title: Pleiotropic mechanisms of action of perhexiline in heart failure.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: George
authors.affiliation: a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
authors.forename: Alice N
authors.initials: AN
authors.lastname: Mitchell
authors.affiliation: a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
authors.forename: Ryan
authors.initials: R
authors.lastname: Preece
authors.affiliation: a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bannister
authors.affiliation: a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Yousef
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D015195:Drug Design; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D058990:Molecular Targeted Therapy; D010330:Patents as Topic; D010480:Perhexiline / Q000493:pharmacokinetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002317:Cardiovascular Agents; D017382:Reactive Oxygen Species; D002334:Carnitine O-Palmitoyltransferase; D010480:Perhexiline
keywords: Perhexiline; carnitine palmitoyltransferase; heart failure; metabolism; modulation; therapy