Search results for "clozapine"

Effects of clozapine metabolites and chronic clozapine treatment on rat brain GABAA receptors

1996

Abstract Similarly to clozapine, a clozapine metabolite, N -desmethylclozapine, but not clozapine N -oxide, antagonized brain γ-aminobutyric acid type A (GABA A ) receptors at high micromolar concentrations. However, daily subcutaneous injections of clozapine (10 and 25 mg/kg) and haloperidol (0.5 mg/kg) for 14 days failed to alter the modulation by GABA of rat cerebrocortical and cerebellar benzodiazepine ([ 3 H]flunitrazepam) or convulsant ( t -[ 35 S]bicyclophosphorothionate) binding sites of the GABA A receptor. The results thus suggest that the GABA A receptor antagonism exerted by chronic in vivo clozapine treatment is weak as compared to this treatment's actions on certain monoamine …

Synthesis and Oxidant Properties of Phase 1 Benzepine N-Oxides of Common Antipsychotic Drugs

2013

There is increasing evidence that cell constituents are oxidized by widely used antipsychotic drugs but until now the underlying chemistry has remained unclear. It is well known that such drugs readily undergo N-oxidation as a first key metabolic step. To gain insight into the problem, the tertiary phase 1 N-oxides of clozapine, olanzapine, quetiapine, and zotepine were synthesized, together with the N,S-dioxides of quetiapine and zotepine. These N-oxides were then subjected to well-established chemical transformations to test their oxidant properties in group VIII transition-metal­-catalyzed reactions. In the osmium tetroxide catalyzed dihydroxylation of styrene or cinnamyl alcohol and in …

A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adul…

2019

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies, but the range in …

Automated determination of clozapine and major metabolites in serum and urine.

1997

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The co…

Development of a nomogram for the estimation of long-term adherence to clozapine therapy using neutrophil fluorescence

2018

Aims: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic-pharmacodynamic model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. Methods: Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3-…

Novel Drug Delivery System for Treatment-Resistant Schizophrenia

2021

How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

2003

This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC- and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 muM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, P1 x 10(-7) cm/s) in the resorptive direct…

Determination of Drug Concentrations in Serum and Dopamine Receptor Occupancy in Brain for Optimal Antipsychotic Drug Therapy

2009

Evidence has been given that antipsychotic effects of dopamine receptor antagonists are associated with 60 and 80% striatal dopamine D2 and D3 receptor occupancy. Receptor occupancy correlates well with concentrations of the antipsychotic drugs in serum or plasma, much better than the dose. The latter is consistent with weak correlations between antipsychotic dose and serum concentrations and explained by the high interindividual variabilities in drug metabolism. Using positron emission tomography (PET) for in vivo determination of dopamine receptor occupancy in conjunction with drug concentration measurements “therapeutic windows” could be calculated for the atypical antipsychotic drugs am…

Chronic oral haloperidol and clozapine in rats: A behavioral evaluation.

1999

The present study evaluated chronic oral treatment of rats with haloperidol or clozapine. Drugs were given in the drinking water for a 23-day period . Rat behavior was analyzed once a week in an open field. Rats ingested either 1.7 mg/kg haloperidol or 40 mg/kg clozapine daily. Blood serum analysis revealed concentrations of 6 ng/ml for haloperidol and 22 ng/ml for clozapine at the end of the treatment. Haloperidol decreased overall activity from the onset of treatment. Clozapine showed similar effects only on the last test day. Control animals showed a slight habituation in exploration-related parameters. In conclusion, these results indicate that oral drug administration through the drink…

Chronical haloperidol and clozapine treatment in rats: Differential RNA display analysis, behavioral studies and serum level determination

1998

1. Adult, female rats were treated orally for 23 days with 1.6 mg/kg haloperidol or 36 mg/kg clozapine per day, to study chronic effects of the two neuroleptics. 2. At five time points during the neuroleptic treatment, animal behavior was recorded in an open field and locomotive activity was analysed. At the end of the experiment, rats were decapitated, blood samples were collected and serum concentrations of haloperidol and clozapine were determined by a radioreceptor or HPLC assay, respectively. RNA was isolated from each brain, without cerebellum, and subjected to differential RNA display. 3. Mean serum concentrations were 8 ng/ml for haloperidol and 21 ng/ml for clozapine. Analysis of o…