Analysis of 935 haloperidol concentration measurements obtained during routine drug monitoring of 134 patients.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
M Gex-Fabry
Publications and source records attributed to M Gex-Fabry.
Crisis intervention in depressed patients with and without DSM-III-R personality disorders.
We compared the relationships between response to a crisis intervention program and long-term outcome in 31 depressed outpatients with and without DSM-III-R personality disorders (PD). The presence of PD predicted a poorer 2-year outcome. PD subjects with better working alliance and increased insight at termination of crisis intervention had increased compliance with long-term psychiatric treatment (p < .005) and better 2-year outcome (p < .005). Increased compliance with long-term psychiatric treatment predicted better long-term outcome in PD patients (p < .005). None of these significant relationships was observed in the comparison group without PD, suggesting that establishing an effective treatment process may be especially important for outcome in PD patients.
Adolescent↗
[Continuity and discontinuity of psychopathology: a study of patients examined as children and as adults. II. Childhood antecedents of drug dependent adults].
The demographic stability of the Swiss Canton of Geneva provided us with the necessary conditions for a follow-up study of the entire childhood population who, having consulted the Child Psychiatry Services between 1963 and 1967, later consulted the adult public psychiatric services (720 cases). We looked for specific clusters of clinical signs which would enable us to differentiate, statistically speaking, the groups of children according to their adult diagnosis. We present here the results for the group of children who were diagnosed at adulthood as drug addicts (DSM III R). We found a specific cluster significantly differentiating these children from the other populations. It includes: a personality disorder (undifferentiated behaviour, and solitary and aggressive behaviour), environmental factors (monoparental, rejecting family) and a lack of mental deficiency.
Adolescent↗
Pharmacokinetics/pharmacodynamics during phase II and III studies: population kinetics and the kinetic screen.
Explore the source record for details and available documents.
Clinical Trials, Phase II as Topic↗
Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients.
The purpose of the present study was to investigate whether the metabolism of clomipramine is altered by chronic alcohol drinking. Eleven recently detoxified alcoholic patients were included (experimental group EG) and compared to a reference group of patients with no history of alcoholism (reference group RG, n = 102). Blood concentrations of clomipramine and its metabolites were measured as part of the routine drug monitoring program. Clearances were estimated from trough concentrations, according to a model developed previously. Results indicate strong inhibition of demethylation clearance in group EG, when compared to group RG (median values 9.9 and 24.2 L/h), with significant increase of the clomipramine to desmethylclomipramine ratio (median values 1.00 and 0.36). No difference was found for hydroxylation. In addition, high correlation is observed between hydroxylation and demethylation clearances in group EG (Spearman rs = 0.82), but not in reference group RG (rs = 0.29). Follow-up data indicate that impairment of demethylation capacity can persist for several weeks or months after withdrawal from alcohol. The interest of calculating clomipramine to desmethylclomipramine ratios during routine drug monitoring is emphasized, values of 1 or larger often being associated with liver disease and/or alcohol-related problems.
Adult↗
Clinical pharmacokinetics of clomipramine.
Clomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its pharmacokinetics have been studied essentially in healthy volunteers. By combining published information obtained during observational studies, it has been possible to derive a fairly precise picture of the behaviour of both parent compound and main metabolite (demethyl-clomipramine) in humans. Clomipramine can be compared with amitriptyline or imipramine so far as its physicochemical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract, but undergoes an important first-pass metabolism to demethyl-clomipramine which is pharmacologically active and participates in both therapeutic and unwanted effects. Protein binding is high, and the apparent volume of distribution is very large (i.e. greater than 1000L). After reaching the systemic circulation, clomipramine is further biotransformed into demethyl-clomipramine, and both active principles are hydroxylated to metabolites which are further conjugated before being excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination half-life of clomipramine is about 24h and that of demethyl-clomipramine, 96h. Accordingly, the time to reach steady-state for both active moieties is in general around 3 weeks. Various pathological or environmental factors influence the behaviour of clomipramine and demethyl-clomipramine. Patients genetically deficient in hydroxylation accumulate demethyl-clomipramine at high concentrations that can produce serious side effects and/or nonresponse. The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking induces demethylation, whereas long term alcohol intake appears to reduce this metabolic pathway. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower daily dose of clomipramine in most elderly patients. Studies relating blood concentrations of clomipramine and demethyl-clomipramine are conflicting. However, analysis of the available information indicates that blood concentrations lower than 150 micrograms/L are usually associated with nonresponse, whereas those above 450 micrograms/L seldom lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined with a high interindividual variability, makes this class of drugs ideal candidates for blood concentration monitoring.
Clomipramine↗
Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data.
A steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations. Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steady-state, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed. Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.
Adult↗
Physiological pharmacokinetic modelling.
1. The different types of models are described, with emphasis on the clearance-based one-compartment model, and on full physiological models which distinguish between a number of anatomical compartments interconnected through the body fluid system. 2. The clearance-based, one-compartment model incorporates physiological concepts, such as apparent volume of distribution, systemic availability, hepatic and renal clearance. As opposed to the classical rate constant-based model, it allows a study of the influence of plasma protein binding, hepatic intrinsic clearance and blood flow. The advantages of such an approach are illustrated in two typical situations, namely renal insufficiency and saturable protein binding. 3. In full physiological models each compartment represents a particular organ or tissue, further divided into vascular, interstitial and cellular spaces. Mass balance equations are written for each of these subcompartments. Shortcomings of such comprehensive models include difficulty in collecting tissue data, especially human, and sophisticated numerical techniques needed for parameter estimation. The main advantages are specific organ metabolism and transport, and the possibility of scaling up from animal to human. 4. The pharmacokinetic parameters important for new drug registration are also listed.
Biological Availability↗
Detection of populations at risk using drug monitoring data.
Explore the source record for details and available documents.
Adolescent↗
Identifying weak signals in the presence of noise: a new method of locating potential ligand contact residues in immunoglobulin-related molecules.
We develop and apply a new method for estimating the locations of hypervariable residues in immunoglobulin-related molecules. The method differs from the standard introduced by Wu and Kabat in two essential ways: (1) we take explicit account of the type of substitution at a given position, rather than just the total number of substitutions, and (2) we use an explicit statistical decision criterion for classifying a site into either the complementarity determining or framework category. Simulations indicate that the method is reliable with relatively little data, approximately 5% of the sites being misclassified when 10 sequences are aligned. The method is applied to immunoglobulin light chains and to class 1 and class 2 products of the major histocompatibility complex.
Filtration↗
Clinical and pharmacokinetic evaluation of zuclopenthixol acetate in Viscoleo.
The purpose of the present study was to evaluate zuclopenthixol acetate in Viscoleo, a new preparation to be administered once every 3 days, in the early treatment of acute psychotic episodes and acute deterioration of chronic psychosis. 21 cases were included in the study: patients received 1 to 3 injections. Clinical evaluation was made at 24, 48 and 72 hours after each injection, using the Clinical Global Impressions (CGI) and the Brief Psychiatric Rating Scale (BPRS). Results at end-point indicated a marked or moderate therapeutic effect in the 11 cases of acute psychosis. A statistically significant decrease was observed for the total BPRS score as well as for its subscales. Among 8 cases of exacerbation of chronic psychosis, 4 patients showed a moderate therapeutic effect, and minimal or no effect was found in the other 4 subjects. The total BPRS decreased significantly, but to a lesser extent than for acute psychosis. Two patients suffering from mania showed a moderate therapeutic effect according to CGI. 8 cases of acute psychosis and 5 cases of chronic psychosis did not suffer from any neurological side-effects. Plasma concentration measurements suggest that a dose of 50 mg per 3 days may be sufficient for early treatment of most acutely ill psychotic patients.
Adolescent↗
[Epidemiology of psychotropic drugs: possibilities and limits of studies on therapeutic monitoring].
Identification of patient subpopulations at risk of non-response or unwanted side effects when given usual doses of a psychotropic drug raises increasing interest among clinicians. Therapeutic Drug Monitoring offers a valuable source of data in this respect. The available information has the advantage of relating to the patient population truly concerned with the medication and of not interfering with therapeutic decisions of the medical staff. Some methodological problems related to the use of such data are nevertheless emphasized, including bias due to patients' selection according to indications for drug monitoring and dosage modifications following blood concentrations measurements. The feasibility of such an approach is discussed with respect to tricyclic antidepressants. Results indicate that concentrations depend on drug interactions, genetic factors as well as sociodemographic parameters, such as age or alcohol consumption.
Antidepressive Agents↗
Multivariate analysis of dietary patterns in 939 Swiss adults: sociodemographic parameters and alcohol consumption profiles.
A dietary survey of 939 Swiss adults, randomly selected from the population of Geneva and its surrounding communities, was performed according to the history method. A factor analysis, using average weekly intakes for 33 food variables, reveals three principal components of the diet: satiating capacity, healthfulness and culinary complexity. These characteristics, together with the energy content of the diet, were analysed for differences according to sex, age, relative weight index, birthplace, marital status and occupation. All of these sociodemographic variables influence some dimension of dietary habits. Alcohol consumption is positively associated with satiating, protein rich diets, but energy intake from foods does not significantly differ between various groups of abstainers and drinkers. Although the energy contribution of alcoholic beverages is globally additive, we suggest that cultural and societal norms may modulate the relationship of alcohol and diet.
Adult↗
[The contribution of alcohol to nutrition: addition or substitution according to cultural origins].
The relation of alcohol intake to diet is analyzed through multiple linear regression for a sample of 475 males living in Geneva. Control variables are age, relative weight index, marital status and employment status. Whereas alcohol is associated with higher dietary intake for people of mediterranean origin, it tends to replace food calories for natives of german speaking areas.
Age Factors↗
Regulation of interacting populations during endocytosis: models of growth factor-tumor promoter dynamics.
A model of growth factor-cell receptor interactions, including internalization, sorting, recycling, and degradation and their modulation by tumor promoters, is developed, analyzed, and tested. In keeping with data and concepts based on a large number of systems, the main assumption is that after receptor-ligand binding the complex associates with a second membrane protein, localized in coated pits, and that this event is a necessary condition for receptor-mediated endocytosis and subsequent intracellular processes. As a consequence of the model, ligands having distinct receptors interfere at the cell surface through competition between their receptor complexes for a limited pool of coated pit proteins. The utility of the model is illustrated by a detailed analysis of binding, endocytosis, and degradation of epidermal growth factor (EGF) and their modulation by phorbol esters. The analysis permits quantitative characterization of the dynamics of the endocytic processes and leads to the following conclusions. The Scatchard plot changes from linear to nonlinear as the ratio of the number of coated pit proteins to the number of receptors decreases. Competition between phorbol ester and EGF-bound receptors for coated pit proteins predicts, in agreement with observation, conversion of nonlinear EGF Scatchard plots to linear plots subsequent to reincubation with phorbol esters. The postulated competition suggests a local homology between the phorbol ester receptor and the EGF receptor. Homologous and heterologous downregulations observed in numerous systems are natural consequences of the model. Preincubation with the heterologous ligand increases the time lag between ligand binding and lysosomal degradation and alters intracellular sorting.
Animals↗
Receptor-mediated endocytosis: a model and its implications for experimental analysis.
We present a mathematical model for analyzing, simulating, and quantitating the dynamic and steady-state characteristics of receptor-mediated endocytosis. The basic processes considered by the model are ligand-receptor binding, diffusion of receptors and ligand-receptor complexes in the plane of the membrane toward and away from coated pits, binding of ligand-receptor complexes to coated pit proteins, endocytosis of coated pit contents, degradation of ligand, and recycling of undegraded receptors. The model accounts quantitatively for a wide variety of kinetic data and makes new predictions about steady-state characteristics. We show that for homogeneous receptors the slope of the Scatchard plot is not necessarily constant but can have a positive or negative derivative, depending on the concentration of coated pit proteins and their reactivity. This finding suggests that binding data, which show linear and concave curves, might be explainable be a simple coated pit-related mechanism. Similarly the relationship between the x-intercept and the number of receptors is also affected by kinetic parameters controlling endocytosis. We briefly discuss these results in terms of possible mechanisms for the action of tumor promoters, the large variations in receptor number and affinity in the literature, and methods for quantitative characterization of parameters.
Animals↗
Prediction of temperature profiles in tumors and surrounding normal tissues during magnetic induction heating.
Explore the source record for details and available documents.
Electromagnetic Fields↗
Stereoselective disposition of flupentixol: influence on steady-state plasma concentrations in schizophrenic patients.
Steady-state plasma concentrations of cis(Z)-flupentixol (active principle) and trans(E)-flupentixol (inactive) were measured in 41 patients at least on one occasion. Results indicate that concentrations of the trans-isomer are significatively higher. This demonstrates that the two isomers are not handled in the same way by the organism. This may be relevant if plasma level monitoring is performed using non-specific analytical methods.
Chromatography, High Pressure Liquid↗