TOXICOLOGICAL AND ANTI-TRYPANOSOMAL EVALUATION OF POLYMER CONJUGATES OF EFAVIRENZ, TENOFOVIR, AND DOLUTEGRAVIR

Ogira Johnson Ogwuche*, Onah Johnson O., Odumosu Patricia O.

ABSTRACT

Background and purpose: Trypanosomes are parasitic protozoa that cause Chagas disease in central and South America and sleeping sickness in sub-Saharan Africa leading to morbidity and mortality of millions of people. T. brucei gambiense accounts for more than 95% of reported cases and endemic in 36 sub -Saharan African countries. The of the study is to determine the toxicological and anti-trypanosomal evaluation of polymer conjugates of efavirenz, tenofovir, and dolutegravir. Method: Toxicity testing and LD50 determination of the Conjugates were carried out using lorke’s method and after which anti-Trypanosoma evaluation was carried out by using a seven-day Trypanosoma brucei suppressive test in albino rat. Statistical analysis using one way ANOVA was carried out where differences with values of p<0.05 were considered statistically significant. Result: From the lorke’s method carried out, Doses of the drug conjugates of 10 -5000mg/kg witnesses no mortality within 24 hours indicating the safety of the drug conjugates (Tenofovir-Chitosan, Efavirenz-Chitosan and Dolutegravir-Alginate). Histological investigation of the Wister rat kidney and liver used for the toxicological study, revealed healthy kidney glomeruli and capillaries and healthy liver hepatocytes at doses between 10-4000mg/kg but at 5000mg/kg, the architecture of the liver revealed mild infiltrating leukocytes and piecemeal necrosis with sinusoid hepatocytes. The drug conjugates (Efavirenz-chitosan, Tenofovir-chitosan and Dolutegravir-alginate) screened against the Trypanosoma parasites had a significant increased ant-Trypanosoma activity compared to the drug alone (Tenofovir, Efavirenz and Dolutegravir), this might be probably due to the synergistic effect of the polymer used in the conjugation. Conclusion: the present study showed that the conjugates of dolutegravir, efavirenz and tenofovir may be considered as comparatively safe of toxicity as none of the conjugates produced any haematological challenge and no distortion of the architecture of the tissue. The study corroborated the application of the drug conjugates as better antitrypanosomal agent with lowest toxicity effect when compared with the melarsoprol, eflornithine, pentamidine and suramin.

Keywords: Efavirenz, Tenofovir, Dolutegravir, Chitosan, Alginate, trypanosomes and Lorkes.