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Czobor P.,Semmelweis University | Czobor P.,Nathan Kline Institute for Psychiatric Research | Skolnick P.,DOV Pharmaceutical Inc. | Skolnick P.,New York University | Lippa A.,DOV Pharmaceutical Inc.
CNS Neuroscience and Therapeutics | Year: 2010

Preclinical studies demonstrated that ocinaplon, a positive allosteric modulator of GABAA receptors, possesses anxiolytic-like actions at doses devoid of the side effects typically associated with benzodiazepines. The aim of this study was to evaluate the effects of ocinaplon in a multicenter, double-blind proof-of-concept trial of male and female outpatients who met DSM-IV criteria for GAD with no coexisting depression, and had a baseline score of ≥20 on the Hamilton Scale for Anxiety (HAM-A). Patients with <20% reduction in HAM-A to placebo in a single-blind 7-day run-in period were randomly assigned to treatment with ocinaplon 90 mg t.i.d. (n = 31) or placebo for 28 days (n = 29). Ocinaplon was more effective than placebo in reducing HAM-A scores (P = 0.009). Patients assigned to ocinaplon exhibited a mean improvement of 14.2 points (SE = 2.6) on the total score of the HAM-A scale at the conclusion of the trial, while patients assigned to placebo obtained a mean improvement of 6.3 points (SE = 2.0). A significant (P = 0.023) difference in improvement between ocinaplon and placebo was observed beginning at and continuing from 1-week after the initiation of dosing. The proportion of patients with treatment-emergent adverse events (TEAE) was not statistically significant between ocinaplon and placebo. One serious adverse event (SAE) occurred in the ocinaplon group that was considered possibly related to study medication (icterus following transaminase elevations). The patient had preexisting medical conditions that may have contributed to this SAE. A full recovery was observed with no residual effects. The overall safety profile revealed no patterns of TEAEs, including those effects typically associated with other anxiolytic and/or benzodiazepine compounds, such as sedation. Ocinaplon appears to be a well-tolerated and effective treatment for GAD. It produces a rapid onset of anxiolytic action absent the side effects (e.g., dizziness, sedation) typically reported following anxiolytic doses of benzodiazepines. © 2009 Blackwell Publishing Ltd. Source


Yang A.R.S.T.,Howard University | Yi H.S.,Howard University | Warnock K.T.,Howard University | Mamczarz J.,University of Maryland Baltimore County | And 6 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2012

Background: Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats. Methods: Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50mg/kg; PO) was given 25minutes or 24hours prior to evaluation. The effects of DOV (12.5 to 50mg/kg; PO) in the FST were evaluated 25minutes posttreatment. Results: DOV (6.25 to 50mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50mg/kg) was sustained for up to 120hours after a single dose. Administration of a single dose of DOV (25, 50mg/kg) 24hours before testing suppressed alcohol responding for 48hours by 59 to 62%. DOV (12.5 to 50mg/kg) also dose-dependently reduced immobility of P rats in the FST. Conclusions: DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans. © 2011 by the Research Society on Alcoholism. Source


June H.L.,Howard University | Warnock K.T.,Howard University | Yang A.R.S.T.,Howard University | Yi H.S.,Howard University | And 4 more authors.
Pharmacology Biochemistry and Behavior | Year: 2012

The co-occurrence of alcoholism and depression is highly prevalent and difficult to treat. In an animal model of binge drinking that exhibits abstinence-induced behaviors reminiscent of negative affective states, the triple monoamine uptake inhibitor, amitifadine, produced a selective, dose dependent attenuation of binge drinking. Amitifadine also reversed abstinence-induced increases in the intracranial self-stimulation threshold, a model of anhedonia, and immobility in the forced swim test, reflecting behavioral despair. In view of the safety profile of amitifadine in humans, including low risk for weight gain, lack of sexual side effects, and low potential for abuse, we hypothesize that amitifadine will be effective in treating co-occurring alcoholism and depression. © 2012 Elsevier Inc. Source

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