Atypical antipsychotic-induced neutropenia in dogs

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects throu gh selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtyp es. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study i n dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, po sitive Coombs' tests, and hypergammaglobulinemia occurred in individual fem ales dosed with 30 mg/kg/day of DMP 406. Related but less severe changes we re also observed in males. Sera or purified immunoglobulins from affected a nd control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406, Neither size nor number of erythroid or myeloid CFUs differed between cultures containing co ntrol or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, sugg esting DMP 406-associated marrow stromal cell-modifying, serum activities t o be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 mu g/mL. Tak en together, DMP 406-induced granulocytopenia and bone marrow dyscrasia app ear likely to result from both immune-mediated and direct drug-induced myel otoxicity. (C) 1999 Academic Press.