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Pleiotropic mechanisms of action of perhexiline in heart failure

George, Christopher, Mitchell, Alice N., Preece, Ryan, Bannister, Mark and Yousef, Zaheer 2016. Pleiotropic mechanisms of action of perhexiline in heart failure. Expert Opinion on Therapeutic Patents 26 (9) , pp. 1049-1059. 10.1080/13543776.2016.1211111

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Abstract

Introduction The re-purposing of the anti-anginal drug perhexiline (PHX) has resulted in symptomatic improvements in heart failure (HF) patients. The inhibition of carnitine palmitoyltransferase-1 (CPT-1) has been proposed as the primary mechanism underlying the therapeutic benefit of PHX. This hypothesis is contentious. Areas covered We reviewed the primary literature and patent landscape of PHX from its initial development in the 1960s through to its emergence as a drug beneficial for HF. We focused on its physico-chemistry, molecular targets, tissue accumulation and clinical dosing. Expert opinion Dogma that the beneficial effects of PHX are due primarily to potent myocardial CPT-1 inhibition is not supported by the literature and all available evidence point to it being extremely unlikely that the major effects of PHX occur via this mechanism. In vivo PHX is much more likely to be an inhibitor of surface membrane ion channels and also to have effects on other components of cellular metabolism and reactive oxygen species (ROS) generation across the cardiovascular system. However, the possibility that minor effects of PHX on CPT-1 underpin disproportionately large effects on myocardial function cannot be entirely excluded, especially given the massive accumulation of the drug in heart tissue.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Taylor & Francis
ISSN: 1354-3776
Funders: British Heart Foundation, Wellcome Trust
Date of First Compliant Deposit: 11 July 2016
Date of Acceptance: 6 July 2016
Last Modified: 03 Jul 2019 10:15
URI: http://orca.cf.ac.uk/id/eprint/92417

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