Three-month effects of MDL 19,660 on the canine platelet and erythrocyte.
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-t hione) for 3 months to determine the long-term effects on hemopoietic cells. Compared to a control platelet range of 353,000-452,000/microliters, a thrombocytopenia reached lowest mean levels of 135,000/microliters in the 15 mg/kg/day dogs after 2 weeks and 81,000/microliters 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/microliters and 203,000/microliters 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. Histologically, 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 reticulocytes 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.
Yarrington
J T
JT
Toxicology Department, Marion Merrell Dow Inc., Cincinnati, Ohio 45215.
Wallace
C D
CD
Loudy
D E
DE
Gibson
J P
JP
D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000648:ultrastructure; D004285:Dogs; D004906:Erythrocyte Count / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009336:Necrosis; D010976:Platelet Count / Q000187:drug effects; D013154:Spleen / Q000473:pathology; D013997:Time Factors; D014230:Triazoles / Q000097:blood / Q000494:pharmacology*
D000928:Antidepressive Agents; D006454:Hemoglobins; D014230:Triazoles; C065325:MDL 19660