Search PubMed⌕ Search

Biomedical subjects

M Gex-Fabry

Publications and source records attributed to M Gex-Fabry.

At least 19 recordsLinked to original sources
PubMed2001

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.

Drug-drug interactions can be associated with patient morbidity due to either increased toxicity or a potentially ineffective concentration. Because interactions cannot always be anticipated during drug development and actual patients receiving a drug for therapeutic use often differ from those included in clinical trials, postmarketing surveillance is essential. Therapeutic drug monitoring (TDM) databases offer a unique opportunity in this respect. Prerequisites for TDM databases to provide valid information in a pharmacoepidemiological perspective include the following: precise description of exposure to the potentially interacting drugs; measurement of parent compound and active metabolites through accurate and precise analytical techniques; documentation of relevant patient characteristics that may act as confounding factors (e.g. gender, age, smoking habits); repeated assessments over time if possible; and sound pharmacokinetic framework for data selection, analysis and interpretation. The contribution of TDM to the documentation of drug-drug interactions takes advantage of different possible study designs, discussed on the basis of recently published studies. The single case report plays an important role as an alert signal. It is illustrated for a patient on long-term treatment, who displayed an unexpectedly high clozapine concentration after the introduction of ciprofloxacin comedication. The prospective on and off comedication panel study shows advantages in terms of carefully selected inclusion criteria and control of treatment modalities. A study of the thioridazine-fluvoxamine interaction is presented, with patients followed on thioridazine monotherapy, after introduction of fluvoxamine and after its discontinuation. The main advantage of the retrospective large-scale TDM database screen is representativeness of patients actually treated, whereas drawbacks are related to quality of data and suitability for valid interpretation. Such an approach is illustrated by a review of data collected over 10 years of routine TDM that allowed documenting induction of nortriptyline metabolism by carbamazepine and inhibition by several phenothiazines. Finally, population pharmacokinetics is well suited to observational data collected for TDM purpose, provided quality is ascertained. Focus is placed on interindividual variability and relationship between pharmacokinetic parameters and patient characteristics, including comedication. The population approach is discussed with respect to a study that documented a 32% increase of haloperidol clearance associated with anticonvulsant comedication, in addition to effects of age and bodyweight. Among factors to consider for improved effectiveness in the use of TDM databases for postmarketing surveillance of drug-drug interactions, integration of efficacy and safety data in future studies and communication of expert recommendations to prescribing physicians are essential.

Databases, Factual↗
PubMed2000

Modelling during drug development.

With the advancement of both biological and computer sciences, new drug development faces the challenge to integrate a huge amount of knowledge accumulated from the very early quantitative structure-activity relationship investigations of the candidate molecule to the large scale clinical trials in patients. Whereas pharmacokinetics and pharmacodynamics are fields in which modelling has long demonstrated its value, its potential in many other areas of drug development has recently been the object of intensive scientific activity. The present review places emphasis on these newer applications; it includes the opinion of many experts in often highly specialised areas such as in vitro to in vivo extrapolation, toxicokinetics, non-continuous response models, population approaches and computer assisted simulation of clinical trials. It is most probable that in the near future many of these areas of research will be the objects of intensive and interesting developments. This will undoubtedly lead to improve developmental strategies for new drugs as well as more individualised pharmacological strategies for patients.

Animals↗
PubMed2000

Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Adult↗
PubMed1999

Development of validated stereoselective methods for methadone determination in clinical samples.

A stereoselective analysis of methadone (Mtd) in whole blood and serum was developed using liquid chromatography on a protein based chiral stationary phase. Liquid-liquid extraction (LLE) and solid phase extraction methods were applied before chromatographic analysis. The extraction procedure, as well as the choice of the biological matrix, showed significant differences in the extraction yield and in the precision of the assays. Serum was selected for this assay and LLE was chosen as the preparation step because of its simplicity and rapidity. The total procedure was validated and applied to clinical samples. Samples taken from 45 heroin-addicted patients were analyzed. A correlation was found between the dose administered and Mtd concentration (total and R-form), but interindividual variability of the total normalized Mtd was seen (concentration varied from 90 to 530 ng/ml). Furthermore, two populations were apparently observed with a mean Mtd concentration of 200 and 475 ng/ml, respectively. Stereoselective analyses showed that more than 50% of the patients presented a nonracemic ratio, and particularly about 25% showed a preferential metabolism of the active R-Mtd enantiomer. Therefore, the stereoselective determination of Mtd is necessary to improve the quality of the treatment of heroin addiction.

Chromatography, Liquid↗
PubMed1999

Clomipramine concentration as a predictor of delayed response: a naturalistic study.

OBJECTIVES: The aim of the present study was to characterise onset of response to clomipramine treatment in a naturalistic setting and to investigate the relationship between concentration and delayed response, postulated to reflect drug-specific response to antidepressant therapy. METHODS: Ninety-eight depressed patients were prescribed clomipramine in an open flexible manner and followed for depressive symptoms (Montgomery-Asberg depression scale) over a maximum 12 weeks follow-up period. All patients had at least one concentration measurement for therapeutic drug monitoring purpose. RESULTS: Firstly, survival analysis revealed a probability of 15.4% for patients not to show 50% improvement over baseline by week 12, and thus to be considered as non-responders. Median time to onset of response was 31 days for responders, indicating a relatively high probability of delayed response under routine treatment. Secondly, pattern analysis indicated a significant association between early and abrupt response on the one hand and delayed and gradual response on the other. A tendency towards an association between delayed and persistent response was also observed. Finally, receiver operating characteristics analysis allowed identification of a highly significant lower threshold of 230 ng x ml(-1) for the sum of clomipramine and desmethyl-clomipramine, as measured at week 3, with respect to response from week 3 onward. Predictive values were 68.8% and 81.0% for concentrations above and below this threshold to predict delayed response and non-response, respectively. Thresholds were 55 ng x ml(-1) for parent compound and 180 ng x ml(-1) for metabolite. CONCLUSION: This approach supports the hypothesis that delayed response may be concentration dependent and thus may reflect true drug effect. As a consequence, monitoring clomipramine concentration about 3 weeks after initiation of therapy may valuably contribute to help clinicians decide about the adequacy of ongoing therapy.

Adult↗
PubMed1999

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors.

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.

Adult↗
PubMed1998

Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections.

In the case of external ophthalmic infections, repeated instillations of antibiotics are required to reach therapeutic level, above the minimal inhibitory concentration (MIC). An additional administration of a corticosteroid is often needed, in order to limit the precorneal damages caused by the infection. However, repeated administration of a corticosteroid can increase intraocular pressure and thus lead to glaucoma. To overcome the disadvantages of separated and repeated instillations of two products and to avoid the side effects of dexamethasone, a soluble insert containing gentamicin sulfate and dexamethasone phosphate was developed. The new system ensures the concomitant release of the two drugs during the first 10 h of treatment, followed by an adequate concentration of gentamicin sulfate, above the MIC of 4.0 microgram ml-1, during 50 h, due to a combination of gentamicin sulfate with cellulose acetate phthalate, which reduces the solubility of gentamicin.

Animals↗
PubMed1998

Comparative pharmacokinetic study of a floating multiple-unit capsule, a high-density multiple-unit capsule and an immediate-release tablet containing 25 mg atenolol.

The purpose of this study was to evaluate the possible advantages of floating and high-density dosage forms and their influence on pharmacokinetic parameters. Atenolol was chosen as a model drug because of its poor absorption in the lower gastrointestinal tract. Three formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The two multiple-unit dosage forms were composed of compressed minitablets and had sustained release properties. The bioavailability of the two gastroretentive preparations with sustained release characteristics was significantly decreased when compared to the immediate-release tablet. The floating minitablets seemed to be retained longer in the stomach than the high-density dosage form. The first atenolol concentration detectable in the plasma and the time to peak Tmax were delayed for the floating dosage form. For the parameters Cmax and AUC 0-infinity, the lower limit of the 90% confidence interval was outside the bioequivalence range (0.80-1.25). This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations. Atenolol absorption was delayed and the maximum plasma concentration was diminished.

Adrenergic beta-Antagonists↗
PubMed1997

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions: evaluation of a paired approach for psychotropic medication.

The present study investigated the potential of therapeutic drug monitoring data to document pharmacokinetic drug interactions with psychotropic medication, both in terms of methodology and applicability. It focused on 105 patients exposed to one of five agents known for their capacity to induce (phenytoine, phenobarbital, and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. These patients were matched by gender, age, and monitored psychotropic medication to 105 patients randomly selected from a pool of subjects nonexposed to target comedication. Such a paired approach was shown to be effective in reducing variability for a majority of substances. Power analysis suggested that eight to 10 pairs of exposed and nonexposed patients would effectively allow the detection of twofold effects of interacting substances. In keeping with the literature, analysis of the ratios of dose-normalized exposed to nonexposed concentrations indicated that phenothiazine comedication led to significantly higher concentrations of desmethylated metabolites but not parent compounds, when clomipramine, imipramine, or amitriptyline were administered. A similar, as yet undocumented interaction was observed for the tetracyclic antidepressant mianserine. In contrast, the present study revealed that maprotiline concentrations were increased, but its metabolite was largely unaffected by phenothiazine comedication. Increased concentrations were also observed for moclobemide, but not citalopram or its metabolite. In addition to its long recognized capacity to decrease haloperidol concentrations, carbamazepine was shown to induce the metabolism of clopenthixol and possibly flupenthixol. The consistency of such a picture substantiates the need to consider therapeutic drug monitoring databases as cost-effective and reliable tools for postmarketing surveillance.

Adolescent↗
PubMed1996

Basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol.

The objective of the present study was to determine the basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol in pigmented rabbits. The gamma scintigraphic technique was used to monitor the changes in precorneal solution retention following instillation. Changes in timolol concentration in the plasma over 120 min and in various anterior segment eye tissues at 30 min following the topical instillation of 25 microliters of 0.65% timolol maleate solutions at various dosing times were monitored using reversed phase HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated that precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorption at 6 a.m. but not at other dosing times, in spite of the lowest corneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conjunctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal changes in ocular as well as systemic timolol absorption in rabbits. In addition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.

Absorption↗
PubMed1995

Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert.

PURPOSE: Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. METHODS: In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff). RESULTS: In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) [micrograms ml-1 h]) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) [micrograms ml-1 h]); the teff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) [micrograms ml-1 h] and 70-76 [h], respectively. The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. CONCLUSIONS: This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.

Animals↗
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↗