FURTHER READING AND WEB MATERIAL
Ernst E. A systematic review of systematic reviews of homeopathy.
British Journal of Clinical Pharmacology2002; 54 : 577–82.
Goggs R, Vaughan-Thomas A, Clegg PD et al. Nutraceutical therapies
for degenerative joint diseases: a critical review. Critical Reviews in
Food Science and Nutrition2005; 45 : 145–64.
Linde K, Berner M, Egger M, Mulrow C. St John’s wort for depression:
meta-analysis of randomised controlled trials. British Journal of
Psychiatry2005; 186 : 99–107.
Linde K, Barrett B, Wolkart K et al. Echinacea for preventing and treat-
ing the common cold. Cochrane Database of Systematic Reviews2006;
CD000530.
Reginster JY, Bruyere O, Fraikin G, Henrotin Y. Current concepts in
the therapeutic management of osteoarthritis with glucosamine.
Bulletin (Hospital for Joint Diseases (New York))2005; 63 : 31–6.
Ross S, Simpson CR, McLay JS. Homoeopathic and herbal prescribing
in general practice in Scotland. British Journal of Clinical
Pharmacology2006; 62 : 646–51.
Sparreboom A, Cox MC, Acahrya MR, Figg WD. Herbal remedies in
the USA: Potential adverse reactions with anti-cancer agents.
Journal of Clinical Oncology2004; 20 : 2489–503.
Walker HA, Dean TS, Sanders TAB et al. The phytoestrogen genistein
produces acute nitric oxide-dependent dilation of human forearm
vasculature with similar potency to 17 beta-estradiol. Circulation
2001; 103 : 258–62.
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Useful websites: http://www.nccam.nih.gov and http://www.fda.gov102 ALTERNATIVE MEDICINES:HERBALS AND NUTRACEUTICALS
Case history
A 45-year-old Caucasian female undergoes a successful liver
transplant for primary biliary cirrhosis. Following the success-
ful operation, her immunosuppressive regimen consists of
tacrolimus, mycophenolic acid and relatively low doses of
prednisolone, which are being further reduced. During the
first six months, she remains well and her trough tacrolimus
concentrations remain between 5 and 15μg/L. This is thera-
peutic. When seen in follow up at approximately nine months
post transplant, she is not quite feeling herself generally. Her
only other symptoms noted on systematic enquiry are that
she has not been sleeping well recently and has been anxious
about driving her car. This was because four weeks ago she
was involved in a head to head collision in a road traffic acci-
dent, but neither she nor the other driver were injured.
Current clinical examination revealed some mild subcostal
tenderness, without guarding and an otherwise normal clin-
ical examination. Her liver function tests show an increased
AST and ALT (five-fold the upper limit of normal) and a
mildly elevated conjugated bilirubin. Thorough clinical and
laboratory investigation revealed no infectious cause. A liver
biopsy is compatible with hepatic rejection and a random
tacrolimus concentration is 2μg/L. She is adamant that she is
adhering to her medication regimen.
Question 1
Could these problems all be attributed to her liver dysfunc-
tion? Is this a possible drug–drug interaction, if so which
CYP450 enzyme system is involved?
Question 2
What else might she be taking in addition to her immunosup-
pressive regimen that could lead to this clinical situation?
Answer 1
The patient’s hepatic dysfunction is most likely due to a late
rejection episode. However, if her hepatic dysfunction were
severe enough to compromise hepatic drug metabolism
this would be accompanied by evidence of hepatic biosyn-
thetic dysfunction and drugs metabolized by the liver
would accumulate to toxic concentrations, rather than be
subtherapeutic. An alternative drug interaction with an
inducer of hepatic drug metabolism could explain the clin-
ical picture, but whereas high-dose corticosteroids would
cause a 15–30% induction of hepatic CYP3A4 enzymes, the
enzymes involved in metabolism of tacrolimus, she is on a
relatively low dose of prednisolone.
Answer 2
It is possible, but should be clarified with the patient, that
she has been taking St John’s wort for anxiety and insom-
nia. The current public view of St John’s wort is that it is a
harmless, herbal therapy that can be used to help patients
with anxiety, insomnia and depression. Some of its chemi-
cal constituents act as GABA and 5-HT receptor agonists. In
addition, one of the constituents of St John’s wort (hyper-
forin) has been shown to be a potent inducer of several
CYP450 enzymes, including 3A4, and the drug efflux trans-
porter protein P-gp (ABCB1). The induction of CYP3A4/
ABCB1 by St John’s wort constituents occurs over eight to
ten days. In the case of the magnitude of the induction
caused by CYP3A and P-gp, St Johns wort is similar to that
caused by rifampicin, and induction of both proteins is
mediated via the pregnane X nuclear receptor. St John’s
wort could be the likely cause of this patient’s subthera-
peutic tacrolimus concentrations (a 3A4/ABCB1 substrate)
and could thus have led over time to this rejection episode.
Carefully enquiring about this possibility with the patient
would be mandatory in this case. Apart from rifampicin,
other drugs that induce 3A4 (but which the patient has not
been prescribed) include phenobarbitone, carbamazepine,
other rifamycins, pioglitazone, nevirapine (see Chapter 13).