Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.
These results indicate that after chronic dosing, casopitant can achieve a degree of NK(1) receptor occupancy higher than those that have previously been tested in studies of clinical depression.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Casopitant is an NK-1 receptor antagonist which has been evaluated for the prevention of chemotherapy-induced and post-operative nausea and vomiting.• Data from in vitro systems suggested that casopitant both inhibits and induces CYP3A. Therefore, a risk of an interaction between casopitant and CYP3A4 substrates is likely. WHAT THIS STUDY ADDS• Casopitant showed a dose and time dependent interaction with CYP3A, resulting in weak inhibition after a single dose, and weak to moderate inhibition after repeated dose administration.• The interaction with nifedipine could be predicted from the midazolam data for acute casopitant administration, but not after 14 days repeated dose casopitant administration, suggesting an induction effect complicating the interaction with nifedipine.• These results suggest that the use of in vitro or in vivo data to predict the interaction potential of other concomitant medications needs to account properly for any potential induction effect. AIMTo evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed.
Over 80% patients on the certification of visual impairment register from Moorfields Eye Hospital with glaucoma as the primary cause had a significant visual disability at presentation, with almost two-thirds of patients presenting bilaterally 'blind'. There appear to be delays to certification. Despite being under the hospital eye service, a number of glaucoma patients still progress to certifiable visual impairment.
Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia. Design: Randomized, double-blind, placebo-controlled 28-day parallel-group study. Setting: Eleven sleep centers in Germany. Patients: One hundred sixty-one patients with primary insomnia. Interventions: Patients received vestipitant (15 mg) or placebo for 28 days; 2-night polysomnographic assessment occurred on nights 1/2 and 27/28. Measurements and Results: Wake after sleep onset (WASO) was improved on nights 1/2 and 27/28 (ratio, vestipitant versus placebo [95% confidence interval]: 0.76 [0.65, 0.90], P = 0.001 and 0.79 [0.65, 0.96], P = 0.02, respectively), demonstrating maintenance of the effect following repeated dosing. Latency to persistent sleep was shorter with vestipitant on nights 1/2 (P = 0.0006 versus placebo), but not on nights 27/28. Total sleep time (TST) improved with vestipitant (nights 1/2: P < 0.0001, nights 27/28: P = 0.02 versus placebo). Next-day cognitive function tests demonstrated no residual effects of vestipitant (P > 0.05 versus placebo). Adverse events (AEs) occurred in 25% of vestipitant patients versus 22% for placebo. Headache was the most common AE (8% of vestipitant patients versus 9% for placebo). Conclusions: Vestipitant improved sleep maintenance in patients with primary insomnia, with no associated next-day cognitive impairment. The effects on wake after sleep onset and total sleep time were maintained following repeated dosing.
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