© 1992 Oxford University Press
research-article |
Three-Month Effects of MDL 19,660 on the Canine Platelet and Erythrocyte
Toxicology Department, Marion Merrell Dow Inc. 2110 East Galbraith Road, Cincinnati, Ohio 45215
Received February 19, 1991; accepted July 25, 1991
Nine male and nine female Beagle dogs were divided into three groups and administered orally 0, 15, or 30 mg/kg/day of the antidepressant compound MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3H-1,2,4-triazole-3-thione) for 3 months to determine the long-term effects on hemopoietic cells. Compared to a control platelet range of 353,000–452,000/µl, a thrombocytopenia reached lowest mean levels of 135,000/µl in the 15 mg/kg/day dogs after 2 weeks and 81,000/µl, in the 30 mg/kg/day dogs after 1 week. Subsequently, platelet numbers progressively increased and by the end of the study averaged 222,000/µl and 203,000/µl in dogs administered 15 and 30 mg/kg/day. Ultrastructural study of the platelet increase in the 30 mg/kg/day dogs revealed more smaller discoid platelets but no change in percentage platelets with vacuolar degeneration. His tologically, megakaryocyte hyperplasia was present in the sternal marrows and spleens of treated dogs. These observations suggest that increased thrombopoiesis rather than reduced destruction was involved in this partial recovery of platelet numbers during continuous treatment. Concurrently, cyclic formation of retic ulocytes and Heinz bodies occurred in dogs given 30 mg/kg/day of MDL 19,660. These dogs had slightly lower erythrocyte counts, hemoglobin levels, and hematocrits in association with hemosiderosis (spleen, liver), extramedullary hematopoiesis (spleen), and bone marrow hypercellularity. These findings indicate that both destructive and regenerative processes followed MDL 19,660-induced Heinz body formation.