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Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 43 - N° 5 - p. 361-370

Ordered anodic aluminium oxide (AAO) films were first prepared by anodising in a phosphoric acid electrolyte and then studied extensively and characterised by field emission gun-scanning electron microscopy (FEG-SEM), X-ray diffraction, Raman and infrared spectroscopy at a macroscopic scale. These analyses showed that the as-prepared AAO film is in fact amorphous, partially hydrated and that its initial global chemical composition can be described, in agreement with previous works, as: Al2O3, 0.186AlPO4 · 0.005H2O. Additional analyses (thermogravimetric analysis, differential thermal analysis and FEG-SEM) showed geometrical changes of the film structure at different scales, explained by various steps of dehydration and allotropic transformations of the resulting crystallised alumina. However, because their structure remains unchanged up to 900 °C, the phosphoric templates appear to be particularly suitable for applications or processes at medium or high temperatures, such as the preparation of carbon nanotubes or oxide rods. Copyright © 2010 John Wiley & Sons, Ltd.

Summary Purpose: To test bioequivalence of oral vitamin E formulations, water-soluble tocofersolan (test) and water-miscible (reference), in healthy adult volunteers, and their bioavailability in children with chronic cholestasis or cystic fibrosis. Methods: In a two-way open randomized single dose cross-over design, 1200 IU were administered in 12 healthy volunteers and 100 IU/kg in 12 children with chronic cholestasis or cystic fibrosis. Results: In healthy volunteers, formulations were not bioequivalent with a higher exposure to tocofersolan. In cholestatic children tocofersolan bioavailability was significantly higher than reference formulation (maximum plasma concentration: P = 0·008 and AUC: P = 0·0026). Bioavailability was not statistically different in cystic fibrosis. Conclusions: Oral tocofersolan was more bioavailable than the reference formulation in children with chronic cholestasis and similarly bioavailable in cystic fibrosis. Tocofersolan may represent an alternative to painful intramuscular vitamin E injections in chronic cholestasis, or to other oral formulations in cystic fibrosis.

In port fuel injection engines, the liquid fuel film accumulated in the vicinity of intake valves is torn away and goes into the cylinder during the intake phase. In order to predict the fuel mixture preparation inside the cylinder, a model for the fuel film separation near the sharp edges of the intake valves has been developed. A separation criterion is set up using an analogy with Rayleigh-Taylor instabilities driven by the inertial forces of the film. The critical value for the separation criterion is adjusted using experimental data obtained in a two-dimensional wind tunnel fitted with different steps shaped as the valve seat and reproducing the main characteristics of the intake of a spark ignition engine. Computational fluid dynamics simulations are performed using the KMB code, a modified version of KIVA-2 already including a film model and a stochastic Lagrangian description of the spray. Computation for the intake stroke on a four-cylinder 1.9 litre port fuel injection engine confirms that the fuel droplets are not completely vaporized at the end of the intake stroke.

Fuel/air mixing is analysed on an optical gasoline direct-injection engine. The fuel concentration field is measured using a laser-induced fluorescence technique. Three conditions, which vary injection timing while keeping constant the ignition timing, are investigated. A qualitative correlation is made between the local fuel/air ratio near the spark plug with ignition and combustion in chamber. It is found that the mean concentration at the ignition point is high when the delay between injection and ignition is short. In some cycles, liquid fuel covers the electrodes resulting in frequent misfires. The best operating point is achieved with near-stoichiometric conditions at the ignition point, and a moderate concentration cyclic variability. On the contrary, early injection timing gives lean conditions and large cyclic variations at the ignition point. Moreover, the mixture is more dilute in the chamber, and combustion is slow and unstable. Cycle to cycle correlation between fuel concentration near the spark gap and combustion initiation shows that locally lean conditions give very slow combustion.

In order to predict the fuel mixture preparation inside the cylinder of port fuel injection engines, a model for the aerodynamic stripping of the fuel film deposited on the manifold walls is discussed, and a model for the fuel film separation and atomization near the sharp edges is developed. A separation criterion is set up using an analogy with Rayleigh-Taylor instabilities driven by the inertial forces of the liquid film. To determine the physical parameters of the resulting droplets, a liquid sheet atomization scheme is used. The critical value for the separation criterion is adjusted using experimental data obtained in 2D wind tunnel equipped with different steps shaped as a valve seat, and reproducing the main characteristics of the intake of spark ignition engine. CFD simulations are performed using the KMB code, a modified version of KIVA-2 already including a stochastic Lagrangian description of the spray, and an Eulerian liquid film model. Computations results for different operating conditions are in good agreement with the images of film separation and measured droplet size distributions.

The effect of 3 dosages of bromazepam administered as single oral doses (1.5, 3 and 6 mg) on anxious inhibition phenomena was studied in a population of 16 young women (18-30 years) with anxiety-traits, selected on the criteria of Cattell's anxiety scale supported by two personality inventory (Eysenck's, MMPI). A double-blind, placebo study design was chosen. The main assessment criteria were based on the go/no-go test (Logan's procedure), slow response rate (SRR) and a task of forced or unforced decision (use of the CFF). Attentional processes and declarative memory were analyzed as secondary criteria. None of the three dosages modified inhibition or acting-out. Sustained attention was reduced with 1.5 mg and 6 mg, as was memory performance with 3 and 6 mg, 3.5 h after drug administration. In contradistinction with studies carried out in healthy volunteers or with other benzodiazepine compounds, bromazepam at single low dosages does not modify inhibition capacity in these subjects with traits of anxiety, in this particular procedure.

Resume La gestion de la crise de l'accident du vol TWA a evolue sur plusieurs periodes: une premiere periode correspondant au 1 er jour, est consacree a la prise en charge des attendants et a l'annonce de la liste des victimes. Cette periode a permis a la compagnie d'installer son PC de crise, PC qui fonctionnera 24 heures sur 24 durant plus de 3 semaines; une deuxieme periode limitee arbitrairement du 2 e au 6 e jour et dominee par: les retentissements traumatiques du 1 er jour, la mise en place des structures d'encadrement des familles. Les infrastructures du CRIC sont mises en sommeil progressivement.

The effects on memory, psychomotor performance and mood of two dosage regimens of befloxatone, a new reversible and selective MAO-A inhibitor were assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 12 healthy young male volunteers. Befloxatone and a placebo were orally administered as single (5 and 10 mg) and repeated doses (10 mg once daily and 5 mg twice daily) at one week wash-out intervals. Objective tests evaluated both memory (working memory, immediate and delayed free recall of a word list, dual coding and faces recognition) and vigilance continuous performance task (CPT), and digit symbol substitution (DSST). Subjective mood and sleep were assessed using visual analogue scales and the Leeds Sleep Evaluation Questionnaire. Statistical analysis was conducted using an ANOVA with pairwise comparisons using the Student Newman Keuls procedure. Both dosage regimens of befloxatone (10 mg once daily or 5 mg twice daily) were free of any detrimental effect on vigilance (CPT) and information processing (DSST) and did not significantly disrupt short- and long-term memory (working memory, free recall of words, dual coding and faces recognition). In addition, no subjective sedation or sleep disturbances were recorded. In conclusion, this study gives no evidence to suggest that befloxatone, at a daily dose which shows potent MAO-A inhibition, has any sedative or amnestic properties likely to interfere with the activities of everyday-life in young subjects and therefore may be safely administered in depressed outpatients.

SummaryThe effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale — Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective “residual” effect.

A prototype twin superconducting quadrupole magnet for the Large Hadron Collider (LHC) is being developed and built at CEN/Saclay in collaboration with CERN. This paper describes the mechanical tests performed to validate the main concepts of the mechanical design in order to meet the requirements of prestress while maintaining a precise geometrical shape of the coils. Moulding tests on samples of superconducting cables have been made in order to evaluate the final size of the coils after curing and under stress. Collaring tests have been made on small length models to verify the process and the resulting prestress. The principal results and conclusions of the tests are summarized. >

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Alzheimer's disease (AD) is a progressive brain disorder that gradually destroys a victim's memory and cognitive processes. • Currently there are no approved treatments for AD capable of modifying the disease process. • Symptomatic agents available target the neurotransmitter systems known to decline during the progression of the disease (including cholinesterase inhibitors); however, overall effects on clinical deterioration are known to be modest. • It has been hypothesized that 5-HT1A antagonists such as lecozotan might function as an effective treatment of the cognitive deficits associated with AD, as they have been shown to improve cognitive performance in multiple animal models of learning and memory. WHAT THIS STUDY ADDS • This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for memory disturbances associated with AD. • Acting through a new mechanism of action, lecozotan antagonizes the 5HT1A receptor potentiating both cholinergic and glutamatergic neurotransmission. • The three initial safety, PK and PD studies described in this study establish that lecozotan immediate release (IR) was safe and well tolerated in both healthy young and elderly subjects at total daily doses up to 10 mg (5 mg every 12 h). • There were no counter-indicative PD findings during the study. • With the development of a sustained-release formulation for once-daily dosing, lecozotan is currently under investigation in advanced Phase II clinical trials. AIMS To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects. METHODS Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD. RESULTS Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at tmax and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly. CONCLUSIONS Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.

The subjective response to the prescription drug zopiclone, an hypnotic agent belonging to the cyclopyrrolone family, was assessed under the usual conditions of prescription of an hypnotic in general practice. The study included 20,513 insomniac outpatients with at least two of the following symptoms: sleep onset latency longer than 1 hour, more than two nocturnal awakenings, early morning awakening 1 hour or more before scheduled time, total sleep time of less than 6 hours, complaint of tiredness on awakening. Insomniac patients were treated with zopiclone and followed for 21 consecutive days within the context of a follow-up surveillance study. The population was predominantly female (62.6%), and the mean age was 52.3 years. The dosage of zopiclone prescribed at the inclusion visit was 7.5 mg per day in 87.5% of the cases and 3.75 mg per day in 10.5%. A total of 93.8% of the patients completed the survey. Spiegel questionnaire improved during the 21-day survey, and 9.2% of the patients reported at least one adverse event that led to treatment discontinuation in only 2.8% of the population. No serious or unexpected adverse events were reported.

L'objectif du projet GSM Moteur de Synthese a Allumage Commandeest de concevoir un moteur fonctionnant en melange pauvre a la fois depollue et econome. La premiere phase analyse finement sur moteur monocylindre les interactions entre l'aerodynamique et la combustion qui determinent l'aptitude au fonctionnement en melange pauvre ou dilue. La procedure employee presente la particularite d'associer des outils complementaires tels que code de calcul tridimensionnel, diagnostics optiques (anemometrie laser et ombroscopie) et mesures classiques sur banc monocylindre. La modelisation tridimensionnelle est utilisee comme moyen efficace de selection et de prediction de l'aerodynamique interne. Les parametres les plus influents sur la stabilite de l'initiation de la combustion sont la direction et l'intensite de la vitesse au point d'allumage et le niveau de turbulence. Le meilleur compromis favorable au fonctionnement en melange pauvre est constitue par une culasse possedant une chambre de combustion en toit avec une seule soupape d'admission. Son aerodynamique interne est caracterisee par la combinaison d'un mouvement de rotation d'axe vertical (swirl) avec un tourbillon d'axe horizontal balayant l'arete du toit (tumble). Son niveau de turbulence est ajuste de maniere a accroitre la vitesse de combustion en limitant les instabilites cycle-a-cycle. La deuxieme phase est consacree a la transposition de cette solution sur un moteur multicylindre. Les principales difficultes rencontrees sont liees aux disparites de comportement entre cylindres accentuees par le fonctionnement en melange pauvre. Seul un controle individuel des parametres de combustion de chaque cylindre (avance, injection, richesse) associe a un ecartement d'electrodes de bougie accru permet de re-trouver des resultats proches de ceux acquis sur monocylindre. Dans ces conditions, les limites pauvres se situent a des richesses comprises entre 0,60 et 0,70 suivant la charge et le regime. La diminution des emissions d'oxydes d'azote qui en resulte atteint en moyenne sur des points representatifs du cycle ECE15 74 % par rapport au fonctionnement a la stoechiometrie. Enfin, des essais avec recyclage des gaz d'echappement ont demontre le potentiel de la solution optimisee d'un point de vue aerodynamique a tout mode de fonctionnement en melange dilue.

The effects of exercise on bisoprolol oral pharmacokinetics were studied in eight healthy male volunteers in an open, randomized, three-period, crossover trial. Oral bisoprolol (20 mg) was given either at rest during 24 h or with iterative stress tests before and 2.5, 5, 10, and 24 h after dosing. Exercise tests were repeated on a third placebo period. Bisoprolol was assayed in plasma and urines, and plasma catecholamines were measured before and after stress tests, Cmax, Tmax, elimination t1/2, and renal clearance of bisoprolol were not significantly modified by exercise. AUC0-infinity significantly decreased by 7.5% (p less than 0.05) with stress test resulting in an increase in apparent oral clearance. The beta-blocking effect peaked at 2.5 h, lasted greater than 24 h, and was related to plasma levels. The exercise-induced increase in plasma norepinephrine levels was significantly augmented with bisoprolol. These results suggest that repeated exercise tests exerted only limited effects on the oral pharmacokinetics of bisoprolol.

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.

The effects of mizolatine, a new H1 receptor antagonist, on safety and pharmacokinetics of digoxin were studied in a double-blind placebo-controlled crossover study. After administration of digoxine alone (0.25 mg o.d. for 7 days), 12 healthy young male volunteers (23+/-2 years) received either placebo and digoxin (0.25 mg o.d.) or mizolastine (10 mg o.d.) and digoxin (0.25 mg o.d.) during 7 days. The assessment criteria consisted in hemodynamic and ECG parameters recordings and the pharmacokinetics of digoxin during the last day of coadministration (day 14). No difference between the 2 treatment groups was evidenced on ECG, hemodynamic, and clinical and laboratory safety parameters. No change in AUC and tmax was recorded. No clinically relevant effect of mizolastine on the digoxin pharmacokinetics was found. However, a statistically significant increase in digoxin Cmax (3.03+/-0.18 nmolxl(-1) vs 2.52+/-0.19 nmolxl(-1), p0.05) and Cmin (0.99+/-0.08 nmolxl(-1) vs 0.87+/-0.07 nmolxl(-1), p=0.05) occurred after the coadministration vs digoxin alone. It can be concluded that mizolastine and digoxin at therapeutic dosages can be safely coadministered.

The department DAPNIA of the CEA Saclay has been involved in High Energy Physics for several decades, working on projects such as Detectors, Superconducting magnets (STCM), Thermonuclear Fusion machine (TORE SUPRA [1]) and accelerator magnets. Considerable research and development effort have gone into the design and production of quadrupole magnets for HERA [2], and, over the last two years, for LHC [3].

CEA/Saclay has a long standing tradition in the area of High Energy Physics, both in equipement and experiments. In the field of Superconducting magnets for accelerators, one can recall the HERA Superconducting quadrupoles1, and the work presently being made on the LHC Superconducting quadrupoles2.

The respective effects of three antidepressant drugs (moclobemide, 450 mg/j; viloxazine, 300 mg/j; maprotiline, 150 mg/j) on vigilance, attention, and memory were compared. Young depressed outpatients (n = 46) entered a double-blind, randomized, monocentre clinical trial lasting for 6 weeks. Drug actions were assessed through the regular determination of critical flicker fusion point (CFF), reaction times (SRT), and a battery to measure memory components. None of the three drugs caused deterioration in cognitive functions. On the other hand, moclobemide improved both vigilance and attention (CFF, SRT) and some crucial components of memory (general memory scores, delayed word recall, recognition of familiar faces). This effect was rapid, stable, and superior to those of viloxazine and maprotiline. It may be explained by moclobemide's selective and reversible inhibition of monoamine oxidase A, as well as by the lack of any anticholinergic action.

Parlodel-SRO is a newly developed slow-release formulation of bromocriptine, which prevents initial plasma peak--a known source of adverse events--and extends the half-life of the compound, an interesting feature for the management of motor symptoms in Parkinsonians. This study was designed to determine the best daily administration schedule for 30 mg Parlodel-SRO in 18 parkinsonians previously treated with levodopa and standard Bromocriptine (Br). The 30 mg dose was replaced from one day to the next, in a randomized, double-blind latin square design trial. Three consecutive 7-day courses were implemented, during which a total daily dose of 30 mg P-SRO was administered in one dose, two intakes (b.i.d.) and three intakes, (t.i.d.) respectively. The b.i.d. schedule produced the best improvement in UPDRS scores, especially as to postural stability, walking, bradykinesia; it also provided greater pharmacological stability throughout the assessment day. Adverse event analysis was not in favor of a single daily dose. It appeared that P-SRO administered in two 15 mg intakes (morning and evening) produces the best benefit-risk ratio in Parkinsonians who were already being treated with levodopa.

1987) was completed daily each morning. Sleep lab studies were carried out on 7 nights (pre-drug placebo nights 6, 7; drug nights I, 27, 28; post-drug placebo nights 1,7) and included polysomnography, evaluation of subjective sleep quality, subjective and objective awakening quality measured by psychometry. An activity monitor was worn by the patients throughout the 6 weeks to investigate the sleep-wake cycle. Preliminary evaluations demonstrated significant improvement of the anxiety syndrome and the sleep quality during both active compounds, as compared with placebo, with a worsening of symptoms on the I st night of placebo substitution, levelling off until the 7th night. Differential drug effects will be discussed.