Conclusion:Male patients and those with a higher body weight were more likely to receive non-standard doses of RBV, likely reflecting the perception that this may lead to higher rates of SVR.The impact of higher RBV doses on relapse and SVR will be determined after ongoing follow-up in this study.

Methods: Results from two Phase 1 studies were pooled for the analysis.Study 1 investigated the antiviral activity of oral filibuvir doses of 100, 300 and 450 mg BID and 300 mg TID or placebo, for 8 days in treatment naïve patients.In the second study, the antiviral activity of filibuvir 450 mg BID in treatment experienced patients dosed for 10 days and 700 mg BID in treatment naïve patients dosed for 3 days was evaluated.Filibuvir exposures achieved over 24 hours (AUC24) were utilized to inform the ER analysis of the maximum log change in viral load from baseline.The relationship was described by an inhibitory E max model using a non-linear mixed effects model.Effects of food, baseline viral load (BVL) and genotype (1a/1b) on relevant model parameters were also evaluated.The antiviral response for a range of doses was simulated from the model. Results:The ER data from 52 subjects were adequately described by the E max model with E max (95% CI) = -2.14(-2.54, -2.02) IU/ml and AUC24 50 (95% CI) = 54,176 (44,606, 102,006) ng•hr/ml.BVL was the only influential covariate which described the maximal response (E max ).The analysis indicated that doses in excess of 300 mg BID were expected to achieve atleast 70% of E max .Furthermore, filibuvir exposures resulting from doses greater than 600 mg BID produced responses close to E max indicating that higher doses (>600 mg BID) are unlikely to provide additional efficacy.Conclusions: Filibuvir exposures adequately described the maximum log change in viral load relative to baseline.The above analysis in conjunction with results from a Phase 2a study (200/300/500 mg BID+SOC, rapid viral response rates of 60-75%) suggests that filibuvir doses of 300 and 600 mg BID are expected to be efficacious when combined with SOC and will be further investigated in Phase 2b studies.

We have investigated the effect of 2-arachidonylglyceryl-ether (Noladin) on food consumption, weight, activity, and cognitive function in mice during diet restriction for 17 days and subsequent ad libitum feeding for 32 days. Female Sabra mice were given food for 2.5h/day (equal to 60% diet restriction), received Noladin (0.001, 0.01, 0.1mg/(kg day) intraperitonially (i.p.)) with or without the CB1 antagonist SR141716A (1mg/kg i.p.) during days 3–17. Noladin (0.001mg/kg) significantly increased food consumption without a change in body weight, probably due to increased activity and there was no change in cognitive function. A higher dose (0.1mg/kg) did not affect food consumption, but increased activity and slightly decreased weight 32 days after termination of Noladin administration; however, cognitive deterioration was observed. At all doses tested, Noladin did not affect weight during the diet-restriction period, whereas the CB1 antagonist (with or without Noladin) caused a very significant decline in weight in this phase. Weight catch-up was observed 1 month after administration of Noladin was discontinued. Weight at day 32 after the termination of Noladin (0.1mg/(kg day)) treatment was 5% less than control. Female C57BL/6mice (same protocol, with 0.001mg/(kg day) Noladin) gave similar results to 0.1mg/kg in Sabra mice as regards weight. CB1 antagonist treatment caused very significant decline in both weight and food consumption; cognition and activity were unchanged. These results indicate that Noladin has a significant dose-dependent effect on food consumption, cognition and weight maintenance after weight loss. Low doses of Noladin may possibly allow an increase in food intake without a gain in weight after dieting. Thus, Noladin could be of potential clinical benefit in treating disorders of body weight. Noladin seems to signal food consumption and weight through CB1 receptors based on effects observed with the CB1 antagonist, while the cognition and activity are probably mediated by non-cannabinoid receptors.

Endocannabinoids function as neurotransmitters and neuromodulators in the central nervous system via specific receptors and apparently have a neuroprotective role. We assumed that the endocannabinoid system could be involved in the pathogenesis of hepatic encephalopathy (HE), a neuropsychiatric syndrome due to liver disease. We used a mouse model of a thioacetamide induced fulminant hepatic failure. We found that the levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) were elevated in the brain. Treatment with either 2-AG or with the CB1 receptor antagonist, SR141716A, improved a neurological score, activity and cognitive function. Activation of the CB2 receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB2 receptor antagonist SR144528A. The CB1 receptor agonist noladin ether was inactive. We conclude that the endocannabinoid system may play an important role in the pathogenesis of HE. Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential.