Altered quality of life in Rendu-Osler-Weber disease related to recurrent epistaxis.

OBJECTIVES: Development and validation of an epistaxis-specific quality-of-life questionnaire (EQQoL) to evaluate the impact on quality of life of epistaxis, during hereditary hemorrhagic telangiectasia (HHT). STUDY DESIGN: Prospective clinical study using QoL instruments administered twice in HHT patients. PATIENTS AND METHODS: In total, 109 patients who had epistaxis and a clinical diagnosis of HHT according to Curacao criteria were included. Invoice of the questionnaire in 2004 and 2006 included SF-36, Jenkins` sleep scale and the new epistaxis-specific13-item EQQoL. RESULTS: EQQoL uptake rate was 98%, mean score 58/100 +- 27, and Cronbach alpha 0.96. EQQoL was sensitive to change with a strong correlation with the course of epistaxis. Factorial analysis showed that EQQoL was clearly distinct from SF-36 and Jenkins sleep scales. In stepwise multivariate ordinal logistic regression, frequency and duration of epistaxis were both associated with lower EQQoL. Conversely, visceral involvement and comorbidity had independent impact on SF-36 scores, but not on EQQoL. CONCLUSIONS: This new epistaxis-specific EQQoL questionnaire provides complementary information on the impact of HHT on patients quality of life relative to the SF-36 generic questionnaire. After international validation, the EQQoL might prove a useful tool for treatment evaluation.

Imipramine, in part through tumor necrosis factor alpha inhibition, prevents cognitive decline and beta-amyloid accumulation in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.

Effects of menstrual cycle, oral contraception, and training on exercise-induced changes in circulating DHEA-sulphate and testosterone in young women.

The objective of this study was to ascertain the effects of menstrual cycle, oral contraception, and training status on the exercise-induced changes in circulating DHEA-sulphate and testosterone in young women. Twenty-eight healthy women were assigned to an untrained group (n = 16) or a trained group (n = 12) depending on their training background. The untrained group was composed of nine oral contraceptive users (OC+) and seven eumenorrheic women (OC-). The trained group was composed of OC+ subjects only. All the OC+ subjects were taking the same low-dose oral contraception. Three laboratory sessions were organised in a randomised order: a prolonged exercise test until exhaustion, a short-term exhaustive exercise test, and a control session. Blood specimens were collected before, during and after the exercise tests and at the same time of the day during the control session. Basal circulating testosterone was significantly lower in trained as compared to untrained subjects. In all subjects, the prolonged exhaustive exercise induced a significant increase in circulating DHEA-s and testosterone. The short-term exercise induced a significant increase in circulating DHEA-s in untrained eumenorrheic and in trained OC users only. Menstrual phases in OC- did not influence the responses. It was found that exhaustive physical exercise induced an increase in circulating DHEA-s and testosterone in young women. Oral contraception may limit short-term exercise-induced changes.

Intravenous nitroglycerin for prevention of pancreatitis after therapeutic endoscopic retrograde cholangiography: a randomized, double-blind, placebo-controlled multicenter trial.

BACKGROUND AND STUDY AIMS: Several studies have suggested that nitroglycerin promotes pancreatic drainage and thereby helps to prevent pancreatitis occurring after endoscopic retrograde cholangiography (ERC). We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of intravenous nitroglycerin for preventing acute pancreatitis in moderate- to high-risk patients undergoing ERC. PATIENTS AND METHODS: The patients underwent therapeutic ERC for gallstone removal, bile duct stenosis, or sphincter of Oddi dysfunction (SOD). They were randomly allocated to receive an intravenous nitroglycerin bolus of 0.1 mg, then 35 microg/kg per minute intravenously (maximum dose 9 mg) for 6 h, or an identical placebo regimen. Serum amylase and lipase levels were determined before and 24 h after ERC. RESULTS: The study was terminated after the interim analysis. The intention-to-treat population consisted of 208 patients enrolled in 20 centers, of whom 105 received nitroglycerin and 103 placebo therapy. Post-ERC pancreatitis (mild/moderate/severe) occurred in 25 patients, comprising 10 (3/5/2) in the nitroglycerin arm and 15 (5/6/4) in the placebo arm (OR 0.62, 95 % CI 0.26 - 1.45; P = 0.26). Pancreatitis-related hospital stays were similar in the two groups (median 4 days, range 2 - 13 days in the nitroglycerin group; median 5 days, range 2 - 20 days in the placebo group). The incidence of pancreatitis in patients with SOD did not differ between the groups (4/11 in the nitroglycerin arm, and 4/15 in the placebo arm). Adverse events were more frequent in the nitroglycerin group and led to cessation of drug infusion in 10 patients in the nitroglycerin arm and in 2 patients in the placebo arm ( P = 0.019). CONCLUSION: In this study, nitroglycerin offered a limited and clinically nonsignificant benefit for the prevention of post-ERC pancreatitis. Its use did not improve the technical success rate of ERC.

[Health behaviours of students at the University Institute of Technology in Poitiers]. / Comportements de santé des étudiants d'IUT de l'Iniversité de Poitiers.

Better knowledge and understanding of students' health attitudes and behaviours are necessary to more effectively plan targeted prevention strategies. A survey conducted among 617 students at the University Institute of Technology in Poitiers showed that although some indicators affirm good health (relationships with friends and family, appropriate contact with care providers in the health system and regular visits to prevention centres, sexual life, and sports and physical fitness), other indicators reveal a certain amount of suffering among the student population. Students reported suicidal thoughts, symptoms of poor well-being (fatigue, sleeping disorders, concentration problems, sadness or depression) and poor eating habits and/or eating disorders. Consumption of both legal and illegal products seems to be a means utilised to facilitate the social integration process for some students. Therefore, this underlines a significant challenge for prevention campaigns to develop an alternative role model, which promotes the image and profile of a healthy student, with a strong sense of self-esteem, who is well-integrated with his peers without having to engage in substance abuse.

The kinetic profiles of amlodipine and of a sustained release form of diltiazem.

This study in normotensive subjects compared plasma concentrations of amlodipine (5 mg) and of a sustained release form of diltiazem (300 mg) after single and multiple oral dosings of the two drugs. As a consequence of the galenic form of administered formulations, plasma concentration of diltiazem versus time curves exhibited two peaks corresponding to fast and slow releases of diltiazem. Conversely, the curves of amlodipine plasma concentration depicted only one peak. There was less variability in plasma concentrations and in pharmacokinetics with amlodipine than with diltiazem after both single and multiple oral dosings of the two drugs. These results suggested that amlodipine displayed less variability in blood pressure response at steady-state. The rate of decrease in plasma levels of diltiazem between 24 and 48 hours post-dose was higher than that of amlodipine. So, even after a missed dose, there is only a small decline in plasma concentrations of amlodipine and therefore it suggests a small repercussion on the blood pressure attenuation.

[Pharmacokinetics of ponsinomycine with repeated ingestion in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée en prises répétées chez le volontaire sain.

Ponsinomycin or miocamycin (MOM) is a new macrolide which is totally metabolized in vivo. The disposition of its 3 major metabolites (Mb12, Mb6 and Mb9a), was investigated following multiple dosing with ponsinomycin at a dose of 800 mg every 12 h, for 8 days, in healthy volunteers. Drug measurements were conducted by high performance liquid chromatography. In agreement with the low values of their apparent elimination half-lives, respectively less than 1.5 h and 3.0 h, metabolites Mb12 and Mb9a did not accumulate with time. Their pharmacokinetics was apparently stable with time. Conversely Mb6 did accumulate, by approximatively a factor 2, although its apparent elimination half-life was only close to 2 h. This value must therefore be considered with caution. A dose dependency effect was previously observed, Mb6 pharmacokinetics could be non linear with time as well. The relative importance of this metabolite is therefore greater at steady-state, following multiple administration than after single dosing with ponsinomycin.

[Pharmacokinetic properties of Bilobalide and Ginkgolides A and B in healthy subjects after intravenous and oral administration of Ginkgo biloba extract (EGb 761)]. / Propriétés pharmacocinétiques du Bilobalide et des Ginkgolides A et B chez le sujet sain après administrations intraveineuses et orales d'extrait de Ginkgo biloba (EGb 761).

The pharmacokinetics of Ginkgolide A, Ginkgolide B and Bilobalide, which are compounds extracted from the dried leaves of the Ginkgo biloba tree, were investigated in 12 young healthy volunteers (six men and six women; mean +/- SD age = 25 +/- 5 years) after single-dose administration of Ginkgo biloba extract. Subjects were given, on three occasions, Ginkgo biloba extract as a solution either orally (in fasting conditions and after a standard meal) or intravenously; corresponding to single doses of Ginkgolide A, Ginkgolide B and Bilobalide ranging from 0.90 mg to 3.36 mg. After each dosing, blood and urine samples were collected for up to 36 h and 48 h, for measurements of Ginkgolide A, Ginkgolide B and Bilobalide. Plasma and urine concentrations of these compounds were quantitatively measured by gas chromatography/mass spectrometry using negative chemical ionization, by applying a very sensitive method which allowed plasma concentrations as low as 0.2 ng/ml of each compound to be measured. When given orally, while fasting, the extents of bioavailability are high, as shown by bioavailability coefficients (FAUC) mean (+/- SD) values equal to 0.80 (+/- 0.09), 0.88 (+/- 0.21) and 0.79 (+/- 0.30) for Ginkgolide A, Ginkgolide B and Bilobalide respectively. Food intake does not change AUC quantitatively but increases Tmax. For the three compounds of interest, after oral dosing while fasting, differences can be noted for the elimination half-lives (T1/2Z), which exhibit mean values equal to 4.50, 10.57 and 3.21 h, as well as mean residence times (MRT), equal to 5.86, 11.25 and 4.89 h, for Ginkgolide A, Ginkgolide B and Bilobalide respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronic renal failure in Poitou-Charentes: prevalence, structure adequacy, and patient satisfaction]. / Insuffisance rénale chronique en Poitou-Charentes: prévalence, adéquation des structures et satisfaction des patients.

The characteristics of the existing cases in the region, the adequacy of the structures with respect to the needs, and the satisfaction of patients undergoing dialysis have been analysed as part of an ongoing project for the development of a Regional Outline for Health Organisation in the Poitou-Charentes region of France. A cross-sectional survey was conducted in the haemodialysis units, dialysis facilities and patient associations in the region and bordering areas where patients were being treated. As of March 31, 2000, the prevalence of chronic renal failure was estimated to be 373 people per one million of the population. According to the nephrologist, the adequacy of the care structures was found to be satisfactory for 82% of the patients. The main reasons for non-adequacy were first, the lack of intermediate structures between centres and outpatient units; second, the patient's refusal to be referred to another structure; and finally, other medical, physical and intellectual factors. For 90% of patients, their treatment method corresponded to their choice of therapy. The lack of a nearby structure was equally recognised as a primary reason for dissatisfaction. It should be noted that 42% of the patients under 60 years old felt that they were either poorly or very poorly informed of their rights, the coverage and the treatment of this illness.

The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza.

BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

Lack of effect of ponsinomycin on the plasma pharmacokinetics of theophylline.

The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline. The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.

[Pharmacokinetic behavior of cefsulodin and cefotiam alone or in combination after intravenous injection of 1 gram]. / Comportement pharmacocinétique de la cefsulodine et du céfotiam seuls ou associés après une injection intraveineuse de 1 gramme.

Simultaneous administration by the intravenous route of 1 g of cefotiam and 1 g of cefsulodin does not alter the pharmacokinetic parameters of either compound.

Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency.

Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.

Lack of effect of ponsinomycin on the pharmacokinetics of nicoumalone enantiomers.

Pharmacokinetic interaction between ponsinomycin-nicoumalone was studied in six subjects who received an 8 mg oral dose of racemic nicoumalone alone and 4 days into an oral regimen of ponsinomycin 800 mg twice daily. The concentrations of R(+) and S(-)-nicoumalone in plasma were measured using a stereospecific h.p.l.c. assay. The disposition characteristics of nicoumalone enantiomers in the control phase of this study were similar to those reported previously with the exception of the data for one subject whose oral clearance for S(-)-nicoumalone was seven times lower than those in the other subjects. A statistically significant effect of ponsinomycin on the kinetics of R(+) and S(-)-nicoumalone was not demonstrated.

Effect of ponsinomycin on single-dose kinetics and metabolism of carbamazepine.

The effect of ponsinomycin (or miocamycin), a new macrolide antibiotic, was investigated on the pharmacokinetics of carbamazepine (CBZ) administered as a single dose in healthy volunteers. Disposition of the active 10,11 epoxycarbamazepine (ECBZ) was investigated as well. For each compound both total and free plasma concentrations were measured. A moderate (+13%) but statistically significant (p less than 0.05) increase of CBZ total area under the curve (AUC), was observed in the presence of ponsinomycin, accompanied by a 26% decrease (p less than 0.01) in the AUC of its metabolite. There was a tendency toward an increase in AUC of unbound CBZ, although it was not statistically significant. Together these data suggest that formation of ECBZ is inhibited in the presence of ponsinomycin. The relative importance of the epoxy-diol metabolic pathway being increased at steady state due to autoinduction, results of this study suggest that CBZ plasma levels should be carefully monitored in patients receiving ponsinomycin.

[Pharmacokinetics of ponsinomycin administered in a syrup form in single 400-800 and 1200 mg doses in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée sous forme de sirop en prises uniques aux doses de 400-800 et 1,200 mg chez le volontaire sain.

Ponsinomycin is a new macrolide. Its pharmacokinetics is characterized by an extensive metabolism. Following oral dosing in human, unchanged ponsinomycin is not found in blood, but 3 main metabolites: Mb12, Mb6 and Mb9a can be assayed. Twelve young healthy volunteers received ponsinomycin orally, at doses equal to 400, 800 and 1,200 mg on 3 separate occasions, according to a cross-over design. Metabolites Mb12, Mb6 and Mb9a were measured in plasma by HPLC. The pharmacokinetics of Mb12 was linear in the range of doses administered. A dose-dependent effect leading to a reduction of the apparent elimination rate when dose increased was observed with Mb9a and more importantly with Mb6.

[Influence of food intake on the bioavailability of ponsinomycin administered in a syrup form]. / Influence de la prise d'aliments sur la biodisponibilité de la ponsinomycine administrée sous forme de sirop.

Ponsinomycin is a new macrolide. Following oral administration, ponsinomycin is totally metabolized, even before reaching blood circulation. Metabolite Mb12 is the first compound on the main metabolic route, which can be assayed. The influence of food on ponsinomycin bioavailability has therefore been estimated from measurements of Mb12 plasma levels. Twelve young healthy volunteers received 800 mg of ponsinomycin as a syrup on two separate occasions, 2 hours before and during a standard meal. The Mb12 metabolite was assayed in plasma by High Pressure Liquid Chromatography (HPLC). Plasma peak concentrations and areas under curves were not significantly different but time to peak was significantly shorter when ponsinomycin was administered during meal. The results suggest that ponsinomycin absorption is faster when administered with food but quantitatively unchanged.

Melatonin secretion occurs at a constant rate in both young and older men and women.

The magnitude and duration of melatonin (MLT) secretion were measured over a period of 25 h with pharmacokinetic studies employing administration of D(7) MLT at midday and at midnight in two separate studies and two groups of subjects, 12 young and 11 older men and women. Plasma levels of endogenous MLT and D(7) MLT were quantified separately by use of a specific and sensitive method (gas chromatography-mass spectrometry) previously developed in our laboratory, enabling us to measure endogenous and exogenous MLT levels down to 0.5 pg/ml in plasma. In the two groups of subjects, MLT secretion occurred only at night: onset time of secretion was from 1915 to 2205 (Greenwich mean time), and offset was from 0305 to 0545. No MLT peak was observed in individual nocturnal MLT profiles that were similar to curves obtained for a rate-constant infusion. Modelization demonstrated the superimposition of observed data and simulated curves. MLT concentrations decreasing from the offset of secretion might correspond to the elimination of MLT present in the body at the end of nocturnal secretion. By use of the MLT clearance given by pharmacokinetics, the amount of secreted MLT was found to be 35.7 and 21.6 microg for men and women, respectively, and the rate of secretion was 4.6 and 2.8 microg/h, respectively. No significant gender difference was observed for these two parameters when normalized to body weight. No significant gender difference was observed for onset times of secretion or duration of secretion (7.6-8.6 h) within the two groups, or between young and older subjects.

Bioavailability of melatonin in humans after day-time administration of D(7) melatonin.

Absolute bioavailability of the neurohormone melatonin (MLT) was studied in 12 young healthy volunteers (six males, six females) after administration at midday, on two separate occasions, of 23 microg by intravenous (i.v.) infusion and 250 microg by oral solution of D(7) MLT, a molecule in which seven deuterium atoms replace seven hydrogen atoms. Exogenous (D(7)) and endogenous (D(0)) MLT were quantified simultaneously but separately by a highly specific assay: gas chromatography/negative ion chemical ionization mass spectrometry, developed in our laboratory, which enabled us to go down to 0.5 pg/mL in plasma samples. After i.v. administration, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) values were significantly different in male and female subjects, but there was no significant gender difference in total body clearance normalized to body weight: 1.27+/-0.20 L/h/kg and 1.18+/-0.22 L/h/kg for males and females, respectively. The apparent terminal half-life (t(1/2(z))) values were 36+/-2 and 41+/-10 min, respectively. After oral administration, pharmacokinetic parameters used to quantify bioavailability were near three-fold greater in female subjects than in males, with large inter-individual variations. The maximum plasma MLT concentration C(max)+/-S.D. was found at 243.7+/-124.6 pg/mL and 623.6+/-575.1 pg/mL for male and female subjects respectively, while the mean values for AUCs were 236+/-107 pg.h/mL and 701+/-645 pg.h/mL. The absolute bioavailability of MLT was from 1 to 37%: mean=8.6+/-3.9% and 16.8+/-12.7% for male and female subjects, respectively.

Steady-state bioavailability and pharmacokinetics of ambroxol and clenbuterol administered alone and combined in a new oral formulation.

Ambroxol and clenbuterol are two drugs with potential pharmacological synergy. The objective of this study was to compare the apparent bioavailabilities at steady-state of these two compounds administered alone or in combination (CHF-023). Nine healthy male volunteers participated in the study. They received 30 mg of ambroxol alone (one Fluibron tablet), or 20 micrograms of clenbuterol alone (one Spiropent tablet), or 30 mg of ambroxol plus 20 micrograms of clenbuterol in combination (one CHF-023 tablet), every 12 hours for 7 days on three separate occasions. Ambroxol and clenbuterol concentrations were measured in plasma by appropriate GC/MS methods. Pharmacokinetic parameters were calculated by non-compartmental methods and submitted to statistical comparisons. Compartmental analysis was also performed on data provided by CHF-023 treatment. It was concluded that apparent bioavailabilities of ambroxol and clenbuterol are almost identical in Fluibron and CHF-023 tablets, and in Spiropent and CHF-023 tablets, respectively, with no statistically significant differences between pharmacokinetic parameters calculated for these two drugs during different treatments, except for peak concentration of ambroxol.