piperidines and Lipidoses

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

The present study deals with the effects of two lipidosis-inducing drugs (chlorphentermine and perhexiline) upon the ultrastructure of large nerve trunks (sciatic and plantar nerves) of adult rats. Subchronic oral administration of high doses of either drug led to comparatively mild lipidosis-like alterations in Schwann cells and in other cell types of both nerve trunks. In addition, plantar nerves, and more rarely sciatic nerves, showed some unspecific lesions such as myelin whorls and ovoids within the outer Schwann cell cytoplasm, intra-axonal accumulations of polymorphous material, and single degenerating fibres. The pathogenetic mechanisms responsible for the non-specific lesions remain to be elucidated. Chlorphentermine was, in all respects, more potent than perhexiline. In general, the drug-induced lesions developing in the fibres of large nerve trunks were less dramatic when compared a) with the severe lipidosis known to occur in neuronal perikarya, and b) with the severe alterations known to develop in preterminal or terminal axon portions of rats kept under similar experimental conditions.

Topics: Animals; Chlorphentermine; Female; Lipidoses; Male; Perhexiline; Peripheral Nerves; Phentermine; Piperidines; Rats; Rats, Inbred Strains; Schwann Cells

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

Perhexiline maleate reduced the growth of human skin fibroblasts in cell culture at a concentration range of 0.3-3 micrograms/ml. At the highest concentration, the cells survived only four days. Pleomorphic inclusions characteristic of drug-induced phospholipidoses appeared in cultured cells. Analysis of the major lipid classes was performed on cells exposed to 3 micrograms/ml at four days. Gangliosides, phospholipids and cholesterol levels four to six times above controls were found. No major qualitative abnormalities were detected in phospholipids. On the contrary, an abnormal pattern of gangliosides was seen by densitometry of silica gel thin-layer plates with increases of GD3 and of an unknown ganglioside. Drug induced lipidosis may involve other lipids than phospholipids, particularly gangliosides.

Topics: Cell Division; Cell Survival; Cells, Cultured; Cholesterol; Fibroblasts; Gangliosides; Humans; Kinetics; Lipidoses; Microscopy, Electron; Perhexiline; Phospholipids; Piperidines

The present study is concerned with the question of whether or not amphiphilic drugs (chloroquine, quinacrine, perhexiline) that fail to induce general lipidosis in the central nervous system (CNS) of adult rats can produce lipidosis in a circumventricular organ (area postrema) not furnished with a blood-brain barrier. Chlorphentermine known to induce general lipidosis in CNS of adult rats served as reference compound. All drugs, when chronically applied in high oral doses, induced significant perikaryal lipidosis in the area postrema. In the adjacent nuclei (nucleus tractus solitarii, nucleus dorsalis nervi vagi, nucleus nervi hypoglossi, nucleus gracilis), only chlorphentermine caused generalized lipidosis, whereas the other drugs had either limited or no effects. The present findings strongly suggest that the exemption, of most regions of the CNS of adult rats, from lipidosis induced by chloroquine and others is due to hindered drug distribution across the blood-brain barrier, rather than being due to non-susceptibility of central neurons toward the lipidosis-inducing action of the drugs.

Topics: Animals; Blood-Brain Barrier; Brain Diseases; Chloroquine; Chlorphentermine; Female; Lipidoses; Male; Medulla Oblongata; Microscopy, Electron; Perhexiline; Piperidines; Quinacrine; Rats; Time Factors

Topics: Animals; Culture Techniques; Ganglia, Spinal; Lipidoses; Mice; Microscopy, Electron; Perhexiline; Piperidines

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.

Topics: Animals; Inclusion Bodies; Lipidoses; Perhexiline; Piperidines; Rats

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.

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Humans; Inclusion Bodies; Lipidoses; Liver; Male; Middle Aged; Neuritis; Perhexiline; Piperidines; Schwann Cells

The effects of 3 lipidosis-inducing drugs on the incorporation and turnover of palmitic acid-1-14C in lung phospholipids was studied. In rats treated with 1 dose of chlorphentermine or RMI 10.393, the incorporation of palmitate-1-14C into most lung phospholipid fractions was moderately decreased, but markedly lowered after 1 dose of Ro 4-4318. Eight doses of chlorphentermine and RMI 10.393 strongly inhibited the incorporation of palmitate-1-14C into lung phospholipids, whereas with 8 doses of Ro 4-4318 the incorporation was highly increased. Thirty hours after the last of 3 injections of the labeled palmitic acid the turnover of most lung phospholipids was considerably lower in chlorphentermine- and RMI 10.393-treated rats than in controls. Ro 4-4318, however, induced a highly increased turnover of most phospholipids. After 54 h, this effect had practically disappeared. Our studies showed that phospholipid storage after treatment with chlorphentermine and RMI 10.393 is mainly due to decreased degradation of phospholipids, whereas increased synthesis accounts for the effect of Ro 4-4318.

Topics: Amitriptyline; Animals; Chlorphentermine; Female; Fluorenes; Lipidoses; Lung; Palmitic Acids; Phentermine; Phospholipids; Piperidines; Rats

Lipidosis and foam cell reaction was induced in rat lungs by repeated administration of chlorphentermine, RMI 10.393 (=5-[p-(fluoren-9-ylidenemethyl)phenyl]-2-piperidineethanol), and 1-chloramitriptyline. Foam cell and lung lipids were extracted and separated in classes by thin-layer chromatography. Phospholipids were determined by phosphorus analysis, while neutral lipids were measured densitometrically. In lungs of drug-treated rats lecithin, phosphatidyl glycerol, phosphatidic acid, phosphatidyl inositol and free fatty acids accumulated in varying amounts. All other lipids were present in normal or reduced concentrations. Foam cells of chlorphentermine- and RMI 10.393-treated rats contained mainly phospholipids, i.e. lecithin and only small amounts of neutral lipids, i.e. cholesterol. Foam cells induced by 1-chloramitriptyline contained besides phospholipids also large amounts of neutral lipids, i.e. cholesterol, free fatty acids and cholesterol esters. This study and recent reports of others show that certain drugs produce a generalized metabolic disturbance characterized by accumulation of various lipids in several tissues. The distribution patterns of lipids induced by various drugs may differ considerably. This indicates that several biochemical mechanisms may be involved in the pathogenesis of drug-induced lipidosis.

Topics: Amitriptyline; Animals; Chlorphentermine; Cholesterol; Cholesterol Esters; Fatty Acids, Nonesterified; Female; Fluorenes; Lipidoses; Lipids; Lung; Phentermine; Phospholipids; Piperidines; Rats; Triglycerides