Romanian Society of Pharmaceutical Sciences
 

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COMPARATIVE EVALUATION OF METHOTREXATE TOXICITY AS SOLUTION FOR INJECTION AND LIPOSOMES FOLLOWING A SHORT-TERM TREATMENT IN A MURINE MODEL OF ARTHRITIS: NOTE II. HISTOPATHOLOGICAL CHANGES

MARIA BÂRCĂ1, DANIELA LUIZA BACONI1*, ANNE-MARIE CIOBANU1, MANUELA MILITARU2, GEORGE TRAIAN ALEXANDRU BURCEA1, CRISTIAN BĂLĂLĂU3

1University of Medicine and Pharmacy “Carol Davila”, Faculty of Pharmacy, Traian Vuia 6, Bucharest, Romania
2 University of Agronomic Science and Veterinary Medicine, Faculty of Veterinary Medicine, Splaiul Independentei 105, Bucharest, Romania,
3University of Medicine and Pharmacy “Carol Davila”, Faculty of Medicine, Sf. Pantelimon Emergency Hospital, Sos Pantelimon 340 – 342, Bucharest, Romania

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The aim of this study was the evaluation of the histopathological changes induced by methotrexate (MTX)-loaded liposomes, comparatively with MTX injectable solution, following a short-term treatment in a rat model of arthritis (adjuvant Freund induced). Liposomes with MTX itself ("hydrophobic MTX") and with its disodium salt ("hydrosoluble MTX") have been prepared. Three different doses of MTX preparations have been intravenously (i.v.) administered, at three doses (0.2 mg/kg b.w., 0.3 mg/kg b.w. and 0.4 mg/kg b.w.), once a week for three weeks. The toxicity of MTX was evaluated in terms of histopathological changes in the liver and kidney. Histopathological observations revealed more pronounced changes in the kidney, comparatively with the liver. Slight changes in the liver were observed in animals treated with hydro-soluble or hydrophobic MTX-loaded liposomes, (moderate and irregular granular dystrophy, discrete mononuclear cell infiltration, and moderate stasis in centro lobular veins), which were not significantly influenced by the type of treatment. The treatment with MTX solution for injection caused the same type of changes, but more pronounced (higher intensity of the dystrophic process, micro-focal points of mononuclear cells infiltrations, moderate steatosis). Glomerullar stases, the increase of the vascular network volume, tubular nephritis and medullary mononuclear cell infiltration have been revealed in the kidney. Short-term treatment with MTX-loaded liposomes or MTX solution for injection in rats with an inflammatory process of arthritis type, did not induce ireversible histopathological changes in the liver or kidney. The results of histopathological examinations indicated reduced toxic effects of MTX in the dosage range administered in this study.