Atypical Antipsychotic-Induced Neutropenia in Dogs

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia...

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Bibliographic Details
Published in:	Toxicology and applied pharmacology Vol. 155; no. 3; pp. 227 - 236
Main Authors:	Lorenz, Meike, Evering, Winston E., Provencher, Anne, Blue, Julia T., Lewis, Hugh B., Hazelette, Jeff R., Rajagopalan, Parthasarathi, Meunier, Paul C., Car, Bruce D.
Format:	Journal Article
Language:	English
Published:	San Diego, CA Elsevier Inc 15-03-1999 Elsevier
Subjects:	Animals Antipsychotic Agents - toxicity Benzodiazepines - toxicity Biological and medical sciences Bone Marrow Cells - drug effects Cell Division - drug effects Culture Media, Conditioned Dogs Drug toxicity and drugs side effects treatment Female Hematopoietic Stem Cells Immunoglobulins - metabolism Male Medical sciences Neutropenia - blood Neutropenia - chemically induced Neutropenia - immunology Neutropenia - pathology Pharmacology. Drug treatments Spleen - drug effects Spleen - metabolism Spleen - pathology Stem Cells - drug effects Toxicity: blood Fissipedia Carnivora Leukopenia Neuroleptic Toxicity Oral administration Hemopathy Myelopathy Vertebrata Mammalia Animal Antipsychotic Dog Neutropenia
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Summary:	DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and 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 control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 μg/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0041-008X 1096-0333
DOI:	10.1006/taap.1998.8582