including hypericin and pseudohypericin. With regard to
the putative antidepressant effects of St John’s wort, the phar-
macological activities of hypericin and hyperforin, which
inhibit synaptic 5HT and catecholamine reuptake, could
contribute.
Adverse effects
Adverse CNS effects include headaches, drowsiness, restless-
ness, serotonin syndrome (Chapter 20) if used with SSRIs or
TCAs, skin photosensitivity. Gastro-intestinal disturbances
involve abdominal pain or discomfort, and xerostomia. Drug
interactions with therapeutic failure of concomitant drugs,
e.g. HIV protease inhibitors, ciclosporin, warfarin, theo-
phylline, antidepressants, oral contraceptives and anti-cancer
agents, such as irinotecan.
Drug interactions
Many clinical trials are now reporting significant pharmacoki-
netic interactions with long-term treatment with St John’s
wort and drugs from a variety of therapeutic classes. These
studies followed a number of case reports of serious inter-
actions between St John’s wort and digoxin,theophylline,
ciclosporin, oral contraceptives, phenprocoumon,warfarin
andsertraline, thought to be secondary to enzyme induction.
The mechanism for most of the interactions observed in subse-
quent clinical trials remains unclear, although for some
agents, induction of CYP3A4 (e.g. indinavir, midazolam,
simvastatin), P-glycoprotein-ABCB1 (e.g. digoxin,fexofena-
dine), or both (e.g. ciclosporin) may explain their increased
clearance. St John’s wort produced significantly greater
increases in CYP3A4 expression in women compared to men,
unexplained by differences in body mass index. More recently,
it was shown that St John’s wort enhanced the activity of tran-
scription factors, including the pregnane X receptor to tran-
scribe the CYP3A4andP-gp (ABCB1) genes. Other drug
metabolism enzymes induced by St John’s wort include
CYP1A2, CYP2C9 and 2C19 and possibly UGT1A1 (Chapter
13). It should be noted that studies of St John’s wort on CYP
activity in vitro suggest acute inhibition, followed by induc-
tion in the long term.
GLUCOSAMINE
Glucosamine is available as a non-prescription dietary supple-
ment and in many products is obtained from shellfish. It is one
of several naturally occurring 6-carbon amino sugars found in
the body. Amino sugars are essential building blocks for
mucopolysaccharides, mucoproteins and mucolipids. Some
commercial products contain glucosamine in combination
with chondroitin. The precise mechanism of action of glu-
cosamine is unknown. In vitro data suggest glucosamine can
stimulate cartilage cells to synthesize glycosaminoglycans and
proteoglycans. It is more likely that the cell produces smaller,
soluble subunits; assembly of these smaller, soluble subunits
outside of the cell into a soluble form of collagen has been
proposed. Solubilized collagen, or tropocollagen, is a precursor
of mature collagen fibres. Chondroitin inhibits the enzymes
that degrade cartilage.
Several clinical studies have documented the efficacy of
glucosamine in the treatment of patients with osteoarthritis:
data from double-blind studies showed glucosamine was super-
ior to placebo and to ibuprofenin patients with osteoarthritis
of the knee. Although there is a scientific basis for administering
glucosamine in combination with chrondroitin, there is cur-
rently no evidence that the combination is more effective than
glucosamine alone for osteoarthritis. A randomized, placebo-
controlled, double-blind study evaluated the effects of glu-
cosamine on disease progression and supported the use of
glucosamine long term (three years) for slowing progression
of knee osteoarthritis.Adverse effects
The adverse effects associated with glucosamine involve
gastro-intestinal disturbances, including dyspepsia, nausea,
constipation and diarrhoea, skin rashes and allergic reactions
in patients with known shellfish allergy.Drug interactions
No drug interactions have been defined with the use of
glucosamine.MISCELLANEOUS HERBS RECENTLY
FOUND TO BE TOXIC OR MERITING THEIR
WITHDRAWAL FROM THE MARKETWarnings about the toxicity of herbal products such as
kava kava (hepatotoxicity), aristocholic acid (nephrotoxicity)
and phen phen (pulmonary hypertension) have recently
been communicated to prescribers and the public. PC-SPES,
which was used by many prostate cancer patients because
of anecdotal and uncontrolled studies of evidence of
activity in prostate cancer, was withdrawn from sale by its
suppliers after the FDA found it contained alprazolamand
phytoestrogens.MISCELLANEOUSHERBS 101Key points- Herbal and nutraceutical products are widely
available over the counter in many shops and are not
regulated. - The most commonly used products are garlic, ginkgo
biloba, echinacea, soy, saw palmetto, ginseng and St
John’s wort. - The efficacy of such products in many cases is not
supported by rigorous clinical trials. - Patients believe herbals are safe and are unaware of
documented or potential toxicities. - Many patients take herbal products in conjunction with
prescription medications, unknowingly risking
herb–drug interactions. - When a patient develops an unusual reaction to his or
her drug therapy (either therapeutic failure or toxicity)
a careful history concerning the use of herbal products
should be obtained.