Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perhexiline was introduced about 30 years ago and rapidly gained a reputation for efficacy in the management of angina pectoris. However, hepatic and neurological adverse effects associated with perhexiline administration led to a marked decline in its use. The drug was originally classified as a coronary vasodilator, and later as a calcium channel antagonist, but recent data suggests that it acts as a cardiac metabolic agent, through inhibition of the enzyme, carnitine palmitoyltransferase-1 (CPT-1). Given the drug's unique anti-ischemic action and favorable hemodynamic profile, together with an improved understanding of the mechanisms underlying the adverse effects of the drug and the clear clinical need for additional therapies in refractory patients, perhexiline is currently being re-appraised as a potentially useful agent in the management of severe myocardial ischemia. Perhexiline is being considered for registration or re-registration in a number of countries and is being evaluated in a large-scale clinical trial in elderly patients with aortic stenosis and myocardial ischemia. This systematic review examines the evidence from available published literature in relation to the efficacy and tolerability of perhexiline in the treatment of cardiac disease. While there is a lack of well designed controlled trials using objective end-points to determine efficacy (almost all trials used a crossover design, included small numbers of patients and had limited statistical analysis of results), there is consistency in the data available that perhexiline is considerably more effective than placebo when used as monotherapy. Furthermore, it affords additional symptom relief in those already receiving maximal conventional anti-anginal therapy. However, there is a paucity of trials demonstrating the efficacy of low dosages of perhexiline (100 to 200 mg/day) in patients with refractory angina pectoris. Available evidence also suggests that the incidence of adverse events can be minimised, and the efficacy maintained, by keeping plasma perhexiline concentrations within a therapeutic range (150 to 600 micro g/L)
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PMID:Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease. 1472 34

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.
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PMID:Perhexiline. 1744 89