Therapeutic Function

Coronary vasodilator

General Description

Perhexiline maleate regulates?coronary vasodilatation and blocks exercise-induced tachycardia. It is used to treat angina pectoris and variant angina. Perhexiline maleate functions as a cardiac metabolic agent. It is associated with peripheral neuropathy, high intracranial pressure with?papilledema?and proximal myopathy.

Biochem/physiol Actions

Perhexiline maleate is an anti-anginal metabolic modulator. It inhibits the mitochondrial enzyme carnitine palmitoyltransferase CPT-1 and to a lesser extent CPT-2. This causes a shift in myocardial substrate utilisation from long chain fatty acids to carbohydrates, resulting in increased glucose and lactate utilization and increased ATP production for the same O2 consumption as before and consequently increases myocardial efficiency. Perhexiline maleate was also recently found to inhibit the activity of mTORC1.

Safety Profile

Poison by intraperitoneal route. Moderately toxic by ingestion.Human systemic effects by ingestion: muscle weakness, paresthesia, and hepatitis. Mutation data reported. Whenheated to decomposition it emits toxic fumes of NOx.

in vitro

perhexiline maleate concentration-dependently and competitively inhibited cpt1 in rat cardiac and hepatic mitochondria, with an ic50 value of 77 and 148 μm, respectively. it was indicated that perhexiline maleate displayed a greater sensitivity of the cardiac than the hepatic enzyme when exhibiting inhibition effect [1]. perhexiline maleate produced concentration-dependent inhibition of cpt2 activity with an ic50 value of 79 μm [2]. in human breast cancer mcf-7 cells, perhexiline maleate blocked mtorc1 signaling at 10 μm and elicited autophagy ~7-fold at a concentration of 10 μm [3].

in vivo

adult mice of swiss nmri strain were orally administrated with perhexiline maleate at a dosage of 100 mg/kg body weight/day for 10 weeks. perhexiline maleate triggered changes in nerve, including a few cytoplasmic inclusions in schwann and perineurial cells of mice treated with perhexiline maleate. after 11 weeks of administration of the drug, and up to 18 weeks, small abnormal zones were displayed on several muscle fibers, which were formed by tubular aggregates [4].

references

[1]. kennedy, j., unger, s., & horowitz, j. inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. biochemical pharmacology. 1996; 52(2): 273-280. [2]. kennedy, j., kiosoglous, a., murphy, g., pelle, m., & horowitz, j. effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. journal of cardiovascular pharmacology. 2000; 36(6): 794-801. [3]. balgi, a., fonseca, b., donohue, e., tsang, t., lajoie, p., & proud, c. et al. screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mtorc1 signaling. plos one. 2009; 4(9): e7124. [4]. fardeau, m., tomé, f., & simon, p. muscle and nerve changes induced by perhexiline maleate in man and mice. muscle & nerve. 1979; 2(1): 24-36.