Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: A potential in vitro system for the study of agranulocytosis

How we evaluate and treat neutropenia in adults

“…37 In the case of clozapine, agranulocytosis appears to result from the toxic effect of a drug metabolite that may also have an impact on the marrow stroma; this may cause a somewhat more prolonged neutropenia than is usually seen in drug-induced agranulocytosis. 38 Other drugs commonly implicated in neutropenia include phenothiazines (eg, chlorpromazine), 39 semisynthetic penicillins (eg, ampicillin) and cephalosporins, 40 thionamides (methimazole, propylthiouracil), and nonsteroidal antiinflammatory drugs. 41 It is important to note that the true potential of each drug to cause neutropenia may not be accurately reflected by the incidence calculated from case reports, because these are not usually normalized to the prescription rate of the drugs.…”

Haematological toxicity of drugs used in psychiatry

“…It appears likely that activation of clozapine, norclozapine and/or a further metabolite, clozapine N-oxide, to electrophilic nitrenium ions is the initial step in the events leading to neutropenia/agranulocytosis (Pereira and Dean, 2006;Pirmohamed and Park, 1997). Oxidation of clozapine by neutrophilgenerated hypochlorous acid (HOCl) via the NADPH oxidase/myeloperoxidase system has been demonstrated (Dettling et al, 2000;Gardner et al, 2005;Hsuanyu and Dunford, 1999;Mosyagin et al, 2004).…”

“…However, the ions may also either bind to neutrophils to cause cell death, or could cause oxidative stress-induced neutrophil apoptosis (Husain et al, 2006). It is possible that the target in agranulocytosis could be stromal cells, neutrophil precursors in the bone marrow (Pereira and Dean, 2006), in addition to mature peripheral neutrophils, whilst the main target in neutropenia may only be the peripheral blood neutrophils (Duggal and Singh, 2005).…”

Clozapine treatment of patients with refractory schizophrenia, concurrent dengue infection and hematological abnormalities: three case reports

“…It is postulated that the activation of metabolites of CLZ to electrophilic nitrenium ions may cause idiosyncratic neutropenia/agranulocytosis events through direct binding of these ions to neutrophils, causing cell death by oxidative stress-induced apoptosis, and finally by directly targeting the bone marrow stroma cells [Pirmohamed and Park, 1997;Husain et al 2006;Pereira and Dean, 2006;Flanagan and Dunk, 2008]. However, the precise mechanisms of CLZ-induced leucopenia/ agranulocytosis are still unclear [Guest et al 1998;Coleman, 2001;Rajagopal, 2005].…”