A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosage) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomised, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1% respectively, p<0.05). At the same time point, a tendency for shorter subjective sleep latency, as well as a higher correlation coefficient between subjective and objective sleep latencies, were observed under valerian treatment. Other improvements in sleep structure - such as an increase in REM percentage and a decrease in NREM1 percentage - took place simultaneously under placebo and valerian treatment. A remarkable finding of the study was the extremely low number of adverse events during the valerian treatment periods (3 vs. 18 in the placebo period). In conclusion, treatment with a herbal extract of radix valerianae demonstrated positive effects on sleep structure and sleep perception of insomnia patients, and can therefore be recommended for the treatment of patients with mild psychophysiological insomnia.

Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment‐refractory metastatic colorectal cancer. In clinical studies, steady‐state exposure to the M‐2 and M‐5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials. Therefore, we assessed the pharmacokinetics and pharmacodynamics of regorafenib, M‐2, and M‐5 in vitro and in murine xenograft models. M‐2 and M‐5 showed similar kinase inhibition profiles and comparable potency to regorafenib in a competitive binding assay. Inhibition of key target kinases by all three compounds was confirmed in cell‐based assays. In murine xenograft models, oral regorafenib, M‐2, and M‐5 significantly inhibited tumor growth versus controls. Total peak plasma drug concentrations and exposure to M‐2 and M‐5 in mice after repeated oral dosing with regorafenib 10 mg/kg/day were comparable to those in humans. In vitro studies showed high binding of regorafenib, M‐2, and M‐5 to plasma proteins, with unbound fractions of ~0.6%, ~0.9%, and ~0.4%, respectively, in murine plasma and ~0.5%, ~0.2%, and ~0.05%, respectively, in human plasma. Estimated free plasma concentrations of regorafenib and M‐2, but not M‐5, exceeded the IC50 at human and murine VEGFR2, suggesting that regorafenib and M‐2 are the primary contributors to the pharmacologic activity of regorafenib in vivo.

We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.

Morningness and eveningness preference, an endogenous component of the circadian clock, is characterized by an interindividual difference in circadian phase and requires of humans a specific timing of behavior. The biological rhythms of morning and evening types are consequently phase shifted with fixed socioeconomic constraints. The impact of this phase shift on health is widely debated. The purpose of the authors' study was to determine the influence of morningness/eveningness preference on self-reported morbidity and health in an active population. A total of 1165 nonshift workers of the French national electrical and gas company, enrolled in the GAZEL cohort and aged 51.3+/-3.3 years, were included in this study. They replied by mail with a completed questionnaire, including morningness/eveningness preference, self-reported morbidity, subjective sleep patterns, and daytime somnolence and sleeping schedules for 3 weeks, during the spring of 1997. Annual self-reported health impairments were assessed with the annual general questionnaire of the GAZEL cohort for 1997. After adjustment for age, sex, and occupational status, morningness-like and eveningness-like participants reported a specific worse self-reported morbidity. Whereas morningness was associated with worse sleep (p = 0.0001), eveningness was associated with feeling less energetic (p = 0.04) and physical mobility (p = 0.02). These relationships were observed even in good sleepers, except for physical mobility. After adjustment for confounding variables, eveningness-like participants reported more sleep (p = 0.0004) and mood (p = 0.00018) disorders than morningness-like participants. Morningness/eveningness preference was related to specific chronic complaints of insomnia: morningness was related with difficulty in maintaining sleep (p = 0.0005) and the impossibility to return to sleep in the early morning (p = 0.0001) (sleep phase-advance syndrome); eveningness was related to difficulty in initiating sleep (p = 0.0001) and morning sleepiness (p = 0.0001). In good sleepers, morningness was related with sleep phase-advance syndrome (p = 0.0001) and eveningness with morning sleepiness (p = 0.0001). In conclusion, the expression (phase advance or delay) of the circadian clock could be related to worse self-reported morbidity and health. These findings must be verified by further epidemiological studies, but they suggest that the impossibility to return to sleep in the early morning is not only associated with age.