clozapine and catechol

Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine-treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Catechols; Clozapine; Dihydroxyphenylalanine; Female; Humans; Male; Metabolic Clearance Rate; Monoamine Oxidase; Norepinephrine; Schizophrenia; Time Factors; Tritium

Selectivity presents a crucial challenge in direct electrochemical sensing. One example is schizophrenia treatment monitoring of the redox-active antipsychotic clozapine. To accurately assess efficacy, differentiation from its metabolite norclozapine-similar in structure and redox potential-is critical. Here, the authors leverage biomaterials integration to study, and effect changes in, diffusion and electron transfer kinetics of these compounds. Specifically, the authors employ a catechol-modified chitosan film, which the authors have previously presented as the first electrochemical detection mechanism capable of quantifying clozapine directly in clinical serum. A key finding in our present work is differing dynamics between clozapine and norclozapine once the authors interface the electrodes with chitosan-based biomaterial films. These additional dimensions of redox information can thus enable selective sensing of largely analogous small molecules.

Topics: Catechols; Chitosan; Clozapine; Electrochemical Techniques; Humans; Membranes, Artificial

This work presents a thorough electrochemical and reliability analysis of a sensing scheme for the antipsychotic clozapine. We have previously demonstrated a novel detection approach for this redox-active drug, highly effective in schizophrenia treatment, based on a catechol-modified chitosan film. The biomaterial film enables amplification of the oxidative current generated by clozapine through redox cycling. Here, we study critical electrochemical and material aspects of the redox cycling system to overcome barriers in point-of-care monitoring in complex biological samples. Specifically, we explore the electrochemical parameter space, showing that enhanced sensing performance depends on the presence of a reducing mediator as well as the electrochemical technique applied. These factors account for up to 1.75-fold and 2.47-fold signal enhancement, respectively. Looking at potential interferents, we illustrate that the redox cycling system allows for differentiation between selected redox-active species, clozapine's structurally largely analogous metabolite norclozapine as well as the representative catecholamine dopamine. Furthermore, we investigate material stability and fouling with reuse as well as storage. We find no evidence of film fouling due to clozapine; slow overall biomaterial degradation with successive use accounts for a 2.2% absolute signal loss and can be controlled for. Storage of the redox cycling system appears feasible over weeks when kept in solution with only 0.26%/day clozapine signal degradation, while ambient air exposure of three or more days reduces performance by 58%. This study not only advances our understanding of the catechol-modified chitosan system, but also further establishes the viability of applying it toward sensing clozapine in a clinical setting. Such point-of-care monitoring will allow for broader use of clozapine by increasing convenience to patients as well as medical professionals, thus improving the lives of people affected by schizophrenia through personalized medicine.

Topics: Catechols; Chitosan; Clozapine; Electrochemistry