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A Mallet

Publications and source records attributed to A Mallet.

At least 55 records · Page 3Linked to original sources
PubMed1994

Handling covariates in population pharmacokinetics.

Population models were developed to analyze processes, described by parametric models, from measurements obtained in a sample of individuals. In order to analyze the sources of interindividual variability, covariates may be incorporated in the population analysis. The exploratory analyses and the two-stage approaches which use standard non-linear regression techniques are simple tools to select meaningful covariates. The global population approaches may be divided into two classes within which the covariates are handled differently: the parametric and the non-parametric methods. The power as well as the limitations of each approach regarding handling of covariates are illustrated and compared using the same data set which concerns the pharmacokinetics of gentamicin in neonates. With parametric approaches a second-stage model between structural parameters and covariates has to be defined. In the non-parametric method the joint distribution of parameters and covariates is estimated without parametric assumptions; however, it is assumed that covariates are observed with some error and parameters involved in functional relationships are not estimated. The important results concerning gentamicin in neonates were found by the two methods.

Age Factors↗
PubMed1994

Nonparametric estimation of population characteristics of the kinetics of lithium from observational and experimental data: individualization of chronic dosing regimen using a new Bayesian approach.

A population analysis of the kinetics of lithium was performed from experimental and observational data in 113 subjects in order to propose a new approach for lithium dosage individualization. The kinetics of lithium is described by a two-compartment model. Age, body weight, height, and serum creatinine are included as covariates. Population analysis was performed by the nonparametric maximum likelihood method, which provides an estimate of the distribution of the five kinetic parameters and covariates. Mean lithium clearance was 1.50 L/h with a coefficient of variation (CV) of 38%, and was found to increase with body weight. Results were consistent with those of earlier studies and confirm a large interindividual variability. Data from a separate group of 35 patients were used to validate results: the estimated a priori and on covariate conditional distributions of the measured 24-h serum lithium concentration following a single dose were consistent with the corresponding measurements. A Bayesian approach for individualizing dosing schemes is proposed. This approach is based on minimization of a risk function expressing the deviation of the trough concentration at steady-state from the therapeutic range.

Adolescent↗
PubMed1994

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6--an evaluation with the nonparametric maximum likelihood method.

Therapeutic drug monitoring data for nortriptyline (674 analyses from 578 patients) were evaluated with the nonparametric maximum likelihood (NPML) method in order to determine the population kinetic parameters of this drug and their relation to age, body weight and duration of treatment. Clearance of nortriptyline during monotherapy exhibited a large interindividual variability and a skewed distribution. A small, separate fraction with a very high clearance, constituting between 0.5% and 2% of the population, was seen in both men and women. This may be explained by the recent discovery of subjects with multiple copies of the gene encoding the cytochrome-P450-enzyme CYP2D6, which catalyses the hydroxylation of nortriptyline. However, erratic compliance with the prescription may also add to this finding. A separate distribution of low clearance values with a frequency corresponding to that of poor metabolizers of CYP2D6 (circa 7% in Caucasian populations) could not be detected. Concomitant therapy with drugs that inhibit CYP2D6 resulted in a major increase in the plasma nortriptyline concentrations. This was caused by a decrease in nortriptyline clearance, whereas the volume of distribution was unchanged. The demographic factors age and body weight had a minor influence on the clearance of nortriptyline which was also unaffected by the duration of treatment.

Administration, Oral↗
PubMed1993

Clinical pharmacokinetics of zidovudine: inter and intraindividual variability and relationship to long term efficacy and toxicity.

The variability of the pharmacokinetics of zidovudine after its oral administration to 36 AIDS patients has been investigated by measuring the plasma and urine levels of zidovudine and its metabolite on Days 1 and 35 of continuous treatment. A two-phase absorption model was first defined from well-documented data in 12 subjects. The population characteristics of the kinetic parameters for both days were estimated by a nonparametric method. On Day 1, the mean (coefficient of variation) volume of distribution of zidovudine was 94.41 (90%), its mean half-life was 0.81 h (107%) and its mean oral clearance was 117 l.h-1 (57%) and on Day 35, these values were, respectively, 1121 (139%), 0.75 h (181%) and 295 l.h-1 (196%). The results confirm the large interindividual and intraindividual variation in zidovudine kinetics. The four covariates included in the population analysis (body weight, serum haemoglobin, creatinine and bilirubin) did not show clear relationship to the kinetic parameters. Thirty-four subjects were follow-up clinically for 99 days to 367 days after initiation of zidovudine therapy. The relationship between individual kinetic parameters (determined by Bayesian estimation), mean concentration profiles and outcome was studied through survival analysis. Long-term efficacy was defined as the prevention of opportunistic infections, which occurred in 13 patients. No clinical or kinetic variables, nor the individual zidovudine concentration profiles were found to predict the occurrence of an opportunistic infection. Toxicity was defined as a 20%-decrease in serum haemoglobin, which occurred in 13 patients. A significant relationship between mean daily concentration and toxicity was found, with an hazard of occurrence of toxicity 4.3-times larger when the mean steady stade concentration was 0.8 mg.l-1 than 0.6. The results indicate that zidovudine dosage should be individualised.

AIDS-Related Complex↗
PubMed1993

Computer-assisted individual estimation of radioiodine thyroid uptake in Grave's disease.

A computer-assisted Bayesian individual estimation of radioiodine thyroid uptake kinetics for patients suffering from Grave's disease is proposed. The program provides a fast computation of the activity to be administered to a given patient to achieve a target thyroid absorbed dose. This determination relies upon the patient biological covariates and upon a small number of measurements performed during a preliminar kinetic study of radioiodine thyroid uptake. Our results indicate that a two-sample Bayesian approach is reliable when external thyroid counts are performed at 2 h and 168 h after a test dose and has advantages over conventional kinetic experiments in terms of patient acceptability. This method is implemented on widespread computers and interfaced with a patient database. An interactive user interface with in-line data checking is provided. The program could be also a tool to better study the relationship between the absorbed dose and the clinical effect.

Adult↗
PubMed1993

Post-transfusional anti-HCV-negative, non-A, non-B hepatitis. (I) a prospective clinical and epidemiological survey.

Despite the identification of hepatitis C virus (HCV) and the detection of anti-HCV antibodies in the serum of infected individuals, a sizeable proportion of patients who develop transfusion-associated acute non-A, non-B hepatitis following surgery do not develop anti-HCV antibodies. The cause of this disease remains unknown. To assess the role of homologous blood transfusion in anti-HCV-positive and -negative, non-A, non-B hepatitis following surgery, patients receiving homologous blood, autologous blood alone, or no transfusions were prospectively studied. Consumption of potentially hepatotoxic drugs was also quantified. Anti-HCV antibodies were tested retrospectively when commercial assays became available. Of the 181 patients who received homologous blood which tested negative for surrogate markers of infectivity, 19 (10.5%) developed non-A, non-B hepatitis, associated with anti-HCV seroconversion in three cases. Of the 90 autologous blood recipients, non-A, non-B hepatitis developed in one (1.1%), who did not seroconvert to anti-HCV. Of the 64 untransfused patients, non-A, non-B hepatitis developed in one (1.6%), who was anti-HCV-positive before surgery. Logistic regression analysis showed that the occurrence of non-A, non-B hepatitis was associated with homologous blood transfusion, but not with the consumption of potentially hepatotoxic drugs. The 16 homologous-blood recipients who developed anti-HCV-negative, non-A, non-B hepatitis had received blood from 70 donors, none of whom had detectable anti-HCV antibodies but six of whom had minimal elevations of serum aminotransferase activity. Anti-HCV-negative, non-A, non-B hepatitis is mainly transfusion-transmitted in the surgical setting. Known hepatotropic agents may be involved despite the absence of usual serum markers, but our results are also consistent with the involvement of an unidentified non-A, non-B, non-C agent.

Adult↗
PubMed1993

Ursodeoxycholic acid improves ethinyl estradiol-induced cholestasis in the rat.

The effect of oral chronic administration of ursodeoxycholic acid has been examined in rats with cholestasis induced by ethinyl estradiol. Ursodeoxycholic acid at the dose of 25 mg kg-1 per day during 4 days, did not improve the decrease in basal bile flow and bile acid secretion induced by ethinyl estradiol alone. In contrast, when ursodeoxycholic acid was given at the same dose during 10 days, basal bile flow was significantly improved and basal bile acid secretion was restored to control values. When ursodeoxycholic acid was given at the dose of 500 mg kg-1 per day, basal bile flow and bile acid output were not further improved. However, bile flow and bile acid output under taurocholate infusion were restored to control values. Bile of rats treated with ursodeoxycholic acid was enriched with this bile acid. These results show a significant improvement of ethinyl estradiol-induced cholestasis in rats after chronic administration of ursodeoxycholic acid and support the use of this bile acid in intrahepatic cholestasis in man.

Alanine Transaminase↗
PubMed1993

An autologistic model for the genetic analysis of familial binary data.

Regressive logistic models specify the probability distribution of familial binary traits by conditioning each individual's phenotype on those of preceding relatives; therefore, the expression of the joint probability of the familial data necessitates ordering the observations. In the present paper, we propose an autologistic model of this familial dependence structure, which does not require specification of a particular ordering of the phenotypic observations. Genetic effects are introduced into the model in order to perform segregation analysis that is aimed at detecting the role of a major locus in the expression of familial phenotypes. In this model, the conditional probabilities have a logistic form, and large patterns of dependence between relatives can be considered with a simple interpretation of the parameters measuring the relationship between two phenotypes. The model is compared with the regressive logistic approach in terms of odds ratios and by using a simulation study.

Computer Simulation↗
PubMed1993

[Schönlein-Henoch purpura. A report of 55 cases].

The clinical, histological and laboratory data from a series of 55 pediatric patients with Henoch-Schönlein purpura studied at the Hospital General de Mexico in a 16-years period are presented herein. Even when there are a few clinical features in this example of Mexican children, the clinical presentation and the course of the disease are similar to what is found in the literature.

Adolescent↗
PubMed1991

Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans.

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.

Adult↗
PubMed1990

Comparison of magnetic resonance imaging and computed tomography in the preoperative staging of rectal cancer.

Nineteen patients with middle and lower rectal carcinomas were operated on, with abdominoperineal resection in 10 patients, lower anterior resection with coloanal anastomosis in 6 patients, and colorectal anastomosis in 3 patients. The distance of the lower margin of the tumor to insertion of the levator ani on the rectal wall was correctly evaluated by computed tomography in 12 (63%) of 19 patients and by magnetic resonance imaging in 13 (68%) of 19 patients, while digital examination correctly assessed the distance in 15 (79%) of 19 patients. Computed tomography and magnetic resonance imaging were unable to assess extension through the rectal wall. No significant difference was observed between computed tomography and magnetic resonance imaging in assessing extension to the perivesical fat, adjacent organs, pelvic side wall, or lymph nodes. According to the TNM classification, magnetic resonance imaging correctly staged 74% (14/19) of carcinomas, while computed tomography correctly staged 68% (13/19).

Aged↗
PubMed1990

[Comparative study of MRI and x-ray computed tomography in the preoperative evaluation of rectal carcinoma].

Twenty-one patients with middle and low rectal carcinomas have been operated by abdominoperineal resection (APR) in 11 patients, and low anterior resection (LAR) with coloanal anastomosis in 7 and colorectal anastomosis in 3. The distance of the lower margin of the tumor to insertion of the levator ani on the rectal wall was correctly evaluated by CT in 15 of 21 cases (71%) and by MR in 14 of 21 (67%) while digital examination correctly assessed the distance in 17 of 21 (81%). CT and MR were unable to assess extension through the rectal wall. No significant discordance was observed between CT and MR in assessing extension to the perivesical fat, adjacent organs, pelvic side wall or lymphnodes. According to the TNM classification, MR correctly staged 76% (16 of 21) of patients while CT correctly staged 71% (15 of 21).

Adenocarcinoma↗
PubMed1990

[Anesthesia using propofol during surgery of strabismus in children. A comparison of two different protocols of induction and maintenance].

The purpose of this study is an investigation of two protocols using propofol as induction and maintenance agent in 100 children scheduled for strabismus surgery (4-8 year, ASA I, NYHA I). Protocol I; Propofol 6 mg.kg-1 in 60 s with fentanyl 2 micrograms.kg-1 and vecuronium bromide 0.08 mg.kg-1 for induction, followed by propofol 11 mg.kg-1 for maintenance; Protocol II; Propofol 3 mg.kg-1 in 20 s with fentanyl 3 micrograms.kg-1 for induction, followed by propofol 12 mg.kg-1.h-1 for maintenance. It appears that the use of protocol I offers significant advantages compared with protocol II: a better quality of induction with a lesser incidence of pain during injection of propofol; a better quality of maintenance with very infrequent bradycardia from oculocardiac reflectivity; and a better recovery with a greatly reduced frequency of nausea and vomiting.

Anesthesia, Intravenous↗
PubMed1989

Modeling the age-of-onset function in segregation analysis: a causal scheme for leprosy.

Several methods have been proposed to take into account the variable age of onset of a disease in genetic analysis. A different approach is presented from an etiological point of view. To illustrate the method, we used leprosy, an infectious disease with a variable age of onset depending on both the time of contamination with the bacillus and the latency of the disease; the role of a major gene in the susceptibility to this disease has been recently detected. The age-of-onset function was modeled to account for the two temporal processes: contamination event and incubation period. For genetic analysis, this function was combined with the probability of being susceptible to the disease, which was expressed by the use of regressive models. To test this new approach, ten sets of 500 nuclear families were simulated considering different hypotheses of contamination risks, which were either constant or dependent on contacts with contagious leprosy patients, and varying the extent to which the disease is heritable. Analyses of these data using two versions of the model indicate that the model can detect familial correlations in variable age of onset and discriminate between the different simulated effects.

Adolescent↗
PubMed1989

[Lymphography and x-ray computed tomography in the evaluation of lymph node invasiveness in cancer of the bladder. Comparison of their diagnostic value].

The diagnostic value of lymphography and computed tomography (CT) in the assessment of lymph node invasion by bladder cancers has been compared on the basis of 30 observations. Although computed tomography apparently yields better results (reliability: 93%) than lymphography (reliability: 87%), these findings have no statistical significance. The study of literature shows that the statistical exploitation of the results was seldom carried out. The combination of both exploration techniques seems to improve predictive values, but this improvement was not statistically significant in our study.

Adult↗