ABSTRACT
OBJECTIVE:: To illustrate the complexities of clozapine metabolism with the use of therapeutic drug monitoring. METHODS:: We describe a case of clozapine toxicity in a patient with schizophrenia treated with the combination of clozapine, valproate and haloperidol. RESULTS:: A 24-year-old CYP2D6 poor metaboliser developed clozapine toxicity corresponding to the additive effects of haloperidol, and increasing clozapine and valproate doses. Saturation of metabolism, evidenced by a high clozapine/norclozapine ratio, was present at this time. CONCLUSIONS:: Clozapine metabolism is complex and influenced by multiple factors, including interactions with hepatic P450 enzyme inducers/inhibitors, genetic polymorphisms and the potential for saturation of the N-demethylation metabolic pathway.
Subject(s)
Antipsychotic Agents/metabolism , Clozapine/metabolism , Clozapine/toxicity , Cytochrome P-450 CYP2D6/metabolism , Haloperidol/metabolism , Schizophrenia/drug therapy , Valproic Acid/metabolism , Adult , Drug Synergism , Humans , Male , Young AdultABSTRACT
Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2ß). Only DCs matured under CThi conditions secreted IL-1ß, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-ß-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-ß-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.
