Effect of perhexiline maleate on lipid metabolism in the rat. II. Liver and lung phospholipids after administration of high doses of perhexiline maleate.
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Effects of perhexiline on survival time and infarct size in experimental myocardial infarction.
The effects of perhexiline on survival time and infarct size were studied in three animal models. Dogs pretreated orally with perhexiline, 200 mg/day/14 days, and monitored under anesthesia for 30 hours after ligation of the left anterior descending coronary artery (LAD) had infarct weights of 9.1+/-1.9 g as compared to 15.2+/-1.0 g in paired untreated controls (P less than .02). Twelve of 15 perhexiline-pretreated dogs survived the duration of these studies while only 5 of 15 control animals survived for the same period of time (P less than .05). Serum creatine phosphokinase activity was significantly lower in the treated dogs at 9, 12 and 15 hours after ligation (P less than .05). Conscious dogs, pretreated orally with perhexiline 200 mg/day/7 days or 400 mg/day/7 days and monitored without anesthesia or analgesia for 72 hours after coronary ligation had smaller infarcts (P200=26+/-5; P400=26+/-4; C=39+/-5 g; P less than .05) lower plasma peak creatine phosphokinase activity (P less than .05) and reduced heart rate (P400=198+/-8; C=226+/-8 beats/min; P less than .05) and reduced incidence of ventricular ectopic beats (P less than .05). In pentobarbital anesthetized open-chest dogs, perhexiline (3 mg/kg i.v.) reduced the sum of S-T segment elevation after left anterior descending coronary artery occlusion from 32+/-3 to 14+/-1 mV (P less than .001); this effect was associated with and/or preceded by a reduction in arterial pressure (101+/-4 to 78+/-5 mm Hg; P less than .001) and heart rate (151+/-8 to 138+/-7 beats/min P less than .025; Circumflex flow increased from 38+/-4 to 83+/-8 ml/min (P less than .01). In noninfarcted open-chest dogs, perhexiline administration (3 mg/kg i.v.) resulted in increases in coronary blood flow, narrowing of arterial-coronary sinus O2 difference and a 14% reduction in myocardial O2 consumption. The protective effects of perhexiline on the ischemic myocardium appear to result from reductions in heart rate and associated decrease in myocardial O2 demand as well as an antiarrhythmic effect.
Animals↗
Pharmacokinetics of perhexiline maleate in anginal patients with and without peripheral neuropathy.
Perhexiline maleate (Pexid) which has been in general use in France with good results for the treatment of angina pectoris since 1973, may be associated with severe side effects including peripheral neuropathy. The present study is a comparison of the pharmacokinetics of perhexiline maleate in anginal patients with and without signs of peripheral neuropathy. Compared to the latter, those with neuropathy had higher plasma levels of perhexiline, slower hepatic metabolism and a longer plasma half-life. Thus, peripheral neuropathy associated with perhexiline maleate treatment appears to be a direct toxic effect due to accumulation of the drug. The accumulation might result either from a decreased volume of distribution secondary to a loss of body weight, possibly drug-induced, or to slow hepatic metabolism of perhexiline of genetic origin or due to hepatic disease, possibly drug-induced. The neuropathy is rarely an isolated event, as it is often associated with one or more adverse effects of perhexiline.
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The effects of perhexiline on the sympathetic nervous system.
The effects of perhexiline on sympathetic nervous system function were studied in vitro and in vivo. Perhexiline decreased the field stimulation-induced contractile response of the isolated vas deferens and significantly decreased the quantity of norepinephrine released during stimulation of this preparation. In vivo studies in dogs showed that perhexiline reduced the heart rate response to cardiac accelerator nerve stimulation, an effect not associated with an increase in cholinergic tone or beta adrenergic blockade. Measurements of norepinephrine released from the heart during cardiac nerve stimulation showed that perhexiline (3 mg/kg) decreased norepinephrine release by approximately 35%. These results suggest that a presynatpic effect of perhexiline, which results in a decrease in norepinephrine release, contributes significantly to the attenuated heart rate response which occurs after administration of this drug. A decrease in transmitter release during sympathetic stimulation could play an important role in the mechanism for the protective effects of perhexiline in myocardial ischemic damage.
Animals↗
Comparative trial of perhexiline maleate and oxprenolol in patients with angina pectoris.
A random single-blind study of oxprenolol against perhexiline has been undertaken in angina pectoris. Both drugs were effective in treatment (P less than 0.01) but perhexiline was better than oxprenolol (P less than 0.05), 12 of the 14 patients preferring perhexiline. Offset against this was the greater incidence of side effects with perhexiline, including one patient who later developed peripheral neuropathy. Despite the greater efficacy of perhexiline, it is suggested that side effects should preclude its routine prescription as a drug of first choice in angina pectoris. It should remain of value in the special situations of resistant angina and angina with heart failure or bronchospasm, when its use should be carefully monitored for these side effects.
Adult↗
[Experimental anti-arrhythmic action of perhexiline].
The antiarrhythmic action of Perhexiline phosphate, in doses of 3 and 6 mg/kg on various experimental cardiac arrhytmias and on the physiological properties of the atrial myocardium has been studied in the anesthetized dog. Its action in concentrations of 3 and 6 mcg/ml on the transmembrane action potentials in isolated Purkinje fibers has also been analyzed. The activity of perhexiline is comparatively greater in the circus movement atrial flutter and in the arrhythmias caused by ouabain and by barium chloride intoxication than in the atrial tachysystolia caused by the local application of aconitine. Perhexiline prolongs the wave length (refractory period times conduction velocity) of the atrial impulse and depresses atrial excitability. These effects may explain its action on experimental atrial flutter. In isolated Purkinje fibers, perhexiline reduces the maximum velocity of depolarization, the overshoot, the amplitude of the action potential and its duration, measured at 50% of its repolarization phase. The relation of these electrophysiological effects of perhexiline to the genesis of each type of arrhythmia may explain its different type of activity in the experimental models studied.
Animals↗
Supression of ventricular extrasystoles by perhexiline.
The antiarrhythmic effects of perhexiline were investigated in 13 of 20 patients with frequent and long standing ventricular extrasystoles in a double blind crossover trial using 24-hour electrocardiograph tape recordings, routine electrocardiograms, and treadmill exercise testing. With a dose of 300 to 400 mg per day, there was a significant decrease (mean 41%) in the number of ventricular extrasystoles per 24 hours. There were large differences in the individual responses to perhexiline, which were significantly related to the diurnal variations of ventricular extrasystoles: those patients whose ventricular extrasystoles disappeared spontaneously during sleep were less likely to respond to perhexiline than those whose ventricular extrasystoles persisted throughout the night. Suppression of ventricular extrasystoles was also apparent from the routine electrocardiogram and the exercise tests. Side effects (dizziness and unsteadiness) were troublesome in 5 of 20 patients. It is concluded that in selected patients perhexiline is an effective antiarrhythmic drug, and is likely to be most useful in patients with coexisting angina and ventricular extrasystoles. Because of its potential toxicity, it should not be used as a drug of first choice.
Cardiac Complexes, Premature↗
Perhexiline maleate in the treatment of severe angina pectoris.
Perhexiline maleate was used as a prophylactic agent in 26 patients suffering from severe angina pectoris. The mean duration of treatment was 8.9 months, with a maximum of 28 months. Fifteen patients experienced a reduction in frequency of attacks to less than one-third of their previous level; six experienced a reduction to two-thirds of their previous level; no patient showed an increase in attack rates. During the period of study, there was one death. Frequently observed side effects included dizziness, gastrointestinal irritation and malaise. One patient developed clinically apparent hepatic dysfunction which resolved on withdrawal of perhexiline maleate, but recurred after rechallenge with a lower dose of the drug; the results of liver function tests in five others showed mild abnormalities. One patient developed peripheral neuropathy after taking perhexiline maleate for 18 months, but this resolved in two months after cessation of therapy. Good responses to perhexiline maleate were observed in patients who were concurrently treated with beta-adrenoreceptor blocking drugs.
Alprenolol↗
Perhexiline maleate-induced cirrhosis.
The authors report the cases of 2 patients who died from cirrhosis after receiving perhexiline maleate, a drug widely used in Europe for the treatment of angina pectoris. Perhexiline maleate had been ingested for 24 and 28 mo, respectively. Manifestations of cirrhosis included jaundice, hepatic encephalopathy, ascites, and portal hypertension. Associated manifestations of intolerance to perhexiline maleate included peripheral neuropathy in 1 patient and marked weight loss in both. Histologic lesions resembled those observed in patients with alcoholic liver disease. Ultrastructural lesions included numerous enlarged lysosomes containing myeloid figures. Histochemical stains demonstrated increased phospholipid content of the hepatocytes. These findings are consistent with the view that prolonged administration of perhexiline maleate may induce both histologic lesions resembling those of alcoholic liver disease and ultrastructural and histochemical lesions resembling those of phospholipidosis.
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Perhexiline maleate in the treatment of angina pectoris. Five years of personal clinical experience.
A five-year personal experience of the use of perhexiline maleate (Pexid) in the treatment of severe angina pectoris is presented. Ninety-four patients, all severely incapacitated by cardiac pain, received perhexiline maleate for an average period of 12.2 months. Perhexiline maleate was used either alone or, more commonly, in conjuction with other antianginal therapy, such as beta-adrenergic receptor blocking agents. The results demonstrate that perhexiline maleate is a very effective agent which appears to be safe for long-term usage. Side effects have been frequent, and occasionally bothersome, but all have been transient and dose-dependent. The possibility that the regimens of treatment may materially improve long-term prognosis is raised.
Adrenergic beta-Antagonists↗
The effects of perhexiline maleate (Pexid) and alcohol on rat liver.
Perhexiline maleate is an anti-anginal drug believed to cause liver damage. The possibility that this effect could be potentiated by alcohol has been investigated. Rats fed both the drug and alcohol did not show more severe liver damage than those fed alcohol alone. Livers from rats fed perhexiline alone did not differ from controls. There is no evidence from this study that alcohol potentiates the effect of perhexiline in rat liver. These results may have a bearing in perhexiline-induced liver damage in humans, but clinical studies are required.
Animals↗
Perhexiline induces generalized lipidosis in rats.
Administration of perhexiline (Pexide) to rats causes generalized occurrence of lamellated and crystalloid cytoplasmic inclusions which resemble those described in patients with perhexiline-induced polyneuropathy. It is concluded that perhexiline being an amphiphilic cationic compound is a potent inducer of generalized lipidosis.
Animals↗
Perhexiline maleate in the treatment of angina pectoris in patients awaiting coronary artery bypass surgery.
Twenty-five patients with angina pectoris due to coronary artery disease who had not responded to other medical therapy and on the waiting list for coronary bypass surgery were treated over a period of 4 weeks with perhexiline maleate (100 mg to 400 mg/day) in addition to their other therapy. There was an 80% reduction in the average number of both anginal attacks and nitroglycerin requirement when the pre-treatment week and the 4th week of perhexiline maleate therapy were compared (p less than 0.0001). Six of the patients had no anginal attacks at all and did not require sublingual nitro glycerin tablets during the 4th week of perhexiline maleate therapy.
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Cardiovascular effects of isoproterenol and possible antagonistic actions of propranolol and perhexiline.
A beta-adrenergic blocking activity of perhexiline was compared with that of propanolol. In the Langendorff's preparation of rabbits, canine heart-lung preparations, open-chest dog preparations and hind-limbs of dogs, perhexiline failed to block isoproterenol-induced changes in cardiovascular functions, which were effectively blocked by propranolol. These data suggest that perhexiline is not a beta-adrenergic receptor blocking agent.
Adrenergic beta-Antagonists↗
A double-blind trial of perhexiline maleate in the prophylaxis of angina pectoris.
Perhexiline maleate, which has no beta adreno-receptor-blocking activity, has been suggested as an effective prophylactic agent for angina pectoris. The effects of perhexilline were compared with those of placebo by a double-blind crossover trial in seven patients with moderate to severe angina pectoris. Attack rates and glyceryl trinitrate consumption were significantly lower during the perhexilline phase than during the placebo phase of treatment. There was also a mild fall in resting heart rate. Three patients who had failed to respond to beta adrenoreceptor-blocking drugs, and one who had suffered reccurrence of symptoms after coronary artery surgery responded favourably to perhexiline. It thus appears that perhexiline maleate is an effective and potentially valuable agent in this condition.
Adult↗
[Clinical efficacy of perhexiline maleate in stable angina pectoris (author's transl)].
The antianginal effect of perhexiline was evaluated in a placebo-controlled double-blind study of 20 patients with stable angina pectoris. Only patients with documented myocardial infarction of more than 6 months' standing and with ST-segment depression on exercise were admitted to the study. Objective parameters of bicycle stress tests at a submaximum level of 50 watts and a maximum exercise level were evaluated. Subjective data such as nitroglycerin consumption and incidence of anginal attacks per week were obtained from the patients' self-maintained records. No negative chronotropic effect of perhexiline was found at rest. At a submaximum exercise level with unchanged double-product, a significantly lower heart rate (p less than 0.05) and a significant reduction in ST-segment depression were observed in comparison with the placebo. At maximum exercise level an increase in exercise tolerance of 8.1% and in aerobic capacity of 8.3% resulted in a significant increase in the double-product (p less than 0.01), with a shift in the blood pressure/heart rate ratio. Discontinuation of exercise occurred at the same heart rate, but at a markedly higher level of exercise attainment. Heart rate on exercise proved to be the most valuable parameter in this study for the evaluation of the aerobic capacity of the individual patient. Nitroglycerin consumption and frequency of anginal attacks per week were reduced, but were not of statistical significance. Side-effects occurred in 6 patients, but these did not require termination or reduction of medication. The selective effect on heart rate during exercise opens a new field of application for perhexiline in comparison with beta-blocking agents.
Adult↗
Liver damage associated with perhexiline maleate.
Two patients who developed biochemical and histological evidence of hepatitis while taking the anti-anginal drug perhexiline maleate are described. The pathological changes were those of mild to moderate fatty change together with a hepatitis which resembled alcoholic hepatitis, including in one patient the presence of material which by light microscopy was indistinguishable from Mallory's alcoholic hyalin. However, the predominantly periportal location of this material contrasted with the centrilobular distribution of Mallory's hyaline. One patient showed, in addition, severe atypia of the hepatocytes which was still present in less pronounced form 10 weeks after stopping perhexiline. The other patient had advanced hepatic fibrosis.
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Perhexiline neuropathy: a clinicopathological study.
Five patients developed a mild to severe polyneuropathy while under treatment with perhexiline maleate, a drug used in long-term treatment of angina pectoris. Recovery took place within a few months after drug withdrawal. We performed qualitative and quantitative light and electron microscopical studies, including teased fiber preparations, in different patients; 16 to 90% of the fibers showed segmental demyelination, an unusual feature in drug-induced neuropathies, and 3 to 20% were undergoing wallerian degeneration. Severe loss of myelinated axons was noted in all 5 patients. In these patients clinical symptoms occurred only when a great number of fibers had already been lost and most of the surviving fibers showed demyelination.
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