Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp).

The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes.

The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan.

Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine.

Nocturnal hormone profiles were measured in patients with schizophrenia with predominantly negative symptoms both under drug-free baseline conditions and after subchronic administration of the atypical antipsychotic olanzapine, with the aim of characterizing its pharmacological properties on the neuroendocrine level. The following hormones were studied in the sleep laboratory under polysomnographic control: adrenocorticotrophic hormone, cortisol, growth hormone (GH), prolactin, testosterone, and melatonin. Blood samples were taken at regular time intervals over the night, and serum concentrations of the hormones were determined.

The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.

Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients. The interdisciplinary TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM. Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended.

Region specific distribution of levomepromazine in the human brain.

Objective: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time.

Methods: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus).

Paroxetine serum concentrations in depressed patients and response to treatment.

Introduction: There is no established relationship between the serum concentration of selective serotonin reuptake inhibitors (SSRIs) and clinical response in depressed patients.

Methods: We analyzed paroxetine concentrations in serum of 46 depressed patients during treatment with a fixed dosage of 40 mg paroxetine.

Results: After 5 weeks 29 patients responded to treatment, while 17 did not.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

Objective: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting.

Methods: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly.

Automated determination of ziprasidone by HPLC with column switching and spectrophotometric detection.

An isocratic high-performance liquid chromatography (HPLC) method with column switching and ultraviolet (UV) detection is described for quantitative analysis of the new antipsychotic drug ziprasidone. After centrifugation of serum or plasma samples and addition of fluperlapine as internal standard, the samples were injected into the HPLC system. On-line sample clean-up was conducted on a column (10 x 4.

Tyrosine hydroxylase Val-81-Met polymorphism associated with early-onset alcoholism.

The present study examined the association of the Tyrosine hydroxylase Val-81-Met polymorphism with alcohol dependence. One hundred and fifty-nine patients in a psychiatric unit with alcohol dependence were genotyped as well as 92 healthy volunteers. The Val allele was more frequent in patients with alcohol dependence (69.

High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia.

The 'atypicality' of the antipsychotic drug, amisulpride, has been attributed to preferential extrastriatal binding. Previous investigations of striatal D2 receptor occupancy by amisulpride revealed conflicting results. The aim of this PET study was to measure the striatal occupancy by amisulpride and to correlate it with the corresponding drug plasma concentrations.

The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics.

Population pharmacokinetic analysis of mirtazapine.

Objective: Mirtazapine belongs to the new generation of antidepressants that is commonly used in clinical routine. Therefore, we feel it mandatory to control compliance in the context of non-response, adverse events or other clinical situations by means of plasma concentration measurements. While controlled clinical studies have evaluated the effect of individual covariates on the pharmacokinetics of mirtazapine, our analysis aims to identify covariates within a naturalistic clinical setting.

Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates.

The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levomepromazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport.

Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline.

TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents.

Therapeutic monitoring of new antipsychotic drugs.

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate.

Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.

Objective: This evaluation focuses on polymorphisms of the cytochrome-P450 (CYP) isoenzymes 2C9, 2C19 and 2D6 and their association with plasma concentrations within a typical clinical setting. Side effects and treatment response were analysed in an exploratory approach in poor and ultra-rapid metabolisers.

Patients And Methods: We analysed 136 Caucasian depressed inpatients treated with amitriptyline, citalopram, clomipramine, doxepin, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine, who underwent weekly plasma concentration measurements, assessment of the severity of illness and side effects during their stay in the hospital.

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells.

Reduction of clozapine-induced hypersalivation by pirenzepine is safe.

Introduction: Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded.

Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum.

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum.

Characterization of Escherichia coli O157:H7 from downer and healthy dairy cattle in the upper Midwest region of the United States.

While cattle in general have been identified as a reservoir of Escherichia coli O157:H7, there are limited data regarding the prevalence and clonality of this pathogen in downer dairy cattle and the potential impact to human health that may occur following consumption of meat derived from downer dairy cattle. In the present study, conducted at two slaughter facilities in Wisconsin between May and October of 2001, we established a higher prevalence of E. coli O157:H7 in fecal and/or tissue samples obtained aseptically from intact colons of downer dairy cattle (10 of 203, 4.