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