline exposure (PO in human study).1676
However, the time to reach
the maximum and the bioavailability were unaffected, and the small though
significant change is unlikely to alter clinical responses.1676
Also, 375 mg daily for 28 days of valerian root extract had no effect on
CYP3A4 substrate
midazolam in another study with 12 men and women.1807 Single valerian extracts
have been shown to be moderate to mild CYP3A4 inhibitors (in vitro).840,1593
Inhibition of CYP3A4 can be found with valerian extracts made with either
water, 70% ethanol, or acetonitrile and is independent of the relative content
of valerenic acids (in vitro).1748
II. 1) Component valerenic acid increases sleep induced by pentobarbital (IP in mice)52 Valeranone has also been shown to prolong
barbiturate sleeping time (in animals).1061
2) dried aqueous extract (2 mg/kg) increases thiopental sleeping time in (PO in
mice).123
The valerian component hesperidin increased
thiopental-induced sleep in doses of 2-4 mg/kg. The slightly increased
thiopental sleep from 2 mg/kg hesperidin and greatly increased with the
addition of 1 mg/kg of 6-methylapigenin, another flavonoid component of
valerian (IP in rats).1529
+ 3)
The monthly intramuscular injection of haloperidol and daily consumption
of 1% valerian tincture, correlating to daily doses of 200-250 mg/kg of the
root, were given both separately or combined for twelve weeks to groups of 12
animals, as was placebos, while liver and kidneys were monitored (PO in rats).
While neither alone affected lipid peroxidation levels or production of marker
reactive species, when combined they increased both of these in the liver.
Their concurrent use also inhibited liver d-aminolevulinate dehydratase and
increased its reactivation index, considered markers of oxidative stress,
unlike use of the single agents.2285
+ 4)
The aqueous, methanolic, and choloform extracts of the rhizome decreased the
naloxone-induced jumping associated with the withdrawal of morphine (IP in mice). This suggests that the rhizome could be
useful in palliating the morphine withdrawal syndrome (speculative).2678
VETIVER NEW
^ Vetiveria
zizanioides root
(khus-khus, cuscus)
Contraindications
1) Pregnancy (empirical)150 due to its abortifacient
effects and emmenagogue and uterine stimulant activities (empirical)74,150
WILD CHERRY [now BLACK CHERRY] p.
198
*Prunus serotina bark
WATERCRESS p.
198
Nasturtium
officinale plant
Drug Interactions
+ 1) A single ingestion of 50 gm of watercress by 10 volunteers increased the bioavailability of the CYP 2E1 substrate chlorzoxazone by increasing the AUC by 56% and its half-life by 53% (PO in human study).1642
+ 2) A single ingestion of 50 gm of watercress by 10 volunteers in a crossover trial 10 hours before acetaminophen decreased the oxidation of the CYP 2E1 drug substrate by 52% and the total and peak of its oxidized NAPQI toxin metabolite by 28% and 21%, respectively (PO in human study). The 24-hour urinary excretion of the toxin metabolite was also reduced. The combined use of watercress with this drug could lead to a decrease in acetaminophen-associated hepatotoxicity (speculative).2009
WHEAT NEW
^ Triticum
vulgare fermented germ
(Avemar®)
Drug Interactions
Ia. 1) In an open-label pilot study a standardized extract of
fermented wheat germ given for 12 months to 15 female rheumatoid arthritis
patients using disease-modifying antirheumatic drugs (5 methrexate,
3 cyclosporine, 1 chloroquine, 1 sulfasalazine) and/or corticosteroids (6 methylprednisolone,
3 prednisolone, 1 triamcinolone, 1 dexamethasone) was
associated with significant improvement in baseline values of morning stiffness
and other measures after both 6 and 12 months (PO in human clinical study).
Steroid doses were reduced in 5 of 11 patients at 6 months and 4 of 11 after 12
months. Antirheumatic drugs were reduced in 3 of 10 during the entire study.
Both types of drugs were increase in 1 patient each after 12 months.2032
2) In an open-label pilot study use of the fermented
wheat germ standardized extract MSC, when taken with cytotoxic chemotherapy
drugs by children and compared to controls in 11 pairs of patients matched
by diagnosis, stage of cancer, age and gender, reduced febrile neutropenic
events from 46 among controls to 30 in the MSC group (PO in human clinical
study). Types of cancer involved were Ewing sarcoma, cerebral PNET, osteosarcoma,
hepatoblastoma, and mesenchymal chondrosarcoma. The number of pairs using
specific cytotoxic drugs included 9 carboplatin, 4 cisplatin, 3 cyclophosphamide,
6 dactinomycin, 11 doxorubicin, 6 epirubicin, 7 etoposide,
10 ifosfamide, 3 methotrexate, and 7 vincristine. The follow-up, patients with
central venous catheters, preventive counterneutropenic interventions, number
of chemotherapy cycles, and type and dosage of antibiotics and antipyretics did
not differ significantly between the groups.2036
In addition 66 patients with colorectal cancer were
given 9 grams of the extract once daily for over 6 months following “curative”
surgery, along with standard chemotherapy [65.2%] and/or radiation [27.3%], and
compared to 104 control patients treated with chemotherapy [51%] and/or
radiotherapy [53.8%] alone (PO in human clinical study). Those receiving the
extract had significantly less progression as shown by new recurrences [3% vs
17.3%], new metastases [7.6% vs 23.1%], and deaths [12.1% vs 31.7%], and significantly
better progression-free and overall survival probability.2247
3) Following surgery for stage III melanoma, the random
addition of standardized extract of fermented wheat germ to treatment with dacarbazine
in 19 patients for 12 months led to a 54.5% 1-year relapse free survival rate,
compared to 38.9% in 23 patients who received only dacarbazine (PO in human
clinical study). Time to progression with the extract was 8.9 months, compared
to 4.2 months without the extract.2246
wILD cARROT (formerly QUEEN ANN’S LACE) p. 166
Daucus carota
seeds or roots
Contraindications
3) Avoid in diabetes mellitus due to its
diuretic effect (speculative)777
and the hypoglycemic effect of a decoction of the
roots equivalent to the 25 grams dry weight of root per kg body weight (PO in
mice).2252
WILD GINGER p.
198
*Asarum canadense root/rhizome
Contraindications
3) Avoid prolonged
use due to toxic and potentially carcinogenic effects of its components
aristolochic acid and beta-asarone (speculative).150
Enzyme activation from the nitroreduction of
aristolochic acid by microsomal CYP1A1 and CYP1A2 or by cytosolic xanthine
oxidase and DT-diaphorase leads to adduct formation and mutagenesis (in
vitro). The powerful nephrotoxic and carcinogenic effects of aristolochic
acid has led to the recommendation that all botanical products containing this
compound should be banned from the world wide market.1357
WILD
LETTUCE p.
199
Lactuca virosa leaves
Contraindications
WILD
MARJORAM [now OREGANO] p.
200
WILD
YAM
Dioscorea villosa root p.
200
Drug
Interactions
III. 1) When human chronic myelogenous leukemia [KBM-5] cells were exposed
to the saponin component diosgenin at 10 mM together with paclitaxel or doxorubicin,
the cytotoxic effect of these agents were synergistically increased (in
vitro). Diosgensin alone was equivalent in cytotoxicity to each of there
chemotherapeutic agents in this cell culture (in vitro).2429
WILLOW p.
200
Salix spp. bark
and leaves
1) Allergic
hypersensitivity to salicylates (empirical)4,150,401
Anaphylaxis occurred in a woman with aspirin allergy after taking a weight loss supplement containing willow bark (PO in human case report).1428 Salicylic acid is derived from absorbed saligenin which is an intestinal metabolite of the salicin found in numerous willow species.1429
+ 3)
Nursing mothers unless following professional advice (speculative).1890
+ 4)
Due to its tannin content of 8-20%, willow bark should not be taken in constipation,
iron-deficiency anemia, or malnutrition (speculative).1890
+ 5)
Due to its high tannin content, prolonged use should be avoided
(speculative).1890
Drug
Interactions
I. + 1)
In 210 patients with chronic low back pain allowed to use 400 mg of the
analgesic tramadol daily, a placebo or daily doses of a willow bark
extract providing 120 mg or 240 mg of salicin for 4 weeks resulted in no pain
during the last week for 6%, 21%, and 39%, respectively (PO in human clinical study)769
However, one source warns
against combining willow bark prepartions with powerful analgesics
(speculative).1890
+ 2)
An open post-marketing surveillance study of low back pain patients assessed
112 using 240 mg salicin in a willow bark extract, 115 using 120 mg salicin in
the extract and 224 who used neither; all patients were allowed conventional
therapies including acetaminophen (paracetamol), NSAIDs, acupuncture,
TENS, or physical therapy. After 4 weeks those pain-free accounted for 40% of
the high dose salicin group. 19% of the low dose group, and only 8% of the
control group (PO in human clinical study).1390.
However, one source warns
against combining willow bark prepartions with powerful analgesics
(speculative).1890
III. 1) May enhance the effects of salicylates (speculative)401
The analgesic effect from using the extract and the
metabolic derivatives of its salicin component in a placebo-controlled study
using 240 mg daily for 2 weeks of salicin in a standardized bark extract
reduced the pain score in 39 patients by 14% compared to 2% for 39 placebo
patients (PO in human clinical study).1391
2) [Formerly IV. 1) ] Salicylates in willow may increase
the risk of bleeding if used with warfarin (speculative),894,1890,1899
since a study found induced platelet aggregation in 19 subjects was 61% when
given 240 mg salicin/day in willow bark extract, compared to 78% for 15
subjects receiving placebo (PO in human study). This willow extract effect was
mild compared to 100 mg aspirin for which induced aggregation was only 13%).1996
3) Due to its high tannin content of 8-20%, it should be
taken separately from oral metal ion supplements, thiamine, and
herbs or medications containing alkaloids (speculative).1890
WILLOW-HERB NEW
^ Epilopbium
spp. herb
Contraindications
II. 1) Due to its tannin content,
willow-herb should not be taken in constipation,
iron-deficiency anemia, or malnutrition
(speculative).1890
2) Due to its high tannin content, prolonged use should be avoided
(speculative).1890
Drug
Interactions
III. 1) Due to its high tannin content, it should be taken
separately from oral metal ion supplements, thiamine, and herbs
or medications containing alkaloids (speculative).1890
WINTERGREEN NEW
^ Gaultheria procumbens leaves
Contraindications
1) Allergic
hypersensitivity to salicylates (speculative)150
Drug
Interactions
I. + 1)
Warfarin potentiation was determined with 11 patients who concurrently used
ointment containing methylsalicylate, the primary component of wintergreen oil.
All of the patients had unusually high INRs after extensive topical use of the
ointment, based on patient history and salicylate blood levels. One had GI
bleeding, 2 were bruising, and 3 had other bleeding events (topically in human
case reports).1392 Several other cases with the same etiology
resulted in significant bleeding problems requiring plasma infusion or
temporary cessation of warfarin intake in 2 cases. A similar case with simply
an elevated INR of 12.2 occurred after applying a low-dose methylsalicylate gel
to both knees for 8 days (topically in human case reports).714,1393,1394
Another case of local application to arthritic knees for two weeks increased
the INR to 6.1 and resulted in multiple bruising. Still another warfarin case
had bleeding and a doubled prothrombin time after using large amounts of methyl
salicylate over arthritic joints (topical in case reports).1426,1427
The methylsalicylate may affect vitamin K metabolism or displace warfarin from
protein binding sites (speculative).1394
WITCH HAZEL p.
201
Hamamelis
virginiana leaves, bark
Drug
Interactions
III. 1) Inhibition of the absorption of minerals and B vitamins
(speculative)777
by forming insoluble tannate precipitates such as
occurs with elemental iron and also plant drug alkaloids,
resulting in their inactivation (speculative)151
+ 2)
Alkaline aqueous extracts of witch hazel bark were shown to potentiate insulin
activity in glucose metabolism (in vitro)1464
WORMWOOD p.
202
Artemisia absinthium herb
Contraindications
1) Pregnancy (empirical)2,150,1890
The use probably of the oil to induce abortion has reportedly resulted in
toxic effects or death with high doses (empirical)1890
2) Stomach ulcers or duodenal ulcers (empirical)6,777
+ or
expressions of stomach hyperacidity (empirical)1890
+ 4)
Allergic hypersensitivity to wormwood or other members of the Composite
family [Asteraceae] (empirical)1890
+ 5)
Nursing mothers (speculative), due to the potential toxicity of the
essential oil with its thujone (empirical)1890
Drug Interactions
I. + 1)
In 20 patients with Crohn’s disease 500 mg of wormwood herb 3 times daily for
10 weeks for 8 weeks allowed a steady tapering of prednisone until
withdrawal after 8 weeks with improvement of symptoms in 18 and remission in
13, though restarting the corticosteroids was necessary in 2 (PO in
clinical study). Remissions persisted until the end of the observation period
10 weeks after the steroids and wormwood were discontinued. In 20 Crohn’s
patients on placebo the symptoms increased and steroids needed to be restarted
in 16 after the 8-week tapering period. Besides previously stable steroids use,
prior stable doses of 5-aminosalicylates (mesalamine) and/or methotrexate
and/or azathioprine were allowed to be continued as concomitant
medications by both groups until the end of the observation period.2201
In a randomized, placebo-controlled study
those 10 subjects with Crohn's disease using 750 mg the same powdered wormwood
herb product 3 times daily for 6 weeks, in conjuntion with steady use of
5-aminosalicylates, azathioprine, methotrexate and/or steroids, had TNF-a levels that were significantly reduced, but not the 10 controls on
standard medication only (PO in human clinical study). Score reductions in
Crohn's Disease Activity Index and Hamilton's Depression Scale showed
respective decreases of 30% or 70 points by 8 and ≥50% by 6 of those
treated with wormwood, compared to 2 and 1 controls, respectively, who
responded similarly.2692
YARROW p.
203
Achillea millefolium herb
Contraindications
+ 3)
High doses should be avoided by nursing mothers who should not otherwise
use it unless following professional advice (speculative)1890
YELLOW
DOCK NEW
^ Rumex
crispus root
(curled dock, narrow dock, sour
dock, garden patience)
Contraindications
1) Intestinal obstruction, due to its laxative effect
(empirical).1890
2) Nursing mothers, unless following professional
advice (speculative).1890
Drug Interactions
III. 1) Used excessively, yellow dock may exacerbate potassium
depletion caused by thiazide diuretics or licorice (speculative)1890
ZEDOARY NEW
^ Curcuma zedoaria rhizome
(Ch.:
e zhu)
Contraindications
1) Pregnancy (empirical)150 due to its abortifacient
effects (empirical)74
Appendix
A
HERBALS
TO BE USED WITH CAUTION
A.
1 Due To Potential Allergic Response
A.1.1 Aster Family p.
209
Calendula
flowers (Calendula officinalis)
Costus root (Saussurea
costus)
Wild lettuce leaves (Lactuca
virosa)
A.1.3 Other Plant Families p.
210
Aloes dried leaf latex *(Aloe spp.)
Bay leaf oil (Laurus
nobilis)
Boswellia resin (Boswellia
serrata)
Chaparral leaves (Larrea
tridentata)
Chickweed herb (Stellaria
media)
Cocoa seed (Theobroma cacao)
Garlic clove juice (Allium
sativum)
Gotu
kola leaves (Centella asiatica = Hydrocotyle
asiatica)
Lavender flower (Lavandula
officinalis)
Linden flowers (Tilia
cordata)
Myrrh gum resin (Commiphora
molmol)
Star anise fruit (Illicium
verum)
Vervain leaf oil (Verbena
officinalis)
A.1.4
Salicylate-Containing Plants p.
211
Cranberry fruit (Vaccinium
macrocarpon)
A.
2 Due To Potential Photosensitizing
Effect
A.2.1 Carrot Family p.
211
Anise seed (Pimpinella
anisum)
Fragrant angelica (Angelica
dahurica)
A.4 In Acute Inflammation of the Urinary Tract
Some herbs have been used to reduce calcium oxalate
stone formation, and a decoction of Herniaria hirsuta aerial herb has
been shown to decrease the size of oxalate crystals and inhibit their
aggregation.1887
(Based on reference 150, 1341,1886,1887,2323.)
A.4.1 Medicinal Plants Containing Urinary
Irritants p.
215
Grindelia plant (Grindelia
robusta, Grindelia squarrosa)
A.4.2 Medicinal Plants Containing Soluble
Oxalates (g/100 g)2644 p.
216
Amaranth leaf (Amaranthus
hypochondriacus) 1.09
Beet leaves (Beta vulgaris) 0.61
Chives leaves (Allium
schoenoprasum) 1.48
Parsley leaves (Petroselinum
sativum) 1.70
Purslane leaves (Portulaca oleracea) 1.31
Spinach leaves (Spinacea oleracea) 0.97
Star fruit sour juice (Averrhoa
carambola)
Turmeric rhizome (Curcuma
longa)
A.5 In Gastrointestinal Irritation
Herbal agents that could aggravate inflammation of
the alimentary tract include mucosal irritants
(I) that act locally, bitters (B)
that increase gastric mucosal and gall bladder secretions
(Based
on reference 150.)
A.5.1 Herbals That Can Upset the GI Tract p.
218
Cranesbill root (Geranium
maculatum) I
Grindelia herb (Grindelia
robusta, Grindelia squarrosa) I, B
A.6 In Hypothyroid Conditions or Euthyroid Goiter
[B.1.1.c High intake of iodine-containing foods and/or
herbs can help to neutralize the anti-thyroid effects of cruciferous
goitrogens. High iodine intake from a low-iodine content seaweed (Alaria
esculenta) resulted in elevated serum TSH but not T4 or T3 elevations.2234
]
(Based on reference 1234.)
A.6.2 Antigoitrogens p.
222
Garlic cloves (Allium sativum)
A.
7 Due to Potential Adverse Effects
Since most of these plants are not commercially available
or commonly utilized, only those among the most familiar appear in the main portion of this text (#). Adverse effects,
contraindications and antagonistic drug interactions (as antidotes) for most of
the potentially toxic plants of the Euro-American traditions can be found in
reference 2 (The Toxicology of Botanical
Medicines).
(Based on reference 1357, 1890.)
A.7.1 Herbals With Toxic Potential p.
223
Asarum
roots/rhizome *(Asarum spp.)
Tylophora
*( Tylophora indica) leaves
Virginia
snakeroot rhizomes *(Aristolochia
serpentaria)
Wild
ginger rhizome *(Asarum canadense) #
Appendix
B
HERBAL-DRUG
INTERACTIONS
B.1 Modifying Intestinal Absorption of Medicines
and Phase III Metabolism p. 227
Since tannins (polymerized polyphenol
mixtures) precipitate alkaloids and metal ions, it stands to reason that the
tannin content would determine the extent of precipitation. This has been shown
with tea, since higher concentrations of tea reduce non-heme iron (iron sources
other than hemoglobin from blood) absorption more than lower concentrations,
even though as little as 20 mg tea tannins reduced iron absorption by almost
70%.1246 Tannins are common throughout the plant kingdom, but plants
with high tannin levels act as astringents.777 Herbs containing
enough tannins to produce a noticeable astringent effect would likely casue
extensive precipitation when taken simultaneously with alkaloids and divalent
cations. For example, astringent herbs should be eliminated from concurrent use
if a patient is not responding to iron therapy, since these inhibit iron
absorption. However, even herbs with non-polymerized phenols including
monomeric flavonoids (from peppermint, European pennyroyal, vervain,
small-leaved linden, and chamomile, in order of diminishing effects) and
phenolic acids (coffee) have been shown to reduce iron absorption when taken
simultaneously. From 20-50 mg total polyphenols can reduce non-heme iron
absorption by 50-70%, while 100-400 mg polyphenols reduces it by 60-90%.1246
However, even black tea with its known high tannin content and astringency does
not prevent adequate iron absorption when used concurrently if the mineral is
provided in high doses383 or when iron is provided as part of the hemoglobin
(“heme”) molecule as is found in meat products.434 In addition, tea
does not affect iron absorption when they are consumed separately.1145
Evidence has been growing that the activity
of P-glycoprotein (Pgp), also know as multidrug resisance protein 1
(MDR1), in cells of the intestinal mucosa in humans is a major factor in
reducing the absorption of some drugs. Pgp is a cell membrane transport protein
that pumps certain hydrophobic substrates, including some carcinogens, out of
cells. Stimulating Pgp by botanical flavonols such as kaempferol, quercetin and
galangin may be a means of chemoprevention in cases of concurrent exposure to
carcinogenic substances such as 7,12-dimethylbenz(a)-anthracene.2104
Glutathione is required as a cofactor. Inducing its activity or increasing its
content by inducing the MDR1 gene in enterocytes reduces absorption of
particular drugs. Since absorption is an
organ as well as an intestinal mucosal event, agents in the lists below that
affect the transport proteins in cells of tissues other than the intestinal
tract will also have those tissues designated in parentheses. When Pgp
enhancement is associated with only a single isolated component (c) from
a particular plant part, the plant part is given this letter designation.
Pgp and similar efflux pumps designated
multidrug resistance-associated proteins (MRP-1 to MRP-9) such as MRP-1 and
2 move metabolized conjugates from liver cells into the bile, while others
remove glucuronidated drugs from kidney cells for excretion into the urine. MRP-1
and -3 also efflux drugs and their conjugates from other organs into the blood.
This efflux activity is now being designated by scientists as “Phase III” drug
detoxification. The enhancement or inhibition of these proteins before or
following metabolism further impacts the bioavailability of drug substrates. Both
Pgp and MRP-2 efflux drugs from intestinal cells into the gut lumen. It is
unclear at this time what impact MRP-1 has on intestinal absorption of drugs.
Decreasing MRP content in the human intestinal cells can impact intestinal
absorption of xenobiotics. The inhibition of Pgp and MRP-2 will
enhance the retention of selective drugs that would otherwise be expelled
from cells by these transporter systems. This has been demonstrated for
several plant parts or isolated polyphenolic components (pc).
The organic
anion transporting polypeptide (OATP) also mediates drug uptake at the
intestinal level. OATP-1A2 (OATP-A) is predominantly expressed in the brain
rather than the intestine, whereas OATP-2B1 (OATP-B) is more like involved with
aiding in intestinal absorption. Several common fruit juices have been shown to
inhibit this mediator, thereby reducing absorption of specific drugs from the
gut. Human oligopeptide transporter 1 (hPepT1) and other transporters are expressed on the brush
border membrane of the intestinal mucosa and transports some drugs such as
beta-lactam antibiotics. This action can be slowed (s) or
decreased (d).
Drugs or
minerals whose absorption has been shown to be affected by a specific herb, its
extract, or its featured component are
indicated and referenced following the herbs in the lists below. These
medications are in bold type when the
documented effects result from concurrent oral ingestion by humans and italicized
for equivalent animal studies.
(Based on references 1145, 1246, 1250, 1331,
1350, 1366, 1533, 1552, 1561, 1562, 2060, 2641.)
Cassia cinnamon bark (Cinnamomum cassia)
English plantain leaves (Plantago lanceolata)
Plantain leaves (Plantago major)
St. John’s wort tops (Hypericum perforatum)
Stinging nettle leaves (Urtica dioica)
Willow-herb herb (Epilobium
spp.)
Chamomile flowers (Matricaria recutita) – iron1246
Coffee
seeds (Coffea arabica) – iron1246
European pennyroyal plant (Mentha pulegium) – iron1246
Green tea leaves (Camellia sinensis) – iron1993
Rosemary leaves (Rosmarinus officinalis) – iron1993
Small-leaved linden flower (Tilia cordata) – iron1246
Peppermint leaves (Mentha piperita) – iron1246
Vervain leaves (Verbena officinalis) – iron1246
Arame kelp (Eisenia bicyclis = Ecklonia bicyclis)
Hiziki seaweed (Hizikia fusiformes) [high in inorganic arsenic]
Sea palm kelp (Postelsia palmaeformis)
[Note: rhodamine-123 is a fluorescent dye used as a marker of influence on P-gp.]
China root c (Alpinia
officinarum) – doxorubicin [adriamycin] (colon)1026
Goldenseal root (Hydrastis
canadensis) – verapamil (baculovirus)2145 [See Note 3.]
Grapefruit fruit/juice (Citrus paradisi) – #digoxin, #
vinblastine,
*fexofenadine1036
Kutaki rhizome/roots c
picroside I (Picrorrhiza kurroa) –
(jejunum)2649
Milk thistle seeds pc
slymarin (Silybum marianum) – metronidazole (intestine)1948
[See Note 1.]
St. John’s wort tops (Hypericum perforatum)^
– amitriptyline (intestine),1614 digoxin (intestine),437,1350,2504
fexofenadine (intestine),1590,1613 simvastatin
(intestine),1250 tacrolimus
(intestine),1552 talinolol (intestine),1972 digoxin
(intestine),1350 rhodamine 123 (intestine)1366
# - also shown to not induce
P-glycoprotein in vitro1097
* - May be due to inhibition
of OATP.1097
^ - Only when providing a
daily hyperforin dose greater than 5 mg.1343,1775
Banaba leaf (Lagerstroemia speciosa) –
estrone (kidney - B)1883
Bilberry fruit (Vaccinium myrtillus) –
estrone (kidney - B)1883
Black cohosh root (Cimicifuga racemosa) –
estrone (kidney - B)1883
Echinacea purpurea flowers/leaves (Echinacea purpurea) – estrone (kidney - B)1883
Eleuthero root (Eleutherococcus senticosus) –
estrone (kidney - B)1883
Ginkgo leaves &/or pc flavonol glycosides (Ginkgo
biloba) – estrone, glibenclamide (kidney - B)1883
Grape seed (Vitis vinifera) – estrone (kidney
- B)1883
Grapefruit fruit juice (Citrus paradisi) – estrone (kidney- B),1922 fexofenadine (intestine
- 1A2),1097,2304 glibenclamide (kidney- B),1922 acebutolol,2054
celiprolol,1581 fexofenadine1097,1919,2304,2305 [See Note 2.]
Tea
green leaves &/or pc catechins (Camellia sinensis) – estrone, glibenclamide (kidney - B)1883
Mulberry leaf (Morus alba) – estrone (kidney
- B)1883
Orange fruit juice (Citrus sinensis) – estrone (kidney- B),1922 fexofenadine (intestine - A),1097 glibenclamide (kidney- B),1922 fexofenadine,1097 celiprolol,1582 ivermectin1628
Soy
bean (Glycine max) – estrone
(kidney - B)1883
Notes
1. Though inhibiting Pgp efflux of substrates daunomycin, doxorubicin, digoxin, and vinblastine in vitro,1562,1837 when tested with the Pgp substrate digoxin in 16 healthy humans 440 mg silymarin in 900 mg standardized extract daily for 14 days did not significantly alter the drug bioavailability. There was a tendency toward reducing digoxin levels, suggesting potential Pgp induction.1806 When tested with Pgp and CYP 2C9/3A4 substrate metronidazole in 12 healthy humans, 140 mg silymarin daily for 9 days increased drug substrate clearance, while reducing the half-life, bioavailability, and urinary excretion of the drug and its active metabolite.1948 Pgp induction is the probable cause, since silymarin does not modulate CYP 3A4 in humans1374,1431,1718,1589 and has an inhibitory effect on CYP 2C9 in vitro.1297
2. Though acting as an
OATP-B inhibitor of glibenclamide in vitro,1922 grapefruit
juice failed to affect its pharmacodynamics in humans.2055 Like the
orange flavonoid hesperidin, the grapefruit flavonoid naringin inhibits the
OATP1A2 transport of fexofenadine in vitro. Based on comparative testing
of the juice, naringin, and a low-naringin juice fraction, naringin appears to
be primarily responsible for the reduced bioavailability of fexofenadine in
humans as well.2305
3. A study in humans with
the Pgp probe drug digoxin in 20 subjects found that 3.2 grams daily for 14
days of an extract of goldenseal containing 3.25% isoquinoline alkaloids failed
to alter the bioavailability of digoxin, though the maximum concentration was
actually increased by 14%.2082
Cranberry fruit juice (Vaccinium
macrocarpon) – amoxicillin (s)2618
Grapefruit fruit juice (Citrus paradisi) – talinolol (d)2619
Black pepper fruit (Piper nigrum) – curcumin1533
Long pepper fruit (Piper longum) – curcumin1533
[Probes: rhodamine-123 is a fluorescent dye used as a marker of influence on P-gp; calcein acetyoxymethyl ester (calcein-AM) also serves as a marker substrate.]
Apple fruit pc phloretin (Malus domestica) – daunomycin,
doxorubicin [adriamycin] (breast)1562
Asian ginseng root,
ginsenosides and/or pc kaempferol (Panax ginseng) – doxorubicin
(leukemia),2103 colchicine (fibroblast),2103 daunorubicin
(myelogenous leukemia),1744,2102 doxorubicin [adriamycin]
(myelogenous leukemia, fibroblast),1744,2103 etoposide (fibroblast),2103
rhodamine-123 (lymphoma,1739 fibroblast2103), ritonavir
(intestine),1854 vincristine (fibroblast)2103
Barberry bark c
berbamine/berberine (Berberis spp.) –
rhodamine-123 (brain capillary endothelium)2105
Bitter orange fruit/juice (Citrus aurantium) – dextromethorphan (intestine)2666
Black cohosh (Cimicifuga
racemosa) – digoxin (intestine)1587 [See Note 1.]
Black pepper fruit c
piperine (Piper nigrum) – digoxin, cyclosporin A1820
Cannabis leaf c
tetrahydrocannabinol and/or cannabidiol (Cannabis
sativa) - rhodamine 123 (colon, kidney;2651 T lymphoblast
[prolonged exposure]2652), doxorubicin (colon, kidney),2651
vinblastine (T lymphoblast [prolonged exposure])2652
Cayenne fruit c capsaicin (Capsicum
frutescens) – digoxin2620
Chaste tree c agnuside (Vitex agnus-castus) – (jejunum)2649
Cranberry
fruit/juice pc quercetin (Vaccinium
macrocarpon) – rhodamine 123 (breast)2132
Crucifers like Brussels
sprouts & cabbage glucobrassicin/I3C (Brassica
oleracea) – vinblastine, vincristine (liver MDR1)2174
Echinacea roots (Echinacea
spp.) – calcein-AM2693
Echinacea whole plant, roots
(Echinacea spp.) – digoxin (intestine)1587 [no effect: digoxin
2504]
Echinacea flowers/leaves (Echinacea
purpurea) – digoxin (intestine)2607
Feverfew (Tanacetum
parthenium) – digoxin (intestine)1587
Fig fruit pc morin (Ficus
carica) – daunomycin, doxorubicin [adriamycin] (breast)1562
Frankincense resin and c keto-boswellic acids (Boswellia serrata) – calcein-AM
(lymphocyte)2663
Garlic clove c allicin (Allium
sativum) – ritonavir
(intestine)1854
Ginkgo leaves (Ginkgo biloba) – digoxin
(intestine),2608 talinolol
(intestine)2680
Grapefruit fruit/juice (Citrus
paradisi) – dextromethorphan (intestine),2666 digoxin (colon),2029
fexofenadine,
rhodamine 123 (intestine),2026 saquinavir (intestine,2026
colon2044), talinolol (colon),2255 vinblastine (colon),1358,2044
vincristine
(myelogenic cells)1627
Kudzu plant pc genistein (Pueraria lobata) – daunorubicin
(breast), rhaodamine 123 (fibroblast)2066
Kutaki rhizome/roots c
picroside II (Picrorrhiza kurroa) –
(jejunum)2649
Long pepper fruit c piperine
(Piper longum) – digoxin, cyclosporin A1820
Milk thistle seeds pc
silymarin (Silybum marianum) – daunomycin, doxorubicin, digoxin,
vinblastine1562,1837 [See
Note 3.]
Mulberry twigs pc morin (Morus
alba) – daunomycin, doxorubicin [adriamycin] (breast)1562
Onion bulbs pc quercetin (Allium cepa) – rhodamine 123 (breast)2132
Orange fruit/juice (Citrus
sinensis) – fexofenadine, rhodamine 123 (intestine),2026
saquinavir (intestine,2026 colon2044), vinblastine
(colon),2044 vincristine (myelogenic cells)1627
Oregon grape root bark c
berbamine/berberine (Mahonia spp.) – rhodamine-123
(brain capillary endothelium)2105
Pomelo fruit and pericarp (Citrus
grandis) – digoxin (colon)2029 [See Note 2.]
Red clover flowers pc biochanin A (Trifolium pratense) – daunomycin, doxorubicin [adriamycin] (breast),1562 digoxin, vinblastine (intestine)1837
Schisandra fruit lignans (Schisandra
chinensis) – digoxin, rhodamine-123 (intestinal)2101
Soy beans pc genistein (Glycine max) – daunorubicin (breast),
rhaodamine 123 (fibroblast)2066
St. John’s wort tops, pc
quercetin, and/or c hypericin (Hypericum
perforatum) – fexofenadine (intestine with
single dose),1331 digoxin (intestine),1587 ritonavir
(intestine)1854
Tea leaves pc quercetin (Camellia
sinensis) – rhodamine 123 (breast)2132
Tea green leaf pc catechins
(Camellia sinensis) – (jejunum),2649 doxorubicin [adriamycin] (breast),2172 rhodamine-123
(ovary),1561 tetrofosmin (breast),2172 vinblastine (intestine)1561
Turmeric root pc curcumin (Curcuma
longa) – rhodamine-123 (liver),1564 (T lymphoblast),2652
(stomach),2184 and (cervix),1853,2173 vinblastine
(cervix),1853,2173,2185 vincristine (stomach),2184
calcein-AM,
bodipy-FL-vinblastine (cervix)1853
Valerian (Valeriana
officinalis) – digoxin (intestine)1587
Wormseed seed c santonin (Artimisia
maritima) – (jejunum)2649
Apricot fruit (Prunus
armeniaca) – sulfasalazine (ileum), sulfasalazine (rat)2287
Fig fruit pc morin (Ficus
carica) – daunomycin, vinblastine (pancreas MRP1) 1805
Grapefruit fruit (Citrus
paradisi) – saquinavir, vinblastine (kidney MRP2) 2044
Kudzu
plant pc genistein (Pueraria lobata)
– daunorubicin (breast)2066
Milk
thistle fruit pc silymarin (Silybum marianum) – daunomycin, vinblastine
(pancreas MRP1) 1805
Mulberry
twigs pc morin (Morus alba) – daunomycin, vinblastine (pancreas
MRP1) 1805
Orange fruit (Citrus
sinensis) – saquinavir, vinblastine (kidney MRP2) 2044
Pineapple (Ananas comosus)
– sulfasalazine (ileum), sulfasalazine (rat)2287
Red clover flowers pc
biochanin A (Trifolium pratense) –
vinblastine (pancreas MRP1) 1805
Soy beans pc genistein (Glycine max) – daunorubicin (breast)2066
Tea green leaves (Camellia sinensis) – methotrexate (kidney MRP2) 1776
Notes
1.
When tested with the Pgp substrate digoxin in 16 healthy humans, black cohosh
extract at 40 mg daily for 14 days had no Pgp effect,1806 though it
is an inhibitor in vitro.1587
2. When tested with the Pgp
substrate digoxin in human colon carcinoma Caco-2 cell culture in vitro,
pomelo fruit juice inhibited Pgp,2029 but the ethyl acetate extract
of the juice failed to inhibit Pgp in vitro in pig kidney LLC-PK1
epithelial cells transfected with human MDR1
DNA to over-express human Pgp.2030
3. Silymarin inhibits Pgp
efflux of substrates in vitro.1562,1837 However, when tested
with the Pgp substrate digoxin in 16 healthy humans 440 mg silymarin in 900 mg
standardized extract daily for 14 days did not significantly alter the drug
bioavailability. There was a tendency toward reducing digoxin levels, suggesting
potential Pgp induction.1806
Black
cohosh extract (Cimicifuga racemosa) – digoxin1806
Goldenseal
root extract (Hydrastis canadensis) – digoxin2082
Kava
rhizome extract (Piper methysticum) – digoxin2082
Milk
thistle 80% silymarin fraction (Silybum marianum) – digoxin1806
B.2 Potentiating Cardiotonic Medicines
Cardiovascular drugs as exemplified by digoxin are
one of the major classes of prescription medications with implications of
significant risk when combined with certain botanicals, particularly St. John’s
wort tops effects on digoxin,
verapamil, and statin absorption and/or metabolism.2277 Other
mechanisms are associated with different botanicals that can also increase the
risk of interfering with expected outcomes from digoxin and similar cardiotonic
drugs.
Some plants contain steroidal cardiac glycosides
similar to those contained in or derived from digitalis. By their additive
effects, such glycosides can produce cardiac toxicity when used with digitalis
glycosides such as digoxin, digitoxin, or similar medicines. Other medicinal
plants that can induce toxic effects of digitaloid glycosides, such as
fibrillations, include those that cause a decrease in serum potassium
levels.
(Based on references
1168-1171)
B.2.2
Increased Potassium Excretion
B.2.2.b
Potentiation by Kaliuretics and/or Diuretics p.
235
Cotton root bark (Gossypium
herbaceum, Gossypium hirsutum)
Scouring rush plant *(Equisetum hyemale)
B.3 Potentiating Sedative or Tranquilizing
Medicines
Sedative agents account for one of the four most
common classes of prescription medications involved in over 90% of the cases
with potential interactions, though actual incidences appear uncommon.2272
A number of plant extracts and some of their components such as flavonoids have
been shown to prolong the hypnotic effect of ethanol (E), barbiturates
(B), or other (O)
hypnotics in animals and /or act as agonist ligands at the benzodiazepine-GABA receptor complex (BDZ) in vitro. Some have sedative and/or anxiolytic effects on their own
or when combined with anxiolytics (A), suggesting an additive effect
when combined with other tranquilizing drugs.
(Based
on references 1100, 1109, 1201, 1222, 1254, 1291, 1510, 1529, 1530, 1626)
B.3.1 Hypnotic and/or Anxiolytic Drug Enhancement p.
236
Bacopa leaves (Bacopa
monniera) B1222, 1291
Bitter orange peel (Citrus
aurantiumi) B1626
Bromelain
pineapple stem extract (Ananas comosus)
B1112
Chinese skullcap root (Scutellaria baicalensis) BDZ,1100,1109 A, O2209
European elder flower and
berry (Sambucus nigra) B1651
Gotu kola leaves (Centella
asiatica) B1201
Hops strobiles (Humulus
lupulus) B,2198 O2197
Hornamo morado plant (Valeriana
adscendens) B1510
Indian valerian
roots/rhizomes (Valerian wallichii) Bc,1529 BDZc1530
Jujube seeds (Ziziphus
spinosa) B1254
Kava rhizome (Piper
methysticum) B2196
Passion flower leaves (Passiflora
incarnata) B2196,2299
Schisandra
fruit (Schisandra chinensis, S.
sphenanthera) B695,2074
Skullcap herb (Scutellaria
lateriflora)1894 A, O2209
B.4 Modifying Blood Sugar In Insulin-Dependent
Diabetics and NIDDM
Antidiabetic agents are one of the common classes of
prescription medications with implications of significant risk when combined
with botanicals, one of the four that account over 90% of the cases with
potential interactions, though actual incidences appear uncommon.2272,2277
Botanicals that lower blood sugar can have dire consequences in type I insulin-dependent
diabetes if the use of these agents results in hypoglycemic shock. The
following have been shown to reduce blood sugar when the herb (h) or its juice (j) or other extracts (e) or components (c) are taken orally. This hypoglycemic
or antihyperglycemic effect in humans is designated in bold and is
indicated as having been demonstrated in
diabetics of undetermined type (db), type I (t1), type II (t2), or in healthy
(hl) individuals.
Potentially beneficial in type II non-insulin dependent
diabetes mellitus (NIDDM), antihyperglycemic herbs when used with oral
hypoglycemic drugs together have been shown to further reduce blood sugar in
type II diabetes in humans.
B.4.1 Hypoglycemic Herbs p.
238
Acacia seeds (Acacia
spp.)1868
Allspice fruit (Pimenta
officinalis)319,1464
American ginseng root (Panax quinquefolius)1574,1685
– h(t2)1114
Andrographis plant (Andrographis
paniculata)1868
Anemarrhena
rhizome (Anemarrhena asphodeloides)1870
Balloon flower root (Platycodon
grandiflorum)1869
Banaba leaves (Lagerstroemia
speciosa)2282 – e(t2)2283
Barberry root bark (Berberis
vulgaris) – c(t2)2315
Bay
leaves (Laurus nobilis)319,1462,1464
Bilberry
leaves (Vaccinium myrtillus)1871
Biophytum plant (Biophytum
sensitivum)1868
Black cumin seed (Nigella
sativa)1868
Caiapo
root (Ipomoea batatas) – h(t2)1252,1647
Cassia (Cinnamomum cassia) – h(t2)1592,1900,2603 [neg h(t2)2139,2237]
Cayenne fruit (Capsicum
frutescens)1706
Cissus stem (Cissus
rotundifolia)1868
Chinese mustard seed (Brassica
juncea)1437
Chirata plant (Swertia
chirayita)1437
Cidra
chayote immature fruit (Cucurbita ficifolia)1868,2579 – j(t2)1209
Cinnamon bark (Cinnamomum
verum)1763
Clove buds (Syzygium aromaticum)319,1462,1464
Cocoa seed (Theobroma
cacao)2119
Cola de caballo aerial plant
(Equisetum myriochaetum)2580 – e(t2)1305
Coptis root (Coptis
spp.) – c(t2)2315
Coriander seeds (Coriandrum
sativum)1868,1873
Cowitch seeds (Mucuna
pruriens)1436,1437
Cuajilote roots, branch,
fruit (Parmentiera edulis= P. aculeata)1868
Curry leaf leaves (Murraya
koeingii) – h(t2)1437
Desert wormwood aerial plant
(Artemisia herb-alba)1868 – e(db)1888,1889
Detarium seeds (Detarium
senegalense)1868
Fenugreek
seeds (Trigonella foenum-graecum)1868,2236,2253,2525 – h(t2),1645
h(t1)1645
French maritime pine bark (Pinus
pinaster) – e(t2)1760
Goat’s rue seeds and herb (Galega
officinalis)1868,2252
Goldenseal root (Hydrastis
canadensis) – c(t2)2315
Guarumbo leaves (Cecropia
obtusifolia)1868,2579 – e(t2)1884
Guayacan bark (Acosmium
panamense syn. Sweetia panamensis)2579
Hibiscus flowers (Hibiscus
rosa-sinensis)1437
Holy fruit leaf (Aegle
marmelose)1657
Horehound leaf (Marrubium
vulgare) – e(t2)1884
Ivy gourd herb (Coccinia indica
= C.cordifolia = C. grandis)2236 – e(t2)2235
Jambolan seeds (Syzygium cumini = Eugenia jambolana)1437,1868,2000
Japanese senega root (Polygala
senega v. latifolia)1868
Kino heartwood (Pterocarpus
marsupium)1868 – e(t2)1437,1965
Kisni leaf (Bridelia
ferruginea)1868
Lotus
rhizome (Nelumbo nucifera)1544
Maitake mushroom fruiting
body (Grifola frondosa)1618 – h(t2)1609
Mango leaf (Mangifera
indica)1868,1874
Margosa leaves (Azadirechta
indica)1657
Marula leaves (Sclerocarya
birrea)1868
Maturi roots, stems (Psacalium
decompositum)1868
Mulberry leaves (Morus spp.)1868 – h(t2)1872
Oregon grape bark (Mahonia
aquifolium) – c(t2)2315
Palo santo leaves (Agarista
mexicana)2579
Pomegranate
flowers, seeds (Punica granatum)1657
Poterium root bark (Poterium
spinosum)1868
Prickly
pear stems (Opuntia spp.)1228,1868
Queen Ann’s lace roots (Daucus
carota)2252
Rhazya leaves (Rhazya
stricta)1964
Sage herb (Salvia
officinalis)2271
Sesame seed oil (Sesamum
indicum) – e(t2)2050
Spirulina algae (Spirulina
spp.) – h(t2)1208
Stevia leaves (Stevia
rebaudiana)1783
Taranome shoots, bark (Aralia
elata)1868
Tarragon herb (Artemisia
dracunculus)2118
Tea (green, oolong, and
black) leaves (Camellia sinensis)319,1464,1576,2284 [neg e(t2)2330]
Walnut leaves (Juglans
regia)2252
Zygophyllum aerial parts (Zygophyllum
gaetulum)1868 – e(t2)1882
B.4.2 Antihyperglycemic Botanicals Enhancing Oral
Hypoglycemic Drugs in Humans NEW
Aloe
leaf juice (Aloe vera) – glyburide122
American
ginseng root (Panax quinquefolium) – sulfonylureas,
sulfonylureas/metformin1114
Asian
ginseng rootlets (Panax ginseng) – acarbose, metformin, rosiglitazone,
and/or sulfonylurea2042
Barberry
root bark (Berberis vulgaris) – sulfonylureas, metformin, acarbose,
and/or insulin2315
Bitter
melon fruit (Momordica charantia) – chlorpropamide360
Cassia
bark extract (Cinnamomum cassia)2603 – glinides,
glitazones, metformin, and/or sulphonlyureas1900 including
glyburide (glibenclamide)1592
Coptis
root (Coptis spp.) – sulfonylureas, metformin, acarbose, and/or
insulin2315
Goldenseal
root (Hydrastis canadensis) – sulfonylureas, metformin, acarbose,
and/or insulin2315
Guar
seed gum (Cyamopsis tetragonolobus) – metformin,431
glyburide (glibenclamide)2148
Gymnema
leaves (Gymnema sylvestre) – glyburide, tolbutamide359
Konjac
tuber (Amorphophallus konjac) –glyburide,430,1666 glipizide,
and/or metformin1666
Oregon
grape root, bark (Mahonia aquifolium) – sulfonylureas, metformin,
acarbose, and/or insulin2315
Prickly
pear pads (Opuntia spp.) – chlorpropamide,952 glyburide,950,951,2126
metformin,2126 tolbutamide945,950
Psyllium
seed husks (Plantago ovata) – sulfonylureas1448
B.5 Modifying the Effects of Anticoagulants
Potential problems involving the use of herbs with anticoagulants
may include plants that contain the parent compound coumarin as a pro-drug.
Coumarin itself does not affect coagulation, clotting factors, or fibrinolysis.1738
However, when converted by fungus or molds (Aspergillus
spp., Penicillium spp. or Mucor spp.) to 4-hydroxycoumarins due to
inadequate drying and/or improper storage, these coumarin derivatives can have
an effect equivalent to pharmaceutical anticoagulants. In contrast, coumarin
derivatives found in plants and referred to generically as coumarins are not
ordinarily prothrombopenic anticoagulants. However, some natural coumarins that
are found in plants, such as esculetin and osthole, in large amounts can
possibly reduce coagulation due to anti-platelet aggregation effects.
Simultaneous consumption of several herbs with warfarin in vivo in animal lab studies (italicized) or in humans (bold) has been associated with a reduction in the metabolism and/or enhancement of the effect of warfarin (W), leading to increased risk of hemorrhage. Decreased plasma neutralization of heparin (H) has also been documented. The research on most of these herbs is limited to studies using platelet-rich plasma in vitro (I) to test an extract/fraction (e) or one or more isolated components (c). For example, a high oral dose of scopoletin (60 mcg/kg body weight) has been shown to increase the bleeding time in guinea pigs by 2-38%.2499 Scopoletin, like other botanical coumarin derivatives umbelliferone, 4-hydroxycoumarin, scoparone, and esculetin, has shown anti-platelet activity in platelet-rich plasma in vitro.2497 The research methodology used is significant, since isolated coumarin derivatives from several plants have shown much greater anti-platelet effects in platelet suspensions than in whole blood and platelet-rich plasma.1542 Under most circumstance, however, in vitro evidence on high concentrations of extracts or isolated constituents is not a reliable means to determine the potential risk of consuming therapeutic quantities of herbs or their extracts or components, but such research mainly serve as a means of examining a possible mechanism of action for an effect demonstrated in vivo.
For a few herbs research studies using internal
consumption of the herbs (h) or extracts by humans or animals
have shown antiplatelet effects when the blood is drawn and tested with
platelet-aggregating compounds ex vivo (E). This is a more reliable
indicator for clinically relevant effects. In vivo (V) studies in animals test an
herbal agent given orally for its enhancement of bleeding time or protective
effects against a clot-inducing agent.
Further substantiation of increased hemorrhagic potential can be based
on case reports (CR) or human studies (HS) findings that best document
increased bleeding tendencies. Since they are the most pertinent, in vivo and ex vivo findings, human case reports, and human studies appear as
bold in the lists below. If seemingly contradicting negative [neg]
findings have been documented in people or animals for botanicals with
anticoagulent or antiplatelet potential, this is likewise documented.
Antithrombotic agents are one of the common classes
of prescription medications with implications of significant risk when combined
with botanicals, one of the four that account over 90% of the cases with
potential interactions, though actual incidences appear uncommon.2272,2277
When possible, the consumption of large therapeutic doses of herbs that
potentiate bleeding should be discontinued 2 weeks before elective surgery.
Likewise, anticoagulants like warfarin (Coumadin®) and platelet
inhibitors such as aspirin and their combination with similar herbs should be
avoided. Otherwise, presurgical coagulation testing and close monitoring are
recommended.972
B.5.1 Increasing Potential for Hemorrhage
B.5.1.a Additive Effect Due To Content of Potential
Prothrombinopenic Components p. 244
Chinese skullcap root (Scutellaria baicalensis)
Ic1237
Pau
d’arco bark (Tabebuia avellanedae) Ic623
B.5.1.c Warfarin or Heparin Metabolism Inhibitors
and/or Anticoagulant Adjuvants p. 245
Birch bark oil (Betula lenta, Betula pendula) Wc714,1392-1394,1426,1427 [moved from B.5.1.d.]
Boldo leaf (Peumos boldus)
We1489
Dong quai root (Angelica sinensis) Wh1230
Fenugreek seeds (Trigonella
foenum-graecum) Wh1489
Garlic cloves (Allium
sativum) neg HSe (aged garlic 10 ml/day chronic)1878
Ginger rhizome (Zingiber officinale) Wh,2206 neg We,1774 neg We1174
Lycium fruit (Lycium
barbarum) We1768
Mango fruit (Mangifera indica)
W1299
Wintergreen leaf oil (Gaultheria procumbens) Wc714,1392-1394,1426,1427
[moved from B.5.1.d.]
B.5.1.d
Platelet Aggregation &/or Adhesion Inhibitors p.
245
Asian ginseng root (Panax
ginseng) Ic,1196 Ie,1194 Ee1194
Boldo leaf (Peumos boldus)
Ic1532
Broccoli flower buds (Brassica oleracea v. italica) Ic, Vc2224
Bromelain from stem (Ananas
comosus) CRe2126
Brussels sprouts buds (Brassica oleracea v. gemmifera) Ic, Vc2224
Cabbage leaves (Brassica oleracea v. capitata) Ic, Vc2224
Capillary artemisia herb (Artemisia
capillaris) Ie,2497 Ic2497,2498
Cassava tuber (Manihot
esculenta) Ic2497-2499
Cayenne fruit (Capsicum
spp.) Ic2270
Chamomile (Matricaria
recutita) CRe,1876 Ic420,1015,2497
Cocoa seed (Theobroma
cacao) HSh1447
French maritime pine bark (Pinus
pinaster) He1570,1571
Garlic cloves (Allium
sativum) Ie(aged),1879 Ih,2038 Ee (aged)2037
Ginger rhizome (Zingiber officinale) Eh (1 gm daily for 1 week),2312
CRh/e,2087 neg Ve1174
Ginkgo leaves (Ginkgo biloba) Ee,2322 CRe1190,1191,2322
Japanese honeysuckle flowers
(Lonicera japonica) Ic1543
Pipsissewa leaves (Chimaphila
umbellata) Ic1502
Prickly pear pulp (Opuntia
spp.) HSh1644
Pyrola whole herb (Pyrola
spp.) Ie1502
Stinging nettle leaves (Urtica
dioica) Ie, Ic1648
Sugar cane polycosanol (Saccharum
officinarum) HS1864
Tarragon leaves (Artemisia
dracunculus) Ie2205
Tomato
fruit (Lycopersicon esculentum) Ee2081
Wasabi roots (Wasabia japonica) Ic,1689 Ec1877
Willow bark (Salix spp.)
HSe1996
Yin chen hao herb (Artemisia
scoparia) – Ic2497
B.5.1.e Fibrin Formation Inhibitors or Fibrinolysis
Promoters p. 246
Asian ginseng root (Panax ginseng) Ee1194
Bromelain from fruit and
stem (Ananas comosus) Ee1110
B.5.2 Increasing Potential for Coagulation
B.5.2.a Warfarin Antagonism by Plants High in Vitamin
K p.
247
Amaranth leaf (Amaranthus
hypochondriacus)1339
Chard leaves (Beta
vulgaris v. cicla)1339
Chives leaves (Allium
schoenoprasum)1339
Cilantro leaves (Coriandrum
sativum)1339
Endive leaves (Cichorium
endivia)1339
Onion green tops (Allium
cepa)1339
Peppermint leaves (Mentha
piperita)1339
Purslane leaves (Portulaca
oleracea)1339
B.5.2.b Warfarin Antagonism by Inducing Its
Metabolism and/or Modifying Its Effect p. 247
Soy bean (Glycine max)
CR1347
St. John’s wort herb (Hypericum perforatum) HS1578
B.5.2.c Herbs that May Accelerate Coagulation with
Internal Use p.
248
Black walnut hulls/leaves (Juglans nigra) Ec1243
Cotton root bark (Gossypium
herbaceum, Gossypium hirsutum) Ee1172
Raspberry leaves (Rubus idaeus) Ec1243
Scouring rush plant (Equisetum hyemale) I11
B.7. Modifying Enzyme Activities in Metabolic
Conversions
The value of in vitro studies is highly questionable for inhibitory studies on CYP isozymes. This is due not only to the changes in botanical and extract content to which these isozymes are exposed in vivo due to variable breakdown, absorption, and bioavailability, especially in the liver. A major drawback in exposing proteinaceous isozymes to botanical extracts in vitro is the tannin content of the botanical preparation that leads to binding and structural transformation of the protein, rendering it inactive (inhibited).1638 Consequently, any tannin-containing preparation is likely to appear inhibitory in vitro though these components will not have the same effect in vivo where the intracellular isozymes will not come in contact with tannins. In addition, inhibition can occur due to a failure to reduce native ferric isozymes to ferrous or reducing binding of the oxygen to the ferrous iron, or interference with the transfer of oxygen from the ferrous ion to the substrate.1639 It has been shown that not only tannins, but other polyphenolic components such as monomeric flavonoids and phenolic acids of herbal preparations, inhibit the ferric iron absorbption in the gut,1246 suggestive of binding to this form and interferring with its absorption (facilitated in the ferrous form). This interference with iron apparently can occur with exposure of non-tannin polyphenols. These factors contribute to the concern that techniques of in vitro screening for potential isozyme inhibitory drug interactions lack adequate validation for in vivo and clinical extrapolation.1640
Whole plant and complex extract studies are necessary to accurately describe the effect observed with normal use. The testing of “herb” effects on metabolic conversions both in vitro and in vivo almost never involves use of the whole powdered herb. In vitro evaluation requires extraction of the herb for adequate cellular and enzymatic exposure. In vivo tests, whether human (in bold) or animal (in italics), also involves dosing in forms that are typically derivatives of the whole herb as either liquid or solid extracts or fractions. There are many different types of extracts for each herb, and these vary in composition and activity. However, each separate form cannot be individually designated in this table format. They are simply described by the name of the herb (which is capitalized). The specific form used, whether powdered herb or extract, may be described in the main body of the text for the drug interaction listed under that herb. Where reduced chemical fractions or isolated derivatives (indicated with small letters) are used, the description of the fraction or isolated constituent is given below along with the herb(s) from which is it is typically obtained.
One major means of inducing drug metabolism is by
gene activation via the nuclear pregnane X receptor (PXR) that regulates phase
I (e.g., CYPs 2B6, 2C9, 2C19, 2E, 3A), Phase II enzymes (e.g., GSTs, UGTs, STs)
and phase III drug transporter proteins (Pgp, MRP-2, OATP).1926-1928,2085 For example, the activation
of PXR in human liver cells in vitro by St. John’s wort extract1002
and its major active component hyperforin1703 indicates the probable
mechanism as an inducer of CYP 3A4, CYP 2C9, and P-glycoprotein1926
which is born out for St. John’s wort in human studies.1350,1578,1590,1613
Another nuclear receptor gene activator that impacts
xenobiotic metabolism is the constitutive androstane receptor (CAR). CAR
regulates mainly CYP 2B but is also involved in expression of CYPs 2C9 and 3A,
phase II UGT 1A1, and phase III MDR-1. The hepatic nuclear factor 4a determines the liver’s PXR
and CAR induction of CYP 3A4. One example of influence on CAR is guggulsterone
in guggul (Commiphora mukul) resin that has been shown to repress CYP
2B10 by inhibiting CAR, as well as acting as an antagonist of the nuclear gene activator
farnesoid X receptor.2111,2112 Other nuclear gene activators include
retinoid X receptor and vitamin D receptor, the latter contributing to the
induction of CYPs 2B6, 2C9, and 3A4. These nuclear gene activators are
important components of bile acid detoxification by CYP 3A4, while bile acids
themselves are PXR inducers that cause induction of CYP 3A4.1928,2085
The CYP 3A4-induction effect of bile acids has important implications for herbs
that have choleretic (bile-producing) activity, versus those that have only
cholagogues (bile-releasing) activity, if the choleretic effect is associated
increased bile salt production and not simply a increase in bile water content.
Aryl hydrocarbon receptor (AhR)
is a cytosolic ligand-dependent inducible transcription factor that exists in
most cell and tissue types in the body. When formed into a ligand-receptor
complex, it accumulates in the nucleus to activate the genes that produce
CYPs 1A1, 1A2, 1B1, and phase II conjugating enzymes GST, UGT, and QR.
Since consumption of herbs, vegetables and fruit provide phytochemicals in
micromolar quantities sufficient to antagonize or activate the AhR signaling
pathway, this is an important aspect to assess in the context of a multifaceted
influence on detoxification pathways. AhR is sometimes referred to as the
dioxin receptor, and those agents that inhibit receptor binding may be useful
in preventing toxicity from synthetic environmental contaminants that are the
strongest ligands such as polychlorinated dibenzo-p-dioxins and
halogenated aromatic hydrocarbons and other toxins including dibenzofurans,
biphenyls, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene
and dibenz[a,h]anthracene. Different assays have shown that not all
botanical extracts that inhibit or stimulate AhR DNA binding in vitro
are potent antagonists or activators, respectively, of DNA expression that
requires passing through cellular membrane intact for bioactivity.1935,1936
Also, activity of a single component is not necessarily reflected in the
complexity of an extract.1937 However, the in vitro induction by
crucifer components of QR (isothiocyantes1195,21550), GST
(sulforaphane860,2154,2415), and CYP 1A1 (indoles790,827,1179,1195)
is somewhat reflected in findings from humans consuming cruciferous vegetables
that induce UGT,100 GST,855,856,857 and CYP 1A2.97,99,620,801,1634,2462
CYP3A5 is expressed in 60% of African Americans but only 33% of Europeans and their American descendants. Since this isozyme represents at least 50% of the CYP3A content for those who have it, it may be the most important genetic contributor to differences in drug clearance and response between individuals and races. Genetic polymorphisms are not only evident in Phase I isozymes but are also found in humans for phase II enzymes such as glutathione S-transferases (GSTs) that exist in the primary classes alpha, pi, mu, theta, and zeta (A, P, M, T, and Z, respectively). UDP-glucuronosyltransferases (UGTs) have two main families, UGT1A and UGT2B, both of which asre highly polymorphic. The influence by inducers and inhibitors on the specific classes and families of these conjugating isozymes are noted when known.
Bold
type face indicates human studies/reports, italics indicate animal studies;
otherwise, studies are in vitro.
[B.1.1.d
& B.1.2.b,c P-glycoprotein (Pgp) and
similar efflux pumps designated multidrug resistance-associated proteins (MRP-1
to MRP-9) such as MRP-1 and 2 move metabolized conjugates from liver cells into
the bile, while others remove glucuronidated drugs from kidney cells for
excretion into the urine. MRP-1 and -3 also efflux drugs and their conjugates
from other organs into the blood. This efflux activity is now being designated
by scientists as “Phase III” drug detoxification. Both Pgp and MRP-2 efflux
drugs from intestinal cells into the gut lumen. The enhancement or inhibition
of these proteins before or following metabolism further impacts the
bioavailability of drug substrates.]
B.7.1 Unspecified Influences of Herbal Agents on
Substrate Pharmacokinetics
B.7.1.a Modulation by Phase I &/or Phase II
Enzymes &/or Other Clearance Factors p. 255
Substrates
benzoxyresorufin [2B1/2/6] – Mg, mg,2266 rs2095 ; my2067
coumarin [2A6] –
rs,2095 sf2070
7-ethoxycoumarin [2E1]– cm,1320 ep,1998
si1296
7-ethoxy-4-(Fl3Me)coumarin [2B1/6] – bi,2062
gb1615
7-ethoxyresorufin [1A1/2] – Bm,1875 cc,1397
cc,1938,2035 Cn,2653 ea,1687 ep,1998
ga,1722,2093 gs,1082 Ku,2268 Kv,1733 na,849
pi,2073 pi2063 pu,2268 rs,1364,2095 sf2070
; ds,1302 gi,859 my,2067
os,1302 tn2091
lauric acid [4A] – rs2095
; Te2098
7-pentoxyresorufin [2B1/2] – io,968 cc,2035
Ku,2268 pu2268 ; ds,1302,2096
ds, Ga,2096,2097 os,1302 pi,2063 tn2091
Drugs: aminopyrine [2C, 3A] – gp,6 Ku,2268
pu,2268 si1296 ; gl,Li,1630 sc1292
amitriptyline – SJ1614
antipyrine – Sc1929
benzphetamine – sc1292
cyclosporine – bc,1572 Hc,2088
Pm1755 ; Cs,1572 Gp,1730
mo2116
ethylmorphine – cm,1320
etoposide – Gf1329
hexobarbital – si1296
nevirapine – SJ1972
nicotine – me2309
nimesulide – pp1821
paclitaxel – Fr, kb,2664 Gb, Go, Mt2145
pentobarbital – bb1215 ; SJ1338
phenytoin – pp205
rhodamine 123 – Cs1572
rosiglitazone – SJ2635
rosuvastatin – SJ2631
saquinavir – Ga1210
taxol – Eu, Gf, Kv, Po2568
warfarin – Ag1600
zoxazolamine – Pg2602
sc1292
Steroids: estradiol – ; gi,2462 is1326
testosterone – Fa,1633 Fa1632
; gl, Li1630
Procarcinogens:
benzo[a]pyrene – bc,1892 cc,1397
cs,1287 ct,1501 ea,1242 Nm,1155
rs,1364 si,1296 Tu,1301,1373 Tu1501
; +cs,1287 og,1155 +my,1284 +sc1292
dimethylbenz[a]anthracene (DMBA) – bi, pi,793 cc,1938 ga,1722,2093 rs,881 sp,1673 sr1723
methylnitrosamino-pyridyl-butanone (tobacco-specific
NNK) – pi,2072 pi2063
Conversion/Clearance
Inhibitors
(known inhibited Phase I CYP
isozymes and inhibited phase II conjugating enzymes noted)
(ap) apigenin as in
chamomile (Matricaria recutita) and Roman chamomile (Chamaemelum
nobile) flowers, parsley (Petroselinum sativum) leaves, etc. – 1A2,
3A1848
(ba) I3,II8-biapigenin as in
St. John’s wort (Hypericum perforatum), etc. – 1A2,1522 2C9,
2D6,1522 3A41522
(bb) berberine as in
barberry (Berberis vulgaris), coptis (Coptis spp.), goldenseal (Hydrastis
canadensis), and Oregon grape (Mahonia spp.) roots/barks
(bc)
baicalin/baicalein and other Chinese skullcap flavones (Scutellaria
baicalensis) – 1A2, 2C9, 3A41893 2B, 2E1, 3A,1892 2E11891
; UGT1892
(bi)
benzyl isothyocyanate in crucifers (Brassica
spp.) – 2B1,2062 2E12061
(Bm) Bitter melon fruit (Momordica
charantia) – 1A1, 2B1,2E11875
(Bt) Black tea leaves (Camellia
sinensis) – 2C9, 2C19. 1D6, 3A41577
(cc) curcumin in turmeric root (Curcuma longa, Curcuma aromatica) – 1A1,1938,2035
1A2,2035 1A1,1397 2B1, 2B22035 ; GST,2035
GST825 [not GST2057] [See Notes 2 & 8.]
(Cc) Cat’s claw bark (Uncaria
tomentosa) – 3A41577
(Ch)
Chamomile flowers (Matricaria recutita)
– 2C9, 2C19, 2D6, 3A41577
(Cl) clove buds (Syzygium aromaticum) – 2C9, 2C19, 2D6,
3A41577
(cn) coumarin as in sweet
clover (Melilotus officinalis), etc.
(Cn) Cannabis leaf tar (Cannabis sativa) – 1A12653
(cs) carnosol from rosemary
leaves (Rosmarinum officinalis) – 1A11287
(ct) catechin as in catechu (Acacia catechu) bark, green tea (Camellia sinensis) leaves, etc.
(db)
dihydroxybergamottin in grapefruit juice (Citrus
paradisi) – 1A2, 2C9, 2C19, 2D6, 3A41458
(ds) diallyl sulfide in
garlic oil (Allium sativum) – 2E11302,2096,2097
[Note 3.]
(ea) ellagic acid as in
strawberry leaves, seeds (Fragaria spp.), raspberry leaves, seeds (Rubus spp.) and black walnut leaves, nuts (Juglans nigra), etc. – 2A2, 2B1/2B2, 2C6, 2C11, 3A1814
; GST1687,2460
(El) Eleuthero roots (Eleutherococcus senticosus) 2C91577
(ep) epicatechins from green
tea leaves (Camellia sinensis) – 1A1/1A21998
(Eu)
Eucalyptus leaf oil (Eucalyptus globulus)
– 2C8, 3A42568
(Fa) Fragrant angelica root
(Angelica dahurica) – 2C9, 2D6, 3A41632
(Fr) Frankincense resin (Boswellia spp.) – 2C8, 2C9, 2C19, 3A42664
(Fv) Feverfew leaves (Tanecetum
parthenium) – 1A2,2568 2C9,1577,2568 2D6, 3A41577
(ga) galangin from China
root (Alpinia officinarum) – 1A11722,2093
(Ga)
Garlic cloves (Allium sativum) – 2E1,540,1629,2096,2097 2E1,540,1629 2E1,1328 3A41594 [Note 3]
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – 2C8,2C9, 3A42145
(gb) glabridin from licorice root (Glycyrrhiza glabra) – 2B6, 2C9, 3A41615
(Gf)
Grapefruit juice (Citrus paradisi)
(Gk) Gotu kola herb (Centella
asiatica) 3A41577
(Go) Goldenseal herb (Hydrastis canadensis) – 2C8,2145
2C9, 2C19,1577 2D6, 3A41577,2145
(gp)
gossypol in cotton root bark (Gossypium herbaceum, Gossypium hirsutum) –
GST6
(Gr) Ginger root/rhizome (Zingiber
officinale) – 2C9, 2C19, 2D6, 3A41577
(Hc)
Hierba del clavo herb (Geum chiloense)
(hp)
hyperforin in St. John’s wort (Hypericum perforatum) – 1A2,1458
2C9, 2D6, 3A41522
(hp) hyperforin in St.
John’s wort (Hypericum perforatum) – 2C9, 2D6, 3A41522
(kb) keto boswellic acids from frankincense resin (Boswellia spp.) – 2C8, 2C9, 2C19, 3A42664
(kl) kavalactones from kava
root (Piper methysticum) – 1A2,1458 2C9, 2D6,1327
2C19, 3A41327,1458
(Ku) Kudzu roots (Pueraria
lobata) – 2B1, 2E1, 3A2268
(Kv) Kava root (Piper
methysticum) – 1A2, 2C19,1327,1733 2C8,2568 2C9,1327,1577,1733
2C19,2568 2D6,1327 3A4,1327,1475,1577,1733
4A9/111327
(me) menthol in peppermint leaves (Mentha
piperita) – 2A62309 ; UGT2309
(Mg) Mango bark (Mangifera
indica) – 1A2, 2B12266
(mg) mangiferin from mango
bark (Mangifera indica) – 1A2, 2B1, 2C6,2E1, 3A12266
(mr) myricetin as in tea
(black and green) leaves (Camellia
sinensis), parsley (Petroselinum sativum) leaves, cranberry
fruit/juice (Vaccinium macrocarpon),
etc. – 1A2, 3A1848
(Mt) Milk thistle silymarin
extract (Silybum marianum) – 2C8,2145 3A41293,1297,1398,2145
(Nm)
Nutmeg oil (Myristica fragrans)
(Or) Oregano leaves (Origanum
vulgare) – 2C19, 2D6, 3A41577
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa) – 2C9,
2C19,1458 2E1,864,1880 2E11302
(Pg) Pomegranate fruit/juice
(Punica granatum) – 3A,1920,1923,2123,2213 3A1920 [no 3A2213]
(pi) phenethyl
isothyocyanate from watercress herb (Nasturtium
officinale), crucifers (Brassica spp.) – 1A,2063 1A2,2072,2073
2B1,2062 2E1,2073 2E1,2063,2073 3A2063
; ST2063
(Pm) Peppermint leaves (Mentha
piperita)
(Po) Peppermint oil (Mentha
piperita) – 2C8, 2C9, 2C192568
(pp) piperine in black
pepper (Piper nigrum) and long pepper fruit (Piper longum) – Pgp,
3A41820
(pu) puerarin in kudzu roots
(Pueraria lobata) – 2B1, 2E1, 3A2268
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry
fruit/juice (Vaccinium macrocarpon),
etc. – 1A2,1522,1848 2C8,2568 2C9,1458,1848
2C19,1458 3A1848
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus spp.), blueberry fruit (Vaccinium spp.) –
1A1,1364,1365,2095,2379 1A2,2095,23791B1, 2A6, 2B6, 4A,2095
2E1,2095,2379 3A41698,2095,2379 ; GST, QR2380
[See Note 8.]
(sf) safrole in sassafras
bark oil (Sassafras albidum) – 1A2, 2A6, 2E12070
(Sg) Sage leaves (Salvia
officinalis) – 1A2,2292 2C9, 2C19,1577 2D6, 3A41577,2292
(si) silymarin/silybin from
milk thistle seeds (Silybum marianum)
– 2C91297; GST,1285 UGT1293
(sp) soy protein isolate
from soybeans (Glycine max) – 1B11673
(sr) sulforaphane from
broccoli sprouts and tops (Brassica
oleracea v. italica)
(Th) Thyme leaves (Thymus
vulgaris) – 2C9, 2C19, 2D6, 3A41577
(Tu)
Turmeric root (Curcuma longa, Curcuma
aromatica) – 2C9, 2C19, 3A41577
Conversion/Clearance
Inducers
(known induced Phase I CYP
isozymes and induced phase II conjugating enzymes noted)
(Ag) American ginseng root (Panax
quinquefolium)
(ar) artemisinin from sweet
annie herb (Artemisia annua) – 2B6,1512,1930 2C19,1512,1931
2C19, 3A41930 [not 3A41931]
(bi) benzyl isothyocyanate
in crucifers (Brassica spp.) – QR,1195,2155
QR2462
(cc) curcumin in turmeric root (Curcuma longa, Curcuma aromatica) – 1A1;1699,1938
GST,1396 QR,2154 ST,910 EH,1397
GST1395,1397 [not GST2057] [See Notes 2 & 8.]
(cs) carnosol from rosemary
leaves (Rosmarinum officinalis) – GST, QR1286,1287 [Note 2.]
(Cr) Crucifers edible parts
(Brassica oleraceae) – 1A2,1987 1A22462 ;
GST,2462 UGT-21987
(Cs) Chinese Skullcap roots (Scutellaria baicalensis)
(ct) catechin as in catechu (Acacia catechu) bark, green tea (Camellia sinensis) leaves, etc. – GST1501
(ds) diallyl sulfide in
garlic cloves (Allium sativum) – 1A1,2096
1A2, 2B1,1302 2B2,1302,2096,2097
[CORRECTION] 2B1,967 3A1;2096 GST2096,2097 [Note
3.]
(Ga) Garlic cloves (Allium sativum) – 1A1, 3A1,1629,2096
1A1, 3A1,1629 2B12096,2097
(Gb) Ginkgo leaf extract (Ginkgo
biloba) – 1A2,2292 1A1, 1A2, 2B, 2C9, 2E1, 3A4,1952 2C191617
(Gf) Grapefruit juice (Citrus
paradisi)
(gi) glucobrassicin indole
metabolites in specific crucifers (Brassica
oleracea) – 1A1,1179,1195 1A2,798 2B1,1179 2B2/2B2,2462
3A12462 ; EH,2462 GST,1179
QR1179,1195 [Note 4.]
(gl) glycyrrhetinic
acid/glycyrrhizin from licorice root (Glycyrrhiza glabra) – 1A2, 2B1,
3A1630
(Gp)
Grape red wine
(Vitis vinifera)
(hp) hyperforin from St.
John’s wort tops (Hypericum perforatum)
– PXR; 1A1, 1A2,1703 2C82107 3A4;1703,2107
GST, EH1703
(is) isoflavones as in soy
beans (Glycine max) [Note 4.]
(Li) Licorice root (Glycyrrhiza
spp.) – 1A1/2, 2B1,1630,1650 2C9,1926
3A1630,1650 [Note 7.]
(mo) morin as in mulberry leaf (Morus alba)
(my) myristicin from parsley
leaf oil (Petroselinum sativum), nutmeg seed (Myristica fragrans),
etc. – 1A1, 1A2, 2B1, 2B2, 2E1;2067 GST1284 [Note
2.]
(og)
oil of ginger root (Zingiber officinale)
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa) – 1A1, 1A2,
2B1/2B21302
(pi) phenethyl
isothyocyanate from watercress herb (Nasturtium
officinale), crucifers (Brassica spp.) – 2B1 ; GST2063
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus spp.), blueberry fruit (Vaccinium spp.) – 1A11699 [See Note 8.]
(sc)
schizandrins from schisandra berry (Schisandra
chinensis) [Note 2.]
(Sc)
Schisandra fruit (Schisandra chinensis) – 2C9, 2C9, 3A1926
(SJ)
St. John’s wort tops (Hypericum
perforatum) –2C19,1584 2E1,1328 3A41328,1478
[Note 5.]
(sr) sulforaphane from
broccoli sprouts and tops (Brassica
oleracea v. italica) – GST,2415
QR,1195,2154-2156.2161,2167,2325,2415 GST, QR,1688
(Te)
Tea (green and black) leaves (Camellia
sinensis) – 1A2, 2B, 4A12098 1A2;2058,2098 GST,858,867,1649
UGT1649
(tn)
tangeritin as in citrus fruit/juice (Citrus
spp.) – 1A1/2, 2B1/21941,2091
Notes:
2. Induction of benzo[a]pyrene metabolism by curcumin,1699,1938 crucifers,98,102,807 carnosol,1287 myristicin, 1284 and schizandrins1292 actually resulted in a reduction of the more genotoxic metabolites and/or of induced tumors, rather than bioactivation into a carcinogen.
3. The reduced
bioavailability of saquinavir, a CYP 3A4/P-glycoprotein substrate, suggests
that garlic induces one or the other or both of these reducers of substrate
bioavailability.1210 However, fresh and aged garlic extracts had a
moderate effect on inhibiting P-glycoprotein in vitro. Also,
freeze-dried, fresh, odorless, aged, and oil products inhibited CYP 3A4 in
descending order, aged and odorless inhibited 2C9, but only odorless products
inhibited 2C19, whereas 2D6 was relatively unaffected by all in vitro.1594
Though CYP 1A1 and 3A1
were induced by steam-distilled garlic oil in vitro,1629,2096
CYP isozymes 1A2, 2D6,
and 3A4 were unaffected by the garlic oil orally in humans.1328 Garlic extract failed to inhibit CYP 2D6 or 3A4
when drug substrates were given following 2 weeks of using 3.6 gm extract daily
orally in humans.1456 Single diallyl sulfide dose 500 mg/kg
depresses CYP450, aniline hydroxylase and aminopyrine N-demythlase activity;
but 50 mg/kg daily for 5 days increases CYP450, benzphetamine N-demethylase,
and aminopyrine N-demythlase activity when injected in rats.1362
4. Conversion of estradiol
by soy isoflavones,1326 crucifers, and their glucobrassicin
metabolite indole-3-carbinol is directed preferentially to 2-hydroxyestrone.2462
5.In vitro St. John’s
wort tea inhibits CYP 2C9, 2C19, and 3A4,1577 its tincture and
component hypericin inhibit CYP 3A4,840 and extract capsules and
tablets diluted in ethanol or DMSO inhibit 2C19, 2D6, and 3A4.1593
6. Though CYP 2D6, 2E1 and
3A4 were inhibited by silybin, silydianin, and silychristin at concentrations
of 10 mcm or greater (in vitro), this was not considered therapeutically
relevant because concentrations of these flavonolignans in the body do not
exceed 0.5 mcm.1398
7.
Though
licorice extract was found to be a CYP 3A4 inhibitor (in
vitro)840 and the extract and glycyrrhizin were 3A4 inducers in
vivo
(PO in mice),1630 a 1 gram dose of a freeze-dried water extract
given twice daily to 10 subjects for 7 days did not affect the pharmacokinetics
or pharmacodynamics of the 3A4 substrate midazolam (PO in human study).1631
8. Resveratrol,1364,1365,2095,2379 curcumin, 1397 galangin,1722
and green tea extract820,1937 have been found to inhibit CYP 1A1 in
vitro. They also mildly induce its activation by AhR,1699,1938
and along with apigenin they all strongly antagonize AhR inductions of CYP 1A1
by the procarcinogenic dioxin TCDD.1699,1722,1937,1938
B.7.1.b Influence on
Pregnane X Receptor (PXR) NEW
Receptor activators
(ar) artemisinin from sweet
annie herb (Artemisia annua) – (liver, intestine)1930
(As) Astragalus root (Astragalus
membranaceus) – (liver)1926
(Dq) Dong quai root (Angelica
sinensis) – (liver)1926
(fr) forskolin in Coleus
roots (Coleum forskohlii) – (liver)2232
(gu)
guggulipid/guggulsterones from guggul resin (Commiphora mukul) – (liver)1636
(hp) hyperforin in St.
John’s wort herb (Hypericum perforatum) – (colon)2127
(Kv) Kava root (Piper
methysticum) – (liver)1696
(CL) Chinese Licorice root (Glycyrrhiza
uralensis) – (liver)1926
(Rh) Chinese Rhubarb root (Rheum
palmatum v. tanguticum –
(liver)1926
(Sc) Schisandra berry (Schisandra chinensis) – (liver)1926
(SJ) St. John’s wort (Hypericum
perforatum) – (liver),1002,1703 (choriocarcinoma),1288
(colon)2127
(vE) vitamin E – (liver)2233
(vK) Vitamin K2 –
(bone)1934
Receptor non-activators
(Em) Epimedium leaf (Epimedium
macranthum) – (liver)1926
(Ft) Fo-ti root (Polygonum
multiflorum) – (liver)1926
(Gs) Ginseng (Asian) root (Panax
ginseng) – (liver)1926
(Ly) Lycium fruit (Lycium
spp.) – (liver)1926
(Rs) Reishi mushroom (Ganodernum
lucidum) – (liver)1926
(Tu) Turmeric rhizome (Curcuma
longa) – (liver)1926
B.7.1.c Influence on Aryl
hydrocarbon Receptor (AhR) NEW
Receptor
inhibitors
(ap)
apigenin as in chamomile (Matricaria
recutita) and Roman chamomile (Chamaemelum
nobile) flowers, parsley (Petroselinum sativum) leaves, etc. – liver1699,1939,1940
(bc) baicalein in skullcap (Scutellaria
lateriflora), Chinese skullcap (Scutellaria baicalensis) – liver1939,1940
(Br)
Broccoli tops (Brassica oleracea v. italica) – liver1936
(cc)
curcumin in turmeric root (Curcuma longa,
Curcuma aromatica) – breast,1938 stomach1397 [See
Note 1.]
(Cl)
Clove buds (Syzygium aromaticum) – liver1936
(Ct)
Citrus (Lemon, Lime, Orange) fruit (Citrus spp.) – liver1936
(cy)
chrysin from passion flower plant (Passiflora incarnata, Passiflora coerulea)
– liver1940
(ga)
galangin from China root (Alpinia officinarum) – liver,1939,1940
breast2093
(Gf)
Grapefruit fruit (Citrus paradisi) – liver1936
(Gv)
Guava leaf (Psidium spp.) – liver1936
(kf)
kaempferol as in tea (black and green) leaves (Camellia sinensis), kale leaves (Brassica oleracea v. acephala),
etc. – liver,1939,1940 breast2092 [See Note 1.]
(lt)
luteolin as in thyme (Thymus spp.), asparagus (Asparagus officinalis),
etc. – liver1939,1940
(Lt)
Lettuce leaves (Lactuca sativa) – liver1936
(Lv)
Lavender (Lavandula spp.) – liver1936
(mo)
morin in Mulberry twigs (Morus alba) – liver1939,1940
(mr)
myricetin as in tea (black and green) leaves (Camellia sinensis), parsley (Petroselinum sativum) leaves,
cranberry fruit/juice (Vaccinium
macrocarpon), etc. – liver1940
(nr)
naringenin as in grapefruit fruit/juice (Citrus
paradisi) – liver1699,1939,1940
(pl)
polyphenols from green tea leaves (Camellia
sinensis) – liver1936,1937
(Pm)
Peppermint leaves (Mentha piperita) – liver1936
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), kale leaves (Brassica oleracea v. acephala), etc. – liver1939,1940,2092 [See Note 2.]
(rs)
resveratrol as in dark-skin grapes (Vitis
vinifera), mulberry fruit (Morus spp.), blueberry fruit (Vaccinium
spp.) – liver1364,1365 [See Note 1.]
(Sg)
Sage leaves (Salvia officinalis) – liver1936
(Sp)
Spinach leaves (Spinacea oleracea) – liver1936
(tn)
tangeritin as in citrus fruit/juice (Citrus
spp.) – liver1939,1940
(Te)
Tea (oolong>black>green) leaves (Camellia sinensis) – liver1936,1937
[See Note 1.]
Receptor activators
(Af)
Alfalfa leaves (Medicago sativa) – liver1935
(Bc)
Black cohosh root (Cimicifuga racemosa) – liver1935,2012
(Bt)
Blessed thistle herb (Cnicus benedictus) – liver1935
(cc)
curcumin in turmeric root (Curcuma longa,
Curcuma aromatica) – breast1938 [See Note 1.]
(Dc)
Devil’s claw rhizome (Harpagophytum procumbens) – liver1935
(dm)
diosmin/diosmetin from citrus fruit (Citrus spp.) – breast2298
(Ft)
Fo-ti root (Polygonum multiflorum) – liver1935
(ga)
galangin from China root (Alpinia officinarum) – breast2093
(Gb)
Ginkgo leaves (Ginkgo biloba) – liver1935
(gi)
glucobrassicin indole metabolites in certain crucifers (Brassica oleracea) – liver1942
(Gs)
Ginseng (Asian) root (Panax ginseng) – liver1935
(Gt)
Green tea leaves (Camellia sinensis)
– liver1699,1937 [See Note 1.]
(Lc)
Licorice root (Glycyrrhiza glabra) – liver1935
(qu)
quercetin as in onion bulbs (Allium cepa),
tea leaves (Camellia sinensis), kale
leaves (Brassica oleracea v. acephala), etc. – breast2092
[See Note 2.]
(rs)
resveratrol as in dark-skin grapes (Vitis
vinifera), mulberry fruit (Morus spp.), blueberry fruit (Vaccinium
spp.) – liver1699,2012 [See Note 1.]
(tn)
tangeritin as in citrus fruit/juice (Citrus
spp.) – liver2091
(Wo)
White oak bark (Quercus alba) – liver1935
No
effect on receptor
(As)
Asparagus stalk (Asparagus officinalis)
– liver1936
(Av)
Avocado fruit (Persea americana) – liver1936
(Bn)
Banana fruit (Musa spp.) – liver1936
(Bs)
Basil leaves (Ocimum basilicum) – liver1936
(Cn)
Catnip herb (Nepeta cataria) – liver1935
(Ct)
Carrot root (Daucus carota) – liver1936
(Cy)
Cherry fruit (Prunus avium) – liver1936
(Cm)
Cinnamon bark (Cinnamomum verum) – liver1936
(Dm)
Damiana leaves (Turnera diffusa) – liver1935
(Dq)
Dong quai root (Angelica sinensis) – liver1935
(Gr)
Ginger root (Zingiber officinale) – liver1935
(Ht)
Hawthorn berries (Crataegus spp.) – liver1935
(Kp)
Kelp thallus (Laminaria spp.) – liver1935
(Lq)
Loquat fruit (Eriobotrya japonica) – liver1936
(Mn)
Mango fruit (Mangifera indica) – liver1936
(Nt)
Nettles herb (Urtica spp.) – liver1935
(PA)
Pau d’Arco inner bark (Tabebuia spp.) – liver1935
(Sp)
Saw palmetto berries (Serenoa repens) – liver1935
(Uu)
Uva ursi leaves (Arctostaphylos uva-ursi) – liver1935
(Va)
Valerian root (Valeriana officinalis) – liver1935
(Ww) White willow bark (Salix alba) – liver1935
Notes
1) Resveratrol,1364,1365 curcumin,1397 kaempferol,1699,939,1940
galangin,1722 and green tea extract820,1699,1937 all
inhibit CYP 1A1 expression in vitro. Though they also mildly induce its
activation by AhR,1699,1938,2093 they strongly antagonize AhR
inductions of CYP 1A1 by the procarcinogenic dioxin TCDD.1699,1722,1937,1938,2092,2093
2) Quercetin has been shown in vitro to inhibit the activation of of AhR by tetrachlorodibenzo-dioxin at
physiological micromolar levels1939,1940,2092 and also to activate
AhR when given by itself in the same concentration range.2092
B.7.2 Influences of Herbal Agents in Phase I on
Specific Cytochrome P450 Substrates
B.7.2.a Influence on CYP 1A2 Metabolic Conversion of Substrates p. 259
Substrates:
3-cyano-7-ethoxy-coumarin – Ch,2013
Ep,2293 gg,
hp, kl,1458 kf, mr, nr, qu,1766 xh2289
7-ethoxyresorufin – An,2230 cc,2035
cf,2059 is,2065 Kv,1733 pi,2073
rs2379 ; my2067
7-methoxyresorufin – a,1766 og,2069
pi2072 ; cf,2058 Gb,1952
gl,1630,1650 Ku,2268 Li,1630,1650
os,1302 pu,2268 Te,2058 tn2091
Drugs: acetanilide – hd,2145 Kv,1327 xh2290,2291
caffeine – ap,1766 bc,1893
cy,1766 Ep,1588 kf, mr, qu1766 Um1634
; Cr,1634 SJ1838
clopidogrel – ; Ts2306
phenacetin – ap,1954 ba,1522 Dq,2671 gf, kf,1954 Mg, mg,2266 mr, qu,1522,1954 Sg,2292
Ch, Dl, Pm1608 ; cf,1608
Gb2292
propranolol – pp206
tacrine – Fv,2568 Kv2568
; Ts2211
theophylline – pp206 ;
Gb,2278 SJ2528
Steroids: estradiol – [CORRECTION] gi,798,2515 gi,803 Ts842
[glucobrassicin
indole metabolites (gi) should be in the inducer column along with Tobacco
smoke, not the inhibitor column.]
Procarcinogens:
2-amino-3-methylimidazo[4,5f]quinoline
– xh2290 ; Cr1987
Isozyme
Inhibitors
(An) Andrographis leaves (Andrographis
paniculata)
(ap)
apigenin as in chamomile (Matricaria
recutita) and Roman
chamomile (Chamaemelum nobile) flowers, parsley (Petroselinum sativum)
leaves, etc.
(ba)
I3,II8-biapigenin as in St. John’s wort (Hypericum perforatum), etc.
(bc)
baicalin/baicalein and other Chinese skullcap flavones (Scutellaria
baicalensis)
(cc)
curcumin in turmeric root (Curcuma longa,
Curcuma aromatica)
(Ch)
Chamomile flowers (Matricaria recutita)
(cy)
chrysin from passion flower plant (Passiflora incarnata, Passiflora coerulea)
(Dl)
Dandelion root (Taraxacum officinale)
(Dq) Dong quai root (Angelica sinensis)
(Ep)
Echinacea purpurea roots and plant (Echinacea purpurea) [See Note 2.]
(Fv) Feverfew leaves (Tanecetum
parthenium)
(ga) galangin from China
root (Alpinia officinarum)
(gf) ginkgo flavonol aglycones in ginkgo leaves (Ginkgo biloba)
(gg) ginkgolic acids in ginkgo leaves (Ginkgo biloba)
(hd) hydrastine in Goldenseal root and herb (Hydrastis canadensis)
(hp)
hyperforin in St. John’s wort (Hypericum perforatum)
(is) isoflavones as in soy
beans (Glycine max), kudzu plant (Pueraria lobata), etc.
(kf) kaempferol as in tea
(black and green) leaves (Camellia
sinensis), kale leaves (Brassica
oleracea v. acephala), etc.
(kl)
kavalactones from kava root (Piper methysticum)
(Kv)
Kava root (Piper methysticum)
(Mg) Mango bark (Mangifera
indica)
(mg)
mangiferin from mango bark (Mangifera indica)
(mr)
myricetin as in tea (black and green) leaves (Camellia sinensis), parsley (Petroselinum sativum) leaves,
cranberry fruit/juice (Vaccinium
macrocarpon), etc.
(nr)
naringenin as in grapefruit juice (Citrus
paradisi)
(og)
oleuropein glycoside from olive fruit oil (Olea europaea)
(pi)
phenethyl isothyocyanate from watercress herb (Nasturtium officinalecrucifers (Brassica
spp.)
(Pm)
Peppermint leaves (Mentha piperita)
(pp) piperine in black
pepper (Piper nigrum) and long pepper fruit (Piper longum)
(qu) quercetin as in onion bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry
fruit/juice (Vaccinium macrocarpon),
etc.
(Sg) Sage leaves (Salvia officinalis)
(Um) Umbellifers: carrots (Daucus
carota), celery (Apium graveolens), dill (Anethum graveolens),
parsley (Petroselinum sativum) & parsnips (Pastinaca sativa)
(xh) xanthohumol and/or
isoxanthohumol in hops strobiles (Humulus lupulus)
Isozyme Inducers
(cf)
caffeine as in coffee (Coffea arabica), cola (Cola nitida), tea (Camellia
sinensis), etc. [See Note 5.]
(Cr) Crucifers: broccoli,
cauliflower, cabbage (Brassica oleracea)
(Gb) Ginkgo leaf extract (Ginkgo
biloba) [See Note 4.]
(gi) glucobrassicin indole
metabolites in specific crucifers (Brassica
oleracea)
(gl) glycyrrhetinic
acid/glycyrrhizin from licorice root (Glycyrrhiza glabra)
(kf) kaempferol as in tea
(black and green) leaves (Camellia
sinensis), kale leaves (Brassica
oleracea v. acephala), etc.
(Ku) Kudzu roots (Pueraria
lobata)
(Li) Licorice root (Glycyrrhiza
glabra)
(my) myristicin from parsley
leaf oil (Petroselinum sativum), nutmeg seed (Myristica fragrans),
etc.
(pu) puerarin in kudzu roots
(Pueraria lobata)
(SJ) St. John’s wort (Hypericum
perforatum) [Women only.1838 See Note 3.]
(Te)
Tea (green and black) leaves (Camellia
sinensis)
(Ts)
Tobacco smoke from leaf *(Nicotiana tabacum) [See Note 6.]
No
Effect in Human Studies with Isozyme CYP 1A2 Substrates ^ NEW
(Al)
Alliums: fresh leeks, onion, chives & garlic (Allium spp.) – caffeine1634
(Bc)
Black cohosh roots/rhizome (Cimicifuga racemosa) – caffeine1807
(Bo)
Bitter orange (Citrus aurantium) – caffeine1589
(Cb)
Cranberry fruit/juice (Vaccinium macrocarpon) – R-warfarin, tizanidine2316
(Ep)
Echinacea purpurea (Echinacea purpurea) – caffeine1589 [See Note 2.]
(Ga)
Garlic oil (Allium sativum) –
caffeine1328,1808
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – caffeine1328,1808,2302 [See Note 4.]
(Go)
Goldenseal herb (Hydrastis canadensis)
– caffeine1807
(Gs)
Ginseng (Asian) root (Panax ginseng)
– caffeine1328,1808
(Kv)
Kava root (Piper methysticum) – caffeine1807
(me)
menthol in peppermint leaves (Mentha piperita) – caffeine2308
(Mt)
Milk thistle silymarin extract (Silybum marianum) – caffeine1589
(Sp)
Saw palmetto liposterolic extract (Serenoa repens) – caffeine1589
(SJ)
St. John’s wort (Hypericum perforatum) – caffeine,1217,1328,1584,1775,1808
theophylline1585 [See Note 3.]
(Va)
Valerian root (Valeriana officinalis) – caffeine1807
Notes:
1. In vivo induction
of estradiol is directed preferentially to 2-hydroxyestrone in humans, thereby
increasing its ratio to 16alpha-hydroxyestrone and estriol and reducing breast
cancer risk.798,2515,2516,2517
2. One study using 1.6 gm/day Echinacea purpurea
root extract for 8 days inhibited intestinal CYP1A2, increasing caffeine
bioavailability.1588 However, another study using a whole plant E.
purpurea extract and dose for 28 days failed to affect the metabolism of
caffeine.1589 This likely reflects the phytochemical differences in
the root extract versus the the whole plant extract. This likely reflects the
phytochemical differences in the root extract versus the the whole plant
extract. While the whole plant extract inhibits CYP 1A2 in vitro, the
alkamides components did not.2610
3. A human study of theophylline metabolism in 12 men found no effect with 900 mg St. John’s wort extract,1585 though a woman needed to increase her dosage when using this drug with 300 mg St. John’s wort.435 Studies on caffeine metabolism with 900 mg/day St. John’s wort extract found no significant changes with 12 men1584 or when combining data from men and women with 5 females and 7 males1217 or 6 females and 6 males.1328,1808 However, another study using caffeine found no effect in 8 men but significantly increased metabolic ratios in 8 women.1838 This may help explain the single likely case of interaction between St. John’s wort and theophylline in the female.
4. Ginkgo extract is a
CYP1A2 inducer at low concentrations (2.2 mcg/ml) but an inhibitor at high
concentrations (22 and 220 mcg/ml) in vitro.2292 At 100 mg/kg
orally and as 0.5% of the diet in rats was shown to induce this isozyme,1952,2278
but normal therapeutic doses do not produce this effect in humans.1328,1808,2302
Recovery from CYP1A2 induction occurs within 2 weeks.1952
5. Caffeine is not only a
substrate of CYP1A2, but also an inducer in vitro1608 and in
rats.2058,2059 However, when caffeine use is suddenly withdrawn in humans,
this can also lead to a reduction of other CYP1A2 substrates like clozapine,458
probably because it no longer acts as a competitor for binding to the isozyme
that it has induced.
6. For the antiplatelet
prodrug clopidogrel the active therapeutic agent is its metabolite. Therefore,
its induced metabolism in tobacco smokers increases rather than decreases its
activity.2306
B.7.2.b Influence on CYP 2E1 Metabolic Conversion of Substrates p. 260
Substrates:
acetone – ds1154
aniline – ; my2067
carbon tetrachloride – ds812
7-ethoxy-4-(triFMe)coumarin – bi2061
p-nitrophenol – al,2609
bb,2145,2609 Dl,1608 eg, eg,1687
Ep, Go, hd,2609 is,2065 Ku,2268 Pm,1608
pu2268 ; Gb1952
Drugs:acetaminophen
– bc,1891 ds,1153 pi,2073
Wc2009
chlorzoxazone – Dq,2671
ds,1717 Ga,1328,1808 Kv,1807 mg,2266 rh,2492 rs,2095,2379
sf,2070 Wc1642 ; Gb,2302 SJ1328,1808
theophylline – SJ435
[CORRECTION: enhanced theophylline metabolism by St.
John’s wort (SJ435) is likely
due to CYP 2E1 induction, rather than CYP 1A2.1328]
Procarcinogens:
NDMA (N-nitrosodimethylamine) – bc,1892 ds,1181,2096
Ga,2096 pi,2073 pi2063
DEN (diethylnitrosamine) – ds, ds,809
Ga1716
Isozyme
Inhibitors
(al)
alkymides from Echinacea purpurea fresh root (Echinacea purpurea) [See
Note 5.]
(bb)
berberine as in barberry (Berberis vulgaris), coptis (Coptis
spp.), goldenseal (Hydrastis canadensis), and Oregon grape (Mahonia spp.)
roots/barks [See Note 4.]
(bc)
baicalin/baicalein and other Chinese skullcap flavones (Scutellaria
baicalensis)
(bi)
benzyl isothyocyanate in crucifers (Brassica
spp.)
(Dl)
Dandelion root (Taraxacum officinale)
(Dq) Dong quai root (Angelica sinensis)
(ds)
diallyl sulfide from garlic cloves (Allium sativum) [See Note 3.]
(ea) ellagic acid as in
strawberry leaves, seeds (Fragaria spp.), raspberry leaves, seeds (Rubus spp.) and black walnut leaves, nuts (Juglans nigra), etc.
(Ep)
Echinacea purpurea fresh root (Echinacea purpurea) [See Note 5.]
(Ga)
Garlic cloves (Allium sativum) [See
Note 3.]
(Go) Goldenseal root (Hydrastis canadensis) [See Note 4.]
(hd) hydrastine in
goldenseal root (Hydrastis canadensis)
[See Note 4.]
(is)
isoflavones as in soy beans (Glycine max),
kudzu plant (Pueraria lobata), etc.
(Ku) Kudzu roots (Pueraria
lobata)
(Kv)
Kava root (Piper methysticum)
(mg)
mangiferin from mango bark (Mangifera indica)
(pi) phenethyl
isothyocyanate from watercress herb (Nasturtium
officinalecrucifers (Brassica
spp.)
(Pm)
Peppermint leaves (Mentha piperita)
(pu)
puerarin in kudzu roots (Pueraria lobata)
(rh) rhein as in Chinese
rhubarb root (Rheum palmatum), aloes (Aloe spp.), etc.
(rs)
resveratrol as in dark-skin grapes (Vitis
vinifera), mulberry fruit (Morus spp.), blueberry fruit (Vaccinium
spp.)
(sf) safrole in sassafras
bark oil (Sassafras albidum) – 1A2, 2A6, 2E12070
(Wc)
Watercress plant (Nasturtium officinale)
Isozyme
Inducers
(Gb)
Ginkgo leaf extract (Ginkgo biloba) [See Note 2.]
(my)
myristicin from parsley leaf oil (Petroselinum sativum), nutmeg seed (Myristica
fragrans), etc.
(SJ) St. John’s wort tops
(Hypericum perforatum) [See Note 1.]
[CORRECTION: Contrary to an
earlier report,1082 no evidence was found of a relevant interaction
of (si) silymarin/silybin from milk thistle seeds (Silybum marianum) inducing CYP 2E1 in other studies.1123,1297,1398
In fact, when hepatotoxicity of 2E1 substrate methotrexate is increased 2 to 3
times by inducers acetaminophen and ethanol, respectively, silymarin abolishes
this enhanced toxicity.1124 An uncharacterized milk thistle product
failed to alter bioavailability of 2E1 substrate chlorzoxazone in 12 humans
after 4 weeks.1589 See B.7.1.a for in vitro evidence that
silymarin/silybin inhibits other phase I isozymes and phase II enzymes.]
No
Effect in Human Studies with Isozyme CYP 2E1 Substrates ^ NEW
(Bc)
Black cohosh roots/rhizome (Cimicifuga racemosa) – chlorzoxazone1807
(Bo)
Bitter orange (Citrus aurantium) – chlorzoxazone1589
(Ep)
Echinacea purpurea whole plant (Echinacea purpurea) – chlorzoxazone1589
[See Note 5.]
(Ga)
Garlic aged clove extract (Allium sativum)
[See Note 3.]
(Go)
Goldenseal root (Hydrastis canadensis) – chlorzoxazone1807
[See Note 4.]
(Gs)
Ginseng (Asian) root (Panax ginseng)
– chlorzoxazone1328,1808
(Mt)
Milk thistle silymarin extract (Silybum marianum) – chlorzoxazone1589
(Sp)
Saw palmetto liposterolic extract (Serenoa repens) – chlorzoxazone1589
(Va)
Valerian root (Valeriana officinalis) – chlorzoxazone1807
Notes:
1.
In spite of one case report suggesting induced theophylline metabolism,435
after 2 weeks St. John’s wort extract 900 mg/day did not reduce theophylline
plasma levels.1585
2. EGb761 at 280 mg twice daily for 12 days in 12
human subjects significantly modulated metabolism of a single dose of the CYP
2E1 substrate chlorzoxazone, showing a mean change of 15.0%,2302
though in other studies normal therapeutic doses do not produce this effect in
humans.1328,1808 Ginkgo extract as 0.5% of the diet in rats was
shown to induce this isozyme. Recovery from CYP2E1 induction occurs within 2
weeks.1952
3. CYP 2E1 was inhibited
with oral consumption of 500 mg of garlic oil 3 times daily in humans1328,1808
and by fresh garlic orally at 0.5 gm/mg in mice.540 Its component
diallyl sulfide is also inhibitory of this isozyme in animals812,1181,1153,1154
and in humans.1717 Diallyl
sulfone, a metabolite of diallyl sulfide, given in oral doses as low as 25
mg/kg prevented acetaminophen hepatotoxicity in mice.1816 However,
10 ml of aged garlic extract daily for 12 weeks in humans caused no effect on
CYP 2E1 metabolism of acetaminophen. This extract had as its major constituent
S-allyl-L-cyseine, but very little diallyl sulfide.1815
4.
Berberine modestly or weakly inhibited CYP2E1 in vitro,2145, 2609
and goldenseal aqueous and alcoholic rhizome extracts and hydrastine had no
effect in one study2145 but a 50% ethanolic root extract had
relatively potent effects in another study in vitro.2609
However, in humans a goldenseal root extract had no effect on CYP 2E1.1807
5.
Though the 95% ethanolic Echinacea purpurea fresh root extract, its
alkamide fraction, and individual isobutylamides inhibit CYP 2E1 in vitro,
the caffeic acid derivatives and a 33% ethanolic extract low in alkamides
showed no inhibition.2609
B.7.2.c Influence on CYP 3A Metabolic Conversion of Substrates p. 260
Substrates:
aminopyrine – Ku, pu, pu2268
; gl, Li1630,1650
7-benzyloxyresorufin – Cs,1894 gs,1812
Bt, Cc, Ch, Cl, Fv, Go, Gr, Kv,1577 Mt,840 Or, Sg, SJ,1577
Sk,1894 Sp,2151 Th, Tu,1577 Va840
7-benzyloxy-4-(Fl3Me)coumarin – db,1458
Ep,2610,2612 gs,1812 Gb,2151 gb, Li,1615
si,2210 SJ,1593 Sp,2151 Va1593
dibenzylfluorescein – So,2208 Va1748
Drugs: alprazolam–
SJ1478
amiodarone – Gf1161,1333
atorvastatin – Gf1161,1333,2047,2048
buspirone – Gf1161,1333,2052
carbamazepine – Gf,1161,1333
Pg, Pg1920
cerivastatin – Gf1161,1333
cisapride – Gf1161,1731,2053
clomipramine – Gf2589
cyclosporine – bb,2281 Bo, Po,2028 Po2021
denitronifedipine – si1297
dextromethorphan – Bo, Gf,2666 kl,1327 Kv,1327 rh,2492 si1297
diazepam – Fa,1632 Gf1161,1333
;
SJ1338
diltiazem – Gb, Gb,1823 Gf2100
docetaxel – hp2107
erythromycin – An,
Az,2123 bc,1892 Bp, Cl, Cu, Li, Pg, Rh, Sw2123
; SJ1350
felodipine – Bo, Gf,1729 Pm1756
halofantrine – Gf1918
imatinib – SJ1668,1692
irinotecan – SJ1342
itraconazole – *Gf2503
ivabradine – SJ2630
lidocaine – ; CL2573
lovastatin – Gf2049
methadone – Gf2591
methylprednisolone – Gf1161
midazolam – Cb,2699
db,476,1454 Ep,1588 Eu,2568 Fr,2664
Gb, Gd, Go, gs,2145 Gb,2015 Gf,1923,2568 Gf,1885,2213
Go,1807,2501 kb,2664 Mb,1885 mg,2266
Mt,2145 Pg, Pp, Sf,1923 Wg1885
; SJ,1217,1328,1590,1613,1808,1809,2599
tn1766
nicardipine – Gf2099
nifedipine – bc,1892 Fa,1632
Gb, Gs,1728 mt, Pm1756 ; SJ1728,2623
quazepam – SJ1819
quinidine – Kv1733
R-warfarin – SJ1578
saquinavir – Ga1210
sertraline – Gf2592
sildenafil – Gf2590
simvastatin – Gf2046
tacrolimus – Gf,2030 Gf,1161,1333
Po,2030 Po2027 ;
SJ1349,1376,1552
triazolam – am, ap, gf, kf, mr, qu,1954
Gf, Pg,2213 Gf2051
verapamil – pp,1820 Gf320,1304,2584
;
SJ1675
voriconazole – SJ1839
[Interactions small and not
clinically significant for the following: ]
alprazolam – Va1676
amlodipine – Gf1161
omeprazole – SJ1674
quinidine – Gf1161,1333
verapamil – Gf1161,1333,2586 ;
SJ1675
Steroids: androstenedione – og2068,2069 ; gl, Li1630,1650
cortisol – SJ1595,1819,1838
desogestrel [3-keto metabolite] – SJ1505
ethinylestradiol – SJ1802
norethindrone – SJ1524,1802,1809
testosterone – An,2230
ba,1522 bc,1893 Bo,1633 db,1637 Dq,1633
Ea,2581 Ep,2292,2581,2608 Fa,1633 Fa,1632
fc,1637 Gb,2292,2608 Gd,2145 Gf,1450,1732,2030
Go,1813,2145
Gp,1698,1732
gs,2145
Hc,2608
hd,1813
hp, hy1522
Kv, kl,1475,2146
Mt,2145 Po,2030 Qi,1633 rs,1698,2095,2379
Sg,2292,2608 si,1293,2210 SJ,2608 Va2608
; Gb,1952 gl, Li,1630,1650
SJ,2292 Va2292
Isozyme
Inhibitors
(am) amentoflavone in ginkgo
leaves (Ginkgo biloba), St. John’s wort flowers (Hypericum perforatum)
(An) Andrographis leaves (Andrographis
paniculata)
(ap)
apigenin as in chamomile (Matricaria
recutita) and Roman
chamomile (Chamaemelum nobile) flowers, parsley (Petroselinum sativum)
leaves, etc.
(Az) Aromatic zingiber
rhizome (Zingiber aromaticum)
(ba)
I3,II8-biapigenin as in St. John’s wort (Hypericum perforatum), etc.
(bb)
berberine as in barberry (Berberis vulgaris), coptis (Coptis
spp.), goldenseal (Hydrastis canadensis), and Oregon grape (Mahonia spp.)
roots/barks [See Note 10.]
(bc)
baicalin/baicalein and other Chinese skullcap flavones (Scutellaria
baicalensis)
(Bo)
Bitter orange fruit (Citrus aurantium) [See Note 8.]
(Bp) Black pepper fruit (Piper nigrum)
(Bt) Black tea leaves (Camellia
sinensis)
(Cb)
Cranberry fruit/juice (Vaccinium macrocarpon) [See Note 18.]
(Cc) Cat’s claw bark (Uncaria
tomentosa)
(Ch)
[CORRECTION] CHAMOMILE herb (Matricaria
recutita)
(Cl)
Clove buds (Syzygium aromaticum)
(Cs)
Chinese skullcap flavones (Scutellaria baicalensis)
(Cu) Cubeb fruit (Piper
cubeba)
(db)
dihydroxybergamottin in grapefruit fruit/juice (Citrus paradisi) and
bitter orange fruit juice (Citrus aurantium) [See Note 8.]
(Dq) Dong quai root (Angelica sinensis) [See Note 17.]
(Ea) Echinacea angustifolia
root (Echinacea angustifolia)
(Ec) Echinacea (Echinacea spp.) [See Note 3.]
(Ep)
Echinacea purpurea roots, plant (Echinacea purpurea) [See Note 3.]
(Eu)
Eucalyptus leaf oil (Eucalyptus globulus)
(Fa) Fragrant angelica root
(Angelica dahurica) [See Note 6.]
(fc) furanocoumarins from
fragrant angelica root (Angelica dahurica)
(Fr) Frankincense resin (Boswellia spp.)
(Fv)
Feverfew leaves (Tanecetum parthenium)
(gb)
glabridin from licorice root (Glycyrrhiza glabra)
(Gb) Ginkgo leaf extract (Ginkgo
biloba) [See Note 15.]
(Gd) Grape seed (Vitis
vinifera)
(gf) ginkgo flavonol aglycones in ginkgo leaves (Ginkgo biloba)
(Gf)
Grapefruit fruit/juice (Citrus paradisi) [intestinal CYP3A4 only] [See
Note 14.]
(Gk) Gotu kola herb (Centella
asiatica)
(Go) Goldenseal root or herb
(Hydrastis canadensis)
(Gp)
Grape red wine
(Vitis vinifera) [See Note 5.]
(Gr) Ginger root/rhizome (Zingiber
officinale)
(gs) ginsenosides (F1, Rd, Rh1)
from Asian ginseng (Panax ginseng)
roots
(Gs) Ginseng (Asian) root (Panax ginseng) [See Note 11.]
(Hc) Horse chestnut seeds (Aesculus
hippocastanum)
(hd) hydrastine in
goldenseal root (Hydrastis canadensis) [See Note 10.]
(hp) hyperforin in St.
John’s wort (Hypericum perforatum)
(kb) keto boswellic acids from frankincense resin (Boswellia spp.)
(kf) kaempferol as in tea
(black and green) leaves (Camellia
sinensis), kale leaves (Brassica
oleracea v. acephala), etc.
(kl) kavalactones from kava
root (Piper methysticum)
(Ku) Kudzu roots (Pueraria
lobata)
(Kv) Kava root (Piper
methysticum) [See Note 9.]
(Li) Licorice root (Glycyrrhiza
glabra) [See Note 4.]
(Mb) Mulberry fruit (Morus
nigra)
(mg)
mangiferin from mango bark (Mangifera indica)
(mn) menthol in peppermint
leaves (Mentha piperita)
(mr)
myricetin as in tea (black and green) leaves (Camellia sinensis), parsley (Petroselinum sativum) leaves,
cranberry fruit/juice (Vaccinium
macrocarpon), etc.
(Mt) Milk thistle seeds (Silybum marianum) [See Note 1.]
(og) oleuropein glycoside
from olive fruit oil (Olea europaea)
(Or) Oregano leaves (Origanum
vulgare)
(Pg) Pomegranate fruit (Punica
granatum) [See Note 16.]
(Pm) Peppermint leaves (Mentha
piperita)
(Po) Pomelo fruit juice (Citrus
grandis)
(pp) piperine in black
pepper (Piper nigrum) and long pepper fruit (Piper longum)
(Pp) Papaya fruit juice (Carica
papaya)
(pu)
puerarin in kudzu roots (Pueraria lobata)
(Qi) Qianghuo root (Notopterygium
incisum, Notopterygium forbesii)
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry
fruit/juice (Vaccinium macrocarpon),
etc. [See Note 9.]
(rh) rhein as in Chinese
rhubarb root (Rheum palmatum), aloes (Aloe spp.), etc.
(Rh) Chinese rhubarb root (Rheum
palmatum) [See Note 17.]
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus spp.), blueberry fruit (Vaccinium spp.)
(Sf) Star fruit fruit juice
(Averrhoa carambola)
(Sg) Sage leaves (Salvia
officinalis)
(si) silymarin/silybin from
milk thistle seeds (Silybum marianum)
[See Note 1.]
(SJ) St. John’s wort tops (Hypericum perforatum) [See Note 2.]
(Sk) Skullcap herb (Scutellaria
lateriflora)
(So) Shrubby sophora (Sophora
flavescens)
(Sp) Saw palmetto
liposterolic extract (Serenoa repens)
(Sw) Sandalwood wood (Santalum
album)
(Th) Thyme leaves (Thymus
vulgaris)
(Tu) Turmeric root (Curcuma longa, Curcuma aromatica)
(Va) Valerian root (Valeriana
officinalis) [See Note 13.]
(Wg) Wild grape fruit (Vitis
coignetiae)
Isozyme Inducers
(CL) Chinese Licorice root (Glycyrrhiza
uralensis) [See Note 4.]
(Dq) Dong quai root (Angelica sinensis) [See Note 17.]
(Ga)
Garlic cloves (Allium sativum) [See
Note 7.]
(Gb)
Ginkgo leaf extract (Ginkgo biloba) [See Note 15.]
(gl) glycyrrhetinic
acid/glycyrrhizin from licorice root (Glycyrrhiza glabra) [See Note 4.]
(hp) hyperforin in St.
John’s wort (Hypericum perforatum)
(Kv) Kava root (Piper
methysticum) [pregnane X receptor activator1696,1702] [See Note
9.]
(Li) Licorice root (Glycyrrhiza
glabra) [See Note 4.]
(Rh) Chinese rhubarb root (Rheum palmatum) [See Note 17.]
(SJ) St. John’s wort tops (Hypericum perforatum) [pregnane X receptor activator1002,1288,1703] [See Note 2.]
(tn) tangeritin as in citrus
fruit/juice (Citrus spp.)
No
Effect in Human Studies with Isozyme CYP 3A4 Substrates ^ NEW
(Ag) American ginseng root (Panax quinquefolium)
– indinavir2530
(ar)
artemisinin from sweet annie herb (Artemisia annua) – cortisol1931
(Bc)
Black cohosh roots/rhizome (Cimicifuga racemosa) – midazolam1807,2500
(Bo)
Bitter orange (Citrus aurantium) – indinavir,2588 midazolam1589
[See Note 8.]
(Ct)
Carrot root juice (Daucus carota) – midazolam1885
(El)
Eleuthero extract (Eleutherococcus
senticosus) – alprazolam2086
(Ep)
Echinacea purpurea root or whole plant (Echinacea purpurea) – midazolam1588,1589 [See
Note 3.]
(Ga)
Garlic cloves (Allium sativum) –
alprazolam,1456 docetaxel,2514 midazolam,1328,1808
ritonavir1734 [See Note 7.]
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – alprazolam,1840
cortisol, omeprazole,2301 donepizil,1824 midazolam1328
[See Note 15.]
(Gf)
Grapefruit furanocoumarin-free juice (Citrus paradisi) – indinavir,2587,2588
felodipine,1862 [See Note 14.]
(Gs)
Ginseng (Asian) root (Panax ginseng)
– cortisol,1811 midazolam1328 [See Note 11.]
(Kv)
Kava root (Piper methysticum) – midazolam1807,2501
(Li)
Licorice root (Glycyrrhiza glabra) – midazolam1631 [See Note 4.]
(me)
menthol in peppermint leaves (Mentha piperita) – felodipine2307
(Mt)
Milk thistle silymarin extract (Silybum marianum) – indinavir,1374,1431,1718 irinotecan,2106 midazolam,1589,2500
nifedipine2265 [See Note 1.]
(Or)
Orange fruit juice (Citrus sinensis)1885
(Pg)
Pomegranate fruit (Punica granatum) [See Note 16.]
(Pl)
Plum fruit (Prunus mume) – midazolam1885
(Sp)
Saw palmetto liposterolic extract (Serenoa repens) – alprazolam,1810
midazolam1589
(SJ) St. John’s wort herb (Hypericum perforatum)
– carbamazepine,1083
prednisone2216 [See
Note 2.]
(Sy)
Soy bean extract (Glycine max) – cortisol1811 [See Note 12.]
(Te)
Tea (green) leaf decaffeinated extract (Camellia
sinensis) – alprazolam1710
(Tm)
Tomato fruit juice (Lycopersicon esculentum) – midazolam1885
Notes:
1. In two separate studies,
milk thistle extract was given to 10 human subjects (153 mg or 173 mg silymarin
3 times daily for 2 or 3 weeks, respectively) and did not inhibit 3A4
metabolism of substrate indinavir.1374,1431 In a controlled human
study, 1350 mg daily of an uncharacterized milk thistle extract likewise
produced no significant change in indinavir levels.1718 Milk thistle
extract (80% silymarin) 350 mg daily failed to alter bioavailability of CYP 3A4
substrate midazolam in 12 humans after 4 weeks,1589 the same
nonresponse as with 300 mg/day in 19 subjects after 2 weeks.2500 Silymarin given is doses
of 160 mg three times daily for 2 weeks slightly decreased bioavailability of
irinotecan given to 6 cancer patients.2106 When 280 mg of silymarin
was given 10 hours and 1.5 hours prior to a single dose of nifedipine to 16
healthy men, the nifedipine bioavailability was increased by 1.3 and the
maximum concentration was decreased by 0.7 with great individual variability,
indicating a probable decrease in rate of absorption.2265 While metabolism of
erythromycin by CYP 3A4 was not siginificantly inhibited by silybin, 3A4
oxidation of denitronifedipine was clearly inhibited in a mostly
non-competitive fashion in vitro.1297 The inhibition of CYP 3A4
by silymarin and its components silybin, silydianin, and silycristin was shown in
vitro to be dose dependent but not therapeutically relevant due to the
concentrations required.1293,1398,2145
2. Extracts have been shown
to induce CYP 3A4 in at least 14 human studies (see above), primarily through
hyperforin activation of pregnane X receptor. 1002,1288,1703 Even though St. John’s wort
tea,1577 3 commercial solid extracts,1593,2608 its
tincture, and its components quercetin,1854 I3,II8-biapigenin,
hyperforin,1522 and hypericin840,1522,1854 all inhibited
CYP 3A4 in vitro, in another in vitro study 10 extracts and 6
commercial extracts showed PXR-mediated induction of CYP 3A4 based on
hyperforin content.2127 St. John’s wort extract inhibits CYP 3A4 at
800 mcg/ml but induced it at 8 and 80 mcg/ml in vitro.2292
Hyperforin also induced docetaxel metabolism in vitro2107 and
prolonged exposure to quercetin and hyperforin caused upregulation of CYP 3A4
gene expression in vitro.1854 A human study with CYP 3A4 and
2C19 substrate voriconazole showed that inhibition can occur during the first
day but induction occurs after 15 days.1839 Two human studies showed
no change in the metabolism of CYP 3A4 substrates carbamazepine and prednisone
after using 300 mg tablets standardized to 0.3% hypericin three times daily for
14 and 28 days, respectively.1083,2216 An extract providing a daily
dose of only 3.5 mg hyperforin failed to induce metabolism of the substrate
alprazolam in humans.1775 Similarly, 500 mg/day of a solid ethanolic
extract with < 0.2% hyperforin providing < 1 mg daily for
14 days did not significantly alter the pharmacokinetics of ethinylestradiol or
desogestrel/3-ketodesogestrel in low-dose contraceptive pills used by 16
healthy females.2569 In 14-day studies using midazolam as a probe
drug, St. John’s wort products reduced its bioavailability compared to
baseline, and the degree of reduction showed a strong correlation to the
relative hyperforin doses, 2598,2599 though the doses of total
flavonoids, but not hypericins, also significantly correlated with the
reductions.2599
3. Echinacea purpurea
root extract 1.6 gm/day for 8 days inhibits intestinal 3A4 but induces liver
3A4. The net result was no increased clearance when E. purpurea extract
was taken with midazolam orally.1588 Another study using 1.6 gm/day E.
purpurea whole plant extract for 28 days also failed to affect the serum
clearance after one hour of oral midazolam.1589 The in
vitro results indicate that the herb juice, fresh plant tincture, and 9 commercial
extracts inhibit 3A4 to different degrees, varying by a factor of 150.2292,2293,2610,2612
The inhibitory potency is associated with the total alkamide content.2610,2612 The tincture of E. purpurea root is a stronger
CYP3A4 inhibitor than the tops, but the root tincture of E.
angustifolia is the strongest in vitro inhibitor.840
4. Though licorice extract was found to be a CYP
3A4 inhibitor in
vitro,840,1615 along with its isoflavan component glabridin,1615 the extract and glycyrrhizin were 3A4 inducers in vivo in mice,1630,1650 as was 3 g/kg of a decoction of G. uralensis
given orally to rats.2573 However, a 1 gram dose of a freeze-dried water extract
given orally twice daily to 10 subjects for 7 days did not affect the
pharmacokinetics or pharmacodynamics of the 3A4 substrate midazolam in human
study.1631
5. Grape red wine, its component resveratrol, and
fractions not containing resveratrol are shown to inhibit CYP 3A4 in vitro.1698,1732 Red wine inhibition of CYP 3A4 in humans slightly
increased cisapride bioavailability after a single 250 ml dose, though not
significantly.1731 Red wine reduced the Pgp and CYP 3A4 substrate
cyclosporine in humans after only one dose, suggesting not induction but
possibly activation or stimulation of Pgp or, unlikely, CYP 3A4.1730
6. Though oral fragrant
angelica extract had little effect on diazepam administered IV to rats, it
increase 4 times the diazepam maximum concentration when both were given
orally.1632
7. Though 2 garlic caplets
for 3 weeks in 10 healthy subjects reduced plasma content of saquinavir by 50%,1210
2 soft caps equivalent to 1 gram of fresh garlic daily for 4 days did not
affect the metabolism of a single dose of ritonavir in 10 healthy humans.1734
In 10 human subjects 1.2 grams/day of garlic with 7.2 mg allicin did not alter
the pharmacokinetics of docetaxel.2514 In 14 healthy human
volunteers 1.8 grams orally of a standardized garlic extract daily for 14 days
did not impact the metabolism of alprazolam,1456 nor did garlic oil
for 28 days affect midazolam in 12 healthy subjects.1328 Odorless
garlic, garlic oil, aged garlic, and especially freeze-dried garlic inhibited
CYP 3A4 in vitro.1594
8. Bitter orange juice in a
single 240 ml dose increased felodipine bioavailability due to
6',7'-dihydroxybergamottin, bergamottin, and begapten inhibiting intestinal CYP
3A4.1729 The bioavailability of indinavir was not impacted by
consumption with bitter orange juice in healthy human subjects, though there
was a delay in indinavir absorption.2588 The juice also reduced
enterocyte CYP3A4 concentrations in humans but did not influence cyclosporine
metabolism in humans, probably because of a lack of effect on Pgp by
6',7'-dihydroxybergamottin as shown in vitro.1031 The juice
did increase dextromethorphan bioavailability by inhibiting intestinal CYP 3A
and affecting a transport protein.2666 A product standardized to 4%
synephrine and given to 12 subjects at a dose of 700 mg daily was devoid of the
CYP 3A4 inhibitor 6',7'-dihydrooxybergamottin.1589 The decoction of
the fruit and unripe fruit were slightly inhibitory for CYP3A4 testosterone
metabolism in vitro.1633
9. Although kava root1327,1475,1577,1733
and quercetin475,915 have been shown to be in vitro
inhibitors of CYP 3A4 substrate metabolism, along with grapeseed extract they
induced production of CYP 3A4 mRNA in vitro; kava induction was mediated
by pregnane X receptor (PXR).1696 The strong CYP3A activators dihydromethysticin and desmethoxyyangonin
only slightly activated PXR in vitro, suggesting an indirect or
independent mechanism.1702 A human study using 1 gram root extract
twice daily for 28 days found no effect on metabolism of the CYP3A4 substrate
midazolam in 12 men and women.1807
10. Goldenseal extracts
and/or the alkaloid hydrastine were strong CYP 3A4 inhibitors tested in
vitro;1813,2145 its root tincture the strongest among 21 herb
extracts840 and its herb tea the strongest among 20 herb and black
teas.1577 Likewise, 2.7 gram daily for 28 days of goldenseal extract inhibited
midazolam metabolism by 40% in 12 men and women,1807 while 3.97
gram/day of the extract for 14 days also significantly reduced midazolam
bioavailability in 16 men and women.2501 Berberine at 0.6 grams
daily for 3 months increased previously stabilized cyclosporin trough blood
concentrations by 90% in 52 renal transplant patients, and when given for 12
days to 6 transplant patients increased the cyclosporine bioavailability by
35%.2281 However, 2.28 grams of the root given daily to 10 healthy volunteers
for 14 days failed to affect the pharmacokinetics of CYP 3A4 substrate
indinavir.1700
11. Daily doses for 28 days
of 1.5 gm Asian ginseng standardized to 5% ginsenosides failed to alter the
metabolism of CYP 3A4 substrate midazolam in humans.1328,1808
Likewise, 200 mg/day for 14 days of ginseng extract standardized to 4%
ginsenosides failed to alter cortisol metabolism in 20 humans.1811
200 mg/day of uncharacterized "ginseng" or 120 mg/day of uncharacterized
ginkgo for 18 days each inhibited metabolism of CYP 3A4 substrate nifedipine,
as indicated by increased peak plasma concentrations of 29% and 53%,
respectively.1728 Ginsenosides inhibit CYP3A4 in vitro.1812
12. Though soy extract with
100 mg isoflavones daily for 14 days produced no effect in humans, unhydrolyzed
soy extracted tended to induce CYP3A4 in vitro, while hydrolyzed soy
extract strongly inhibited CYP3A4 in vitro.1811
13. Though valerian
preparations have been shown to induce2292 and inhibit CYP3A4 in
vitro,840, 1593,1748,2608 a 1 gram extract dose for 14 days in 12 healthy
subjects increased the maximum concentration of a single dose of the CYP3A4
substrate alprazolam. However, the time to reach the maximum and the
bioavailability were unaffected, and the small though significant change is
unlikely to alter clinical responses.1676 Also, 375 mg daily for 28
days of valerian root extract had no effect on midazolam in another study with
12 men and women.1807
14. Furanocoumarin-free
grapefruit juice did not alter felodipine pharmacokinetics compared with
grapefruit juice that did not have the furanocoumarins removed in a human study
with 18 subjects. Other CYP 3A4 substrates will theoretically also not have
their metabolism altered by grapefruit juice, if the furanocoumarins are
removed from the juice.1862
Itraconazole oral clearance was reduced and
bioavailability was increased in 10 women taking 240 ml juice compared to water,
whereas the juice produced no differences in 10 men. The juice-induced
clearance differences between the women and the men were not significant,
although after water women has significantly greater clearance of itraconazole
than men.2503
The bioavailability of the HIV drug indinavir was not
impacted by consumption with grapefruit juice in either healthy subjects or
HIV-positive subjects in human studies. There was a delay in indinavir
absorption in those with HIV with grapefruit juice.2587,2588
15. Concerning ginkgo, 360
mg/day EGb 671 increased midazolam and decreased its oral clearance,2015
but 240 mg standardized ginkgo failed to alter the metabolism of CYP 3A4
substrate midazolam in humans,1328,1808 nor did 280 mg standard
extract for 12 days impact cortisol metabolism in 18 healthy men or increase
omeprazole metabolism to omeprazole sulfone.2301 Also, 90 mg/day of
its extract for 30 days did not affect metabolism of CYP3A4 substrate donepezil
in 14 patients during long-term use.1824 However, 120 mg/day of
uncharacterized ginkgo for 18 days inhibited metabolism of CYP 3A4 substrate
nifedipine, as indicated by increased peak plasma concentration 53%.1728
On the other hand, 240 mg daily for 14 days of ginkgo extract slightly
decreased alprazolam availability, suggesting CYP 3A4 induction.1840
Recovery from CYP 3A4 induction occurs within 1 week in rats given the extract
as 0.5% of their diet.1952 Ginkgo leaf extract is a CYP3A4 inhibitor
in vitro.1823,2145,2151,2292,2608 Ginkgo flavonol aglycones
quercetin, kaempferol, apigenin, myricetin, and tamarixetin all inhibited CYP
3A4 in micromolar concentrations in vitro, but its flavonol glycosides
and terpene lactones did not.1848
16. Though pomegranate juice
inhibited CYP 3A in rats1920 and in vitro,1920,1923,2123,2213
2 doses of 8 oz each given about 12 hrs and 1 hr prior to midazolam had no
effect on IV or oral midazolam clearance in healthy human volunteers.2213
17. The aqueous extract of dong quai root increased
strongly the N-demethylation of dextromethorphan in rats, but dong quai
ethanolic extract inhibited this metabolism.2671 Similarly, in
vitro a 40% ethanol extract inhibited testosterone metabolism, but it was
unaffected by an aqueous decoction.1633 In contrast the Chinese rhubarb
root aqueous extract inhibited dextromethorphan N-demethylation but its
ethanolic extract increased its metabolism in rats.2671
18. Only 1 of 5 commercial cranberry juice samples tested in vitro at 0.05% showed inhibitory effects on metabolism of midazolam by CYP3A, and this inhibition was confirmed for intestinal but not hepatic CYP3A by this brand in 16 human subjects after orally consuming 3 glasses with 240 ml of double-strength cranberry juice prior to a single dose of midazolam.2699 In prior human studies no inhibition was shown by cranberry juice with midazolam2316 or CYP3A substrate cyclosporine. 2021
B.7.2.d Influence on CYP 2C9 Metabolic Conversion of
Substrates ^ NEW
Substrates:
7-ethoxy-3-cyanocoumarin
– Cl, Gr, Sg, Th, Tu1577
7-ethoxy-4-(Fl3Me)coumarin
– gl,1615 si2210
7-methoxy-4-(Fl3Me)coumarin
– db, gg, hp,os, qu,1458 Ch,1577 Ea,2581 Ep,2151,2581
Fv,1577 Gb,2151 Go,1577 Ga,1594 Kv,1733
Sp2151
Drugs: diclofenac – ba,1522 bc,1893
br,2288 Go,1813 hp, hy,1522 mg,2266
Pi2288
flurbiprofen – am, qu1954
gliclazide – SJ2624
tolbutamide – An,2230 Dq,2671 Fa1632
Fr,2664 Fv,2568 Gb, Gd,2145 kb,2664
kl, Kv,1327,1733,2146 Pi,2288 Po,2568 rh2492
;
Gb,2015 Go2145
S-warfarin – Gb,2011 si1297
; Ag,1600
Gb,1952 Li, Sc,1926 SJ1578
Isozyme
Inhibitors
(am) amentoflavone in ginkgo
leaves (Ginkgo biloba), St. John’s wort flowers (Hypericum perforatum)
(An) Andrographis leaves (Andrographis
paniculata)
(ba) I3,II8-biapigenin as in
St. John’s wort (Hypericum perforatum), etc. [See Note 1.]
(bc) baicalin/baicalein and
other Chinese skullcap flavones (Scutellaria baicalensis)
(br) bromelain in pineapple
(Ananas comosus)
(Ch) Chamomile (Matricaria recutita)
(Cl) Clove buds (Syzygium aromaticum)
(db) dihydroxybergamottin in
grapefruit juice (Citrus paradisi)
(Dq) Dong quai root (Angelica sinensis)
(Ea) Echinacea angustifolia
root (Echinacea angustifolia) [See Note 5.]
(Ep) Echinacea purpurea
herb, root (Echinacea purpurea) [See Note 5.]
(Fa) Fragrant angelica root
(Angelica dahurica)
(Fr) Frankincense resin (Boswellia spp.)
(Fv) Feverfew leaves (Tanecetum
parthenium)
(Ga) Garlic cloves (Allium sativum) [See Note 6.]
(Gb) Ginkgo leaf extract (Ginkgo
biloba) [See Note 3.]
(Gd) Grape seed (Vitis vinifera)
(gg)
ginkgolic acids in ginkgo leaves (Ginkgo biloba)
(gl)
glabridin from licorice root (Glycyrrhiza glabra)
(Go) Goldenseal root or herb
(Hydrastis canadensis)
(Gr) Ginger root/rhizome (Zingiber
officinale) [See Note 4.]
(hp) hyperforin in St.
John’s wort (Hypericum perforatum) [See Note 1.]
(hy) hypericin as in St.
John’s wort (Hypericum perforatum)
[See Note 1.]
(kb) keto boswellic acids from frankincense resin (Boswellia spp.)
(kl) kavalactones from kava
root (Piper methysticum)
(Kv) Kava root (Piper
methysticum)
(mg)
mangiferin from mango bark (Mangifera indica)
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa)
(Pi) Pineapple fruit (Ananas
comosus)
(Po) Peppermint oil (Mentha
piperita)
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry
fruit/juice (Vaccinium macrocarpon),
etc.
(rh) rhein as in Chinese
rhubarb root (Rheum palmatum), aloes (Aloe spp.), etc.
(Sg) Sage leaves (Salvia
officinalis)
(si) silymarin/silybin from
milk thistle seeds (Silybum marianum)
(Sp) Saw palmetto
liposterolic extract (Serenoa repens)
(Th) Thyme leaves (Thymus
vulgaris)
(Tu) Turmeric root (Curcuma longa, Curcuma aromatica)
Isozyme
Inducers
(Ag) American ginseng root (Panax
quinquefolium)
(Ea) Echinacea angustifolia
root (Echinacea angustifolia) [See Note 5.]
(Ep) Echinacea purpurea
herb, root (Echinacea purpurea) [See Note 5.]
(Gb) Ginkgo leaf extract (Ginkgo
biloba) [See Note 3.]
(CL)
Chinese Licorice root (Glycyrrhiza uralensis)
(Sc)
Schisandra berry (Schisandra chinensis)
(SJ) St. John’s wort tops (Hypericum perforatum) [See Note 1.]
No
Effect in Human Studies with Isozyme CYP 2C9 substrates NEW
(ar)
artemisinin from sweet annie herb (Artemisia annua) – tolbutamide1512
(Bt)
Black tea leaves (Camellia sinensis)
– flurbiprofen1947 [See Note 2.]
(Cb)
Cranberry fruit/juice (Vaccinium macrocarpon) – flurbiprofen,1947
S-warfarin2316,2509
(Ep)
Echinacea purpurea root (Echinacea purpurea) – tolbutamide1588
(Ga) Garlic cloves (Allium sativum) – warfarin2509
[See Note 6.]
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – diclofenac,2011
flurbiprofen,1842 tolbutamide,2011 S-warfarin1433,1774
[See Note 3.]
(Gp)
Grape fruit/juice (Vitis vinifera) – flurbiprofen1947 [See
Note 2.]
(Gr)
Ginger root (Zingiber officinale) – S-warfarin1774 [See Note 4.]
(Gs)
Ginseng (Asian) root (Panax ginseng)
– S-warfarin1578,2326
(SJ)
St. John’s wort herb (Hypericum
perforatum) – ibuprofen,2079
tolbutamide1217,1775 [See Note 1.]
Notes:
1. In vitro St. Johns wort extracts were
inhibitory to CYP 2C9,1522 though human studies found extracts to
have either no effect on CYP 2C9 substrate tolbutamide1217,1775 or ibuprofen2079
and induction of metabolism of the CYP 2C9 substrate S-warfarin.1578
In one tolbutamide human pharmacokinetic study, the extract that failed to
induce metabolism provided a daily dose of only 3.5 mg hyperforin.1775
The activation of pregnane X receptor in human liver
cells in vitro by St. John’s wort extract1002 and its major
active component hyperforin1703 indicates the probable mechanism of
St. John’s wort acting as an inducer of CYP 3A4, CYP 2C9, and P-glycoprotein1926
which is born out in human studies.1350,1578,1590,1613 The product
that failed to alter ibuprofen metabolism in humans after 22 days of taking 900
mg daily was standardized to 0.3% hypericin, so its hyperforin content, if any,
is unknown.2079
2. Though brewed black tea
and grape juice both failed to alter the metabolism of CYP 2C9 substrate
flurbipofen in humans, they both inhibited its hydroxylation in human liver
microsomes in vitro1947 as black tea had previously inhibited
a marker substrate in vitro.1577
3. Though ginkgo leaf
extract acts as an inhibitor in vitro,2011,2145,2151 at 360
mg/day EGb 761 in humans2015 and as 0.5% of the diet in rats it was
shown to induce this isozyme.1952 Normal therapeutic doses do not
produce either effect in humans.1433,1774,1842,2011 Rat recovery
from CYP 2C9 induction occurs within 1 week.1952
4. The in vitro
inhibition evidence for ginger1577 is superceded by its lack of
effect in the metabolism of warfarin in humans.1774
5. While both Echinacea
angustifolia and E. purpurea root preparations were shown in vitro to
inhibit metabolism of CYP2C9 substrates,2581 a combination extract
from these two roots given 4 times daily for 14 days to 12 men followed by
racemic warfarin resulted in increased S-warfarin clearance but no effect on
R-warfarin clearance or on the anticoagulant response.2582
6. Though garlic inhibited the metabolism of a probe
substrate in vitro,1594 an
enteric-coated garlic tablet from 2 gm of fresh garlic with 3.7 mg allicin per tablet
given twice daily for 3 weeks to 12 healthy subjects, no change in
bioavailability of warfarin isomers as reflected by the plasma
concentration-time profiles nor in INR was detected over the next week,
indicating a lack of effect on CYP 2C9.2509
B.7.2.e Influence on CYP 2C19 Metabolic Conversion of
Substrates ^ NEW
Substrates:
7-ethoxy-3-cyanocoumarin
– db, gg, hp, kl, os, qu,1458 Bt, Ch, Cl,1577 Ea, Ep,2581
Go, Gr, Or, Sg, Th, Tu,1577 Ga1594
Drugs:
amitriptyline – SJ1614
imiprimine – Fr, kb,2664
Gf, Kv, Po2568
mephenytoin – kl, Kv,1327,2146 mg2266
; ar,1512 Gb,2302 SJ1584
omeprazole – ar,1931
Gb,1617,2301 SJ1674
voriconazole – SJ1839
Isozyme Inhibitors
(Bt) Black tea leaves (Camellia
sinensis)
(Ch) Chamomile (Matricaria recutita)
(Cl) Clove buds (Syzygium aromaticum)
(db) dihydroxybergamottin in
grapefruit juice (Citrus paradisi)
(Ea) Echinacea angustifolia
root (Echinacea angustifolia)
(Ep) Echinacea purpurea
herb, root (Echinacea purpurea)
(Fr) Frankincense resin (Boswellia spp.)
(Ga) Garlic cloves (Allium sativum)
(gg)
ginkgolic acids in ginkgo leaves (Ginkgo biloba)
(Go) Goldenseal herb (Hydrastis canadensis)
(Gf) Grapefruit fruit/juice
(Citrus paradisi)
(Gr) Ginger root/rhizome (Zingiber
officinale)
(hp) hyperforin in St.
John’s wort (Hypericum perforatum)
(kb) keto boswellic acids from frankincense resin (Boswellia spp.)
(kl) kavalactones from kava
root (Piper methysticum)
(Kv) Kava root (Piper
methysticum)
(mg)
mangiferin from mango bark (Mangifera indica)
(Or) Oregano leaves (Origanum
vulgare)
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa)
(Po) Peppermint oil (Mentha
piperita)
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry
fruit/juice (Vaccinium macrocarpon),
etc.
(Sg) Sage leaves (Salvia
officinalis)
(Th) Thyme leaves (Thymus
vulgaris)
(Tu) Turmeric root (Curcuma longa, Curcuma aromatica)
Isozyme Inducers
(ar) artemisinin from sweet
annie herb (Artemisia annua)
(Gb) Ginkgo leaf extract (Ginkgo biloba) [See Note 1.]
(SJ) St. John’s wort tops (Hypericum perforatum)
Notes:
1. In a 12-day study with 18 healthy Chinese men, an ethnic group known for 15-20% CYP2C19 genetic polymorphism, 6 were homozygous and 5 were heterozygous excellent metabolizers while 7 were poor metabolizers. Though ginkgo standardized extract at 280 mg daily increased metabolism of omeprazole in all three groups, the increase for the poor metabolizers was significantly greater than for both groups of excellent metabolizers.2301 However, a reportedly standardized ginkgo extract at 120 mg daily for 12 days in 7 poor and 7 extensive CYP2C19 metabolizers did not change the metabolism of the substrate voriconazole in either group of healthy humans. This may be due to an inhibitory effect on CYP3A4 metabolism of voriconazole.2679
B.7.2.f Influence on CYP 2D6 Metabolic Conversion of
Substrates ^ NEW
Substrates:
2-(N,N-diethylamino)ethyl-7OH-4MeCoumarin
– Ea, Ep2581
7-ethoxy-3-cyanocoumarin
– Cl, Gr, Or, Sg, Th1577
3-[A]-7-methoxy-4-methylcoumarin
– db, gg,1458 gs,1812 Bt, Ch, Fv, Go,1577 Sp2151
Drugs: bufuralol – ba,1522 br, Go,1813
hp, hy,1522 Fa1632
debrisoquin – Bc,1807
Gs,1808 Go1807,2502
dextromethorphan – Ag, Az, Bp, Cl,2123
Ep,2292 Gb,2292 Gd, Go,2145 kl, Kv,1327
Li, Mp, Pg, Rh, 2123 Sg,2292 Sw2123
propranolol – pp206
sparteine – pp204
Isozyme Inhibitors
(An) Andrographis herb (Andrographis
paniculata)
(Az) Aromatic zingiber
rhizome (Zingiber aromaticum)
(ba) I3,II8-biapigenin as in
St. John’s wort (Hypericum perforatum), etc. [See Note 2.]
(Bc) Black cohosh roots/rhizome (Cimicifuga
racemosa) [See Note 3.]
(Bp) Black pepper fruit (Piper nigrum)
(bn) berberine in goldenseal
root (Hydrastis canadensis)
(Bt) Black tea leaves (Camellia
sinensis)
(Ch) Chamomile (Matricaria recutita)
(Cl) Clove buds (Syzygium aromaticum)
(db) dihydroxybergamottin in
grapefruit juice (Citrus paradisi)
and bitter orange fruit juice (Citrus aurantium) [Note 1]
(Ea) Echinacea angustifolia
root (Echinacea angustifolia)
(Ep) Echinacea purpurea
herb, root (Echinacea purpurea)
(Fa) Fragrant angelica root
(Angelica dahurica)
(Fv) Feverfew leaves (Tanecetum
parthenium)
(Gb) Ginkgo leaf extract (Ginkgo biloba)
(Gd) Grape seed (Vitis
vinifera)
(gg)
ginkgolic acids in ginkgo leaves (Ginkgo biloba)
(Go) Goldenseal root or herb
(Hydrastis canadensis)
(Gr) Ginger root/rhizome (Zingiber
officinale)
(Gs) Ginseng (Asian) root (Panax ginseng) [See Note 4.]
(gs) ginsenoside (Rd) from Asian ginseng (Panax ginseng) roots
(hp) hyperforin in St.
John’s wort (Hypericum perforatum) [See Note 2.]
(hy) hypericin as in St.
John’s wort (Hypericum perforatum)
[See Note 2.]
(kl) kavalactones from kava
root (Piper methysticum)
(Kv) Kava root (Piper
methysticum)
(Li) Licorice root (Glycyrrhiza glabra)
(Mp) Madagascar periwinkle
herb (Catharanthus roseus)
(Or) Oregano leaves (Origanum
vulgare)
(Pg) Pomegranate fruit (Punica
granatum)
(pp) piperine in black
pepper (Piper nigrum) and long pepper fruit (Piper longum)
(Rh) Chinese Rhubarb root (Rheum
palmatum)
(Sg) Sage leaves (Salvia
officinalis)
(Sp) Saw palmetto
liposterolic extract (Serenoa repens)
(Sw) Sandalwood wood (Santalum
album)
(Th) Thyme leaves (Thymus vulgaris)
Isozyme Inducers
[The constitutive isozyme CYP 2D6 is not considered inducible. However, it has been activated at high concentrations in vitro by ginkgo extract and valerian extract2292 and in vivo by aqueous and ethanolic extracts of dong quai and aqueous extract of rhubarb root in rats.2671]
No
Effect in Human Studies with Isozyme CYP 2D6 substrates NEW
(Bc)
Black cohosh roots/rhizome (Cimicifuga racemosa) – debrisoquin2502
[See Note 3.]
(Bo)
Bitter orange (Citrus aurantium) – debrisoquin1589 [See Note
1.]
(El)
Eleuthero extract (Eleutherococcus
senticosus) – dextromethorphan2086
(Ep)
Echinacea purpurea root or whole plant (Echinacea purpurea) –
debrisoquin,1589,2502 dextromethorphan1588
(Ga)
Garlic oil (Allium sativum) –
debrisoquin1328,1808
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – debrisoquin,1328,1808,2302
dextromethorphan1840
(Kv)
Kava root (Piper methysticum) – debrisoquin1807,2502
(Mt)
Milk thistle silymarin extract (Silybum marianum) – debrisoquin1589,2502
(Sp)
Saw palmetto liposterolic extract (Serenoa repens) – debrisoquin,1589
dextromethorphan1810
(SJ)
St. John’s wort (Hypericum perforatum) – debrisoquin,1328,1808,2502
dextromethorphan1217,1478,1838 [See Note 2.]
(Te)
Tea (green) leaf decaffeinated extract (Camellia
sinensis) – dextromethorphan1710
(Va)
Valerian root (Valeriana officinalis) – debrisoquin,1807
dextromethorphan1676
Notes:
1. A study with 12 humans given a bitter orange
(Citrus aurantium) product that did not inhibit metabolism of the CYP
2D6 substrate debrisoquine was lacking 6,7-dihydroxybergamottin.1589
2. In vitro St. Johns
wort extracts were inhibitory to CYP 2D61522 but were found to have
no effect on CYP 2D6 substates debrisoquin and dextromethorphan in humans.1217,1328,1478,1808
3. The inhibition of
debrisoquin metabolism by black cohosh extract (2.18 grams daily) for 28 days
in 12 volunteers was statistically significant at 7%, but this is not likely
significant clinically.1807 Another human study using 40 mg of
extract twice daily for 2 weeks in 18 healthy volunteers found no effect on CYP
2D6.2502
4. Though inhibition of
debrisoquin metabolism by Asian ginseng root extract (1.5 gram daily) was
statistically significant at 7%, this effect is probably not clinically
significant.1808 While this inhibitory effect by ginseng extract was
found in those between ages of 60 and 76 years,1808 another study of
the Asian ginseng extract and dose did not alter the metabolism of debrisoquin
in those between the ages of 21 and 29 years.1328
B.7.3 Specific Enzyme Influences of Herbal Agents
on Phase II Conjugation
B.7.3.a Influence on Glutathione S-Transferase [GST] Activity or Levels p. 262
Conjugation Inhibitors
(ao) anthocyanins from
blueberry fruit (Vaccinium spp.) – colon2419
(ar) artemisinin from
Chinese wormwood plant (Artemisia annua) – (A1-1)1547
(cc) curcumin in turmeric
root (Curcuma longa, Curcuma aromatica)
– liver,2035 liver825,2593 [See Note 1.]
(Cl) Chaparral leaves (Larrea
tridentata) – liver1322
(dp)
diospyrin from Indian persimmon stem bark (Diospyros montana) – (A1-1,
M1-1, P1-1)1670
(ge)
geshoidin from African dogwood leaves and bark (Rhamnus prinoides) –
(M1-1)1670
(gp) gossypol in cotton root
bark (Gossypium herbaceum, Gossypium hirsutum) – liver6
(qn) quinine/quinidine from
cinchona bark (Cinchona spp.) – (M1-1)1547
(si)
silymarin/silybin in milk thistleseeds (Silybum marianum) – liver (1-1,
2-2, 3-3, 4-4)1285
(Sn) Stinging nettle
leaves/herb (Urtica dioica) – brain, liver, kidney2303
(Tb) Tobacco leaves *(Nicotiana tabacum) – liver1182
(Tu)
Turmeric root (Curcuma longa) – lymphocyte (M1, P1, T1)2488
Conjugation
Inducers
(ac) S-allylcysteine in garlic
cloves (Allium sativum) – liver,865,1180 intestine,1180
colon865
(Bm) Black mustard seeds (Brassica
nigra) – liver1182
(cc) curcumin in turmeric
root (Curcuma longa, Curcuma aromatica)
– liver (A4-4),1396 liver (A8-8),1395 (P1-1)1397
[See Note 1.]
(cs) carnosol from rosemary
leaves (Rosmarinum officinalis) – liver (P),1287 liver1286
(ct) catechin as in catechu
(Acacia catechu) bark, green tea (Camellia sinensis) leaves, etc.
– stomach, liver1501
(Cy)
Celery seed oil (Apium graveolens) – liver1155
(Cn)
Coriander oil (Coriandrum sativum) – liver1155
(ds) diallyl sulfide in
garlic cloves (Allium sativum) – liver,1302,
2083,2097 placenta2096,2097
(ea) ellagic acid as in
strawberry leaves, seeds (Fragaria spp.), raspberry leaves, seeds (Rubus spp.) and black walnut leaves, nuts (Juglans nigra), etc. – liver1687,2460
(Ga)
Garlic cloves (Allium sativum) – liver,861,1179,1182,2097 (Ya,
Yb1, Yc)1629 breast,861
placenta2096,2097
(Gb)
Ginkgo leaf extract (Ginkgo biloba) – liver1952
(gi)
glucobrassicin indole metabolites in specific crucifers (Brassica oleracea) – liver (Yc2),1179 liver 858,859,1179
(Gr)
Ginger oil (Zingiber officinale) – liver1155
(Hn)
Henna leaves (Lawsonia inermis) – liver1960
(mi)
6-methylsulfinylhexyl isothocyanate in wasabi roots (Wasabia japonica) –
liver (A1, P1),1688,1689 (Ya),1689,1877 liver1688,1689
(my)
myristicin from parsley leaf oil (Petroselinum sativum), nutmeg seed (Myristica
fragrans), etc. – liver, intestine1284,1295
(Nm)
Nutmeg oil *(Myristica fragrans) – liver1155
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa) – intestine,
liver1302
(pi) phenethyl
isothyocyanate from watercress (Nasturtium
officinale), crucifers (Brassica
spp.) – liver,1179,2063,2460 (Yc2)1179
(qu) quercetin as in onion
bulbs (Allium cepa), tea leaves (Camellia sinensis), kale leaves (Brassica oleracea v. acephala), etc. – liver1179
(Rm) Rosemary leaves (Rosmarinum
officinalis) – liver1286
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus spp.), blueberry fruit (Vaccinium spp.)
– heart2380
(Sc)
Schisandra berry (Schisandra chinensis)
– liver1294
(si) silymarin/silybin in
milk thistle seeds (Silybum marianum) – liver, lung, skin, stomach,
intestine1622
(sn) sinigrin in Chinese
mustard (Brassica juncea) and black mustard seeds (Brassica nigra)
– liver1179
(sr) sulforaphane from
broccoli sprouts and tops (Brassica
oleracea v. italica) – liver (A1,
P1),1688 liver,1688 bladder2415
(Te) Tea (green and black)
leaves (Camellia sinensis) – liver1649
1. No effect on GST isozymes
were observed in 15 cancer patients receiving oral curcumin doses between
0,45-3.6 grams/day for up to 4 months.2057
B.7.3.b Influence on
Activity and/or Content of UDP-Glucuronosyltransferases [UGT] p. 263
Conjugation Inhibitors
(bc)
baicalin/baicalein and other Chinese skullcap flavones (Scutellaria
baicalensis) – liver, kidney1892
(Cl) Chaparral leaves (Larrea
tridentata) – liver1322
(is)
isoflavones as in soy beans (Glycine max),
kudzu plant (Pueraria lobata), etc. –
liver2064
(si)
silymarin/silybin from milk thistle seeds (Silybum
marianum) – purified (potent 1A1),2210 liver & purified
(mild 1A6/9)1293,2210 [not in 6 cancer patients
2106]
(Sy) Soy bean extract (Glycine
max) – liver (2B15; dihydrotestosterone)1811
Conjugation
Inducers
(Cr) Crucifers, especially broccoli, cauliflower, cabbage (Brassica oleracea) – colon, liver (2),1987
(cu)
coumarins of Eriostemon (Philotheca spp.) and Phebalium (Phebalum spp.)
– liver (1A1)2144
(cy)
chrysin from passion flower plant (Passiflora incarnata, Passiflora coerulea)
– liver (1A1)2144
(ds) diallyl sulfide in
garlic cloves (Allium sativum) – liver
(1)1302
(ea) ellagic acid as in strawberry
leaves, seeds (Fragaria spp.), raspberry leaves, seeds (Rubus spp.) and black walnut leaves, nuts (Juglans nigra), etc. – liver1687
(Gt) Green tea leaves (Camellia sinensis) – liver1999
(os) organosulfides in
garlic cloves (Allium sativum) and onion
bulbs (Allium cepa) – intestine,
liver1302
(Te) Tea (green and black)
leaves (Camellia sinensis) – liver1649
B.7.3.c Influence
on NADPH-Quinone Reductase [QR]
(NAD(P)H:Quinone Oxidoreductase 1 or DT-Diaphorase) Activity and/or Content p. 263
Conjugation Inhibiters
(ao) anthocyanins from
blueberry fruit (Vaccinium spp.) – colon2419
(fg) flavone glucuronides of
Chinese skullcap root (Scutellaria baicalensis) – liver1237
Conjugation
Inducers
(Ag) American ginseng root (Panax
quinquefolium) – liver2325
(As) Asparagus stalk (Asparagus officinalis) – liver1363
(At)
Ashitaba (Angelica keiskei) – liver2171
(Bb) Bilberry fruit extract
(Vaccinium myrtillus) – liver1259,1354
(bi) benzyl isothyocyanate in crucifers (Brassica spp.) – colon,1195 liver2155
(Br)
Broccoli florets (Brassica oleracea v.
italica) – liver1363,2162,2171
(Cb) Cranberry fruit extract (Vaccinium macrocarpus) – liver1259,1354
(cc) curcumin in turmeric
root (Curcuma longa, Curcuma aromatica)
– liver,2154,2561 kidney2154
(Cr) Crucifers, especially
Brussels sprouts, cabbage, cauliflower, kale, and kohlrabi (Brassica oleracea) – liver1363
(cs) carnosol from rosemary leaves (Rosmarinum officinalis) – liver,1287 liver1286
(Cy) Celery seed oil (Apium
graveolens) – liver1363,2171
(Dl)
Dandelion root (Taraxacum officinale) – liver1608
(ds) diallyl sulfide in
garlic cloves (Allium sativum) – lungs,1178
heart, bladder, GI, colon, brain2154
(ea) ellagic acid as in
strawberry leaves, seeds (Fragaria spp.), raspberry leaves, seeds (Rubus spp.) and black walnut leaves, nuts (Juglans nigra), etc. – liver1687
(Gi) Ginger rhizome (Zingiber officinale) – liver1363
(Gb)
Green bean pods (Phaseolus vulgaris) – liver1363
(gm) glucosinolates and/or
indole metabolites in crucifers (Brassica
oleracea) – colon,1195 liver2159,2160
(Hn)
Henna leaves (Lawsonia inermis) – liver1960
(Lk)
Leek stems (Allium porrum) – liver1363
(Lt) Lettuce leaves (Lactuca sativa) – liver1363
(mi) methylsulfinyl
isothocyanates in wasabi roots (Wasabia japonica), watercress herb (Nasturtium officinale), Broccoli florets
[See (sr).] (Brassica oleracea v. italica) – liver,2157-8,2162 liver1688
(Ms)
Mitsuba (Cryptotaenia japonica) liver2171
(On) Onion green tops (Allium
cepa) – liver1363
(os) organosulfides in garlic cloves (Allium sativum) and onion bulbs (Allium cepa) – forestomach,1178 lung, heart, bladder, GI, colon, brain2154
(pf) prenylflavonoids from
hops strobiles (Humulus lupulus) – liver1591
(Pc)
Pak choi leaves (Brassica campestris v.
chinesensis) – liver1363
(pi) phenethyl isothiocyanate from watercress herb (Nasturtium officinale), crucifers (Brassica spp.) – colon,1195 liver1179
(Ps)
Parsley leaf (Petroselinum sativum) – liver2171
(qu)
quercetin as in onion bulbs (Allium cepa),
tea leaves (Camellia sinensis),
cranberry fruit/juice (Vaccinium
macrocarpon), etc. – liver,2169,2170 breast2154
(Rd)
Radish root (Raphanus sativus) –
liver1363
(Rm) Rosemary leaves (Rosmarinum officinalis) – liver1286
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus spp.), blueberry fruit (Vaccinium spp.) – liver,881 heart2380
(si) silymarin/silybin in
milk thistle seeds (Silybum marianum) – liver, lung, skin, stomach,
intestine1622
(Sp) Spinach leaves (Spinacea oleracea) – liver1363
(sr) sulforaphane from broccoli sprouts and tops (Brassica oleracea v. italica) – bladder,2415 breast,2154 colon,1195 liver,1688,2155-6,2161,2167,2325
(Tg)
Thai ginger rhizome (Boesenbergia pandurata) – liver2169
(Tp)
Tephrosia flowers and fruit (Tephrosia purpurea) – liver2178
(Tt)
Tomatillo fruit (Physalis philadelphica) – liver2167,2168
(xh) xanthohumol and/or
isoxanthohumol in hops strobiles (Humulus lupulus) – liver2289
B.7.3.d Influence on
Epoxide Hydrolase (Epoxide Hydratase)[EH] Activity p. 264
Conjugation Inducers
(cc) curcumin in turmeric
root (Curcuma longa, Curcuma aromatica)
–liver1397
(ds) diallyl sulfide in
garlic cloves (Allium sativum) – intestine,
liver1302
(os) organosulfides in
garlic cloves (Allium sativum) and
onion bulbs (Allium cepa) – intestine,
liver1302
B.7.3.e Influence on
Activity of Phenol Sulfotransferases [PSTs or SULT1A1]
(pi)
phenethyl isothyocyanate from watercress herb (Nasturtium officinale), crucifers (Brassica spp.) – liver2063
(xn)
xanthones from guanadi heartwood (Calophyllum brasiliense) – liver2571
B.7.4 Specific Enzyme Influences of Herbal Agents
on Steroid Metabolism
(Bold abbreviations indicate human studies with subject criteria noted; organ enzyme sources identified for in vitro tissue studies [non-italicized] and animal studies [italicized])
B.7.4.a Aromatase (CYP19) Conversion of
Androstenedione to Estrone and Testosterone to 17beta-Estradiol p. 265
Conversion Inhibitors
(ap) apigenin as in
chamomile (Matricaria recutita)
and Roman chamomile (Chamaemelum nobile) flowers, parsley (Petroselinum
sativum) leaves, etc. – placenta1766,1780
(bA) biochanin A from red
clover leaves, flowers (Trifolium
pratense), etc. – fat1435
(Cu) Cubeb seeds (Piper
cubeba) – (androstenedione)2264
(cy) chrysin from passion
flower plant (Passiflora incarnata, Passiflora coerulea) – fat,1435
placenta1766,1780,2040
(er) eriodictyol as in lemon
fruit/juice (Citrus limon), peppermint (Mentha piperita), etc.. –
placenta1779
(et) ellagitannins from pomegranate (Punica granatum) – breast2645
(Gp) Grape red wine (Vitis
vinifera) – placenta2040
(hs) hesperetin as in orange
fruit/juice (Citrus sinensis), lemon fruit/juice (Citrus limon),
etc. – placenta1779
(kf) kaempferol as in tea
(black and green) leaves (Camellia
sinensis), kale leaves (Brassica
oleracea v. acephala), etc. –
fat, 914 placenta2040
(ln)
lignan metabolites from flax seed (Linum usitatissimum) – placenta,913 fat914
(lt)
luteolin as in thyme (Thymus spp.), asparagus (Asparagus officinalis),
etc. – placenta1779
(mr)
myricetin as in tea (black and green) leaves (Camellia sinensis), parsley (Petroselinum sativum) leaves,
cranberry fruit/juice (Vaccinium
macrocarpon), etc. – placenta1766,2040
(nr)
naringenin as in grapefruit fruit/juice (Citrus
paradisi) – placenta1766,1779,2040
(pl)
polyphenols from green tea leaves (Camellia
sinensis) – placenta1599
(Qc) Quinine conk mushroom (Fomitopsis
officinalis) – prostate1861
(qu) quercetin as in onion bulbs (Allium cepa), tea leaves (Camellia sinensis), cranberry fruit/juice (Vaccinium macrocarpon), etc. – placenta2040
(rs) resveratrol as in
dark-skin grapes (Vitis vinifera),
mulberry fruit (Morus nigra), blueberry fruit (Vaccinium spp.) – placenta2040
(Rs) Reishi mushrooms (Ganoderma
lucidum) – prostate1861
(Te) Tea (green and black)
leaves (Camellia sinensis) – placenta2040
(Wb)
White button mushroom (Agaricus bisporus) – prostate, prostate1861
Conversion Inducers
(Cs)
Cordyceps mycelium (Cordyceps sinensis) – granulose-lutein cells1932
B.7.4.b 5alpha-Reductase Conversion of Testosterone to Dihydrotestosterone p. 265
Conversion
Inhibitors
(Bc) Black cohosh
roots/rhizome (Cimicifuga racemosa) – prostate2056
(Cu) Cubeb seeds (Piper
cubeba) – prostate2254
(is) isoflavones as in soy beans (Glycine max), kudzu plant (Pueraria lobata), red clover flowers (Trifolium pratense), etc. – prostate,
foreskin1652
(ln) lignan metabolites from flax seed (Linum usitatissimum) – prostate, foreskin1652
(Py)
Pygeum bark (Pygeum africanum) –
[neg. prostate2249]
(Qc) Quinine conk mushroom (Fomitopsis
officinalis) – prostate1861
(Rs) Reishi mushrooms (Ganoderma
lucidum) – prostate1861
(SJ)
St. John’s wort tops (Hypericum
perforatum) – men and women2122
(Sn)
Stinging nettle root (Urtica dioica) – [neg. prostate2249]
(Sw)
Saw palmetto fruit extracts (Serenoa
repens) – skin,1677 prostate,1678 in balding men1679
(Tj)
Thuja seeds (Thuja occidentalis) – kidney, skin2136
(Wb)
White button mushroom (Agaricus bisporus) – prostate, prostate1861
B.7.4.d 11beta-Hydroxysteroid Dehydrogenase type 2
Conversion of Cortisol to Cortisone p.
266
Conversion Inhibitors
(gl)
glycyrrhetinic acid/glycyrrhizin from licorice (Glycyrrhiza glabra, Glycyrrhiza
uralensis) – in healthy young adults1667
B.7.4.e 17beta-Hydroxysteroid Dehydrogenase type 5
Conversion of Androstanediol to Androsterone
and Androstenedione
to Testosterone p.
266
Conversion Inhibitors
(bA)
biochanin A from red clover leaves, flowers (Trifolium pratense), etc. – microsomes1778
(cm)
coumestrol as in alfalfa herb (Medicago
sativa) – microsomes1778
(gl)
glycyrrhetinic acid/glycyrrhizin from licorice (Glycyrrhiza glabra, Glycyrrhiza
uralensis) – microsomes1778
(Li)
Licorice root (Glycyrrhiza glabra, Glycyrrhiza uralensis) – in
healthy young women1767
(og)
oleuropein glycoside from olive fruit oil (Olea europaea) – liver
microsomes2068
(qu)
quercetin as in onion bulbs (Allium cepa),
tea leaves (Camellia sinensis),
cranberry fruit/juice (Vaccinium
macrocarpon), etc. – microsomes1778
B.7.4.f 17beta-Hydroxysteroid Dehydrogenase type 2
Conversion
of Testosterone to Androstenedione or Estradiol to Estrone NEW
Conversion Inhibitors
(ga) galangin from China
root (Alpinia officinarum) – prostate1858
(kf) kaempferol as in tea
(black and green) leaves (Camellia
sinensis), kale leaves (Brassica
oleracea v. acephala), etc. –
prostate1858
(is) isoflavones as in soy beans (Glycine max), kudzu plant (Pueraria lobata), red clover flowers (Trifolium pratense), etc. – foreskin,1652 microsomes1950
(ln) lignan metabolites from flax seed (Linum usitatissimum) – foreskin1652
B.7.4.g 17beta-Hydroxysteroid Dehydrogenase type 1
Conversion of Estrone to Estradiol NEW
Conversion
Inhibitors
(ap)
apigenin as in chamomile (Matricaria
recutita) and Roman
chamomile (Chamaemelum nobile) flowers, parsley (Petroselinum sativum)
leaves, etc. – placenta1777,1779,1780,1858
(cm)
coumestrol as in alfalfa herb (Medicago
sativa) – placenta1777,1780
(is)
isoflavones daidzein and/or genistein as in soy beans (Glycine max), kudzu plant (Pueraria
lobata), etc. – placenta1777,1780
(lt)
luteolin as in thyme (Thymus spp.), asparagus (Asparagus officinalis),
etc. – placenta1779
B.7.4.h 3beta-Hydroxysteroid Dehydrogenase type 1 or
2 Conversion
of DHEA to
Androstenedione and/or Pregnenolone to Progesterone NEW
Conversion
Inhibitors
(is) isoflavones as in soy
beans (Glycine max), kudzu plant (Pueraria lobata), red clover flowers (Trifolium pratense), etc. – microsomes1950
B.7.5 Herbs containing Monoamine Oxidase –A
&/or –B Inhibitors p.
266
(Kv)
Kava root *(Piper methysticum) – pos B (platelet)514
Appendix
C
HERBALS
CONTRAINDICATED FOR MOTHERS AND CHILDREN
C.1 During Pregnancy p.
269
Use of herbs during pregnancy does
not appear to be as extensive as the 22% incidence reported among presurgical
patients. A 2002 survey of 1203 pregnant women seen at a Boston hospital at 20
weeks gestation resulted in responses from 734 indicating that only 7.1% used
herbal remedies while 75.6% used over the counter medications, mostly cold
remedies, pain relievers, and heartburn medication. Echinacea (2.6%), ephedra
(1.8%) [before in became unavailable], and St. John's wort (1.4%) were the most
commonly used botanicals. Of all those who had used herbal remedies, 46% did so
at the recommendation of their health care provider, and 8.9% ceased use,
mostly of ephedra, once pregnancy was confirmed. Those most likely to use
botanicals were in the age range of 41-50 years (17.1% of this group).1671
Pregnancy is a special time,
when ordinary influences can have extraordinary consequences. Uterine
contractions or changes in uterine tone can have disruptive effects, since
carrying a baby to term necessitates normal development for the uterus as well
as the child. Alterations in uterine circulation may disturb developmental
processes. Rapid system and organ growth is especially vulnerable to substances
that interfere with cellular division. Abnormal hormonal influences may result
in permanent developmental alterations. The occassional consumption of a cup of
a weak herbal beverage tea is unlikely to have any more untoward effects that
eating plate of garden vegetables. As with higher risk medicinal interventions,
herbal disruptive effects during pregnancy are most likely to occur with large
doses, regular consumption, and/or prolonged use.
Non-nutritive substances
affecting vital functions in the human body should be avoided during pregnancy,
unless there is a recognized need for such agents. Such needs would include
enhancing nutrition, such as by palliating nausea and vomiting or improving
appetite and digestion. Otherwise, the focus should be on optimizing dietary
intake, while possibly supplementing essential vitamins, minerals, and
essential oils in proper amounts. Indiscriminate or excessive consumption of
synthetic or herbal medicines is especially irresponsible when it endangers the
life, health, and future of a vulnerable developing embryo or fetus. Trained
doctors, pharmacists, or other practitioners knowledgeable in the art and science
of utilizing medicinal agents should be consulted for information, advice, or
instructions on their proper use or avoidance during pregnancy.
While deltrimental effects by potentially fetotoxic
and genotoxic botanical agents on fetal development should be, and have been,
studied in cell systems in vitro and
in animals to identify agents to be avoided by humans, these are not the only
influences that can interfere with pregnancy. Plant substances that stimulate
the uterus during labor as oxytocics may also produce this effect in early
pregnancy when it is most undesirable; some women can be more sensitive to this
influence than others. Small doses of certain tonic herbs a few weeks prior to
labor may be valuable if there is a history of inadequate contractions in prior
labors.
A number of herbal advocates believe that it is an
inappropriate and unnecessary to emphasize avoidance in pregnancy of plants
that simply have a reputation for being used traditionally, or in isolated
cultures, for stimulating the onset of menses or strengthening labor
contractions. It has occasionally been suggested that such warnings amount to
scare tactics, since these effects have not been confirmed by modern in vivo research. Human studies on
botanicals for their potential as uterine stimulants can not ethically be
performed on pregnant women, so it is reasonable to examine the historical and
cultural records to identify those agents that have been used empirically and
found potentially active in this regard. This is especially necessary to warn
about those agents that have been used as abortifacients, even though
scientific confirmation is lacking. To inadvertently disrupt normal healthy
human functions and growth development through negligence is tragically bad
medicine, but to risk destroying a developing human life by willfully
disregarding empirical herbal knowledge is an inexcusable version of Russian
roulette. Intentionally employing plants as abortifacients carries high risks,
not only for the fetus but for the mother as well.
A number of native American plants have been identified as emmenogogues
(E) or abortifacients (A) according to their internal uses
by indigenous tribes. Some of these
plants may not currently be popular herbal medicines. However, with a renewed regional
interest in herbs and exploration of ethnopharmacological applications,
personal experimentation or the re-introduction of such plants into use as
alternative remedies is not unlikely. For these reasons it is important to list
potential risks that have been identified concerning traditional remedies based
on their empirical use. Unfortunately, in a few cases the plant part is not
identified.1125 A number of these plants or their components have
been previously identified as either abortifacients, emmenogogues, or uterine
stimulants74 or designated as contraindicated in pregnancy without a
specified rationale.150
In the cases of gender-specific
reproductive organs, plants shown in humans or animals to cause hormonal (H) changes may alter normal
expression. Mutagens (M) and genotoxins (G) can likewise disturb
normal growth as shown by in vitro
studies. Teratogens (T) have been
shown to interfere with normal development of particular structures, and plants
with fetotoxins (F) endanger the
very life of the developing child. In cases where these effects occur, birth
defects are a possible unfortunate result.
In many cases specific parts
of the plant or certain extracts are known to have the above-mentioned effects,
but in other instances only isolated components
( c ) of the plant have been shown
to demonstrate a particular activity. If only the isolated constituent has
shown activity, the use of the plant part itself or its native extract may be
safe if used in small quantities. Also, the particular part of the plant
utilized and the components found therein have everything to do with the
relative risk. For example, critics who have inferred that this book warned
against the use of chamomile flowers during pregnancy were not perceptive
enough to recognize that it actually identifies the plant itself as being
traditionally used as an emmenogogue.
(Based on references 75, 1125, 1308,
1441, 1573, 1636, 1825, 1890, 1944,1945, 2221.)
C.1.1 Herbals That May Impact the Uterus or Fetal
Development
Aloe leaf extract (Aloe
vera) US, A; T
Altamisa leaves (Artemisia
franserioides) E
American
beech bark (Fagus grandifolia) A
American
bittersweet root, leaves, stem (Celastrus scandens) E
American
hellebore juice *(Veratrum viride) A
American
mistletoe roots *(Phoradendron leucacarpum) A
American
skunkcabbage raw root (Lysichiton americanus) A
American
strawberry-bush plant (Euonymus americana) E
American
sycamore (Platanus occidentalis) E
Anise-scented
goldenrod (Solidago odora) E
Asian
ginseng root (Panax ginseng) H
Balsam
fir pitch (Abies balsamea) E
Beelieswari balli plant (Aristolochia
indica) A
Bittersweet
stem (Solanum dulcumara) F
Black
cohosh root (Cimicifuga racemosa) E
Blazing
star root *(Aletris farinose) E
Bloodroot
rhizome *(Sanguinaria canadensis) E, A
Boldo leaves (Peumus boldus) F
Boneset
root (Eupatorium perfoliatum) E
Bur
oak inner bark (Quercus macrocarpa) E
Calamus
root *(Acorus calamus) A
California
croton *(Croton californicus) A
Canada
yew branches (Taxus canadensis) E
Canadian
blacksnake root (Sanicula canadensis) E
Canadian
lily plant (Lillium canadense) E
Canadian
lousewort leaves (Pedicularis canadensis) A
Cedron
(Aloysia spp.) A
Chamiso hediondo leaves (Artemisia
tridentata) E
Chaparral leaves (Larrea
tridentate) A
Cola de quirquincho plant (Lycopodium
saururus) A
Common
sowthistle plant (Sonchus oleraceus) E
Common
twinpod plant (Physaria didymocarpa) A
Common
vetch plant (Vicia sativa ssp. nigra) E
Crataeva bark (Crataeva
nurvala, Crataeva religiosa) F
Cup
plant root (Silphium perfoliatum) E
Douglas’s
sagewort plant (Artemisia douglasiana) E
Dwarf
red blackberry plant (Rubus pubescens v. pubescens) E
Eastern
red cedar *(Juniperus virginiana) E
Espina
colorada (Solanum sisymbriifolium) A
Estafiate leaves (Artemisia
ludoviciana v. mexicana) E, A
Feverwort
root (Triosteum perfoliatum) E
Field
sagewort leaves (Artemisia campestris) A
Floripon (Brugmansia
arborea) A
Francisco
alvarez (Luhea divaricata) A
Fringed
sagewort plant (Artemisia frigida) E
Guggul
gum-resin (Commiphora mukul) H, F
Hackberry
bark (Celtis occidentalis) E
Hairy
skullcap root (Scutellaria elliptica) E
Hoary
skullcap root (Scutellaria incana) E
Horseradish
root (Armoracia rusticana) E
Indian
frankincense gum resin (Boswellia serrata) E
Indian
hemp root *(Apocynum cannabinum) E
Jamaica
dogwood root (Piscidia erythrina)
F
Lajalo leaves (Mimosa
pudica) A
Maidenhair
spleenwort (Asplenium trichomanes) E
Maryland
sanicle root (Sanicula marilandica) E
Meadowsweet
herb (Filipendula ulmaria)
F
Mexican
dock root (Rumex salicifolius v. mexicanus) E
Mountain
alder (Alnus incana) E
Northern
bedstraw plant (Galium boreale) E
Northern
spicebush (Lindera benzoin) E
Northwestern
Indian paintbrush plant (Castilleja angustifolia) E
Orangegrass
(Hypericum gentianoides) E
Pacific
anemone plant *(Anemone multifida) A
Pacific
mistletoe leaves, plant *(Phoradendron villosum) E, A
Pacific
red elder leaves (Sambucus racemosa ssp. pubens v. arborescens)
A
Partridge
berry plant (Mitchella repens) E
Pau d’arco bark (Tabebuia
spp.) A; Fc
Ponderosa
pine green buds (Pinus ponderosa) A
Poverty
weed plant (Iva axillaris) A
Prickly
ash bark (Zanthoxylum americanum) A
Puncture
vine seeds (Tribulus terrestris) A, USc
Purplestem
angelica root (Angelica atropurpurea) E
Purplestem
aster roots (Aster puniceus) E
Red
bay leaves (Persea borbonia) A
Red
currant stalk (Ribes triste) E
Red
root dried root (Ceanothus americanus) A
Rehmannia
uncured root (Rehmannia glutinosa)
Robin’s
plantain (Erigeron pulchellus) E
Romerillo leaves (Artemisia
cana, Artemisia filifolia) E, A
Round-lobed
hepatica roots (Hepatica nobilis v. obtusa) E
Sampson’s
snakeroot (Orbexilum pedunculatum v. psoralioides) E
Sand
hickory (Carya pallica) E
Scouring
rush plant (Equisetum hymenale) E
Skullcap
root (Scutellaria lateriflora ) E
Sedge
leaves (Carex spp.) A
Senega
root *(Polygala senega) E
Sidebeak
pencilflower (Stylosanthes biflora) E
Slender
poreleaf root, plant (Porophyllum gracile) E
Small
spikenard root (Aralia nudicaulis) E
Smooth
horsetail plant (Equisetum laevigatum) E
Snow
trillium root (Trillium grandiflorum) E
Snowberry
branches (Symphoricarpos albus) E
Spikenard
root, plant (Aralia racemosa) E
St.
Andrew’s cross (Hypericum hypericoides) E
St.
John’s wort plant (Hypericum perforatum)
H, T
Sweet
crabapple root (Malus coronaria v. coronaria) E
Sweet
viburnum roots (Viburnum lentago) E
Toyon
leaves (Heteromeles arbutifolia) E
Tylophora leaves *(Tylophora
indica) F
Uva
ursi leaves (Arctostaphylos uva-ursi) E
Velvetleaf
huckleberry leaves, stems (Vaccinium myrtilloides) E
Virginia
mountain-mint root (Pycnanthemum virginianum) E
Virginia
snakeroot *(Aristolochia serpentaria) E
Virginia
strawberry plant (Fragaria virginiana) E
Virginia
tephrosia plant (Tephrosia virginiana) E
Wand
blackroot plant (Pterocaulon virgatum) E
Water
birch leaves, flowers (Betula occidentalis) E
Wavyleaf
silktassel leaves (Garrya elliptica) E
Western
red cedar bark (Thuja plicata) E
Western
yarrow leaves/stem (Achillea millefolium v. occidentalis) A
White
ash bark (Fraxinus americana) E
White
crownbeard plant (Verbesina virginica) E
Wild
cucumber (Echinocystis lobata) E
Yankee
blackberry root (Rubus frondosus) E
Yellowstone
whitlowgrass plant (Draba incerta) A
Yerba de la perdiz (Margiricarpus
pinnatus) A
C.2 While Breast Feeding p.
279
Some contain compounds that are potentially toxic (T) to small children. Normal
development may also be impaired with exposure to substances having a hormonal (H) influence. Certain plants
should be avoided while nursing due to their antiprolactin (AP) effects. Some galactogogues used to stimulated
milk production have shown toxicity in infants when used in excess (E)
of 2 liters daily. The risk due to some potentially disruptive herbal
components is unknown (U), so due to
this uncertainty their use while nursing is not recommended.
(Based on references 1141, 1319, 1890, 1944,
1945.)
C.2.1 Herbals to be Avoided in Medicinal Amounts by
Nursing Mothers
Anise seed/fruit (Pimpinella
anisum) E
Arnica flowers *(Arnica
montana) T
Blue cohosh root *(Caulophyllum
thalictroides) T
Boldo leaves (Peumus boldus) T
Buchu leaves (Agathosma
betulina) U
Celandine root and leaves (Chelidonium
majus) T
Chaparral leaves (Larrea tridentata, Larrea divaricata) AP
European pennyroyal herb (Mentha
pulegium) T
Fennel fruit (Foeniculum vulgare) E
Guggul resin (Commiphora
mukul) U
Jamaica dogwood root bark (Piscidia
erythrina) T
St.
John’s wort plant (Hypericum perforatum)
H, T
Tansy herb (Tanacetum
vulgare) T
Thuja leaves *(Thuja occidentalis) T
Tylophora leaves *(Tylophora
indica) T
Willow bark (Salix
spp.) U
Wormwood herb (Artemisia
absinthium) T
C.3 In Children p. 281
Great care should be taken to insure
proper dosage in utilizing a plant with any record of adverse effects, but this
applies most especially when medicating the young who are often more reactive
to large doses (LD). The age limits
for restricted use can vary, such as infants
under one (<1), young children under
six (<6), or teens under eighteen
(<18) years of age, depending
on the agent and the effect. The
possibility of creating an imbalance exists even when employing plants that are
relatively safe in adults. Children tend
to be more sensitive to certain local irritants
(I) and effects produced on the nervous
system (NS). The following representative herb restrictions are designated
by age limits, dosage, herb form, type of application, and/or effect to be
avoided.
The use of concentrated essential oils (EO)
containing volatile aromatic components should not be given internally (orally)
to anyone, especially children, except by practitioners specially trained in
this approach. Some oils that are safe for adults should not be used in
toddlers or younger children in this form. Teas containing small amounts of
these components are safe and effective in most cases. Tinctures have higher
concentrations of essential oil components than the teas but are generally safe
for children if the herbs are nontoxic. (The alcohol used as an extracting
solvent and preservative in tinctures is not toxic in normal doses given to
children.) Certain aromatic components have been shown to exert an adverse
influence on the nervous system even when used as an inhalant or near the nose of infants (N) or toddlers under two (<2) years of age.
(Based on reference 400, 1370.)
C.3.1 Herbals Whose Medicinal Use Should be
Restricted in Children
Horse chestnut seed/escin (Aesculus
hippocastanum) <18, I
Oregano leaf (Origanum
vulgare) <2, EO
Valerian root (Valeriana
officinalis) < 3, C, NS
Appendix
D
VITAMIN/MINERAL/DRUG
INTERACTIONS
D.1 Drug and Mineral Interactions with Vitamin
Supplements p. 286
Interference between
vitamins and drugs or prescription mineral supplements can work both ways. In some cases drugs will lower vitamin (LV) oral absorption and/or serum levels or increase
excretion or metabolism, while in other cases medications can raise vitamin (RV) bioavailability or
increase their effects. Vitamins may
also raise drug (RD) or mineral (RM) serum levels or increase
their effects, or they may lower drug
(LD) or mineral (LM) levels or
reduce their effects. Vitamin/drug or
vitamin/mineral interactions listed below which have caused either toxicity (t) or insufficient (i) effects for one or the other clinically in humans are emphasized in bold. The other interactions listed have produced observable
changes without clinically-demonstrated effects.
Other types of interactions are now receiving attention. In these cases a vitamin is shown to prevent drug toxicity (PDt) or reduce adverse drug effects or to enhance drug effects (EDe) by making it more efficacious.
Plants included in the lists as having high content
of certain vitamins are mostly herbs. Some common vegetable leaves, roots,
flower buds, and berries are mentioned elsewhere in the text have been
included. However, fleshy fruit and vegetables, nuts and seeds are generally
excluded since these have less crossover uses for medicinal applications.
(Based
on primary references 1164-1166, 1199, 1280, 1324, 1325, 1340, 1361, 1474,
1654,1745,1934, 1985, 2078, 2317, 2646, 2647)
D.1.1.a
Provitamin A (Beta-Carotene)-Rich Herb and Vegetable Sources p.
288
Beet leaves (Beta
vulgaris)
Calendula flowers (Calendula
officinalis)
Mustard leaves (Brassica
juncea)
Stinging nettle leaf (Urtica dioica)
D.1.4 Vitamin B3 (Niacin, Niacinamide)
Drug Interaction p. 289
Atorvastatin – RDt, EDt (very-low-dose
niacin)
Busulfan