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We report on a case of perhexiline maleate-induced hepatitis secondary to a long-term administration of recommended daily dosages of 300 mg. The patient had a spectacular weight loss of 29 kg. He developed hepatitis, which subsided after drug withdrawal. Our electron-microscopic findings with the typical inclusion bodies and impaired hydroxylation capacity point to an underlying metabolic disorder as the pathogenetic mechanism.
Case report of polyneuritis and liver dysfunction induced by perhexiline maleate in a 64 years old male patient. The ultrastructural study of nerve, liver, muscle and skin biopsies shows polymorphous, membrane bound, often multilamellar, lysosome-like inclusions, the content of which is probably complex lipids. The histochemical study of liver reveals a lipid storage, consisting mainly of triglycerides and of smaller amount of phospholipids and free fatty acids, the pattern of which is abnormal. The biochemical study of nerve tissue shows a decrease of phospholipids levels and some qualitative disturbances in gangliosides. These changes, some of which are similar to those reported in amphiphilic drug intoxications, are prevalent in high lipid metabolism cells such as hepatic and Schwann cells.
Ten new cases of perhexiline induced peripheral neuropathies are reported. The authors emphasize the possible association of other neurological disorders: cerebellar symptoms in one case, complex tremor in two other cases, marked decrease of photomotor reflexes in one case and disgeusia in another one. The pharmacocinetic study of 4 cases revealed the presence of a low metabolism of the drug in one of them. Polymorphous inclusions have been seen in Schwann cell and endothelial cell cytoplasm in the three patients with electron microscopic study of the nerves. The pathological study of one case showed the demyelination of spinal cord posterior columns. In another case, who died from hepatic coma, the biochemical study of cerebral lipids revealed the low values of cerebrosides and sulfatides in cerebellum and cerebral white matter.
The improvement in the electrocardiographic signs of coronary insufficiency under the influence of perhexiline maleate is the object of an ergometric study in 28 patients. Ergometric tests repeated at regular over an average period of 8.3 months show a rapid ECG improvement, sustained over the period of the study. The heart rate, registered while at rest, which diminshes between that noted at the beginning of the study and that noted at the first registration under treatment, remains stable during the three following registrations. At the end of the effort, on the other hand, a significant reduction in tachycardia is observed during all the registrations.
The effectiveness of perhexiline maleate in the suppression of ventricular ectopic activity has been studied in 10 patients after myocardial infarction. Before treatment all patients exhibited frequent ectopic beats, i.e. more than 8 per hour. Numerous Holter magnetic tape recordings were made over a 9 - 10-month period of treatment. During the entire period of monitoring significant suppression of ectopic activity was observed in 5 patients and transient suppression in 4, of whom 3 subsequently showed a transient increase. The drug was discontinued in 1 patient because of nausea, anorexia and weight loss. No other adverse effects were encountered.
The authors describe a case of cirrhogenic hepatitis due to Pexid which was given for 8 months at 400 mg/day for a severe angina pectoris. We find here the anatomo-clinical profile of perhexiline maleate hepatiits already described in approximately 20 cases. There was a cirrhogenic evolution in our case as in 5 others : but here cirrhosis was revealing and seems stabilized since the treatment was stopped. The cirrhogenic evolution could be due to a cumulative effect of the drug and/or to an immuno-allergic mechanism as in alcoholic cirrhosis which is very similar, especially from an anatomical point of view. However cirrhogenic hepatitis differs by a characteristic lysosomal overload : brown pigment under microscopic observation and lipolysosomes with in some cases a lamellar structure under electron microscopic observation. The prescription of such a drug should be limited to cases of refractory angina pectoris and needed a regular clinical and biological survey.
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 effect of long-term (7-11 weeks) administration of perhexiline maleate (Pexid) on liver, lung, plasma and bile lipids was studied in adult male Sprague-Dawley rats. Maximum non-toxic doses of the drug (80 mg/kg/day) produced a fall of total cholesterol concentration in liver, lung and plasma, a fall of total lung phospholipid concentration, and an elevation of bile flow and biliary bile acid excretion. Minimum lethal doses (160 mg/kg/day) produced an increased liver concentration of total phospholipids and gangliosides and decreased lung concentration of gangliosides. Plasma transaminase activity was not significantly affected in either of the treated groups.
A questionnaire was distributed to doctors requesting reasons for cessation of therapy in patients on three drugs being intensively monitored. Adverse events were given as the reason in 20 percent of patients stopping treatment with perhexiline, 15 percent with sodium valproate and 43 percent with labetalol. These adverse events are listed and compared with those reported spontaneously to the medical assessor for the same period. Deaths reported do not appear to be drug related. Enquiry concerning reasons for cessation of therapy would appear to be a useful adjunct to spontaneous reporting of adverse events for drugs being monitored intensively. The number of additional adverse events derived from the questionnaires approximately equalled those from spontaneous reporting.
The effects of amiodarone, perhexiline and bepridil, which decrease effort cardioacceleration although they have no adrenergic beta blocking properties, were studied in the unanesthetized dog in chronic heart block. All three products decreased atrial rate in a durable way after an initial phase of tachycardia. Amiodarone had no depressant effect on idioventricular rate; however, this was significantly slowed by the other two compounds.
Perhexiline maleate is an agent currently under investigation in Canada that is used for angina unresponsive to other treatment. This paper describes a possible side effect previously unreported--papilledema not associated with peripheral neuropathy.
A seven-days treatment, with Perhexilline Maleate induces changes in the structural latency of lysosomes isolated from liver or kidney and of the respiratory activity of mitochondria isolated from liver, kidney or heart. While the effect on lysosomal structural latency appears very similar in the liver and kidney lysosomes, the oxidative properties of liver mitochondria appears clearly more disturbed than those of the heart or kidney. It is concluded that liver mitochondria might be strongly involved in the mechanism of Perhexiline Maleate hepatotoxicity.
Perhexiline maleate (PM) is an anti-anginal agent of amphiphilic character involved in lipidosis disorders. Experiments were carried out to study PM action on LH release from rat anterior pituitary cell aggregates. PM caused significant and dose-dependent increases of basal LH release when the aggregates had been previously treated with PM for 20 min, then incubated for 30 min with the same concentration of drug after renewal of the culture medium. The increases of basal LH secretion induced by PM were 69% (p < 0.001) at a concentration of 10(-7)M, 130% (p < 0.001) at a concentration of 10(-5)M and 250% (p < 0.001) at a concentration of 10(-4)M. PM also increased the LHRH-stimulated LH release by 25.5% (p < 0.05) at a concentration of 10(-5)M and by 74.5% (p < 0.01) at the concentration of 10(-4)M. The results showed that PM was more potent on basal LH release than on LH stimulated by LHRH. The mechanism of this action remains unclear. It may be due to the lipidosis property of the drug.
The anti-arrhythmic efficacy of perhexiline maleate, disopyramide and mexiletine has been evaluated in 27 patients with chronic ischaemic heart disease who exhibited frequent ventricular ectopic beats (i.e. greater than or equal to 8/h). Holter tape recordings were made during normal working hours before, during and after the sequential administration of the three drugs. Each drug was administered to each patient for a 2-month period. The drug had to be discontinued in 4 cases because of side-effects. A significant reduction (P less than 0,001) in ectopic beat frequency occurred with all three drugs. No significant difference in anti-arrhythmic potency could be demonstrated between the drugs.
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The basic cellular lesion in CNS of suckling rats treated with Pexid was studied by light and electron miroscopy. The most pronounced abnormality, the formation of various intracytoplasmic inclusions, was found in neurons, astrocytes, oligodendrocytes, ependymal cells, endothelial cells and fibroblasts. These abnormal inclusions were generally membrane-bound, although clearly non-membrane-bound inclusions were occasionally found. The several internal patterns of the inclusions were (1) lamellar, both concentric and parallel, (2) reticular and (3) crystalloid. These alterations were completely reversed following withdrawal of the drug. The structural characteristics of the abnormal inclusions in Pexid-treated animals were similar to those found with certain hypocholesterolemic, neuroleptic, anorectic, and antimalarial drugs. This suggests that the inclusions occurring within the cells of animals treated with any of these drugs may develop in a similar manner, and that the formation of such inclusions is likely to be a form of cellular reaction common to certain metabolic disturbances.
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