Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist.

The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid use, and this can be treated with a localized drug distribution of a non-CNS penetrant, peripherally restricted opioid receptor antagonist. Herein, we describe the application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the -substituted--3-(8-aza-bicyclo[3.

Ethanol Forensic Toxicology.

Ethanol abuse can lead to negative consequences that oftentimes result in criminal charges and civil lawsuits. When an individual is suspected of driving under the influence, law enforcement agents can determine the extent of intoxication by measuring the blood alcohol concentration (BAC) and performing a standardized field sobriety test. The BAC is dependent on rates of absorption, distribution, and elimination, which are influenced mostly by the dose of ethanol ingested and rate of consumption.

Concomitant calcium channel blocker and antipsychotic therapy in patients with schizophrenia: Efficacy analysis of the CATIE-Sz phase 1 data.

Background: This study evaluated the influence of concomitant calcium channel blocker (CCB) and antipsychotic (AP) therapy on efficacy measures in patients with schizophrenia.

Methods: Data from the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study were used to evaluate the effect of concomitant CCB therapy on the Clinical Global Impression-Severity (CGI-S) score, Positive and Negative Syndrome Scale (PANSS) score, and time to all-cause discontinuation of AP treatment. Concomitant treatment participants (CCB plus AP) were matched with controls (AP alone) by propensity scores using a 3:1 greedy match algorithm, then analyzed using a mixed linear effects model adjusted for fixed covariates.

A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.

A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.