TV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethylene

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dc.contributor.authorShemesh-Darvish, Liron
dc.contributor.authorShinar, Doron
dc.contributor.authorHallak, Hussein
dc.contributor.authorGross, Aviva
dc.contributor.authorRosenstock, Moti
dc.date.accessioned2019-12-11T12:41:32Z
dc.date.available2019-12-11T12:41:32Z
dc.date.issued2018-01-11
dc.description.abstractBackground: TV-1380 is a rationally mutated, human BChE fused to human serum albumin that has high hydrolytic enzymatic activity against cocaine and as well as an extended elimination half-life. Objective: The present studies examined the safety of TV-1380 and its protective effect when given to monkeys alone or concomitantly with cocaine and ethanol. Methods: A set of studies was conducted in monkeys with TV-1380. The parameters tested included telemetric assessment of cardiovascular parameters, clinical pathology, plasma analysis of cardiac troponin I, ex-vivo analyses of cocaethylene and PK analysis of serum concentrations of TV-1380, cocaine and its metabolites, and histopathological examinations. Results: TV-1380 treatment in monkeys was well tolerated. TV-1380 pretreatment prior to cocaine significantly attenuated the cardiac effects of cocaine and reduced cocaine-induced elevations in serum cardiac troponin I. TV-1380 changed the metabolic fate of cocaine resulting in decreased exposure to benzoylecgonine, while increasing the exposure to ecgonine methyl ester in plasma.TV-1380 reduced the plasma levels of the toxic metabolite cocaethylene formed after co-administration of ethanol and cocaine. Conclusion: The results of this study demonstrate that TV-1380 not only accelerates the elimination of cocaine, but also protects the treated animal from the cardiac effects of cocaine, and inhibits the formation of the toxic cocaethylene metabolite when cocaine is given together with ethanol, supporting further clinical development of modified BChE products as possible treatments for cocaine abuse.en_US
dc.description.sponsorshipThe authors appreciate the help of Pippa Loupe PhD (Global Research and Development, Teva Pharmaceutical Industries, Overland Park KS USA), Oren Bar Ilan (Non-Clinical Statistics, Teva Pharmaceutical Industries, Netanya, Abic, Israel) and Dale Owens (Scientific Presentations, West Chester, PA USA) in the development of this manuscript. The National Institute on Drug Abuse, National Institute of Health, (Bethesda MD USA) provided support for the study assessing cardiovascular and respiratory effects.en_US
dc.identifier.citationTY - JOUR AU - Shemesh-Darvish, Liron AU - Shinar, Doron AU - Hallak, Hussein AU - Gross, Aviva AU - Rosenstock, Moti PY - 2018/03/01 SP - T1 - TV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethylene VL - 188 DO - 10.1016/j.drugalcdep.2018.01.033 JO - Drug and Alcohol Dependence ER -en_US
dc.identifier.issn0376-8716
dc.identifier.urihttps://dspace.alquds.edu/handle/20.500.12213/5020
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.subjectAddictionen_US
dc.subjectButycholinesteraseen_US
dc.subjectCardiac troponin Ien_US
dc.subjectCocaethyleneen_US
dc.subjectCocaineen_US
dc.subjectTV-1380en_US
dc.titleTV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethyleneen_US
dc.typeArticleen_US
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