IN-VITRO EFFECT OF CLOZAPINE ON HEMATOPOIETIC PROGENITOR CELLS

Background and Objective. Clozapine is a diabenzodiazepine derivative characterized by a high therapeutic index in schizophrenic patients re sistant to traditional neuroleptic drugs, because of the rarity of any extrapyramidal side effects, and its particular hematologic toxicity. According to the international literature, clozapine-induced neutrope nia occurs mainly during the first 4-6 months of treatment, and its in cidence decreases considerably over time. This neutropenic effect is n ot dose-dependent and normally clears up after drug discontinuation, a lthough it may evolve into agranulocytosis. The aim of this study is t o evaluate the in vitro toxic effect of clozapine and N-desmethylcloza pine on both committed and immature human hematopoietic progenitor cel ls. Design and Methods. Cytotoxic assays were performed in vitro on no rmal human bone marrow samples treated with clozapine or with its meta bolite N-desmethylclozapine. The clonogenic potential after treatment with both compounds was assessed on low density mononuclear cells (LD- MNC), purified CD34(+) cells, cytokine driven liquid cultures and long term culture initiating cell (LTC-IC). Results. Clozapine and N-desme thylclozapine had a dose-dependent inhibitory effect on in vitro growt h of CFU-GM and BN-E from normal bone marrow. The two drugs had toxic effects on purified CD34(+) progenitor cells but no significant effect on LTI-IC. Interpretations and Conclusions. Our data indicate a cytot oxic effect, which is more pronounced with N-desmethylclozapine and at high doses, on the committed progenitor cell compartment but not on p rimitive hematopoietic cells. Furthermore, our data show that clozapin e and N-desmethylclozapine have a direct effect on treated cells and d o not induce apoptotic death. (C) 1998, Ferrata Storti Foundation.