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Nicolas Simon

Publications and source records attributed to Nicolas Simon.

10 recordsLinked to original sources
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↗
PubMed2003

Pharmacokinetics of the low molecular weight heparin enoxaparin during 48 h after bolus administration as an anticoagulant in haemodialysis.

BACKGROUND: The interest of low molecular weight heparins (LMWH) regarding bleeding risk is controversial in renal failure patients. In haemodialysis patients, there are very few data on the pharmacokinetics of LMWH after the end of the session. The aim of the study was to evaluate the duration of anticoagulation after bolus administration of the LMWH enoxaparin at the start of haemodialysis. METHODS: The pharmacokinetics of enoxaparin were studied during the 48 h following a single bolus injection at the start of the dialysis session in 30 chronic haemodialysis patients. Pharmacokinetics were determined using a population approach (Non Linear Mixed Effects Modelling). RESULTS: A single injection of enoxaparin at 60 U IU/kg (4000 +/- 455 IU) led to an anti-Xa activity higher than 1.2 IU/ml during the first 2 h of the session, and between 0.4 and 1.2 IU during the third and fourth hours. After the end of the session, anti-Xa activity remained higher than 0.4 IU/ml up to 10 h after injection, and higher than 0.1 IU/ml up to 24 h. The pharmacokinetic model showed that only weight improved the predicted vs observed anti-Xa activity plot. The model was used to simulate single and multiple dosing with decreased enoxaparin doses. Whatever the procedure, anti-Xa activity remained high (>0.22 +/- 0.99 UI/ml) up to 12 h after the start of the dialysis session. CONCLUSIONS: These results suggest that haemodialysis patients receiving the LMWH enoxaparin during dialysis are at risk of bleeding up to 10 h after the injection.

Adult↗
PubMed2003

Performance of target-controlled sufentanil infusion in obese patients.

BACKGROUND: Because obesity might affect pharmacokinetic parameters, the authors evaluated the accuracy of target-controlled sufentanil infusion in morbidly obese patients using a pharmacokinetic model usually applied to a normal-weight population. METHODS: Target-controlled propofol and sufentanil coinfusions were administered to 11 morbidly obese patients (body mass index: 45.0 +/- 6.5 kg/m2 ) undergoing laparoscopic gastroplasty. The target plasma propofol concentration was 3 micro g/ml. The effect-site sufentanil target concentration was initially 0.4 ng/ml but was modified during surgery as a function of blood pressure and heart rate. Plasma sufentanil concentrations were measured from the onset of infusion until 24 h after its termination. The predicted sufentanil target concentrations were calculated by STANPUMP software. Intrasubject data analyzed included calculation of performance error, median performance error, median absolute performance error, divergence, and wobble. Pharmacokinetic analysis was performed using a nonlinear mixed effect model. RESULTS: Applied sufentanil target concentrations ranged from 0.3 to 0.65 ng/ml. The mean +/- SD plasma sufentanil concentration measured during spontaneous ventilation was 0.13 +/- 0.03 ng/ml. Median performance error (range) was -13% (-42 to 36%). Median absolute performance error was 26% (8-44%) during infusion and 17% (12-59%) for the 24 h after its completion. The pharmacokinetic sets used slightly overpredicted the concentrations, with a median divergence of -3.4% (-10.2 to 3.1%) during infusion. For body mass index greater than 40, the overestimation of plasma sufentanil concentrations was greater. A two-compartment model with proportional error for interindividual variability best fitted the data. The residual variability was modeled as an additive (0.016 ng/ml) or proportional error (23%). Clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution (coefficient of variation) were 1.27 l/min (23%), 37.1 l (20%), 0.87 l/min (44%), and 92.7 l (22%), respectively. CONCLUSION: The pharmacokinetic parameter set derived from a normal-weight population accurately predicted plasma sufentanil concentrations in morbidly obese patients.

Adolescent↗
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↗