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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.
In order to find a substitute for perhexiline maleate, an antiangina drug, for which several side effects due to poor hydroxylation have been reported, an arylalkylamine series with antianginal properties has been synthesized. The aim of the present work was to select a more rapidly hydroxylated compound than perhexiline maleate in this series. Two criteria have been retained. The binding of the molecules to liver microsomal cytochrome P-450 and their rate of hydroxylation were both studied in vitro using phenobarbital induced rat liver microsomes. Incubation with cofactors and extraction procedures have been tested on one of the molecules of the series taken as example: N-2-dicyclohexyl-2-phenethylamine. All of the molecules tested in the series substrates were type I substrates; nevertheless, no correlation was found between binding on cytochrome P-450 and oxidative metabolism of the drugs. Two of the studied molecules were more easily hydroxylated than the others and than perhexiline maleate: (N-2-dicyclohexyl-2-phenethylamine) and (II) (N-cyclohexyl-2-diphenylethylamine) with the following respective kinetics: Apparent Vmax: 0.073 and 0.32 units, apparent Km: 6.9 X 10(-5) M and 22.2 X 10(-5) M.
A method for the quantitative determination of perhexiline and its main hydroxylated metabolites in human plasma, based on liquid chromatography-mass spectrometry (LC-MS), was developed. The method used protein precipitation with acetonitrile followed by dilution with water and subsequent direct injection of the extract into the LC-MS system. Hexadiline was used as internal standard and the intra-assay coefficients of variation were <or=5% for perhexiline and cis-hydroxyperhexiline over the target concentration range in patients. The lower limits of quantification were 0.005mg/l for perhexiline and 0.015mg/l for cis-hydroxyperhexiline, and the measuring ranges were from 0.05 to 3.0 and from 0.2 to 6.0mg/l, respectively. The method was compared with an established HPLC method with fluorescence detection and the correlation between the methods was close to 1 for both compounds. The predominant form of hydroxyperhexiline in 87% of the patient samples was found to be one of the diastereomeric pairs of cis-hydroxyperhexiline. In patients not forming this metabolite, trans-hydroxyperhexiline could be detected. We conclude that the present LC-MS method is suitable for use in a clinical routine laboratory.
In the hope of reducing the toxicity of perhexiline, a series of 27 cyclohexylaralkylamines II based on the "soft drug" concept and incorporating an amide function were synthesized. In a preliminary screening, compounds were evaluated for their alpha-adrenolytic activities. Several derivatives, especially N-(cyclohexylphenylmethyl)-2-(cyclohexyl-methylamino)acetamide (3), N-(cyclohexylphenylmethyl)-2-(homoveratrylmethylamino)acetam ide (7), and N-[2-(cyclohexylamino)ethyl]-alpha-cyclohexylbenzeneacetamide (23) had the same activity range as perhexiline in vitro in rat aorta strips. The in vitro metabolism of these three molecules was then investigated and compared to that of perhexiline. The effect upon the alpha-adrenolytic activity of introducing various N-aralkylamine groups on II was examined. Structure/activity relationships are discussed.
A series of 24 cyclohexylaralkylamine derivatives related to perhexiline has been synthesized and screened for cardiovascular activity. All the compounds contained an exocyclic amine which was substituted either by an alkyl, cycloalkyl, or aralkyl group. In the hope of further reducing toxicity, the synthesis of p-tolyl- and p-hydroxyphenyl derivatives 23 and 24 was undertaken. The effect of separating the cyclohexylamine moiety with respect to the aromatic nucleus has been systematically examined. The pharmacological investigations were directed to a search for compounds having an activity better than perhexiline according to the following order of criteria: (1) alpha-adrenolytic activity; (2) increase of coronary blood flow; (3) calcium antagonism. Several compounds were more potent and exhibited lower toxicity than perhexiline. Further detailed pharmacological investigations (tension time index and decreased cardiac work) have led to the selection of N,2-dicyclohexyl-2-phenethylamine (3) for clinical trials, which are now under way.
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.
Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.
The electrophysiologic effects of perhexiline maleate were studied with glass microelectrodes in three types of isolated rabbit heart preparations: (a) sinoatrial node preparation; (b) left atrial free-wall preparation; and (c) atrioventricular node preparation. The spontaneous firing rate of the sinoatrial node was decreased by 10-15% at a concentration of 10(-5) g/ml. The sinus node recovery time after atrial overdrive was prolonged by about 50%. The effective refractory period of the left atrial free wall showed concentration-dependent prolongation at concentrations above 10(-7) g/ml. Although this period was shortened after washing with perhexiline-free Tyrode solution, it did not return to the control lever. The effective refractory period of the right atrium was prolonged by 15% at a concentration of 10(-5) g/ml, but the functional refractory period did not change. The conduction time, effective refractory period, and functional refractory period of the atrioventricular node were significantly increased. Previous reports had claimed that perhexiline had pharmacologic effects on Purkinje fibers and ventricular myocardium at lower concentrations than on the atrium, but we found significant actions on the atrium and the atrioventricular node in therapeutic concentrations.
Perhexiline maleate, originally classified as a calcium antagonist, is in use as an antianginal agent. The mechanism of its protective effect is unknown, but there is speculation that it involves a modification of myocardial substrate utilization, in which glycolytic sources are used rather than fatty acids. This hypothesis was tested by employing [13C]NMR isotopomer analysis to measure substrate selection in the working rat heart. Substrate utilization was measured from a mixture of substrates present at their physiological concentration, as follows: acetoacetate, glucose, lactate and long-chain fatty acids. Control perfusions were compared with those perfused with perhexiline. It was found that perhexiline increased lactate utilization, which reduced the extent of fatty acid and endogenous substrate oxidation. There was also a significant increase in cardiac output for a small and insignificant increase in oxygen consumption, which suggested an improvement in myocardial efficiency. Thus, it was confirmed by direct measurement that this drug does modify substrate oxidation, which suggests that further investigations of the role that this agent can play in the management of ischemic heart disease would be beneficial.
Patients taking oral doses of perhexiline maleate have been examined. Measurement of serum perhexiline concentrations established that different dose requirements between patients were necessary due to the different doses at which drug saturation was achieved. Measurement of serum perhexiline concentrations are essential if side-effects from the drug are to be avoided.
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.
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.
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.
Cardiovascular effects of nitroglycerin, perhexiline and the combination of these two drugs were studied in dogs with myocardial ischemia. Nitroglycerin decreased arterial blood pressure and O2 consumption (MVO2), although heart rate increased. Perhexiline decreased blood pressure, heart rate, MVO2 and modified the tachycardia and the hypotensive actions of nitroglycerin without altering the ability of nitroglycerin to reduce MVO2. These data show that the pharmacologic actions of nitroglycerin in the treatment of ischemic heart disease are enhanced when given in combination with perhexiline or similar calcium antagonists.
The authors report the case of a 65 year old man treated with amiodarone chlorhydrate since 4 years and perhexiline maleate since 15 months, admitted for constitutional symptoms with fever, neurologic troubles particularly polyneuritis and pronounced hypoglycemia. A diagnostic of hyperthyroidism was made and attributed to amiodarone. The hypoglycemia and the polyneuritis were related to perhexiline maleate as other signs presented by the patient. All the symptoms disappeared after discontinuation of the drugs. The complications secondary to maleate perhexiline administration are reviewed.
Two patients developed cirrhosis of the liver following therapy with perhexiline maleate. Liver failure and polyneuropathy caused death in one patient who had received 300 mg daily for three years. Cirrhosis was an unexpected finding in the other patient whose perhexiline dose was 200 mg daily for five years. Perhexiline should be prescribed cautiously and discontinued if liver function tests become abnormal. Monitoring of blood levels may lead to a reduction of toxicity.
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.
The effects of amiodarone (10 mg/kg i.v.), bepridil (2.5 mg/kg i.v.) and perhexiline (2.5 mg/kg i.v.) were compared in the anesthetized dog at doses inducing a decrease in heart rate of same intensity. This bradycardial effect existed for amiodarone and bepridil whether the heart was denervated or not. Perhexiline did not modify the rate of the denervated heart. Amiodarone decreased dp/dt max whether the heart was denervated, innervated or paced at constant rate. PO2 in coronary venous blood was transiently increased with no significant variations in coronary flow. Bepridil reduced dp/dt max only after cardiac denervation; coronary PVO2 was increased in a durable way although the rise in coronary flow did not exceed a few minutes. Perhexiline decreased dp/dt max in a durable way only when cardiac innervation was respected. It had no effect on coronary flow. The increase in coronary PVO2 was transient and depended upon bradycardia.