Generalized Phospholipidosis Induced by an Amphiphilic Cationic Psychotropic Drug

Abstract

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 (1 10%) in rats treated with 200-125. Drug metabolism studies employing "C-labeled 200-125 showed an affinity for the drug to concentrate in the lungs and lymphoreticular system (spleen, lymph nodes) a s 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.

Avaliação lectino-histoquímica de fígado e rim de ovinos com fotossensibilização causada por Brachiaria decumbens

“…Drogas catiônicas anfifílicas têm sido responsabilizadas por induzirem à fosfolipidose, um acúmulo intracelular excessivo de fosfolipídeos, que pode ocorrer em qualquer tecido do corpo, mas, principalmente, na língua, fígado, rim, tecido ocular, coração, adrenal, tecido hematopoético e linfócitos circulantes. Ainda não foi possível definir o mecanismo exato da fosfolipidose induzida por drogas (Robison et al 1985). Até o momento não foram realizadas avaliações lectino-histoquímica dessas células.…”

Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

“…At the time of the publication, however, it was not recognized that the response was a PLDsis because this phenomenon was unknown. Subsequent research has confirmed that the foamy macrophages develop as a result of the accumulation of phospholipids within the cell and are a common response to so-called cationic amphiphilic drugs (CADs) 5,6 . Since that time, over 50 marketed and experimental CADs have been reported to induce PLDsis following in vitro and in vivo administration and/or under ex vivo conditions.…”

Synthesis of di‐docosahexaenoyl (C22:6)‐bis(monoacylglycerol) phosphate in unlabelled and C‐13 labelled forms for use as a biomarker of drug induced phospholipidosis

“…9 Reactions were magnetically stirred and were run under an atmosphere of N 2 . 1 H, 13 C, and 31 P NMR spectra were acquired on a Bruker Avance I spectrometer running at a proton frequency of 500.1 MHz, and chemical shifts are reported in ppm (δ) relative to tetramethylsilane or the residual solvent resonance (7.26 and 77.16 ppm for CDCl 3 ). Flash column chromatography was carried out using prepacked silica gel columns supplied by Biotage and using a Biotage automated flash system with UV detection.…”