piperidines and perhexiline-maleate

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; France; Humans; Perhexiline; Piperidines

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.

Topics: Algorithms; Animals; Anti-Arrhythmia Agents; Cardiovascular Agents; Cation Transport Proteins; CHO Cells; Cricetinae; Electric Stimulation; Ether-A-Go-Go Potassium Channels; In Vitro Techniques; Membrane Potentials; Oocytes; Patch-Clamp Techniques; Perhexiline; Piperidines; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Xenopus laevis

We performed a double-blind controlled crossover trial of perhexiline maleate versus identical placebo in daily doses of 100-400 mg in 20 male patients who were severely limited with angina pectoris despite therapy with beta-adrenoreceptor blockers. All patients had documented coronary artery disease and were awaiting coronary artery bypass grafting. Beta-blocker therapy was continued unchanged. A significant response compared to placebo was evident after 100 mg of perhexiline, and incremental therapeutic effects were evident up to 400 mg. The mean weekly angina rate fell from 18.2 +/- 2.8 basal to 6.2 +/- 1.5 on 200 mg (P less than 0.05) to 2.8 +/- 0.9 on 400 mg perhexiline (P less than 0.05). Nitroglycerin consumption fell in parallel. The mean exercise duration increased from 261 +/- 57 sec to 384 +/- 75 sec (P less than 0.05). Five patients became asymptomatic on perhexiline, and the number of pain-free days increased 100% (P less than 0.01) compared to placebo. No patient experienced hypotension or heart failure. This study shows that the addition of perhexiline to beta-adrenoreceptor antagonists in patients with severe angina pectoris is effective and represents an alternative therapy.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angina Pectoris; Double-Blind Method; Drug Resistance; Humans; Male; Middle Aged; Perhexiline; Piperidines

Perhexiline maleate is an amphiphilic molecule. Along with many other drugs it is responsible for experimental and, in some instances, clinical lipidoses. Sphingomyelinase deficiency has been evidenced in cell cultures incubated with perhexiline maleate. We describe the occurrence of a similar defect in a patient. The disturbances in the phospholipid turnover which are responsible for the thesaurismosis may originate in the sphingomyelinase deficiency.

Topics: Cerebellar Ataxia; Female; Humans; Lipidoses; Middle Aged; Neuromuscular Diseases; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Piperidines; Schwann Cells

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.

Topics: Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Perhexiline; Piperidines

Topics: Angina Pectoris; Humans; Perhexiline; Piperidines; Premedication

Perhexiline maleate is a potent anti-anginal drug which may cause alcoholic-type hepatitis and cirrhosis. We report a case of a patient who developed cirrhosis on a relatively low dose within 16 mth.

Topics: Aged; Angina Pectoris; Female; Humans; Liver; Liver Cirrhosis; Perhexiline; Piperidines

Topics: Adult; Aged; Angina Pectoris; Female; Humans; Liver Cirrhosis; Male; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Angina Pectoris; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Genes; Hepatitis, Alcoholic; HLA Antigens; HLA-B Antigens; Humans; Middle Aged; Perhexiline; Piperidines

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption. The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline. Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use.

Topics: Adult; Aged; Alcohol Drinking; Angina Pectoris; Debrisoquin; Female; Humans; Isoquinolines; Liver Function Tests; Male; Middle Aged; Oxidation-Reduction; Perhexiline; Peripheral Nervous System Diseases; Piperidines; Smoking

Topics: France; Humans; Liver Cirrhosis; Long-Term Care; Male; Malpractice; Middle Aged; Perhexiline; Piperidines

Topics: Chemical and Drug Induced Liver Injury; Perhexiline; Piperidines

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.

Topics: Adult; Angina Pectoris; Fluorescein Angiography; Humans; Male; Papilledema; Perhexiline; Piperidines; Visual Fields

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.

Topics: Acetylglucosaminidase; Animals; Heart; In Vitro Techniques; Kidney; Liver; Lysosomes; Male; Mitochondria; Mitochondria, Heart; Mitochondria, Liver; Perhexiline; Piperidines; Rats; Rats, Inbred Strains

In a 78-year-old woman receiving perhexiline maleate for intractable angina pectoris, a syndrome of parkinsonism and peripheral neuropathy developed. The neuropathy was confirmed by electromyographic and nerve conduction studies. The parkinsonism and peripheral neuropathy disappeared when perhexiline maleate was discontinued.

Topics: Aged; Angina Pectoris; Female; Humans; Parkinson Disease, Secondary; Perhexiline; Peripheral Nervous System Diseases; Piperidines

The effects of different doses of Pexid on cultured liver cells have been studied by ultrastructural and histoenzymological techniques. Two types of abnormal lysosomal inclusions were seen: clear matrix inclusions with either homogeneous or tiny lamellar structures, and dark matrix inclusions with clear vacuoles and either random or myelin-like lamellar structures. These patterns correspond to storage of triglycerides, phospholipids and gangliosides, either singly or together.

Topics: Cells, Cultured; Gangliosides; Glycogen; Humans; Inclusion Bodies; Lipid Metabolism; Liver; Microscopy, Electron; Perhexiline; Piperidines

Topics: Cells, Cultured; Fibroblasts; Humans; Lipidoses; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Piperidines

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.

Topics: Data Collection; Ethanolamines; Humans; Labetalol; Perhexiline; Piperidines; Surveys and Questionnaires; Valproic Acid

Topics: Angina Pectoris; Humans; Perhexiline; Piperidines

Hepatic toxicity was observed in mice which had received Griseofulvin or Perhexilin Maleate over a period of several months. Treatment of griseofulvin alone gave rise to hepatitis with the presence of Mallory bodies (MB) whereas the same length of treatment with Perhexilin Maleate was associated with steatonecrosis with an absence of MB. When treatment was followed by a one month rest period hepatic lesions disappeared with no trace of sequelae. Cross-treatment studies showed that one week of Perhexiline Maleate was sufficient to induce MB in mice pretreated with Griseofulvin. Similarly, Griseofulvin administered to mice pretreated with Perhexilin Maleate gave rise to MB formation after one week as opposed to the usual two months incubation time (DENK et al.). The histological nature and mode of formation of these MB was identical to that encountered in acute alcoholic hepatitis. On addition, combined drug therapy employing Perhexilin Maleate suggests a particular hepatic toxicity in man in cases where the liver has become predisposed due to other therapeutic.

Topics: Animals; Chemical and Drug Induced Liver Injury; Griseofulvin; Liver; Male; Mice; Perhexiline; Piperidines; Time Factors

To understand the mechanism of the lysosomal lipid storage induced by perhexiline maleate, we performed simultaneous lipid analysis and lysosomal enzymes determinations. Human fibroblasts were cultured for 5 days in the presence of perhexiline maleate at a concentration of 2 micrograms/ml of culture medium. Lipid analysis showed that those non toxic levels determined the same changes as seen with higher concentrations of the drug (Hauw et al. 1980) i. e. increase of cholesterol and of all major phospholipids. Qualitative phospholipid pattern was not markedly changed. Lysosomal enzymes activities were not modified with the exception of sphingomyelinase which was reduced to 12% of its normal level.

Topics: Cells, Cultured; Cholesterol; Fibroblasts; Gangliosides; Humans; Lipid Metabolism; Lysosomes; Perhexiline; Phospholipids; Piperidines

Topics: Chemical and Drug Induced Liver Injury; Humans; Liver; Perhexiline; Piperidines