Avanir Pharmaceuticals Announces Publication of Research Showing Dextromethorphan has Antidepressant-like Effects In Vivo Data shows that dextromethorphan exerts antidepressant-like actions mediated at least in part through sigma-1 receptors
ALISO VIEJO, Calif., March 20, 2014 /PRNewswire/ -- Avanir Pharmaceuticals, Inc. (NASDAQ: AVNR) today announced the publication of data showing that dextromethorphan has antidepressant-like effects in vivo. The study, published in PLOS ONE, an international, peer-reviewed, open-access medical journal, examined the antidepressant activity of dextromethorphan and the potential involvement of sigma-1 receptors. A link to the online article can be accessed at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0089985.
"The study is the first to show that dextromethorphan has antidepressant-like effects in an in vivo model and provides evidence that this effect occurs at least in part through a sigma-1 receptor dependent mechanism," said Joao Siffert, MD, chief medical officer of Avanir. "Together with preliminary clinical observations, and based on dextromethorphan modulatory effects on glutamate and monoamine pathways, these data support our belief that dextromethorphan should be further explored as an antidepressant drug and we look forward to initiating a phase II clinical development program with our investigational drug AVP-786 in treatment resistant depression later this year."
Results revealed dextromethorphan displays antidepressant-like effects in a well validated animal model to predict antidepressant effects, the forced swim test, which can be attenuated by pretreatment with the sigma-1 receptor antagonist BD1063. Concomitant administration of the CYP2D6 reversible inhibitor quinidine potentiated the effects of dextromethorphan in the forced swim test. This demonstrated that the antidepressant-like effects are most likely mediated by dextromethorphan rather than its major metabolite dextrorphan.
Dextromethorphan is a non-opioid morphinan compound with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 receptors, which are believed to be protein targets for a potential new class of antidepressant medications, and inhibits the serotonin transporter (SERT) and norepinephrine transporter (NET).
About the Study
The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and to determine the involvement of sigma-1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, sigma-1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of sigma-1 receptors in its antidepressant-like effects. Quinidine, a CYP2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the sigma-1 receptor. This study and personnel were funded by Avanir Pharmaceuticals, West Virginia University, and the National Institutes of Health (DA013978, DA013583).
AVP-786 is a novel investigational drug product consisting of a combination of deuterium modified dextromethorphan and ultra-low dose quinidine, used as a metabolic inhibitor. Incorporation of deuterium into specific positions of the dextromethorphan molecule strengthens the chemical bonds and reduces susceptibility to enzyme cleavage and first pass metabolism, but without altering its pharmacology. AVP-786 is an investigational drug not approved by the FDA.
About Avanir Pharmaceuticals, Inc.
Avanir Pharmaceuticals, Inc. is a biopharmaceutical company focused on bringing innovative medicines to patients with central nervous system disorders of high unmet medical need. As part of our commitment, we have extensively invested in our pipeline and are dedicated to advancing medicines that can substantially improve the lives of patients and their loved ones. For more information about Avanir, please visit www.avanir.com.
AVANIR® is a trademark or registered trademark of Avanir Pharmaceuticals, Inc. in the United States and other countries.
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