Effects Of Perhexiline Research Articles

Effects of Perhexiline on Insulin and Nitric Oxide Signalling in Diabetics

Effects of Perhexiline on Insulin and Nitric Oxide Signalling in Diabetics

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

OBJECTIVESPerhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome.METHODSIn a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics.RESULTSOver a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56–1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07–0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34–0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis.CONCLUSIONSPreoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery.ClinicalTrials.Gov IDNCT00845364.

Effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre randomised double-blind placebo-controlled trial

BackgroundPerhexiline is thought to modulate metabolism through the inhibition of mitochondrial carnitine palmitoyltransferase, reducing fatty acid uptake and increasing carbohydrate utilisation. Our group has shown that a glucose-insulin-potassium infusion enhances myocardial protection during coronary artery bypass graft (CABG) surgery through metabolic manipulation. This study assessed whether perhexiline improves clinical or biochemical markers of myocardial protection and analysed its effect on the myocardial metabolome. MethodsIn a prospective randomised double-blind placebo-controlled trial, patients undergoing CABG at two centres were randomised to receive oral perhexiline or placebo for at least 5 days before surgery. The primary outcome was a low cardiac output episode in the first 6 h after removal of the aortic cross-clamp. A low cardiac output episode was defined as a cardiac index of less than 2·2 L/min/m2 in the presence of adequate preload, afterload, and heart rate. All analyses were conducted according to the intention-to-treat principle with a 90% power to detect a relative risk of 0·5 with a one-sided α of 0·025. Left ventricular biopsy samples were taken before ischaemia, snap-frozen, and analysed with mass spectrometry-based (MS) metabolomics. This trial is registered with ClinicalTrials.gov, number NCT00845364. FindingsOver a 3-year period, 286 patients were randomised, received the intervention, and included in the analysis. There were no important baseline differences between groups. The incidence of a low cardiac output episode in the perhexiline arm was 36·7% (51/139) versus 34·7% (51/147) in the control arm (odds ratio 0·92 [95% CI 0·56–1·50]; p=0·74). There were no significant differences in inotrope usage, myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction, or length of hospital stay. No difference in pre-ischaemia left ventricular metabolism was identified between groups. InterpretationPreoperative perhexiline does not improve myocardial protection in patients undergoing CABG. That perhexiline has no significant effect on the MS-visible polar myocardial metabolome in vivo in human beings supports the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition. FundingBritish Heart Foundation and Sussex Heart Charity.

Effects of perhexiline and nitroglycerin on vascular, neutrophil and platelet function in patients with stable angina pectoris

Perhexiline, a “metabolic” anti-anginal agent currently under investigation in management of congestive heart failure and acute coronary syndromes improves platelet nitric oxide responsiveness in patients with impaired responsiveness. The current study investigated possible interactions between perhexiline and the nitric oxide donor nitroglycerin on arterial stiffness, neutrophil superoxide release and on platelet nitric oxide responsiveness. Patients ( n = 39) with stable angina pectoris, awaiting cardiac catheterization were randomized to additional perhexiline or unchanged drug therapy; all patients received nitroglycerin infusion for 2 h. Vasomotor responses to perhexiline and combined perhexiline/nitroglycerin were examined using changes in augmentation index, measured via applanation tonometry. Neutrophil superoxide release was measured ex vivo utilizing lucigenin mediated chemiluminescence and effect of perhexiline on inhibition of platelet aggregation by sodium nitroprusside was also measured. Perhexiline alone did not affect augmentation index, neutrophil superoxide release, or ex vivo platelet sodium nitroprusside response. Nitroglycerin decreased augmentation index ( P < 0.01) and superoxide release ( P < 0.05). Magnitude of inhibition of superoxide release was significantly enhanced by perhexiline pre-treatment ( P < 0.05); however perhexiline had no effect on magnitude of vasomotor response to nitroglycerin. In conclusion, perhexiline exerts no effects on arterial stiffness and does not potentiate nitroglycerin induced dilatation. In patients with normal platelet function perhexiline does not affect platelet nitric oxide responsiveness. In vivo low dose nitroglycerin inhibits neutrophil superoxide release; this effect is potentiated by pre-treatment with perhexiline. These “anti-inflammatory” effects of nitroglycerin may contribute to utility in acute coronary syndromes and congestive heart failure.

Comparison of effects of perhexiline on superoxide generation by neutrophils, vascular and valvular tissue

Comparison of effects of perhexiline on superoxide generation by neutrophils, vascular and valvular tissue

The effects of perhexiline on the rat coronary vasculature

The predominant site and mechanism(s) of perhexiline-induced coronary vasodilatation were investigated in the rat heart. Perhexiline was more potent in the Langendorff perfused heart than in the left anterior descending coronary artery (EC 50; 0.27 μM, confidence limits 0.19–0.39: 2.7 μM, 2.0–3.4, respectively). Selective endothelial inactivation with Triton X-100 in the perfused heart, reduced the response to perhexiline 1 μM (76+8% to 30+3% of control). 1 H-[1,2,4]Oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) 3 μM, Nϖ-nitro- l-arginine 100 μM, or a combination of the latter with indomethacin 10 μM, had no significant effect on responses to perhexiline in the perfused heart. Unlike bradykinin-induced vasodilatation, responses to perhexiline were not inhibited by tetrabutylammonium 1 mM, or charybdotoxin 20 nM. SKF525A 5 μM inhibited both perhexiline and bradykinin responses, while apamin 1 μM and glibenclamide 3 μM inhibited neither. Perhexiline exerts partially endothelium-dependent coronary vasodilator effects in the rat, predominantly on small coronary arteries, which appear to be independent of nitric oxide (NO), prostacyclin and the endothelium-derived hyperpolarising factor (EDHF) released by bradykinin.

A novel approach using 123I-iodophenyl pentadecanoic acid (IPPA) to investigate the effect of perhexiline on cardiac metabolism in sheep

A novel approach using 123I-iodophenyl pentadecanoic acid (IPPA) to investigate the effect of perhexiline on cardiac metabolism in sheep

The effects of perhexiline maleate on low density lipoprotein processing and cholesterol metabolism in cultured human fibroblasts.

The effects of perhexiline maleate (PM, Pexid) on low density lipoprotein (LDL) processing and cholesterol metabolism were investigated after a 24 h pretreatment with the drug. Perhexiline maleate increased LDL uptake in the range 10(-6) to 10(-5) M (180% of control for 10(-5) M), whereas LDL binding and degradation were not affected. Sterol synthesis from sodium acetate was enhanced by perhexiline maleate (X 2.2 for 10(-5) M), while cholesterol esterification with oleic acid was decreased (40% of control for 10(-5) M). These effects of perhexiline on cholesterol metabolism are specific, since the synthesis of triacylglycerols from sodium acetate is not affected and since the incorporation of oleic acid into triacylglycerols is much less impaired. The decreased cholesterol esterification is accompanied by a reduction of acylcoenzyme A-cholesterol-O-acyltransferase (ACAT) activity measured in vitro on cell extracts.

Vasodilating effects of perhexiline, glyceryl trinitrate, and verapamil on the coronary, femoral, renal, and mesenteric vasculature of the dog.

We compared the vasodilator effects of perhexiline on canine coronary, femoral, renal, and mesenteric arteries with those of glyceryl trinitrate and verapamil. Intravenous perhexiline produced vasodilation of all four vascular beds and decreased peripheral vascular resistance. High doses of perhexiline sometimes increased peripheral vascular resistance and reduced peripheral blood flow. This increase in resistance was abolished by hexamethonium. Intra-arterial perhexiline caused dose-dependent dilation in all four vascular beds without selectivity for the coronary circulation. Neither the autonomic nervous system nor inhibition of adenosine deaminase was involved in the vasodilator action of perhexiline. Perhexiline abolished renal blood flow autoregulation, an effect which was reversed by simultaneous administration of CaCl2. These results suggest that the vasodilator effect of perhexiline is mediated by its Ca2+-antagonistic activity. However, some differences in its effects from those of other Ca2+-antagonists remain to be clarified.

Effects of perhexiline on myocardial phosphorylase activity, myocardial catecholamine content and heart rate.

A study was conducted on the effects of perhexiline on myocardial phosphorylase activity, myocardial catecholamine content and heart rate. Phosphorylase a activity and heart rate were investigated as an indicator of sympathetic nerve tone in order to clarify the characteristic of perhexiline with regard to the effects on myocardial metabolism in hyperthyroid rats and catecholamine deficient rats. Myocardial catecholamine and phosphorylase a activity were measured by von Euler's method and Cori's method respectively. Conclusion of this study are summarized as follows: 1) Perhexiline reduces the heart rate, and its effect is not always dependent upon the changes in myocardial norepinephrine content. 2) Perhexiline reduces myocardial phosphorylase a activity. It cannot be always said that the reduction is dependent upon the changes in myocardial norepinephrine. 3) Though slightly different from propranolol and dichloroisoproterenol, perhexiline possesses cardiac effects resembling beta-blockers.

Effects of perhexiline on contractile response of rabbit aorta to norepinephrine and potassium

Perhexiline (3.2 × 10 −7 -6.4 × 10 −6 M) and verapamil (2 × 10 −8 -2 × 10 −7 M) inhibited the contraction of rabbit aorta induced with 40 mM K + and with low concentrations (5.9 × 10 −9 -5.9 × 10 −8 M) of norepinephrine more effectively than the contraction induced by higher concentrations of norepinephrine. The tension induced by 1.2 × 10 ∂ M norepinephrine was augmented with the above concentrations of perhexiline and verapamil. Higher concentrations (3.2 × 10 −5 -6.4 × 10 −5 M) of perhexiline significantly reduced the peak tension induced by norepinephrine. The results suggest that perhexiline is a Ca 2+ antagonist and also has an unspecific spasmolytic action.

116) - Effect of perhexiline on experimental arrhythmias induced by ouabain and by aconitine in dogs

116) - Effect of perhexiline on experimental arrhythmias induced by ouabain and by aconitine in dogs

Electrophysiologic properties of perhexiline

Perhexiline maleate (Pexid), a promising clinical antiarrhythmic and antianginal drug, was evaluated for its electrophysiologic effects on the entire conduction system of the intact canine heart throughout a wide range of therapeutic and potentially toxic doses. Intracardiac conduction times were measured by bipolar intramyocardial and transvenous endocardial electrodes before and following the intravenous administration of each dose of perhexiline maleate, 3 mg/kg every 30 min for a total of 4 doses in 7 open-chest anesthetized dogs. Eight animals served as controls in which similar operative technique and electrophysiologic variables were recorded after infusion of the maleate diluent. In addition, the effects of perhexiline on atrial and ventricular thresholds to electrical stimulation were recorded, as well as the QRS and QT intervals, sinus rate, and rhythm disorders. It was observed that perhexiline did not significantly (p greater than .05) alter sinus rate, QT interval, QRS duration, PR interval, intra-atrial conduction time, atrioventricular nodal conduction time, and His-Purkinje conduction velocity. The drug did not affect the cardiac threshold to electrical stimulation of less than 0.1 ma. No ectopic atrial or ventricular activity emerged during the accumulated influence of the agent. From this study, it is concluded that perhexiline does not exert deleterious actions on the conduction system of the intact canine heart. In view of the negligible toxic effects and its efficacy in treating ventricular tachyarrhythmias in patients, the drug deserves further clinical evaluation.

Effects of perhexiline on symptomatic and hemodynamic responses to exercise in patients with angina pectoris

The effects of perhexiline on symptomatic and hemodynamic responses to exercise stress were evaluated in 16 patients with coronary artery disease and angina pectoris. Exercise-induced angina was prevented (12 of 16) or delayed during perhexiline treatment and exercise heart rate decreased (117.4 ± 6.1 [standard error of the mean] to 105.3 ± 3.6 beats/min, P < 0.05). Ischemia-related indexes of left ventricular dysfunction were attenuated (stroke work index 70.9 ± 5.7 to 86.4 ± 5.3 g-m/beat per m 2 and filling pressure 26.4 ± 3.0 to 17.7 ± 2.5 mm Hg, P < 0.01) without evidence for depression of other indexes of ventricular function. Additionally, the exercise diastolic pressuretime index increased 36.5 ( P < 0.01) and the diastolic pressure-time/ tension-time ratio increased 38 percent ( P < 0.05) with perhexiline in the patients who were free of angina. During increased exercise stress six patients achieved higher tension-time indexes before being limited by fatigue or dyspnea. The observed beneficial effects appear to be partly a result of reduced myocardial oxygen needs and improved oxygen supply.

Effects of Perhexiline on Coronary Hemodynamic and Myocardial Metabolic Responses to Tachycardia

Coronary hemodynamic and myocardial metabolic responses before and after perhexiline administration were studied in 21 patients with coronary heart disease during pacing-induced angina pectoris. Perhexiline increased the threshold to tachycardia-induced angina pectoris in 16 of the 21 patients (HR 123 ± 3 to 134 ± 3 beats/min, P &lt; 0.01). Anaerobic myocardial lactate extraction was reduced by –6.1 ± 6.3 to 10.7 ± 4% after perhexiline, although lactate extraction declined in four patients and ST segment depression was not significantly changed. Myocardial oxygen extraction was enhanced, 64 ± 2 to 69 ± 2% ( P &lt; 0.05). Coronary flow as reflected by coronary sinus blood flow was not altered (165 ± 24 to 173 ± 26 cc/min) as left ventricular oxygen utilization was increased (18.9 ± 4 to 20.9 ± 4 ml/min, P &lt; 0.05). These findings are interpreted to indicate decreased myocardial ischemia in certain patients on perhexiline.

Pharmacology of a New Antianginal Drug: Perhexiline: I. Coronary Circulation and Myocardial Metabolism

In the anesthetized dog with right-heart bypass the injection of perhexiline was followed by the vasodilatation of the coronary, systemic and pulmonary vascular beds. There was a fall in left ventricular work, index of energy utilization, and myocardial oxygen consumption. The ratio of Δ cardiac output/Δ oxygen consumption was elevated following the administration of perhexiline. All these effects of perhexiline are potentially desirable in the treatment of coronary insufficiency.