Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers.

PURPOSE: We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761® with respect to the activities of major cytochrome P450 (CYP) enzymes. METHODS: A single-center, open-label, randomized, three-fold crossover, cocktail phenotyping design was applied. In random order, the following treatments were administered to 18 healthy men and women for 8 days each: placebo twice daily, EGb 761® 120 mg twice daily, and EGb 761® 240 mg in the morning and placebo in the evening. In the morning of day 8, administration was performed together with the orally administered phenotyping cocktail (enzyme, metric): 150 mg caffeine (CYP1A2, paraxanthine/caffeine plasma ratio 6-h postdose), 125 mg tolbutamide (CYP2C9, plasma concentration 24-h postdose), 20 mg omeprazole (CYP2C19, omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose), 30 mg dextromethorphan (CYP2D6, dextromethorphan/dextrorphan plasma ratio 3-h postdose), and 2 mg of midazolam (CYP3A, plasma concentration 6-h postdose). Formally, absence of a relevant interaction was assumed if the 90% confidence intervals (CIs) for EGb 761®/placebo ratios of the metrics were within the 0.70-1.43 range. RESULTS: EGb 761®/placebo ratios for phenotyping metrics were close to unity for all CYPs. Furthermore, respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761® 120 mg twice daily (90% CI 0.681-1.122) and for CYP2D6 for EGb 761® 240 mg once daily (90% CI 0.667-1.281). These findings were attributed to the intraindividual variability of the metrics used. All treatments were well tolerated. CONCLUSION: EGb 761® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug-drug interactions.

Comparison of Hypericum extract WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study.

OBJECTIVE: To test and compare the efficacy and safety of Hypericum extract WS 5570 to paroxetine, a potent SSRI, in patients suffering from moderate or severe depression according to DSM-IV criteria. METHODS: In a multicenter, randomized, double-blind phase III study, the changes in moderate to severe major depression DSM-IV; 17-item Hamilton Depression Rating Scale (HAM-D total>or=22) after an acute treatment with Hypericum extract WS 5570 or paroxetine were analyzed in a 16-week continuation phase for relapse prevention. Patients with a HAM-D total score decrease of >or=50% during the 6 weeks of acute treatment were asked to continue the treatment for another 4 months. One-hundred and thirty-three adult out-patients who received maintenance doses of 900 (n=33) or 1800 mg/d (n=38) of WS 5570 and 20 (n=28) or 40 mg/d (n=34) of paroxetine, respectively, were included. The relevant dosage was already fixed during the acute treatment. RESULTS: Between baseline of the acute phase and end of continuation treatment the HAM-D total score decreased from 25.3+/-2.5 (mean+/-SD) to 4.3+/-6.2 points for WS 5570 and from 25.3+/-2.6 to 5.2+/-5.5 points for paroxetine (p=0.49, two-sided t-test; median relative decrease: 92.0 and 85.5%, respectively). During maintenance treatment alone (day 154-day 42), 61.6% of the patients randomized to WS 5570 and 54.6% treated with paroxetine showed an additional reduction (p=0.59) with respect to the HAM-D total score. Remission (HAM-D endpoint total score below 8) occurred in 81.6% (31 patients) of the patients for WS 5570 and in 71.4% (30 patients) for paroxetine (p=0.29). Three patients in the WS 5570 group and 2 patients in the paroxetine group showed a HAM-D increase>5 points during continuation treatment. In the continuation phase there were 0.006 adverse events per day of exposure for WS 5570 and 0.007 events for paroxetine. CONCLUSION: This study showed that WS 5570 and paroxetine were similarly effective in preventing relapse in a continuation treatment after recovery from an episode of moderate to severe depression and point therefore to an important alternative treatment option for long-term relapse-prevention.

A combination of valerian and lemon balm is effective in the treatment of restlessness and dyssomnia in children.

Efficacy and tolerability of a combined valerian/lemon balm preparation were investigated in an open, multicentre study in children less than 12 years suffering from restlessness and nervous dyskoimesis. Patients were dosed individually by the investigators. In total, 918 children were evaluated for therapeutic efficacy and tolerability. A distinct and convincing reduction in severity was found for all symptoms in the investigators' and parents' ratings. The core symptoms dyssomnia and restlessness were reduced from "moderate/severe" to "mild" or "absent" in most of the patients. In total, 80.9% of the patients who suffered from dyssomnia experienced an improvement for this symptom and 70.4% of the patients with restlessness improved clearly. For the other listed symptoms the total improvement was 37.8% on average. Both, parents and investigators assessed efficacy as to be "very good" or "good" (60.5% and 67.7%, respectively). The tolerability of Euvegal forte was considered as "good" (in 96.7% of the patients it was judged to be "very good" or "good"). No study medication-related adverse events occurred. In conclusion, Euvegal forte was effective in the treatment of younger children with restlessness and dyssomnia and it was very well tolerated.

Efficacy and safety of Losigamone in partial seizures: a randomized double-blind study.

The objective of the study was to investigate the efficacy and safety of two different dosages of Losigamone (LSG) in add-on treatment of partial seizures. In a multi-center, double-blind, randomized clinical trial, patients received one of three 12-week treatments: placebo, LSG 1200 mg/day, or 1500 mg/day, in addition to up to three standard anticonvulsants after a prospective period of 12 weeks to assess baseline seizure frequency. The primary efficacy measure was the relative reduction of seizure frequency per 4 weeks in the double-blind phase as compared to baseline. In the intention-to-treat population of 264 patients, the relative median reduction of partial seizure frequency was 3.3% for placebo, 19.7% for LSG 1200 mg/day, and 25.3% for LSG 1500 mg/day. The differences of both LSG groups versus placebo were significant (P<0.01, two-tailed). In the responder analysis, 11.8% of the patients in the placebo group, 17.2% in the LSG 1200 mg/day group, and 29.3% in the LSG 1500 mg/day group showed a seizure reduction versus baseline of at least 50%. A positive association between dosage and response was observed (P=0.003). Adverse events during treatment were reported by 58.8% of the patients for placebo, by 62.1% for LSG 1200 mg/day and by 76.1% for LSG 1500 mg/day. Most events in the LSG groups occurred during the first 4 weeks of double-blind (during or immediately after up-titration) and subsided quickly. Over the last 4 weeks of treatment, the incidence of adverse events in the LSG groups was close to the placebo level. Based on the study's results, LSG is an effective and safe add-on drug for refractory partial epilepsy in adults.