Publications (5)22.78 Total impact
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Article: Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.
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ABSTRACT: Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.Journal of Psychopharmacology 03/2013; · 3.04 Impact Factor -
Article: Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.
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ABSTRACT: 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.Journal of clinical psychopharmacology 12/2011; 31(6):727-33. · 5.09 Impact Factor -
Article: Anxiolytic-like effects of the neurokinin 1 receptor antagonist GR-205171 in the elevated plus maze and contextual fear-potentiated startle model of anxiety in gerbils.
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ABSTRACT: Gerbils show a neurokinin (NK)1 receptor pharmacological profile, which is similar to that observed in humans, and thus have become a commonly used species to test efficacy of NK1 receptor antagonists. The aim of this study was to determine whether systemic administration of the NK1 receptor antagonist GR-205171 produced anxiolytic-like effects in the elevated plus maze and in a novel contextual conditioned fear test using fear-potentiated startle (FPS). On the elevated plus maze, treatment with GR-205171 at 0, 0.3, 1.0, and 5.0 mg/kg doses, 30 min before testing produced anxiolytic-like effects in an increasing dose-response manner as measured by the percentage of open arm time and percentage of open arm entries. For contextual fear conditioning, gerbils were given 10 unsignaled footshocks (0.6 mA) at a 2-min variable interstimulus interval in a distinctive training context. Twenty-four hours after training, gerbils received treatment of GR-205171 at 0, 0.3, 1.0, and 5.0 mg/kg doses, 30 min before testing in which startle was elicited in the same context in which they were trained. Contextual FPS was defined as an increase in startle over pretraining baseline values. All drug dose levels (0.3, 1.0, and 5.0 mg/kg) significantly attenuated contextual FPS when compared with the vehicle control group. A control group, which received testing in a different context, showed little FPS. These findings support other evidence for anxiolytic activity of NK1 receptor antagonists and provide a novel conditioned fear test that may be an appropriate procedure to test other NK1 antagonists for preclinical anxiolytic activity in gerbils.Behavioural pharmacology 09/2009; 20(7):584-95. · 2.85 Impact Factor -
Article: Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses.
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ABSTRACT: The amplitude of the acoustic startle response is increased when elicited in the presence of brief cues that predict shock (fear-potentiated startle) and also when elicited during sustained exposure to bright light (light-enhanced startle). Although both effects are thought to reflect fear or anxiety, their neuroanatomical substrates differ. Although fear-potentiated startle is disrupted by reversible inactivation of the central nucleus of the amygdala (CeA) but not the closely related bed nucleus of the stria terminalis (BNST), light-enhanced startle is disrupted by BNST inactivation but not by CeA inactivation. Intraventricular infusions of corticotropin-releasing factor (CRF) also increase startle (CRF-enhanced startle) and this effect is mediated by CRF receptors within the BNST, with no involvement of the CeA. Together, these observations suggest that CeA- and BNST-dependent fear and anxiety may be differentially sensitive to CRF receptor blockade. We tested this by orally administering the novel, potent, and selective CRF-R1 antagonist GSK876008 to rats before CRF-enhanced, light-enhanced, or fear-potentiated startle testing. GSK876008 disrupted CRF-enhanced startle with a linear dose-response curve, and light-enhanced startle with a U-shaped dose-response curve, but did not disrupt fear-potentiated startle to a visual stimulus at any dose tested, and even augmented the response in some animals. GSK876008 also disrupted shock-related 'baseline' startle increases, which may have reflected context conditioning (shown elsewhere to also be BNST-dependent). Overall, these results suggest that short-duration CeA-dependent threat responses can be pharmacologically dissociated from longer duration BNST-dependent responses in terms of their sensitivity to CRF1 receptor antagonists.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2009; 34(6):1533-42. · 6.99 Impact Factor -
Article: Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.
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ABSTRACT: To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.Journal of Medicinal Chemistry 12/2008; 51(23):7370-9. · 4.80 Impact Factor
