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Pleiotropic mechanisms of action of perhexiline in heart failure
Christopher H George1, Alice N Mitchell1, Ryan Preece1
1a Wales Heart Research Institute, School of Medicine , Cardiff University , Cardiff , UK.
Insights
Perhexiline (PHX) shows benefits in heart failure (HF), but its mechanism isn't primarily carnitine palmitoyltransferase-1 (CPT-1) inhibition. Evidence suggests PHX affects ion channels and cellular metabolism more significantly in cardiovascular disease.
Area of Science:
- Cardiovascular Pharmacology
- Drug Repurposing
- Heart Failure Pathophysiology
Background:
- Perhexiline (PHX), an anti-anginal drug, demonstrates symptomatic benefits in heart failure (HF) patients.
- The proposed mechanism involves inhibition of carnitine palmitoyltransferase-1 (CPT-1), a hypothesis under debate.
Purpose of the Study:
- To critically evaluate the proposed mechanism of PHX in HF.
- To investigate the physico-chemistry, molecular targets, tissue accumulation, and clinical dosing of PHX.
Main Methods:
- Comprehensive literature and patent review of PHX from its inception.
- Focus on PHX's properties, targets, and clinical application in HF.
Main Results:
- The established dogma of PHX's primary mechanism via potent myocardial CPT-1 inhibition is not supported by current literature.
- In vivo evidence suggests PHX's major effects are likely through inhibition of surface membrane ion channels and impacts on cellular metabolism and ROS generation.
Conclusions:
- The primary mechanism of PHX in HF is unlikely to be potent CPT-1 inhibition.
- PHX's effects on ion channels, cellular metabolism, and reactive oxygen species (ROS) are more probable major contributors.
- Minor effects on CPT-1 cannot be entirely excluded due to significant cardiac accumulation and potential for disproportionate functional impact.
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.
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