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Bernard Bruguerolle

Publications and source records attributed to Bernard Bruguerolle.

13 recordsLinked to original sources
PubMed2006

Effects of a seven-day continuous infusion of ropivacaine on circadian rhythms in the rat.

The present study was conducted to evaluate the effect of a 7 d continuous infusion of ropivacaine on the 24 h rhythms of body temperature, heart rate, and locomotor activity. After an initial 7 d baseline, rats were randomly divided into two groups of 4 rats each to receive ropivacaine or saline via an osmotic pump for 7 consecutive days. The pumps were removed thereafter and observed during a 7 d recovery span. The studied circadian rhythms were measured by radiotelemetry throughout each of the 7 d periods. An additional group of 4 rats was studied under the same experimental conditions to assess the plasma levels of ropivacaine on days 3 and 8 following pump implantation. Our results indicate that ropivacaine does not induce loss of the circadian rhythms of body temperature, heart rate, or locomotor activity; a prominent period of 24 h was found for all variables in all animals, before, during, and after ropivacaine treatment. However, ropivacaine treatment did modify some characteristics of the rhythms; it increased the MESOR (24 h mean) of the heart rate and locomotor activity rhythms and advanced the acrophase (peak time) of the locomotor activity circadian rhythm. The present study indicates that the circadian rhythms of heart rate and locomotor activity are modified after continuous infusion of ropivacaine, which is of particular interest, given the potential cardiotoxicity of this local anesthetic agent.

Amides↗
PubMed2006

Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients.

OBJECTIVES: To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. METHODS: Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC). RESULTS: The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively. CONCLUSIONS: On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, some patients were at risk of achieving a concentration below the MIC (1 mg/L), particularly if the second administration occurred 72 hours after the first dosing. Thus, a dose of ceftriaxone 2 g intravenously is recommended immediately following dialysis, particularly in patients with severe infections or when the dosing interval will be higher than 48 hours.

Adult↗
PubMed2005

Cluster analysis: an alternative method for covariate selection in population pharmacokinetic modeling.

To be analyzed, the heterogeneity characterizing biological data calls for using appropriate models involving numerous variables. A high variable number could become problematic when one needs to determine a priori the most significant variable combination in order to reduce the inter-individual variability (IIV). Alternatively to multiple introductions of single variables, we propose a single introduction of a multivariate variable. We present cluster analysis as a stratification strategy that combines the initial single covariates to build a multivariate categorical covariate. It is an exploratory multivariate analysis that outlines homogeneous categories of individuals (clusters) according to similarities from the set of covariates. It includes many clustering techniques combining a distance measure and a linkage algorithm, and leading to various stratification patterns. The cluster analysis approach is illustrated by a case study on cortisol kinetics in 82 patients after intravenous bolus administration of synacthen (synthetic corticotropin). Using NONMEM, a basic infusion model was initially achieved for cortisol, and then a classical covariate selection was applied to improve IIV. The best fit was between the elimination rate constant k and the body mass index (BMI), which improved IIV of k. An alternative method is presented consisting in the population into homogeneous and non-overlapping groups by applying a cluster analysis. Such categorization (or clustering) was carried out using Euclidean distance and complete-linkage algorithm. This algorithm gave five dissimilar clusters that differed by increasing BMI, obesity duration, and waist-hip ratio. The dispersion of k according to the five clusters showed three distinctvariation ranges a priori, which corresponded a posteriori(after NONMEM modeling) to three sub-populations of k. After grouping the clusters that had similar variation ranges of k, we obtained three final clusters representing non-obese, intermediate, and extreme obese sub-populations. The pharmacokinetic model based on three clusters was better than the basic model, similar to the classical covariate model, but had a stronger interpretability: It showed that the stimulation and elimination of cortisol were higher in the extreme obese followed by intermediate then non-obese subjects.

Adrenocorticotropic Hormone↗
PubMed2004

Method for simultaneous measurement of norepinephrine, 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol by liquid chromatography with electrochemical detection: application in rat cerebral cortex and plasma after lithium chloride treatment.

An assay was developed to quantify norepinephrine (NE) and its metabolites (MHPG and DHPG) by high-performance liquid chromatography with electrochemical detection method (HPLC-ECD) in brain tissue and plasma of rats treated by LiCl. Separation on C(18) column was obtained by a mobile phase consisting of 4.5% methanol in buffer (0.1 M sodium acetate, 0.2 M citric acid) containing 0.2 mM ethylenediaminetetraacetic acid disodium salt (EDTA Na(2)) and 0.4 mM sodium octylsulfate, operated at a flow rate of 0.8 ml/min. A potential of +0.78 V was applied across the working and reference electrodes of the detector. The precision was in the range 2.88-4.35% for NE, 5.94-11.0% for MHPG and 1.97-4.40% for DHPG. Accuracy was 98.8-99.3% for NE, 97.4-100% for MHPG and 96.1-101% for DHPG. The limit of detection was 0.6 ng/ml for NE, 0.5 ng/ml for MHPG and 0.2 ng/ml for DHPG. The linearity is over the range 20-60 ng/ml for NE, 7-23 ng/ml for MHPG and 6-20 ng/ml for DHPG. The assay has been applied successfully to measure simultaneously cortex and plasmas concentrations of these three catecholamines in rats.

Animals↗
PubMed2004

The effects of a normal protein diet on levodopa plasma kinetics in advanced Parkinson's disease.

LevoDOPA given orally may compete with the neutral aminoacids contained in food for its absorption in the small intestine. LevoDOPA plasma kinetics of the morning intake with 'french' breakfast (low protein content) were compared with those of the noon intake with lunch (normal protein content) in 20 advanced parkinsonian patients (mean disease duration: 10 years). The galenic form and the dosage of levoDOPA were strictly the same for morning and noon intakes in each patient. Blood samplings were collected at T0 (just before intake) and successively at 15, 30, 45, 60, 90, 120, 150 and 180 min after intake. LevoDOPA plasma levels were further measured with HPLC method, then giving the following variables: Cmax (peak concentration), Tmax (time corresponding to Cmax), AUC (area under curve). The results showed no significant difference for Cmax and Tmax whereas the AUC was significantly (P < 0.001) increased for the noon intake, due to the trough concentration effect. These data suggest that, since rich protein diet has been shown to impair the clinical effect of LevoDOPA, this protein effect is probably not due to competitive intestinal absorption of LevoDOPA.

Adult↗
PubMed2003

Population pharmacokinetics of moxifloxacin in plasma and bronchial secretions in patients with severe bronchopneumonia.

OBJECTIVE: Our objective was to construct a population pharmacokinetic model for moxifloxacin disposition in plasma and bronchial secretions in patients with severe bronchopneumonia who were mechanically ventilated. METHODS: Seventeen patients receiving 400 mg moxifloxacin intravenously daily were enrolled in this multicenter, prospective, open-label study. Blood and bronchial samples were collected on days 1 and 4. The population pharmacokinetic modeling was performed with NONMEM. RESULTS: Moxifloxacin rapidly appeared in bronchial secretions and reached maximum concentrations within 1 to 2 hours. The concentrations achieved in plasma and bronchial secretions showed parallel profiles versus time on days 1 and 4. The pharmacokinetics was best described by a 2-compartment model with a link to bronchial secretions. The population pharmacokinetic parameters were as follows (given as estimate with percent interindividual variability in parentheses except where otherwise indicated): clearance, 14.3 L/h (25%); central distribution volume, 62.9 L (14%); intercompartmental clearance, 27.2 L/h (36%); peripheral distribution volume; 71 L (32%); fraction of moxifloxacin clearance to bronchial secretions, 0.11 (range, 0.06-0.16); and elimination rate constant for bronchial secretions, 1.7 h(-1) (40%). The plasma terminal half-life was 6.7 hours. The bronchial-to-plasma exposure ratio was 1.0 (range, 0.6-2.0). With a conservative 90% minimum inhibitory concentration (MIC(90)) of 0.25 mg/L, the maximum concentration/MIC(90) ratios were higher than 10 and the area under the curve/MIC(90) ratios were roughly 100 for plasma and bronchial secretions. CONCLUSIONS: This study showed the fast diffusion of moxifloxacin into the lungs in ventilated patients with severe respiratory infection. The bronchial secretions reached bactericidal levels for common germs found in respiratory tract infections.

Adult↗
PubMed2003

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

Animals↗
PubMed2003

Circadian rhythms of oxidative phosphorylation: effects of rotenone and melatonin on isolated rat brain mitochondria.

Mitochondrial experiments are of increasing interest in different fields of research. Inhibition of mitochondrian activities seems to play a role in Parkinson's disease and in this regard several animal models have used inhibitors of mitochondrial respiration such as rotenone or MPTP. Most of these experiments were done during the daytime. However, there is no reason for mitochondrial respiration to be constant during the 24 h. This study investigated the circadian variation of oxidative phosphorylation in isolated rat brain mitochondria and the administration-time-dependent effect of rotenone and melatonin. The respiratory control ratio, state 3 and state 4, displayed a circadian fluctuation. The highest respiratory control ratio value (3.01) occurred at 04:00 h, and the lowest value (2.63) at 08:00 h. The highest value of state 3 and state 4 oxidative respiration occurred at 12:00 h and the lowest one at 20:00 h. The 24 h mean decrease in the respiratory control ratio following incubation with melatonin and rotenone was 7 and 32%, respectively; however, the exact amount of the inhibition exerted by these agents varied according to the time of the mitochondria isolation. Our results show the time of mitochondrial isolation could lead to interindividual variability. When studies require mitochondrial isolation from several animals, the time between animal experiments has to be minimized. In oxidative phosphorylation studies, the time of mitochondria isolation must be taken into account, or at least specified in the methods section.

Animals↗
PubMed2002

Time-of-day dependent pharmacodynamic and pharmacokinetic profiles of caffeine in rats.

This study aims to investigate the effects of caffeine on the daily rhythms of heart rate (HR), body temperature (BT) and locomotor activity (LA) in rats in relation to time-of-day of administration, as well as their possible mechanisms, particularly related to caffeine pharmacokinetics. During the pharmacodynamic study, HR, BT and LA were measured every 10 min by radiotelemetry and analysed by Cosinor. This study was divided into three periods: a control period P1, a treatment period P2 and a recovery period P3. During P2, rats of the morning group ( M(tel)) received a 25 mg/kg s.c. dose of caffeine at 08.00 while rats of the evening group ( E(tel)) received the same dose of caffeine at 20.00. The pharmacokinetic study was conducted in parallel with the telemetric study and was divided into two periods: a control period P1, and a treatment period P2. During P2, animals of the morning ( M(pk)) and the evening ( E(pk)) groups received the same treatment as the animals of the telemetric study. At the last day of P2, blood samples were drawn 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h after the last morning and the last evening administration in order to determine the pharmacokinetics of M(pk) and E(pk). Our results showed that morning administration of caffeine suppressed the daily rhythmicity of LA and modified the mesors and amplitudes of the HR and BT daily rhythms, while the evening administration did not suppress the daily rhythm of LA, but altered the mesors, amplitudes and acrophases of the three rhythms, indicating a chronopharmacological effect. With respect to the pharmacokinetic effects, the area under the curve (AUC) was significantly lower in rats of E(pk) compared with M(pk), due to an increase of the total plasma clearance and the volume of distribution. Our data suggest that the chronopharmacokinetic effects of caffeine may explain, at least in part, the observed caffeine-induced modifications on the daily rhythms.

Animals↗
PubMedDate not supplied

Biologic rhythms and Parkinson's disease: a chronopharmacologic approach to considering fluctuations in function.

The existence of circadian rhythms and their implication in many pathologic processes have been underlined in several diseases but have not been evaluated in Parkinson's disease. The aim of this paper is to review diurnal variations of clinical, biologic, or experimental factors described with Parkinson's disease. Clinical data often report daily fluctuations of motor activity pattern, but the effect of the stage of the disease and the respective roles of drugs are difficult to evaluate. Sleep disturbances in Parkinson's disease patients also reveal alterations of circadian rhythms. Autonomic dysfunction, described in Parkinson's disease, reveals numerous alterations in circadian regulations including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability, and postprandial hypotension. Many biologic indices such as cortisol, catecholamines, and melatonin are also altered. Circadian rhythms in dopaminergic systems as well as possible daily fluctuations in kinetics of drug treatments are likely involved in such variations. Few clinical studies have been devoted to circadian patterns of drug response. As for other diseases where biologic rhythms are concerned Parkinson's disease therapy may be influenced by further understanding of circadian influence.

Animals↗
PubMedDate not supplied

[Involvement of a public pharmacology laboratory in pharmacokinetic studies].

Pharmacokinetic studies can be performed before or after a drug is marketed. Indeed, extensive use of a new drug can uncover situations that it has not been possible to investigate before market application. Hospital departments of pharmacology are often involved in these complementary studies. They can design the study, initiate it in a clinical investigation centre, measure plasma concentrations, analyse the pharmacokinetic data, and write the report. If the extent of the scientific involvement of public pharmacology laboratories is strictly demarcated, financial support for nonsponsored studies by the pharmaceutical industry is problematical. Indeed, it is difficult to obtain funds to study the concentration-toxicity relationship or a drug-drug interaction for a compound for which the patent has expired. In addition, such studies have an excess cost, mainly because of the expense associated with drug measurements. Also, the medical time devoted to research is not rewarded by institutions. This situation will become more complicated because of the restrictive legislative framework imposed by the European directive.

Laboratories, Hospital↗