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Toxicologic Pathology
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Journal Article

Generalized Phospholipidosis Induced by an Amphiphilic Cationic Psychotropic Drug

Rodney L. Robison

Sandoz Research Institute, East Hanover, New Jersey 07936

George E. Visscher

Sandoz Research Institute, East Hanover, New Jersey 07936

Stanley A. Roberts

Sandoz Research Institute, East Hanover, New Jersey 07936

Robert G. Engstrom

Sandoz Research Institute, East Hanover, New Jersey 07936

Howard A. Hartman

Sandoz Research Institute, East Hanover, New Jersey 07936

Frances H. Ballard

Sandoz Research Institute, East Hanover, New Jersey 07936

Numerous amphiphilic cationic drugs cause generalized phospholipidosis in animals; one of these drugs is the Sandoz compound 200–125, a psychotropic agent. During a 6-month toxicity study in Charles River CD rats, a dramatic increase in foamy macrophages was seen in the lungs. A follow-up experiment was done to study the pathologic basis of these changes including a reversibility phase. Generalized phospholipidosis was induced after 4 weeks of 500 mg/kg/day of 200–125 by gavage. Characteristic pulmonary lesions consisted of extensive accumulations of large pale foamy macrophages as well as granular eosinophilic extracellular material. Lipid analyses of lungs showed marked increases in phospholipids (144%) and cholesterol esters (110%) in rats treated with 200–125. Drug metabolism studies employing 14C-labeled 200–125 showed an affinity for the drug to concentrate in the lungs and lymphoreticular system (spleen, lymph nodes) as well as in the adrenals, liver, and kidney. Reversibility of the phospholipidosis was nearly complete 4 weeks after drug withdrawal. The tissue changes were characterized by transmission and scanning electron microscopy. The potential pulmonary toxicity in humans with the amphiphiles is discussed.

Toxicologic Pathology, Vol. 13, No. 4, 335-348 (1985)
DOI: 10.1177/019262338501300410
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