Abstract
Treatment of refractory schizophrenia with the atypical antipsychotic drug clozapine is associated with life-threatening agranulocytosis, characterised by a drop in neutrophil count. Theoretically, toxicity may be accounted for by direct action of parent drug or one of its stable metabolites on bone marrow stroma given importance of these cells to neutrophil maturation. Effects of clozapine, N-desmethylclozapine and clozapine N-oxide on stromal cell viability were therefore assessed using human primary long-term bone marrow culture and stromal cell lines, HAS303 and LP101, to define cell-specificity of response. Clozapine, N-desmethylclozapine and clozapine N-oxide had no significant effect on bone marrow stromal, HAS303 and LP101 viability over a wide drug concentration range (10-20000 ng mLˉ1) compared with cells in absence of drug. Hence it is unlikely that parent drug or its stable metabolites are directly toxic to stroma under clinical conditions. Reduced capability of stroma to support myelopoiesis, however, cannot be excluded.
Highlights
Clinical studies have defined the effectiveness of the antipsychotic drug clozapine in the treatment of refactory schizophrenia[1]
Cells cultured in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% fetal calf serum (FCS) (Gibco BRL), penicillin-streptomycin-amphotericin antibiotic/antimycotic mixture (Gibco BRL), 1 μM hydrocortisone and 50 μM mercaptoethanol (SigmaAldrich) termed complete IMDM were maintained in a 37oC, 5% CO2 humidified incubator, for up to 17 days
Oxide had no significant effect on bone marrow primary stromal, HAS303 and LP101 cell viability over the drug concentration range 10 to 20000 ng mL 1 compared with cells in the absence of drug (p > 0.05, in all cases) (Fig. 1 A-C, Fig. 2 A-C and Fig. 3 A-C, respectively)
Summary
Clinical studies have defined the effectiveness of the antipsychotic drug clozapine in the treatment of refactory schizophrenia[1]. The mechanism by which clozapine-induced agranulocytosis occurs has been posited to involve direct drug toxicity to hematopoietic progenitor cells of the bone marrow[3].
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