Biomedical subjects

Nicolas Simon

Publications and source records attributed to Nicolas Simon.

5 recordsLinked to original sources

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

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↗