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- Ginkgo (Ginkgo biloba, Ginkgoaceae)
- Toxicology
- Tolerability and Safety
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Date:
05-15-2015 | HC# 011555-520
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Re: Comprehensive Assessment Concludes Ginkgo Leaf Extract Is Safe and Well Tolerated
Heinonen
T, Gaus W. Cross matching
observations on toxicological and clinical data for the assessment of
tolerability and safety of Ginkgo biloba
leaf extract. Toxicology.
2015;327:95-115.
Ginkgo
(Ginkgo biloba, Ginkgoaceae) leaf
extract is one of the herbal products most commonly used in the United States
and Europe. The most popular ginkgo formulation is the standardized extract EGb
761® (Tebonin®; Dr. Willmar Schwabe GmbH & Co. KG;
Karlsruhe, Germany). The purpose of this review was to analyze the tolerability
and safety of ginkgo in humans. The authors used a tool that they designed
called cross matching. The purpose of cross matching is to combine different
fields of knowledge and types of data into a consolidated result. It is
important to evaluate not only ginkgo but also its components because various manufacturers
produce ginkgo preparations differently. It is also important to evaluate the
animal data because, at this time, in vivo animal tests are the first screening
methods for safety and tolerability. Therefore, the authors cross matched
toxicological data, adverse events (AEs) from clinical trials, epidemiological
data, and data reported in the scientific and medical literature.
The
pharmacologically active components of ginkgo are terpene trilactones
(ginkgolides and bilobalide), flavonoid glycosides (metabolized by intestinal
microflora to release quercetin, kaempferol, and isorhamnetin), ginkgolic acids,
and organic acids. Products contain differing amounts of these constituents.
Data
pertaining to hepatic metabolism in mice, rats, and humans were extracted from
the literature. Animal metabolic enzymes differ between species and between
animals and humans. The authors conclude that ginkgo is an inducer of various cytochrome
P450 (CYP) and conjugation enzymes in mice. Bilobalide, but not the other
terpene trilactones, can induce isoforms of CYP and DT-diaphorase in mice. Ginkgolide
A and bilobalide induce glutathione S-transferase in mice. In rats, ginkgo is a
potent inducer of hepatic metabolic enzymes. Bilobalide is an inducer of CYP isoenzymes
in rats. The flavonoids are mainly conjugated with uridine 5'-diphospho (UDP)-glucuronide.
In humans, chronic therapeutic doses have demonstrated no definitive inhibitory
or inducing effect on major human CYPs.
Data
pertaining to the pharmacokinetics of ginkgo in mice, rats, and humans were also
extracted and showed differences among species. Mice and rats were exposed in
toxicity studies to several hundred- to several thousand-fold higher doses of ginkgo
constituents than would be used therapeutically in humans. Accordingly, the peak
plasma levels of ginkgolides A and B and bilobalide were several ten- to
hundred-fold higher than in humans at therapeutic doses.
Data
pertaining to the genotoxicity (damage to the genetic material, which can lead
to cancer) and mutagenicity (mutations in the genetic material) of ginkgo in mice
and rats were reviewed. Very high concentrations of ginkgo or its components
caused cytotoxicity, which appeared positive on in vitro genotoxic tests. Even doses
much higher than what would be used therapeutically were not genotoxic or
mutagenic in vivo. There was no indication of carcinogenicity in mice and rats with
dose levels of EGb 761 25 or 50 times greater than the human therapeutic dosage.
The
National Toxicology Program conducted studies that showed thyroid and liver
tumor induction in ginkgo-treated mice and rats. The mechanism for this effect was
increased activity of hepatic drug metabolism enzymes, which caused accelerated
cell proliferation and concomitant liver neoplasm (tumor), while thyroid
proliferation from elevated thyroid-stimulating hormone resulted from increased
glucuronidation of rodent thyroid hormones. Increased olfactory epithelium
pigmentation and hyaline drop accumulation in the nose without carcinogenicity
and benign respiratory tumors (adenomas) were observed in two rats treated with
an intermediate dose (300 mg/kg). These findings may be random or caused by
esophageal reflux due to gavage administration. There is no indication of ginkgo
carcinogenicity in humans.
The
clinical tolerability and safety of ginkgo were also evaluated via a literature
search. The specific search engine and terms were not reported. A total of 88
publications describing 75 studies were included. Nearly all of the studies
were conducted with EGb 761. Only tolerability and safety data were extracted.
Patients receiving placebo or another comparative treatment other than ginkgo
were excluded from the analysis. The 75 studies include a total of 7115 ginkgo-treated
patients. The authors evaluated all 75 clinical trials and "saw no specific
and serious undesired drug reaction of G.
biloba. If adverse events were observed, they were as frequent with G. biloba as with placebo treatment."
The authors calculated an AE rate and confidence interval. The calculation
showed that the probability for one person to have a specific adverse reaction from
ginkgo is ≤0.000518. They calculate that at least 1930 patients have to be
treated with ginkgo to find one patient with an adverse drug reaction.
Possible
adverse reactions to ginkgo have been reported; specifically, bleeding of
individual organs (eye, nose, cerebral, and gastrointestinal hemorrhage), headache,
dizziness, mild gastrointestinal complaints (such as diarrhea, abdominal pain,
nausea, and vomiting), hypersensitivity reactions (allergic shock), and
allergic skin reactions (erythema, edema, itching, and rash). However, these AEs
are based on spontaneous reports. In controlled, clinical trials, AEs have
never exceeded placebo rates. The authors conclude that they are unable to
establish that ginkgo provokes any specific adverse reaction.
None
of the animal studies provide ample evidence of the toxicity of ginkgo in
humans. The data necessitated cross matching as many sources as possible
because there is a poor relationship between animal and clinical results. Hence,
the following four sources were cross matched: (1) In controlled, clinical
trials including a total of 7115 patients, ginkgo was well tolerated. The
numerous clinical studies evaluated different diseases, doses, duration of
treatment, populations, and diagnostic measures; nonetheless, "no
reasonable suspicion of an adverse drug reaction to G. biloba was found." (2) A long history of modern commercial
use (since 1965) supports the tolerability observed in the clinical studies.
According to the manufacturer of EGb 761, on average for the past 25 years, approximately
360 million doses/year or 1 million doses/day of EGb 761 have been consumed. (3)
There are a wide variety of preclinical toxicological studies with reports from
independent sources on diverse ginkgo preparations and doses used. (4) A long history
of traditional use without expressed safety concerns suggests good
tolerability.
The
authors "certify" that adverse reactions to ginkgo would be extremely
rare. They conclude that ginkgo leaf extract is well tolerated and safe. Despite
the cross matching, this does not mean that AEs are not possible. In
particular, there could be adverse herb-drug interactions to new drugs under
development. It is well known that the elderly population often take numerous
drugs simultaneously and this same population would be interested in taking
ginkgo preparations. The authors do discuss the possibility of pharmacokinetic
ginkgo-drug interactions, but did not find evidence of suggesting such
interactions.
—Heather S. Oliff,
PhD
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