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Aims: To examine whether the prophylactic antianginal agent perhexiline potentiates platelet responsiveness to nitric oxide (NO) in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris or non-Q-wave myocardial infarction)., Methods and Results: Blood samples were obtained from patients before and after initiation of treatment with perhexiline. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP) were determined via impedance aggregometry in whole blood (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In patients with ACS not receiving perhexiline (n=12), platelet responsiveness to SNP did not vary significantly over the first 3 days post admission to hospital. Therapy with perhexiline for 3 days was associated with increases in SNP-induced inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from 20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia (n=39) was associated with significantly greater (P<0.01) increases than non-resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred following institution of perhexiline therapy in patients with SAP (n=30), associated with a 85% decrease in anginal frequency. Treatment with perhexiline potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03). Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it inhibited (P<0.01) O(2)(-) release from neutrophils in vitro., Conclusion: Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS patients; in the latter group this improvement was predictive of resolution of ischaemic symptoms. The predominant mechanism of perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for NO clearance by neutrophil-derived O(2)(-).

In 15 patients with angiographically proven coronary heart disease and reproducible exercise induced ischemic ST-segment depression the antianginal effect of Perhexilinmaleat was tested in a cross-over randomized double-blind trial. The patients were treated 4 weeks with a placebo, 2 weeks with 200 mg and 2 weeks with 400 mg/day Perhexilinmaleat. The exercise-induced ischemic ST-segment depression was significantly reduced (p less than 0.001) by Perhexilinmaleat. This calcium-antagonist drug also prolonged the PQ-interval and reduced the heart rate during exercise. Some liver specific enzymes were slightly elevated. These and other side effects more often occurred at the higher dose of 400 mg/day.

Intravenous perhexiline maleate in a canine preparation with fixed coronary flow increases coronary diastolic pressure. It also redistributes coronary flow so as to preserve endocardial flow. Myocardial oxygen consumption was reduced and lactate uptake enhanced by the drug. It had no effect upon the threshold for ischemic-induced left ventricular failure.

In a preliminary study which lasted 14 weeks, an anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dosage of 200 mg twice a day to 7 patients who were suffering from cardiac arrhythmias associated with ischaemic heart disease. There was a significant reduction in ventricular extrasystoles during the 4th and 8th weeks of the study in 6 of the patients who had multiple ventricular ectopic beats. In 4 of these patients, an effective anti-arrhythmic response was maintained until the end of the study. These findings confirm other studies regarding the efficacy of the preparation in reducing ventricular extrasystoles in patients with cardiac ischaemia.

The effects of low-dose perhexiline on the exercise training response of 22 male patients, 14 after myocardial infarction and 8 after coronary artery bypass who underwent exercise training, were examined. All subjects underwent treadmill exercise testing and resting left ventricular function evaluation by radionuclide ventriculography before and after an 8-wk course of three-times-weekly exercise training. Blood levels of perhexiline confirmed that there was a steady state sufficient for antianginal therapy. There were no side effects. There were improvements in exercise tolerance in treated and placebo groups. There were no significant intergroup differences. Resting left ventricular ejection fraction and end-systolic and diastolic dimensions were not altered. Resting blood pressures were not affected by treatment. There was no evidence of a beta-adrenoceptor-blocking effect. Perhexiline during exercise training did not impair the training response.