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N Simon

Publications and source records attributed to N Simon.

At least 19 recordsLinked to original sources
PubMed2005

Effects of three-hour restricted food access during the light period on circadian rhythms of temperature, locomotor activity, and heart rate in rats.

The effects of food on biological rhythms may influence the findings of chronopharmacological studies. The present study evaluated the influence of a restricted food access during the rest (light) span of nocturnally active Wistar rats on the 24 h time organization of biological functions in terms of the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (LA) in preparation for subsequent studies aimed at evaluating the influence of timed food access on the pharmacokinetics and pharmacodynamics of medications. Ten-wk-old male Wistar rats were housed under controlled 12:12 h light:dark (LD) environmental conditions. Food and water were available ad libitum, excepted during a 3 wk period of restriction. Radiotelemetry transmitters were implanted to record daily rhythms in T, HR, and LA. The study lasted 7 wk and began after a 21-d recovery span following surgery. Control baseline data were collected during the first wk (W1). The second span of 3 wk duration (W2 to W4) consisted of the restricted feeding regimen (only 3 h access to food between 11:00 and 14:00 h daily) during the L (rest span) under 12:12 h LD conditions. The third period of 3 wk duration (W5 to W7) consisted of the recovery span with ad libitium normal feeding. Weight loss in the amount of 5% of baseline was observed during W1 with stabilization of body weight thereafter during the remaining 2 wk of food restriction. The 3 h restricted food access during the L rest span induced a partial loss of circadian rhythmicity and the emergence of 12 h rhythms in T, HR, and LA. Return to ad libitum feeding conditions restored circadian rhythmicity in the manner evidenced during the baseline control span. Moreover, the MESORS and amplitudes of the T, HR, and LA 24 h patterns were significantly attenuated during food restriction (p < 0.001) and then returned to initial values during recovery. These changes may be interpreted as a masking effect, since T, HR, and LA are known to directly react to food intake. The consequences of such findings on the methods used to conduct chronokinetic studies, such as the fasting of animals the day before testing, are important since they may alter the temporal structure of the organism receiving the drug and thereby compromise findings.

Animals↗
PubMed2004

High plasma ropivacaine concentrations after fascia iliaca compartment block in children.

BACKGROUND: The pharmacokinetic profile of local anaesthetics is influenced by the mode of administration. We sought to compare the pharmacokinetics of two doses of ropivacaine after fascia iliaca compartment (FIC) block in children. METHODS: In this prospective, double-blind study, children received an FIC block as a part of their anaesthetic management during elective orthopaedic surgery on the thigh. They were randomized to receive ropivacaine 0.7 ml x kg(-1) using either a 0.375% or 0.5% solution. Venous blood samples were drawn up to 6 h after injection. Plasma concentrations of ropivacaine were measured by gas-liquid chromatography. RESULTS: Six children (10.2 (range 5-15) yr, 35.6 (sd 10) kg were included. FIC block provided satisfactory peroperative pain relief. No signs of toxicity were observed, but high maximal plasma concentrations (C(max) 4.33-5.6 microg ml(-1)), were observed for three of four patients in the ropivacaine 0.5% group. The two patients in the 0.375% group showed values within the safe range (C(max) 0.66 and 0.98 microg ml(-1) respectively). Even though no toxic effects were observed, these results led us to discontinue the study. CONCLUSIONS: The administration of ropivacaine 3.5 mg x kg(-1) can be associated with sustained high plasma concentrations of ropivacaine, outside the tolerable range. In view of these results, we recommend the use of lower ropivacaine dosage during FIC block in children.

Adolescent↗
PubMed2004

Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.

AIMS: To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS: Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS: Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION: This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.

Adolescent↗
PubMed2003

Chromatographic determination of the association constant between 8-methoxypsoralen and modified beta-cyclodextrin: protective effect of hydroxypropyl-beta-cyclodextrin on 8-methoxypsoralen toxicity in human keratinocytes.

The retention of 8-methoxypsoralen (8-MOP) on an immobilised hydroxypropyl-beta-cyclodextrin (HP-beta-CD) column was analysed in HPLC by the determination of its Langmuir distribution isotherm. A such method was used to confirm the potential drug complexing role of this cyclodextrin. The 8-MOP/HP-beta-CD association constant (K) was equal to 29.5 and 18.7 M-1, respectively, at a temperature equal to 5 and 25 degrees C, respectively. These association constant values were used to determine the cytotoxicity profile of human keratinocyte cell line (HaCaT) in relation to the complex concentration. It was showed through these data that HP-beta-CD had a cytoprotective since a reverse effect of HP-beta-CD on 8-MOP cytotoxicity was observed.

Cell Line↗
PubMed2003

Population pharmacokinetics of short intravenous vinorelbine infusions in patients with metastatic breast cancer.

PURPOSE: To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients. METHODS: Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method. RESULTS: Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V(1)) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V(1) were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data. CONCLUSION: This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.

Adult↗
PubMed2002

Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.

The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%. Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.

Adenosine Triphosphatases↗
PubMed2002

Lack of daily rhythms major modifications despite continuous infusion of melatonin in the rat.

The present study was conducted to evaluate the effect of melatonin on the daily rhythms of temperature, heart rate and locomotor activity in rats that received subcutaneously a continuous infusion of two different doses e.g. 1 and 5 mg/kg per day for seven days. Our results indicate that melatonin does not induce a loss of the daily rhythmicity of temperature, heart rate and locomotor activity. Whatever the dose, melatonin slightly modifies the main parameters of these rhythms e.g. a decrease of the amplitude of the daily rhythms of temperature and heart rate and an increase of the mesor of temperature. Taking into account these results obtained after constant rate delivery in normal rats, we plan now to investigate the effects of melatonin on our experimental model of Parkinson's disease (double bilateral intrastriatal 6-hydroxydopamine injection).

Analysis of Variance↗
PubMed2001

An improved procedure for the generation of recombinant single-chain Fv antibody fragments reacting with human CD13 on intact cells.

A procedure was developed to generate recombinant single chain Fv (scFv) antibody fragments reacting with the extracellular domain of human cell surface antigen CD13 (hCD13; aminopeptidase N) on intact cells. Membrane fractions prepared from a stably transfected hCD13-positive murine NIH/3T3 cell line were used to immunize BALB/c mice, with the intention that hCD13 would be the major immunogenic molecule recognized by the immune system. Spleen RNA from the immunized mice served to generate a combinatorial scFv phage display library. The library was adsorbed against non-transfected NIH/3T3 or Sf21 insect cells to eliminate nonrelevant binders. The supernatant was then used for panning with either hCD13-transfected Sf21 insect cells or a hCD13-expressing human leukemia-derived cell line. Therefore, the key concepts of the procedure were the presentation of hCD13 as the sole human antigen on murine NIH/3T3 cells and a screening strategy where hCD13 was the major common antigen of the material used for immunization and panning. Two different hCD13-reactive phages were isolated and the soluble scFvs were expressed in E. coli and purified. The two scFvs, anti-hCD13-1 and anti-hCD13-3, differed at four amino acid positions in their V(H) regions and both had high affinities for hCD13 as determined by surface plasmon resonance (K(D)=7 and 33x10(-10) M, respectively). Both efficiently recognized hCD13 on intact cells. Therefore, the procedure allowed the production of high affinity scFvs reacting with a desired antigen in its native conformation without requiring extensive purification of the antigen and should be useful for the preparation of scFvs against other conformation-sensitive cell-surface antigens.

3T3 Cells↗
PubMed2001

[Acute pyelonephritis. Randomized multicenter double-blind study comparing ciprofloxacin with combined ciprofloxacin and tobramycin].

OBJECTIVES: To investigate the effects of an intravenous injection of tobramycin (T) in female patients with acute uncomplicated pyelonephritis treated with ciprofloxacin (CIP) (500 mg bid per os). METHODS: It was a randomized, multicenter, double-blind study conducted in six departments of emergency medicine. The main exclusion criteria were: previous history of urinary tract malformation of lithiasis, a recent urological procedure, pregnancy, diabetes mellitus, immunodepression, or severe sepsis. The primary criteria for evaluation were: the percentage and rate of clinical recovery, as well as bacteriological efficacy. RESULTS: 118 women were enrolled, 60 in the tobramycin group and 58 in the placebo group. E. coli was the most commonly isolated organism; all organisms were susceptible to ciprofloxacin and tobramycin. Two women in the CIP + T group and four women in the CIP + P group failed to respond clinically. The recovery rate was similar in the two groups (96 and 93% respectively). CONCLUSION: Administration of a dose of tobramycin did not demonstrate its clinical benefit in treatment of acute uncomplicated pyelonephritis treated by oral ciprofloxacin.

Acute Disease↗
PubMed2001

[Acute severe pain in emergencies. The key for efficient analgesia].

OBJECTIVE: To measure severe acute pain (SAP) frequency, to describe SAP management and to bring to view the conditions of analgesia success in emergency medicine. DESIGN: Multicentre prospective survey: 7 days in Emergency Departments (ED), 30 days in Mobile Intensive Care Units (MICU). Multivariate analysis to measure the independent effect on pain relief of factors identified by Chi squared test. SETTING: All of 6 ED and 8 MICU of a French region. PATIENTS: Over 15 years of age. MAIN OUTCOME MEASURES: Pain intensity was assessed with Visual Analog Scale (VAS) before and after ED or MICU management. SAP group (defined by initial VAS score > 40 mm) was analyzed for pain relief (defined by final VAS score < or = 40 mm). Influence on pain relief through pain aetiology, initial pain intensity, treatment delay and opioid use was analyzed. RESULTS: 1,082 fulfilled medical forms for 3,419 eligible patients. SAP frequency was estimated 36% (CI95 = 34-38%) in ED and 29% (CI95 = 25-33%) in MICU. SAP (n = 368) was often persistent: 45% (CI95 = 43-47%) after discharge from ED and 26% (CI95 = 22-30%) after MICU intervention. The prognostic factors of pain control success revealed by Chi squared test were: MICU (vs ED), treatment delay < or = 3 hours (vs > 3 hours), opioid use (vs non opioid use) and VAS pain level < or = 70 mm (vs > 70 mm). The last 3 factors were confirmed by multivariate analysis. Treatment delay, opioid use, and pain level were found to be determinants of efficient analgesia for SAP. CONCLUSION: Despite the high frequency of SAP in ED and MICU, pain control is not satisfying. Opioid use and early treatment are determinant in analgesia efficiency for SAP and should be therefore encouraged to improve pain relief in emergency medicine.

Acute Disease↗
PubMed2001

Awareness and use of the Ottawa ankle and knee rules in 5 countries: can publication alone be enough to change practice?

STUDY OBJECTIVES: We evaluate the international diffusion of the Ottawa Ankle and Knee Rules and determine emergency physicians' attitudes toward clinical decision rules in general. METHODS: We conducted a cross-sectional, self-administered mail survey of random samples of 500 members each of the American College of Emergency Physicians, Canadian Association of Emergency Physicians, British Association for Accident and Emergency Medicine, Spanish Society for Emergency Medicine, and all members (n=1,350) of the French Speaking Society of Emergency Physicians, France. Main outcome measures were awareness of the Ottawa Ankle and Knee Rules, reported use of these rules, and attitudes toward clinical decision rules in general. RESULTS: A total of 1,769 (57%) emergency physicians responded, with country-specific response rates between 49% (United States and France) and 79% (Canada). More than 69% of physicians in all countries, except Spain, were aware of the Ottawa Ankle Rules. Use of the Ottawa Ankle Rules differed by country with more than 70% of all responding Canadian and United Kingdom physicians reporting frequent use of the rules compared with fewer than one third of US, French, and Spanish physicians. The Ottawa Knee Rule was less well known and less used by physicians in all countries. Most physicians in all countries viewed decision rules as intended to improve the quality of health care (>78%), a convenient source of advice (>67%), and good educational tools (>61%). Of all physicians, those from the United States held the least positive attitudes toward decision rules. CONCLUSION: This constitutes the largest international survey of emergency physicians' attitudes toward and use of clinical decision rules. Striking differences were apparent among countries with regard to knowledge and use of decision rules. Despite similar awareness in the United States, Canada, and the United Kingdom, US physicians appeared much less likely to use the Ottawa Ankle Rules. Future research should investigate factors leading to differences in rates of diffusion among countries and address strategies to enhance dissemination and implementation of such rules in the emergency department.

Adult↗
PubMed2000

Effects of a seven-day continuous infusion of L-DOPA on daily rhythms in the rat.

The present study was conducted to evaluate the effect of L-3, 4-dihydroxyphenylalanine (L-DOPA) on the daily rhythms of temperature, heart rate and locomotor activity in rats that received a 7-day continuous infusion. Our results indicate that L-DOPA does not induce a loss of the daily rhythmicity of temperature, heart rate and locomotor activity but modifies the main parameters of these rhythms, e.g. it increased the MESOR (midline estimating statistic of rhythm) of temperature and heart rate and increased the amplitude of temperature but decreased the amplitude of heart rate. Taking into account these results obtained after constant rate delivery, we now plan to investigate the effects of DOPA therapy by changing the time of its administration.

Analysis of Variance↗
PubMed2000

Peptide YY and vitamin E inhibit hormone-sensitive and -insensitive breast cancer cells.

We have shown that peptide YY, an endogenous gut hormone, and vitamin E succinate (VES) inhibit pancreatic cancer cell growth in vitro. We hypothesized that PYY and VES would inhibit breast cancer cell viability regardless of the hormone receptor status. Human breast ZR-75 ductal carcinoma (estrogen receptor negative) and MCF-7 adenocarcinoma (estrogen receptor positive) cells were cultured and exposed to VES (10 pg/ml), PYY (500 pmol), or both agents together. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability. At every time interval, PYY and VES significantly inhibited cell growth compared to control. The effects of PYY were similar in magnitude to those of VES. Combining the agents resulted in a significant additive inhibition of growth with the greatest effect seen at 72 h. We have shown that PYY and vitamin E inhibit in vitro growth of breast cancer cells with variable hormone receptor status. When used in combination, the agents have a significant increase in effect. Further studies are ongoing to define the mechanism of action of these agents and to translate the experiments to an in vivo model.

Breast Neoplasms↗
PubMed2000

Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth.

BACKGROUND: Vitamin E succinate (VES) significantly inhibits cell growth in vitro in breast, prostate, and skin cancer cell lines. Our study demonstrated similar inhibitory effects on Mia PaCa-2 pancreatic cancer cells at the same concentration of VES (10 pg/ml). Peptide YY (PYY) also inhibits pancreatic cancer cell growth in vitro. We observed a significant additive effect on growth inhibition in Mia PaCa cells treated with both VES and PYY. METHODS: Human pancreatic ductal adenocarcinoma Mia PaCa-2 cells were cultured and treated once with either 10 pg/ml of VES or 500 pmols of PYY or with both agents together. The control group received an equivalent volume of solvents. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability. RESULTS: Pancreatic cancer cell growth was reduced in all groups treated with PYY and VES. Student's t test was used to analyze the data for each treatment group. At 72 h, both PYY and vitamin E significantly inhibited cell growth compared to control. Combining the agents resulted in a dramatic additive inhibition of growth. CONCLUSION: PYY and vitamin E both inhibit growth of pancreatic cancer cells in vitro with a significant increase in effect when used in combination.

Cell Division↗