Hepatoxicity And Hematological Effects Of Combination First Line Antituberculosis Drugs In Healthy Sprague-Dawley Albino Rats

ABSTRACT

The commonly used antituberculosis (anti-TB) drugs, pyrazinamide (PZA), isoniazid (INH), ethambutol (EMB), and rifampicin (RMP) were administered to albino rats for the purpose of investigating the toxic consequences of combination therapies on the hematological and hepatic systems. The drugs were evaluated by simulating the normal clinical dosage. A 24-week oral administration studies of standard therapy with anti-TB drugs in albino rats without disease were carried out. The doses employed were: INH, 5 mg kg' day*'; RMP, 10 mg kg-' day!: EMB, 20 mg kg-' day'' and PZA, 25 mg kg-' day". Groups of healthy rats weighing 150-200g were given daily doses of combination anti-TB regimen to simulate the full course of administration in humans. PZA and EMB were withdrawn from the regimen after 8 weeks and the remaining rats were maintained on only INH and RMP until the 24th week. After 1, 2, 4, 8, 12, 18 and 24 weeks of daily exposure, groups of rats were sacrificed and relevant parameters were determined at various times in the course of the drug administration in different animal groups. The regimen showed evidence of protection against hemolysis both in-vitro and in-vivo although there are evidences of distorted erythrocyte membranes which appeared echinocytic and star-shaped configuration and an enhanced antihemolytic effect in hypotonic saline solution.

The hematologic consequences of exposure included severe anemia and leucopenia, which were attributed to: i) depression of bone marrow function and sequestration by the reticuloendothelia system; spherocytic, microcytic and echinicytic membryopathy, the degree of which is correlated with the incidence of anemia possibly due to loss of ATP; and ii) protection against hemolysis; with RMP showing the greatest anti-hemolytic activity. The intensity of these effects was greater during the first 8 weeks when the regimen contained four drugs and was ameliorated when PZA and EMB were withdrawn from the regimen.