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In this article the importance of knowledge about herbal remedies in general practice is discussed using guarana (Paullinia cupana), St John's wort (Hypericum perforatum), and gingko (Ginkgo biloba) as examples. Obtaining information about herbal remedies can be difficult. Lack of clinical data about the use, safety, efficacy and general practitioner attitudes to herbal remedies creates research opportunities in this area of general practice.
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To address whether St John's wort is useful for the treatment of depression we attempted to retrieve all English-language articles with data on the efficacy, safety, and availability of St John's wort. Randomized, controlled, double-blind trials were selected and assessed for methodological quality using a standardized checklist, and data on pharmacology, cost, regulation, and safety were extracted. Eight studies were identified, found to be of generally good methodological quality, and determined to provide a modest amount of data to suggest that St John's wort is more effective than placebo in the treatment of mild to moderate depression. The absolute increased response rate with the use of St John's wort ranged from 23% to 55% higher than with placebo, but ranged from 6% to 18% lower compared with tricyclic antidepressants. More data are required to assess both its use in severe depression and its efficacy compared with other antidepressants. Rates of side effects were low. As a dietary supplement, St John's wort is currently largely unregulated, but the Food and Drug Administration is reviewing plans to tighten its regulatory oversight.
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HYPOTHESIS: St John's wort is one of the most popular herbal medicines, and health care professionals often are unaware that their patients take such supplements. St John's wort causes a decrease in cyclosporine levels, thus endangering the success of organ transplantations. DESIGN: Systematic review. METHODS: Five independent computerized literature searches were conducted to identify all reports of such interactions. Data were extracted and are summarized in narrative form. RESULTS: Eleven case reports and 2 case series were located. In most instances, causality between St John's wort and the clinical or biochemical result is well established. The mechanism of interaction between St John's wort and cyclosporine has been recently elucidated and involves both P-glycoprotein and cytochrome P 450 3A4 expression. Collectively these data leave little doubt that St John's wort interacts with cyclosporine, causing a decrease of cyclosporine blood levels and leading in several cases to transplant rejection. CONCLUSIONS: St John's wort can endanger the success of organ transplantations. Adequate information may be the best way to avoid future incidences.
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CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.
CONTEXT: Widespread use of herbal medications among the presurgical population may have a negative impact on perioperative patient care. OBJECTIVES: To review the literature on commonly used herbal medications in the context of the perioperative period and provide rational strategies for managing their preoperative use. DATA SOURCES: The MEDLINE and Cochrane Collaboration databases were searched for articles published between January 1966 and December 2000 using the search terms herbal medicine, phytotherapy, and alternative medicine and the names of the 16 most commonly used herbal medications. Additional data sources were obtained from manual searches of recent journal articles and textbooks. STUDY SELECTION: We selected studies, case reports, and reviews addressing the safety and pharmacology of 8 commonly used herbal medications for which safety information pertinent to the perioperative period was available. DATA EXTRACTION: We extracted safety, pharmacodynamic, and pharmacokinetic information from the selected literature and reached consensus about any discrepancies. DATA SYNTHESIS: Echinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and valerian are commonly used herbal medications that may pose a concern during the perioperative period. Complications can arise from these herbs' direct and pharmacodynamic or pharmacokinetic effects. Direct effects include bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions include potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic herb-drug interactions include increased metabolism of many drugs used in the perioperative period by St John's wort. CONCLUSIONS: During the preoperative evaluation, physicians should explicitly elicit and document a history of herbal medication use. Physicians should be familiar with the potential perioperative effects of the commonly used herbal medications to prevent, recognize, and treat potentially serious problems associated with their use and discontinuation.
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CONTEXT: St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. OBJECTIVE: To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism. DESIGN, SETTING, AND PARTICIPANTS: Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St John's wort. INTERVENTION: Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St John's wort administration, participants were given the probe drugs along with 1 St John's wort tablet to establish postadministration CYP activity; the St John's wort dosing regimen was continued for 48 hours. MAIN OUTCOME MEASURES: Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity. RESULTS: A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St John's wort administration (P =.26). CONCLUSIONS: A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.
When designing a clinical trial, there is usually some uncertainty about the variability of the primary outcome variable. This may lead to an unnecessarily high or inadequately low sample size. The internal pilot study approach uses data from patients recruited up to an interim stage to re-estimate the variance and to re-calculate the final sample size accordingly. Previously, simulation studies have shown that this methodology may highly improve the chance to obtain a well-powered trial. However, it also turned out that the type I error rate may be inflated by this procedure. We quantify the maximum excess of the type I error rate for normally distributed outcomes. If strict control of the alpha-level is considered to be an important issue, a method is proposed to achieve this when re-calculating the sample size in internal pilot studies. The characteristics of the power distributions are investigated for various sample size adaptation rules and implications are discussed.
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Hyperforin, a phloroglucinol derivative found in St. John's wort related mainly to its antidepressant effects, has been reported recently to induce apoptosis in tumour cells and to inhibit cancer invasion and metastasis. We show that hyperforin inhibits angiogenesis in vitro in bovine aortic endothelial cells and in vivo in the chorioallantoic membrane assay. In a variety of experimental systems representing the sequential events of the angiogenic process, hyperforin treatment of endothelial cells resulted in strong inhibitory effects. Hyperforin inhibited the growth of endothelial cells in culture. Capillary tube formation on Matrigel was abrogated completely by addition of hypeforin at the low micromolar range. Hyperforin also exhibited a clear inhibitory effect on the invasive capabilities of endothelial cells. Zymographic assays showed that hyperforin treatment produced a complete inhibition of urokinase and a remarkable inhibition of matrix metalloproteinase 2. Our data indicates that hyperforin is a compound that interferes with key events in angiogenesis, confirming the recent and growing evidence about a potential role of this compound in cancer and metastasis inhibition and making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies.
St. John's wort, a popular herbal remedy for depression, is known to interact with many Western drugs because of the ability of its components to induce liver enzymes. Lower concentrations of various drugs due to increased clearance have been reported. Because immunoassays are commonly used in clinical laboratories for therapeutic drug monitoring, we studied the potential interference of St. John's wort with commonly monitored therapeutic drugs. Drug-free serum pools were supplemented with St. John's wort to achieve in vitro St. John's wort concentrations mimicking in vivo concentrations after both recommended use and overdose. Concentrations of digoxin, tricyclic antidepressants (TCAs), phenytoin, carbamazepine, theophylline, valproic acid, quinidine, phenobarbital, procainamide, and N-acetyl procainamide were measured in serum. Pooled serum specimens from patients who were taking a particular drug were also supplemented in vitro with concentrations of St. John's wort to investigate whether observed concentrations changed after supplementation with St. John's wort. The effect of St. John's wort on cyclosporine and tacrolimus (FK 506) was studied in whole blood. We found no significant interference from St. John's wort with any assay studied. Moreover, when drug-free serum was supplemented with very high concentrations of hypericin (2 microg/mL) and hyperforin (2 microg/mL) pure standard, we observed no apparent drug level with any immunoassay. The presence of both hypericin and hyperforin was also confirmed by thin layer chromatography (TLC) in both preparations of St. John's wort. We conclude that immunoassays may be used to measure levels of therapeutic drugs in patients who self-medicate with St. John's wort.
At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to compounds including aristolochic acids, pyrrolizidine alkaloids, beta-carotene, coumarin, the alkenylbenzenes safrole, methyleugenol and estragole, ephedrine alkaloids and synephrine, kavalactones, anisatin, St. John's wort ingredients, cyanogenic glycosides, solanine and chaconine, thujone, and glycyrrhizinic acid. It can be concluded that several of these phytotoxins cause concern, because of their bioactivation to reactive alkylating intermediates that are able to react with cellular macromolecules causing cellular toxicity, and, upon their reaction with DNA, genotoxicity resulting in tumors. Another group of the phytotoxins presented is active without the requirement for bioactivation and, in most cases, these compounds appear to act as neurotoxins interacting with one of the neurotransmitter systems. Altogether, the examples presented illustrate that natural does not equal safe and that in modern society adverse health effects, upon either acute or chronic exposure to phytochemicals, can occur as a result of use of plant- or herb-based foods, teas, or other extracts.
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