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M Gex-Fabry

Publications and source records attributed to M Gex-Fabry.

At least 19 recordsLinked to original sources
PubMed1995

Potential of concentration monitoring data for a short half-life drug: analysis of pharmacokinetic variability for moclobemide.

The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21-96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was approximately 300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.

Adult↗
PubMed1994

Clomipramine therapy in the geriatric hospital: experience with therapeutic drug monitoring.

Sixty-nine patients, aged 63-98 years and admitted at the Geneva Geriatric Hospital, were included in the present retrospective study. They received clomipramine orally, 50 or 75 mg/day. Blood concentrations of clomipramine were measured as part of a routine drug monitoring program. Comparison with a reference population of patients aged < or = 65 years indicated that elderly patients with concomitant somatic diseases reach higher dose-normalized concentrations of clomipramine and increased parent drug to demethylated metabolite ratios, as a consequence of impaired demethylation (approximately 50%) and hydroxylation (approximately 25%). Sixty-five percent of patients showed clinical improvement, with a maximum rate of satisfactory response observed in major depression. Severe side effects, such as symptomatic hypotension or confusion, were seen in 20% of patients. Because of 10- and 15-fold interindividual variations in the concentrations of clomipramine and its metabolite, respectively, therapeutic drug monitoring can provide valuable assistance to clinical judgment in individual dose adjustment for patients whose old age, associated somatic diseases, and comedication necessitate additional precautions.

Adult↗
PubMed1993

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↗
PubMed1993

[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↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

[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↗
PubMed1988

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↗
PubMed1986

[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↗