EXPERIMENTAL MYOPATHY INDUCED BY AMPHIPHILIC CATIONIC COMPOUNDS INCLUDING SEVERAL PSYCHOTROPIC-DRUGS

In rats, chronic administration of high oral doses of chlorphentermine, chlorcyclizine, 1-chloro-amitriptyline, triparanol, quinacrine (Mepacrine), iprindole or imipramine caused a myopathy closely resembling the chloroquine-induced myopathy described earlier. The essential features were, in decreasing order of frequency of observation: longitudinal branching of muscle fibers giving rise to clusters of subfibers with greatly varying diameters; cytoplasmic vacuoles of varying sizes; and necrosis of muscle fibers. As shown by sequential investigations, fiber branching resulted from incomplete regeneration subsequent to fiber necrosis. Upon withdrawal of the drugs, the myopathy was slowly reversible. Cytoplasmic vacuolation and necrosis of muscle fibers appear to be, at least primarily, independent events. Necrosis is probably not causally related to the drug-induced generalized lipidosis or to the drug-induced alterations previously described in motor nerve endings. Development of necrosis is tentatively suggested as being triggered by a direct effect of the cationic amphiphilic compounds upon the plasma membrane. Both side effects of the present drugs, myopathy and generalized lipidosis, are thought to be directly related to the physicochemical characteristics of the compounds.