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After 2 days of dosing, platelet counts progressively declined in dogs treated orally with 30 mg/kg/day of the antidepressant compound MDL 19,660 for 8 days. Accompanying the decrease in platelet counts was an increase in both large and vacuolated degenerating platelets. Upon cessation of dosing, the platelet counts returned to levels equal to or exceeding predosing levels within 4-7 days. Co-administration with aspirin, a known antiaggregating agent, had no protective effect on the drug-induced thrombocytopenia. In vitro testing of normal canine platelets in the presence of MDL 19,660 further revealed that spontaneous aggregation did not occur and that ADP-induced aggregation was inhibited. Drug-related platelet loss was also not prevented by the co-administration of prednisone, a steroid with immunosuppressive effects and inhibitory properties against reticuloendothelial cell phagocytosis of platelets. The results of the present investigation indicate that MDL 19,660 may produce in the dog a reversible thrombocytopenia in the form of vacuolar degeneration and subsequent destruction of the platelet by means other than aggregation or steroid-responsive mechanisms.

After 2 days of dosing, platelet counts progressively declined in dogs treated orally with 30 mg/kg/day of the antidepressant compound MDL 19,660 for 8 days. Accompanying the decrease in platelet counts was an increase in both large and vacuolated degenerating platelets. Upon cessation of dosing, the platelet counts returned to levels equal to or exceeding predosing levels within 4-7 days. Co-administration with aspirin, a known antiaggregating agent, had no protective effect on the drug-induced thrombocytopenia. In vitro testing of normal canine platelets in the presence ofMDL 19,660 further revealed that spontaneous aggregation did not occur and that ADP-induced aggregation was inhibited. Drug-related platelet loss was also not prevented by the co-administration of prednisone, a steroid with immunosuppressive effects and inhibitory properties against reticuloendothelial cell phagocytosis of platelets. The results of the present investigation indicate that MDL 19,660 may produce in the dog a reversible thrombocytopenia in the form of vacuolar degeneration and subsequent destruction of the platelet by means other than aggregation or steroid-responsive mechanisms.

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.