Toxicological study of olivamide in chronic experiment on rabbits

Introduction. Antibiotics of aureolic acid group are highly effective anticancer drugs. New data about their mode of action caused the need for creation of analogs with improved pharmacological properties. The methods of selective chemical modification of aureolic acid antibiotic olivomycin A were developed at the Gause Institute of New Antibiotics. Some semisynthetic derivatives have been prepared. The most active compound – N, N-dimethylaminoethylamide 1’-des-(2,3-dihydroxybutteroil)-1’-carboxy-olivomycin A (olivamide) – was selected for advanced preclinical testing.

Objective. The aim of the study was to investigate the toxicological safety of olivamide drug formulation in chronic experiment on rabbits.

Materials and methods. The study was performed in male and female “Soviet chinchilla” rabbits. Drug formulation was administrated intravenously at the total doses of maximum tolerated dose and 50 % lethal dose (15 × 0.02 mg/kg or 15 × 0.04 mg/kg with 24-h inter
val). During the experiment body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed. Animals were sacrificed 1 and 30 days post treatment. The internal organs were subjected to histological evaluation.

Results. It has been shown that the treatment with total dose of olivamide maximum tolerated dose produces an increase of aspartate aminotransferase, urea and creatinine level in serum. Urinalysis revealed the elevation of protein, urobilinogen and urine specific grav
ity. Administration of high dose of olivamide in addition to the above-mentioned laboratory parameter caused the raising of alkaline phosphatase and total bilirubin level in serum. Microscopic pathology observation showed structure abnormalities of varying severity in liver and kidneys.

Conclusion. Olivamide drug formulation displayed dose-dependent toxic properties. Multiple administration of low dose of the drug produces transient toxic effects completely reversible within 30 days.

olivamide, olivomycin, aureolic acid, chronic toxicity, rabbits

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