A case report has suggested a possible interaction between
ginseng consumption and warfarin, but animal studies do not
support this.
GINKGO BILOBA
Originating from Chinese medicine, ginkgo (derived from the
nuts of Ginkgo biloba– a beautiful and threatened tree rather
than the western culinary stereotype of a ‘herb’) is used for a
variety of ailments and has multiple purported actions,
including antihypoxic, antioxidant, antiplatelet, free radical-
scavenging and microcirculatory properties. It has been used
in patients with asthma, brain trauma, cochlear deafness,
depression, retinitis, impotence, myocardial reperfusion and
vertigo. The evidence for efficacy in many of these conditions
is unconvincing. A recent clinical trial, in which a leading
ginkgo extract did not improve cognitive function, may have
contributed to a decline of ginkgo from the top-selling pos-
ition it had held among such products since 1995. One of the
principal components of ginkgo, ginkgolide B, is a moderately
potent antagonist of platelet-activating factor. ‘Anti-stress’
effects claimed for ginkgo products are postulated to be due to
monamine oxidase inhibition by ginkgolides.
Adverse effects
Serious or fatal side effects of gingko include spontaneous
bleeding, fatal intracerebral bleeding, seizures and anaphyl-
actic shock. Less serious side effects are nausea, vomiting, flat-
ulence, diarrhoea, headaches and pruritus.
Drug interactions
In vitro data suggest ginkgo can inhibit hepatic drug metab-
olizing enzymes. Long-term administration of ginkgo to volun-
teers (for up to 28 days) had no effect on the pharmacokinetics
ofmidazolam, a marker of CYP3A4 activity. In another study,
however, ginkgo increased the plasma concentrations of the
CYP3A4 substrate nifedipineby 53%, confirming the potential
for enzyme inhibition observed in vitro. The discrepant find-
ings for effects of ginkgo on CYP3A4 observed in this trial and
in the phenotyping studies is possibly related to the highly
variable phytochemical composition of commercially available
ginkgo extracts. The potential importance of the change in
CYP2C19 activity noted previously in a cocktail screening
approach, was verified by the observation that ginkgo signifi-
cantly reduced the metabolism of omeprazole, a CYP2C19
substrate, in Chinese patients. Collectively, these clinical data
indicate that ginkgo may interfere with the pharmacokinetics
of drugs metabolized by CYP2C19 or CYP3A4. If it does inhibit
MAO at therapeutic doses, adverse interactions with tyramine-
containing foods and possibly with selective serotonin reup-
take inhibitors (SSRI) (Chapter 20) are to be anticipated.
ECHINACEA
Echinacea is one of the most commonly used alternative medi-
cines, representing 10% of the herbal market. There are nine
species of the genus Echinacea, a member of the sunflower fam-
ily, found in North America. The most common and widespread
of these are Echinacea angustifolia,E. purpureaandE. pallida, each
of which has a long history of medicinal use. The majority of
pharmacologic studies since 1939 have been conducted on
E. purpureapreparations made from the fresh pressed juice of the
flowering plant. Many chemical compounds have been identi-
fied from Echinaceaspecies and it is currently not possible to
attribute the pharmacological effects to any specific substance.
Constituents that have been identified include volatile oil, caffeic
acid derivatives, polysaccharides, polyines, polyenes, isobuty-
lamides and flavonoids of the quercetin and kaempferol type.
Many studies of echinacea have pointed to effects on the immune
system. Proposed mechanisms of action include increased circu-
lating granulocytes, enhanced phagocytosis, inhibition of virus
proliferation, cytokine activation, increased T-lymphocyte pro-
duction and an increase in the CD4/CD8 T-cell ratio. Echinacea
is currently most widely used in attempts to prevent the com-
mon cold and influenza symptoms, but is also used for Candida
infections, chronic respiratory infections, prostatitis and rheuma-
toid arthritis. Well-controlled studies have shown little, if any,
benefit. One recent placebo-controlled study of echinacea in the
treatment of the common cold actually suggested echinacea did
not prevent people catching a ‘cold’ and if they did get symp-
toms they lasted slightly longer in patients taking echinacea.Adverse effects
Adverse effects of echinacea use involve rashes, including
erythema multiforme, arthralgias, allergic reactions, gastro-
intestinal disturbances including dysgeusia, dyspepsia and
diarrhoea.Drug interactions
Some flavonoids present in echinacea extracts can either
inhibit or activate human CYPs and drug transporters,
depending on their structures, concentrations and assay con-
ditions.Midazolam, a substrate for CYP3A4 and CYP3A5,
was cleared 42% faster during an eight-day echinacea treat-
ment in 12 volunteers and there was a 23% reduction in mida-
zolamarea under the curve (AUC). The oral bioavailability of
midazolamin this study was significantly increased from 24
to 36% in the presence of echinacea, indicating that the hepatic
and intestinal availabilities were altered in opposite direc-
tions. These data suggest that echinacea is likely to interact
with other oral drugs that are substrates for CYP3A4 and that
the interaction will depend on the relative extraction of drugs
at the hepatic and intestinal sites and the route of administra-
tion. Echinacea from retail stores often does not contain the
labelled species (a similar situation affects other herbal prepa-
rations). The high variability observed in concentration of
constituents of the herb has implications for echinacea’s abil-
ity to modulate drug absorption and disposition.SOY
The use of soy (Glycine max) and soy-derived products for the
treatment of menopause in women is growing with the fear ofSOY 99