Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Hypericum may be an answer
- Dr. Herbert H. Nehrlich (3 July 2004)
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Re: Hypericum may be an answer
- David N. Juurlink (8 July 2004)
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Does Hypericum protect?
- Dr. Herbert H. Nehrlich (10 July 2004)
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ST JOHN’S WORT: MULTIPLE CASE REPORTS HIGHLIGHT DRUG INTERACTIONS
- Angelo A Izzo, Francesco Capasso (14 July 2004)
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Re: Does Hypericum protect?
- David N. Juurlink (14 July 2004)
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Ethical considerations of St. John's wort interaction studies
- Ron H.J. Mathijssen, Jaap Verweij, MD, PhD, and Alex Sparreboom, PhD (27 July 2004)
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Data quality and alternative therapies
- Tracy Weller (16 September 2004)
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Herbs are potent
- Barry L Parnas (12 February 2005)
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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While I do not even for a minute believe that Hypericum would affect the bio-availability of various drugs I await to be corrected . Particularly in Germany, St John's Wort has been very popular for decades and I know of physicians who routinely prescribed it as a 'complementary' medicine whenever a prescription for a 'real' drug was written. If there was an effect upon drug efficacy it may have been of benefit for some patients in the Pharmaceutical Republic of Germany. For the rest of the world, and in the current climate of statin frenzy, may I suggest to administer Hypericum and Statins concomitantly (at least it will reduce worries about devastating side effects of statins), I would call this "partial defusion". We seem to worry about the dumbest little things (or is it part of the anti nutritional supplement conspiracy?) while forgetting to uphold the "First Do No Harm" Principle of Hippocrates. Dr. Kendrick said it nicely, so did Dr. Smith. Will anyone listen? Competing interests: None declared |
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David N. Juurlink, Clinical Pharmacologist Sunnybrook and Women's College Health Sciences Centre, Univeristy of Toronto, Canada M4N 3M5
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The work of Mills et al. draws attention to the problem of drug-drug interactions involving nonprescription medications. Dr. Nehrlich questions (rather astonishingly) whether St. John's wort really influences the bioavailability of other medications, and alludes to a consipracy against the complementary medicine movement. In fact, the basis of pharmacokinetic drug-drug interactions involving St. John's wort is well established: induction of both cytochrome P450 (CYP) 3A4 and the multidrug efflux transporter P-glycoprotein. Several reports highlight the clinical consequences of these interactions, including transplant rejection resulting from reduced cyclosporine levels. Call me a conspirator, but those who dismiss legitimate concerns about the safety of complementary medicines do so at the peril of their patients. Competing interests: None declared |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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Well, Mr. Pharmacist, I am aware of your objections but stand by my comments. The interference of Hypericum is as irrelevant as the 2 people out of 100 entering a hospital, only to come out in a pine (or pressboard) box. Being too technical can have its drawbacks. Wouldn't it shock you to find that Hypericum will do a better job than all your other potions? Well it may just do that. Competing interests: None declared |
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Angelo A Izzo, Associate Professor Department of Experimental Pharmacology, University Federico II, via D Montesano 49, 80131 Naples, Francesco Capasso
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EDITOR, In their recent article BMJ article1, Mills and colleagues identified clinical trials examining drug interactions of St John’s wort (SJW) and conventional drugs. However, most of the available information about SJW interactions is gleaned from case reports. Here, I would like to draw attention to a number of relevant and, in some cases, potentially life- threatening of such cases. Documented SJW interactions include: 1) reduced plasma cyclosporin concentration by SJW, as suggested by at least 60 case reports. The common clinical features of these cases are that heart, renal or liver transplant patients stabilized on cyclosporine showed decreased plasma levels (associated, in some cases, to acute rejection episodes) after taking SJW at therapeutic dosage2. The clinical picture improved in all cases following discontinuation of the herbal extract. Induction of P- glycoprotein and/or cytochrome P450 enzymes by SJW could explain such pharmacokinetic interaction3. 2) Serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors (e.g. the antidepressants sertaline, paroxetine or nefazodone). The symptoms resolved upon discontinuation of the medications. The syndrome (which can be fatal, especially in the elderly) may be the result of an additive effect on serotonin reuptake because hyperforin in SJW inhibits the reuptake of several brain neurotransmitters including serotonin4. 3) Unwanted pregnancies in women while using oral contraceptives and SJW. Current advice from the FDA in the US and the MHRA in the UK, is that concurrent use should be avoided. Details of such interactions, in addition to an exhaustive analysis of many SJW interactions, can be found elsewhere.2,5 Obviously, case reports have to be interpreted with great caution, as causality is not usually established beyond reasonable doubt. Multiple SJW case reports, however, should prompt both public health advisories and clinical studies to delineate the extent and severity of interactions. References 1. Mills E, Montori VM, Wu P, Gallicano K, Clarke M, Guyatt G. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ 2004; 329:27-30. 2. Izzo AA. Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther 2004; 42:139-148. 3. Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD. Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 2003; 290:1500-1504. 4. Di Carlo G, Borrelli F, Ernst E, Izzo AA. St John's wort: Prozac from the plant kingdom. Trends Pharmacol Sci 2001; 22:292-297. 5. Williamson EM. Drug interactions between herbal and prescription medicines. Drug Saf 2003; 26:1075-1092 Competing interests: None declared |
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David N. Juurlink, Clinical Pharmacologist (and Attending Internist, Clinical Toxicologist, & Clinical Epidemiologist) Sunnybrook & Women's College Health Sciences Centre
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I agree with the tacit insinuation of Dr. Nehrlich that classically trained physicians (of which I am one) should not summarily dismiss or anathemzatize complementary medicines simply because they are derived from natural sources. However, the corollary is that clinicians and patients should not assume a product is safe, effective, or free of drug interactions simply because it is 'natural'. Despite the abundance of literature regarding the interactions of hypericum (165 hits on PubMed as of today), new knowledge cannot help our patients when its diffusion is impeded by a lack of circumspection. Competing interests: None declared |
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Ron H.J. Mathijssen, MD, PhD ErasmusMC - Daniel den Hoed Cancer Center, 3008 AE, Rotterdam, the Netherlands, Jaap Verweij, MD, PhD, and Alex Sparreboom, PhD
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Dear Editor, with great interest we read the article by Mills et al.,1 in which they studied the methodological quality of trials examining drug interactions with St John’s wort (SJW). According to classic epidemiological standards, studies employing a crossover design, control group, blinding, randomisation, and herb analysis were considered to be superior. We agree that a solid methodology for this kind of study is essential in order to be conclusive. At the same time, certain circumstances make it impossible to meet all criteria. In case of our study,2 the effect of SJW on the pharmacokinetics of irinotecan was studied in cancer patients. At the time our study was designed, preliminary data were available that suggested an influence of SJW on cytochrome P450 3A4 and P-glycoprotein,3 and hence an interaction between irinotecan and SJW with potentially dramatic consequences was speculated. Like other anti-neoplastic agents, irinotecan has a small therapeutic window and is highly cytotoxic, which precluded the use of healthy volunteers to study this interaction. During an interim-analysis, it was found that the exposure to irinotecan’s active metabolite was more than 40% reduced. This provided incentive to discontinue the study, as it was considered unethical to expose additional patients to this drug combination with the possibility of inactivation of cancer treatment. As this argument was not taken into account by Mills et al., it was striking to note that the five studies that enrolled patients instead of volunteers were among the “worst” studies. In addition, one should wonder whether the degree of interaction seen in patients is comparible to that seen in healthy volunteers. Regardless, although there may currently not be enough high quality information to guide the decision to use SJW, we would like to stress that patients should be aware of the possibility for dangerous interactions with their conventional drug(s). References: 1 Mills E, Montori VM, Wu P, Gallicano K, Clarke M, Guyatt G. Interaction of St John’s wort with conventional drugs: systematic review of clinical trials. BMJ 2004;329:27-30. 2 Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst 2002;94:1247-9. 3 Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-45. Competing interests: None declared |
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Tracy Weller, Primary Care Data Quality Facilitator Surrey Health Informatics Service, 18 Mole Business Park, Leatherhead, Surrey KT22 7AD
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Dear Editor I am a Data Quality Facilitator working in Primary Care. I read with great interest the article by Mills et al.,1 in which they studied the methodological quality of trials examining drug interactions with St John’s Wort (SJW). I particularly noted the comment that “clinicians and patients do not currently have high quality information to guide their decisions…” (vol 329, p29). The General Practitioner (GP) is custodian of the patient record in Primary Care. The GP also has overall responsibility for the health and health care of each patient and needs a complete record on which to base advice. However, staff in Primary Care are physically not able to record information on complementary or alternative medication due to: (a) The clinical computer system (if used) not allowing data entry of this type or (b) The very limited selection of Read codes that is currently available on this topic (published by the NHS Information Authority [NHSIA]). There is also the issue of awareness, where: (c) The patient doesn’t know to volunteer information and/or (d) The GP or their staff doesn’t always ask the question. Lack of recording also impacts on the ability of others to undertake future studies and/or research simply because the data may not be available. It is vital for all healthcare staff to have access to a complete and accurate record, providing an overview of all aspects of a patient’s healthcare and particularly the medications that a patient may be taking. Ultimately, the result of poor data quality is the same - a potential risk to patient safety. It is to be hoped that the introduction of the NHS care record via the National Programme for Information Technology (NPfIT) will support data entry of this type, but in the meantime is it acceptable to leave this important issue un-addressed? Competing interests: None declared |
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Barry L Parnas, Research Chemist and Licensed Massage Therapist St. Louis, MO
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As a person who uses herbs for himself regularly to treat illnesses and increase a sense of well-being, energy, and maintain health, I find the responses interesting. Herbs are potent. According to Chinese and Ayurvedic traditions, incorrect use of herbs can cause harmful effects. This, of course, refers to ordinarily beneficial herbs. To gleen some competence in herbal medicine, one must look to authentic herbal traditions, the Chinese and Ayurvedic being the most well-known though hardly the only reliable ones. I do not think that one can state that SJW *cannot* have side effects of the nature that other people have espoused. Nor, do I think that the established medical-scientific industrial complex can be trusted to properly regulate herbal medicine. Mixing herbal therapies with Western drugs requires expertise for two reasons: one is, do no harm; two is, do benefit. Both require caring and expertise on the part of the practitioner. I can only speak for the US, where I live. We need competently trained herbalists, and this means students are trained by competently trained herbalists, and this means seeking out those with an authentic tradition in herbal medicine. Competing interests: I am an employee of a pharmaceutical company. |
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