PRECLINICAL TOXICITY STUDY OF THE NEW ANTIFUNGAL DRUG AMPHAMID

Abstract

Introduction.Amphotericin B remains the drug of first choice in the treatment of most severe systemic fungal infections. However, it is characterized by very low solubility and high toxicity. Amphamide – semisynthetic derivative of Amphotericin B – have been prepared at the Gause Institute of New Antibiotics. It showed several advantages over amphotericin B in vivo.Objective.The aim of the study was to investigate the toxicological safety of amphamide drug formulation in chronic experiment on rats.Materials and methods.The study was performed in male and female Wistar rats. Amphamide drug formulation was injected intraperitonealy at the total doses of MTD and LD50(30 × 0,07 mg/kg or 30 × 0,17 mg/kg with 24-h interval). During the experiment body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed. Animals were sacrificed on 1st and 30th day after the end of treatment. At necropsy, the mass coefficients of heart, liver, kidneys, spleen and thymus were calculated. The internal organs were subjected to histological evaluation.Results.It has been shown that the treatment with total dose of amphamide produces an increase of urea and creatinine level in serum, changes in urine composition and its specific gravity. Microscopic pathology observation showed dose-dependent structure abnormalities in kidneys, liver, lungs, stomach, and testes. Multiple administration of low dose of the drug produces transient toxic effects completely reversible within 30 days. When amphamide was used in a high dose, morphological signs of toxic cardiomyopathy were found.Conclusion.The results of the clinical and laboratory studies and microscopic pathology observation of kidneys demonstrate that nephrotoxicity is the main limiting type of drug toxicity. Dose dependence and reversibility within a month of toxic effects of amphamide allows us to recommend it to further advance.