Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

AIMS: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. METHODS: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. RESULTS: The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. CONCLUSION: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men - An explorative randomized placebo-controlled double-blind study.

BACKGROUND: Considering the negative effects of stress on health, there is a growing interest in stress-reducing interventions. The present study examines the effects of a fixed combination of valerian, passion flower, lemon balm, and butterbur extracts (Ze 185) on biological and affective responses to a standardized psychosocial stress paradigm. PURPOSE: The aim of the present study was to investigate the efficacy of Ze 185 on cortisol and anxiety stress responses to acute psychosocial stress in healthy subjects. STUDY DESIGN: This study was a randomized, placebo-controlled, double blind study with 3 parallel groups. METHODS: 72 healthy male participants were randomized to 3 groups (Ze 185, placebo or no treatment) during 4 days prior to a standardized psychosocial stress paradigm. Principle outcomes were salivary cortisol and self-reported anxiety responses to stress assessed at the fourth day. RESULTS: The stress paradigm induced significant and large cortisol and self-reported anxiety responses. Groups did not differ significantly in their salivary cortisol response to stress, but participants in the Ze 185 condition showed significantly attenuated responses in self-reported anxiety in comparison to placebo (F(3, 41) = 3.33, p = 0.03) and no treatment (F(3, 43) = 2.77, p = 0.05). CONCLUSION: The results show that Ze 185 significantly attenuated the subjective emotional stress response during an acute stress situation, without affecting biological stress responses. Given that a circumscribed biological stress response is to be considered as an adaptive mechanism, Ze 185 reduces self-reported anxiety response to stress without affecting assumingly adaptive biological stress responses.

Reduction of hyperbilirubinemia with hypericum extract (St. John's Wort) in a patient with Crigler-Najjar syndrome type II.

AIMS: Crigler-Najjar syndrome (CN) type II is a congenital disease with unconjugated hyperbilirubinemia due to a deficiency of uridine 5'-diphospho-glucuronosyltransferase 1A1. Since the currently proposed treatment with phenobarbital is associated with adverse reactions, we investigated the effect of hypericum extract. METHODS: Repetitive determination of total serum bilirubin in a female with CN type II before, during and after daily treatment with 900 mg hypericum extract on two occasions for 8 weeks. Confirmation of the enzyme-inducing effect of hypericum using the cytochrome P450 3A4 probe drug i.v. midazolam. RESULTS: Hypericum reduced midazolam exposure by 42% and the total serum bilirubin concentration by 30 to 35%. CONCLUSIONS: Hypericum extract is a potential alternative to phenobarbital in patients with CN type II.

Green tea extract enhances parieto-frontal connectivity during working memory processing.

RATIONALE: It has been proposed that green tea extract may have a beneficial impact on cognitive functioning, suggesting promising clinical implications. However, the neural mechanisms underlying this putative cognitive enhancing effect of green tea extract still remain unknown. OBJECTIVES: This study investigates whether the intake of green tea extract modulates effective brain connectivity during working memory processing and whether connectivity parameters are related to task performance. MATERIAL AND METHODS: Using a double-blind, counterbalanced, within-subject design, 12 healthy volunteers received a milk whey-based soft drink containing 27.5 g of green tea extract or a milk whey-based soft drink without green tea as control substance while undergoing functional magnetic resonance imaging. Working memory effect on effective connectivity between frontal and parietal brain regions was evaluated using dynamic causal modeling. RESULTS: Green tea extract increased the working memory induced modulation of connectivity from the right superior parietal lobule to the middle frontal gyrus. Notably, the magnitude of green tea induced increase in parieto-frontal connectivity positively correlated with improvement in task performance. CONCLUSIONS: Our findings provide first evidence for the putative beneficial effect of green tea on cognitive functioning, in particular, on working memory processing at the neural system level by suggesting changes in short-term plasticity of parieto-frontal brain connections. Modeling effective connectivity among frontal and parietal brain regions during working memory processing might help to assess the efficacy of green tea for the treatment of cognitive impairments in psychiatric disorders such as dementia.