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BACKGROUND: Systemic antibiotics are routinely prescribed for severe acute malnutrition (SAM). However, there is no consensus regarding the most suitable regimen. In a therapeutic feeding centre in Khartoum, Sudan, a randomised, unblinded, superiority-controlled trial was conducted, comparing once daily intramuscular injection with ceftriaxone for 2 days with oral amoxicillin twice daily for 5 days in children aged 6-59 months with SAM. METHODS: Commencing with the first measured weight gain (WG) following admission, the risk difference and 95% confidence interval (95% CI) for children with a WG > or = 10 g/kg/day were calculated over a 14-day period. The recovery rate and case fatality ratio (CFR) between the two groups were also calculated. RESULTS: In an intention-to-treat analysis of 458 children, 53.5% (123/230) in the amoxicillin group and 55.7% (127/228, difference 2.2%, 95% CI -6.9-11.3) in the ceftriaxone group had a WG > or = 10 g/kg/day during a 14-day period. Recovery rate was 70% (161/230) in the amoxicillin group and 74.6% (170/228) in the ceftriaxone group (p=0.27). CFR was 3.9% (9/230) and 3.1% (7/228), respectively (p=0.67). Most deaths occurred within the 1st 2 weeks of admission. CONCLUSION: In the absence of severe complications, either ceftriaxone or amoxicillin is appropriate for malnourished children. However, in ambulatory programmes, especially where there are large numbers of admissions, ceftriaxone should facilitate the work of medical personnel., Epicentre

Introduction et but de l’etude La douleur chronique est frequente dans l’obesite. La privation du sommeil abaisse le seuil de perception de la douleur (SD) et sa restauration ameliore celui-ci. Le syndrome d’apnees obstructives du sommeil (SAOS), induit des perturbations majeures de l’architecture du sommeil. Le SAOS pourrait ainsi generer des troubles de perception de la douleur. Nous avons donc etudie au sein d’une population de sujets obeses, l’impact de la presence d’un SAOS sur le SD et l’efficacite du traitement par pression positive continue (PPC) a moyen terme. Materiel et methodes Cette etude prospective, longitudinale, controlee a inclus des patients obeses (IMC ≥ a 30) issus des services de nutrition ou de pneumologie du CHU de Clermont-Ferrand entre fevrier 2010 et fevrier 2017. Une polygraphie nocturne ambulatoire etait realisee afin de confirmer ou d’infirmer la presence d’un SAOS. Les patients etaient soumis a des tests de douleurs mecaniques (appareil de Von Frey electronique) et electriques (PainMatcher®) dans la semaine suivant la polygraphie et pour ceux presentant un SAOS severe (index apnee hypopnee ≥ 30) 1 mois apres la mise en place du traitement par PPC. Les variables quantitatives etaient comparees a l’aide d’un test de Student si normales, sinon avec le test de Wilcoxon, et ajustee sur l’âge, le sexe, l’IMC et le tabagisme. Resultats et analyse statistique Quatre-vingt-cinq patients ont ete inclus : 58 depourvus d’apnee et 27 apneiques dont 11 SAOS severes necessitant un appareillage par PPC. On notait une predominance feminine (69 %) un age moyen de 40 ± 13,2 ans et un IMC moyen a 42 ± 7,2. Les patients apneiques presentaient un SD plus faible selon la modalite mecanique (240 vs 328 g ; p = 0,019) mais pas electrique (10,2 vs 12,9 ; p = 0,12). Les apneiques severes presentaient un SD significativement inferieur aux non apneiques dans les modalites mecaniques (177 vs 328 g ; p Conclusion Chez les patients obeses, la presence d’un SAOS est associee a un SD diminue, notamment en cas de SAOS severe et sur la modalite mecanique. L’appareillage par PPC tend a normaliser ce SD. Le depistage et la prise en charge du syndrome d’apnee du sommeil est donc plus que jamais un enjeu majeur de qualite de vie chez l’obese.

Introduction La survenue groupee de 12 cas d’infections invasives a meningocoques C (IIM-C) (C2a, P1-5, P1-2, P1-2,5) severes (8/12 purpura fulminans ; 3/12 deces liees au CC-ST37) chez des jeunes enfants et adolescents, fin 2001–debut 2002, a conduit, en fevrier 2002, a une campagne de primo-vaccination de masse ciblant principalement les personnes âgees Materiels et methodes La primo-vaccination a ete administree en fevrier-mars 2002 a 65 536 personnes âgees de moins de 24 ans (taux de couverture vaccinale > 70 % chez les 1–24 ans). L’impact de la campagne vaccinale a ete mesure par la survenue ulterieure de cas incidents d’IIM-C dans le departement grâce aux donnees du laboratoire de microbiologie du CHU et a la Declaration obligatoire (DO) adressee a la CIRE de 2002 a 2017. Une enquete cas-temoins, en 2016, a inclu des personnes âgees de 14 a 39 ans (âgees de 1 a 24 ans en 2002) vaccinees (cas) ou non (temoins) pendant la campagne : 116 cas et 68 temoins (âge moyen : 24 ans). Les personnes vaccinees, depuis la campagne vaccinale, avec un autre vaccin antimeningococcique n’etaient pas inclues. Le titre sanguin d’Ac hSBA, realise, au CNR des Meningocoques a ete considere comme protecteur si ce dernier etait superieur ou egal a 1/8. Resultats Aucun cas d’IIM-C n’a ete identifie au cours de la periode 2002–2017 chez des personnes vaccinees pendant la campagne de 2002. La pharmacovigilance n’a rapporte aucun effet indesirable grave. De 2002 a 2009, 9 cas d’IIM-C sont survenus chez des patients non vaccines. De 2010 a 2017, 3 cas d’IIM-C sont survenus chez des patients non vaccines. 48 cas d’autres IIM sont survenus sans augmentation tendancielle annuelle. Quatorze ans plus tard, la proportion des personnes vaccinees ayant un titre considere comme protecteur (hSBA > 1/8) etait statistiquement superieure a celle des personnes non-vaccinees : 64 %(55–73) versus 16 %(8–27) ; p 1/4, la proportion des personnes vaccinees etait aussi significativement plus elevee : 75 % (66–83) versus 35 % (24–48) ; p Conclusion La primo-vaccination pratiquee lors de la campagne vaccinale de 2002 confere une protection d’au moins 14 ans chez au moins les 2/3 des vaccines. La presence d’un signal chez les non vaccines temoigne d’une circulation active des meninogocoques C chez les enfants et adultes jeunes qui justifie pleinement les recommandations en vigueur.

Background: This randomized, double blind trial determined the short and long-term clinical and hemodynamic vasodilator effects induced by percutaneous applications of natural CO2 gas in patients with moderate Fontaine stage II. Patients and methods: 62 patients with intermittent claudication (100-500 meters) were randomized to 18 consecutive days of CO2 treatment or placebo (air). The gas fluids were applied at a constant temperature of 30°C on pre-humidified skin. The effects of the treatment were evaluated by total distance walked (primary criterion) and hemodynamic and microcirculatory findings. Patients also answered a quality of life questionnaire. Results: The Strandness test showed a significant increase in total distance walked (+ 131 meters, 66%; p = 0.001) and pain-free distance (+ 81 meters, 73%; p = 0.02) after 18 days of CO2 treatment. The improvement was maintained 3 and 12 months later. The systolic pressure index (ABI) increased by 37% (p = 0.001) 1 minute after treadmill walking and ABI recovery time decreased significantly by 38% (p = 0.002). Microcirculatory findings showed an increase in systolic pressure of the great toe (13%; p

Resume La douleur est souvent associee aux perturbations physiologiques et psychologiques avec alterations significatives de la qualite et de la quantite du sommeil. Il s’agit des difficultes d’endormissements, des reveils nocturnes multiples et du raccourcissement de la duree totale du sommeil, suivis d’un etat de mal-etre physique et psychique. Dans les affections douloureuses chroniques, les enregistrements polysomnographiques retrouvent une augmentation du nombre d’eveils intrasommeil et une baisse de l’index d’efficacite du sommeil. Un certain nombre d’auteurs evoquent egalement une augmentation proportionnelle du pattern alterne cyclique ou « cyclic alternating pattern » avec l’intensite des symptomes douloureux traduisant l’instabilite du sommeil.

Les cliniciens rencontrent de nombreuses difficultes pour mettre en evidence et quantifier l’effet analgesique des nouvelles molecules. Une des principales explications a ces echecs est le decalage entre le developpement de molecules agissant sur des cibles pharmacologiques tres specifiques et l’heterogeneite des mecanismes physiopathologiques impliques dans la douleur. Les methodes visant a attenuer les facteurs de variabilite dans les reponses aux traitements peuvent ameliorer la puissance des essais cliniques. Une autre piste consiste a selectionner les patients sur des criteres qui ont une reelle pertinence pharmacologique. Cette approche peut avoir des retombees positives dans l’individualisation des traitements.

The safety and immunogenicity of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae was evaluated in 84 volunteers according to the route of administration, i.e., subcutaneous (SC) or intramuscular (IM), in a double-blind randomised trial. The volunteers were randomised into four groups: SC vaccine; IM vaccine; SC placebo; and IM placebo. Primary vaccination comprised two injections on day 0 and day 14, with a booster after 6 months. A second booster was given 30 months after primary vaccination. Local reactions within 1 h of injections were rare, with no difference between vaccine groups. Local reactions within 3 h were more frequent after the second, third and fourth SC injections than after IM injections. Systemic reactions never occurred within 1 h of vaccination and were rare within 3 days; the rates were comparable for the different vaccine groups. Evolution of the antibody responses, as assessed by microscopic agglutination tests and specific IgG and IgM ELISAs, were similar for both injection routes. IgG seroconversion rates after the first booster were 97% (95% CI 80–100%) for the SC vaccine group, and 96% (95% CI 80–100%) for the IM vaccine group, and both reached 100% for IgG after the second booster. The safety and immunogenicity of the anti-leptospiral vaccine were both good. Monitoring of antibody levels established that a booster dose triggered a strong antibody response in fully vaccinated subjects at 30 months after primary vaccination.

The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day(-1)).A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24-h period.In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, Cmax was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for Cmax and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 micro g ml(-1) (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 microg ml(-1) (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10-14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 micro g ml(-1). Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets.These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects.

Jusqu’a une date recente, aucun antalgique de palier II ne pouvait etre prescrit en France chez l’enfant de moins de 15 ans, si l’on voulait respecter les conditions d’Autorisation de Mise sur le Marche. Pour certains de ces antalgiques tels que le dextropropoxyphene ou le tramadol, on dispose aujourd’hui de trop peu de recul clinique et d’un manque d’etudes realisees chez l’enfant avec une methodologie rigoureuse, pour en recommander l’usage pediatrique. Ce n’est pas le cas de la codeine, qui est assez largement prescrite en pediatrie dans de nombreux pays, notamment les pays anglo-saxons, a des posologies de 0,5 a 1 mg/kg toutes les 4 a 6 heures, si necessaire et ceci a partir de l’âge de 30 mois. Actuellement les medecins attendent avec impatience la mise a disposition de formes galeniques de codeine adaptees a un usage pediatrique. La nalbuphine, qui peut etre prescrite a partir de l’âge de 18 mois, occupe une place particuliere, dans la mesure ou elle est utilisable par voie parenterale, en principe reservee a un usage hospitalier.

Chronic postsurgical pain (CPSP) is a common clinical situation which is still poorly assessed and often treated too late. An understanding of the neuropathic or inflammatory nature of CPSP will lead to an appropriate therapeutic approach. In everyday practice and in the majority of treatment studies, pain assessment is based on validated scales or questionnaires and simple clinical examination tools. Sophisticated investigations (electrophysiology, psychophysical techniques, or functional cerebral imaging) are reserved for pathophysiological studies or for clinical trials seeking to understand the mechanism of action of analgesic drugs. Postsurgical neuropathic pain (PSNP), due to its frequency, its relative homogeneity and its rather stereotyped time of onset, offers an excellent model for clinical research into neuropathic pain, which has been little used until now.

L’evaluation de la DCPC est abordee de maniere tres differente selon que l’on se place dans le cadre d’une prise en charge therapeutique courante, d’un essai therapeutique ou d’une etude des processus physiopathologiques en jeu.

Plasma norepinephrine (NE) concentration increases with altitude exposure while maximal heart rate (HR) and chronotropic response to isoproterenol (IP) are blunted. Downregulation of cardiac beta-adrenergic receptors (beta-AR) has been evoked to explain this phenomenon. Chronotropic response was studied at extreme altitude in 10 subjects (4 women, 6 men; aged 35 +/- 6 yr). Observations were made in normoxia (N) and after 1 (H1) and 3 (H3) wk at 6,542 m. Acclimatization was accomplished by gradual climbing from 4,000 to 6,542 m over 10 days. Plasma NE was obtained at rest and during submaximal exercise. Successive doses of IP (0.02, 0.04, and 0.06 microgram/kg-1.min-1) were infused for 5 min each. Density and affinity of lymphocyte beta 2-AR were also measured. Increase in HR for maximal dose of IP decreased from 57 +/- 12 to 34 +/- 7 and 37 +/- 10 min-1 in H1 and H3, respectively (P < 0.001 for both). IP dose for which HR rises by 25 min-1 (I25) increased from 27 +/- 5 in N to 42 +/- 10 and 43 +/- 17 ng.kg-1.min-1 in H1 and H3, respectively (P < 0.001 for both). Arterial O2 saturation at rest was 98 +/- 2% in N, 72 +/- 6% in H1 (P < 0.001), and 79 +/- 5% in H3 (P < 0.001). The chronotropic response was neither restored nor further attenuated after 3 wk at 6,542 m. Plasma NE levels at rest and during exercise were higher at 6,542 m than values obtained in previous studies at 4,350 and 4,800 m.(ABSTRACT TRUNCATED AT 250 WORDS)

The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This model has been used to compare the long term in vivo effects of CV 205-502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. These two drugs were given for 2 months to female Wistar-Furth rats bearing either small or large tumors 4 and 6 months after the graft. Untreated grafted rats served as control. In all rats treated with 5 or 10 mg/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL or CV or BR-treated rats, < 15 ng/ml vs. 28253 ng/ml in control rats 8 months after graft). An inhibition of tumor growth was found for both small and large tumors, but the tumors never disappeared completely (mean tumor weights at autopsy, 440 and 660 mg in BR and CV groups vs. 5270 mg in control group 8 months after graft). Experiments performed with increasing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicated that CV is effective at doses 5-10 times lower than those of BR. A shrinkage under treatment and a regrowth after drug withdrawal were demonstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybridization. In conclusion, CV and BR exhibit similar inhibitory effects on tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions comparable to those used in the treatment of human prolactinomas.

Summary Variations of Ca 2+ influx (evaluated by the initial rate of 45 Ca 2+ uptake) and cytosolic free Ca 2+ concentration ([Ca 2+ ] i , measured with fura-2) were investigated in human erythrocytes. When external Ca 2+ concentration ([Ca 2+ ] o) rose from 1 to 2 mM, the initial rate of Ca 2+ influx nearly doubled whereas [Ca 2+ ] i increased only by 15%. Nicardipine dose-dependently decreased both initial rate of Ca 2+ influx and [Ca 2+ ] i (up to 53 and 18%, respectively at 10 −6 M). The less marked changes in [Ca 2+ ] i than in Ca 2+ influx indicate a partial adjustment of the Ca 2+ extruding-pump activity to of Ca 2+ influx. In vivo administration of nicardipine reduced [Ca 2+ ] i only when its initial value exceeded 80nM and prevented the rise in [Ca 2+ ] i induced by the increase in [Ca 2+ ] o . Our results indicate that nicardipine may reduce Ca 2+ influx in human erythrocytes and participate in the control of [Ca 2+ ] i when elevated.

Background: Despite the comprehensive World Health Organization (WHO)/United Nations Children's Fund (UNICEF) measles mortality-reduction strategy and the Measles Initiative, a partnership of international organizations supporting measles mortality reduction in Africa, certain high-burden countries continue to face recurrent epidemics. To our knowledge, few recent studies have documented measles mortality in sub-Saharan Africa. The objective of our study was to investigate measles mortality in three recent epidemics in Niamey (Niger), N'Djamena (Chad), and Adamawa State (Nigeria). Methods and Findings: We conducted three exhaustive household retrospective mortality surveys in one neighbourhood of each of the three affected areas: Boukoki, Niamey, Niger (April 2004, n = 26,795); Moursal, N'Djamena, Chad (June 2005, n = 21,812); and Dong District, Adamawa State, Nigeria (April 2005, n = 16,249), where n is the total surveyed population in each of the respective areas. Study populations included all persons resident for at least 2 wk prior to the study, a duration encompassing the measles incubation period. Heads of households provided information on measles cases, clinical outcomes up to 30 d after rash onset, and health-seeking behaviour during the epidemic. Measles cases and deaths were ascertained using standard WHO surveillance-case definitions. Our main outcome measures were measles attack rates (ARs) and case fatality ratios (CFRs) by age group, and descriptions of measles complications and health-seeking behaviour. Measles ARs were the highest in children under 5 y old (under 5 y): 17.1% in Boukoki, 17.2% in Moursal, and 24.3% in Dong District. CFRs in under 5-y-olds were 4.6%, 4.0%, and 10.8% in Boukoki, Moursal, and Dong District, respectively. In all sites, more than half of measles cases in children aged under 5 y experienced acute respiratory infection and/or diarrhoea in the 30 d following rash onset. Of measles cases, it was reported that 85.7% (979/1,142) of patients visited a health-care facility within 30 d after rash onset in Boukoki, 73.5% (519/706) in Moursal, and 52.8% (603/1,142) in Dong District. Conclusions: Children in these countries still face unacceptably high mortality from a completely preventable disease. While the successes of measles mortality-reduction strategies and progress observed in measles control in other countries of the region are laudable and evident, they should not overshadow the need for intensive efforts in countries that have just begun implementation of the WHO/UNICEF comprehensive strategy. © 2007 Grais et al.

Low measles vaccination coverage (VC) leads to recurrent epidemics in many African countries. We describe VC before and after late reinforcement of vaccination activities during a measles epidemic in Niamey, Niger (2003-2004) assessed by Lot Quality Assurance Sampling (LQAS). Neighborhoods of Niamey were grouped into 46 lots based on geographic proximity and population homogeneity. Before reinforcement activities, 96% of lots had a VC below 70%. After reinforcement, this proportion fell to 78%. During the intervention 50% of children who had no previous record of measles vaccination received their first dose (vaccination card or parental recall). Our results highlight the benefits and limitations of vaccine reinforcement activities performed late in the epidemic.

The current WHO policy during measles outbreaks focuses on case management rather than reactive vaccination campaigns in urban areas of resource-poor countries having low vaccine coverage. Vaccination campaigns may be costly, or not timely enough to impact significantly on morbidity and mortality. We explored the time available for intervention during two recent epidemics. Our analysis suggests that the spread of measles in African urban settings may not be as fast as expected. Examining measles epidemic spread in Kinshasa (DRC), and Niamey (Niger) reveals a progression of smaller epidemics. Intervening with a mass campaign or in areas where cases have not yet been reported could slow the epidemic spread. The results of this preliminary analysis illustrate the importance of revisiting outbreak response plans.

To compare the ocular tolerance of nonpreserved diclofenac versus thiomersal-preserved diclofenac in healthy volunteers.Forty healthy volunteers instilled Dicloabak in the randomised eye and thiomersal-preserved diclofenac in the other eye, according to a strictly identical dosing regimen, for 28 days. Each volunteer thus served as his or her own control. The dose regimen was five drops/day for 7 days followed by three drops/day for 20 days. Ocular tolerance was assessed by the discomfort upon instillation (measured on a visual analogue scale [VAS]), subjective ocular symptoms following instillation (irritation/burning/stinging, eye dryness and foreign body sensation) and finally by an objective examination of the ocular surface. These criteria were evaluated on days 0, 14, 21 and 28.The subjective ocular symptoms following instillation were significantly lower in the nonpreserved group at Day 7 and nearly significantly lower until the end of the study. The biomicroscopy exam confirmed that there was better tolerance without thiomersal. There was less follicular-papillary conjunctivitis and a significantly better lissamine green score in the Dicloabak group.The results of this study demonstrate that the nonpreserved formulation of diclofenac is better tolerated by the ocular surface and thus constitutes a therapeutic benefit.

The principal stakes of depression treatment are to accelerate and enhance the clinical effects of antidepressant drug. The onset of antidepressant action of Serotonin (5HT) selective reuptake inhibitors (SSRIs) was attributed in part to the decrease in firing activity of serotonin neurons produced by the activation of raphe 5HT1A autoreceptors at the time of treatment initiation. Pindolol, an antagonist at somatodendritic pre-synaptic 5HT1A receptors has been investigated as a potential accelerator or potentialisator of antidepressant response. Six open label studies and 12 controlled studies were identified for revue. The first open-label pilot study was conducted by Artigas et al. They showed promising results with pindolol, both in the acceleration of antidepressant response and in improving the efficacy of antidepressant. On the basis of these results five open-label studies were conducted. The open label studies suggest that pindolol accelerate the antidepressant response of serotoninergics therapeutics. The augmentation of antidepressant response was not clearly demonstrated by these studies particularly in the treatment of refractory depression. For example, Dinan et Scott that found the addition of pindolol in association with SSRI therapy had a poor efficacy. In the twelve controlled studies, 4 tried to underscore the shortening of the onset and the augmentation of efficacy of SSRI by pindolol [Berman et al., Maes et al., Perez et al., Tome et al. ], 3 tried to underscore shortening of the onset [Bordet, Zanardi ] and 3 tried to underscore the augmentation of efficacy [Maes et al., Moreno et al., Perez et al. ]. One study tried to underscore the augmentation of efficacy of sleep deprivation by pindolol and another one the shortening of the onset of ECT. Six studies included depressive resistant patients. Three studies were carried out with fluoxetine, 1 with fluvoxamine, 3 with paroxetine, 1 with trazodone. Two -studies were investigated with several antidepressant treatments. The results of the studies indicate one acceleration of antidepressant response in 6 studies, one augmentation of efficacy in 5 studies. Two studies clearly demonstrate that pindolol may -augment and accelerate antidepressant response. Three studies did not confirm these observations. Several points can be examined. For pindolol: 3 authors have demonstrated that the effect of pindolol did not rely upon small antidepressant effect mediated by b-blockers properties, because anxiety was not predominantly improved by pindolol plus SSRI while depressive symptoms were clearly improved. On the basis of data issues from recent positron emission tomography (PET) studies, several authors suggested that the dose of pindolol used in most clinical trials (3 yen 2,5 mg day-1) might be insufficient to induce a substantial occupancy of 5-HTA receptors (Rabiner et al. It is possible that higher doses will show a more evident benefit. On the whole, pindolol seemed to be well tolerated. Adverse effects most commonly reported were increased irritability, insomnia and nausea. Pindolol had poor adverse effects in cardiovascular functions. The variation of the results of the controlled studies can be explained by different points: Firstly by difficulty to determine good criterion of resistance. The most simplistic definition of treatment resistance is the failure to achieve and sustain euthymia with adequate antidepressant treatment. Secondly by the fact that depressive patients who present antecedents of depressive illness seem to be worst responders to the association pindolol/serotoninergic antidepressant than patients suffering of first episode of depression. We observed one antecedent of depression in the group of resistant patients who were good responders to the association pindolol/antidepressant therapy. We observed three anterior episodes of depression in negatives studies of the association pindolol/antidepressant therapy. Thirdly by the fact that the failure of the antidepressant treatment at the time of earlier (or actual) episode seems to be a criterion for less responsiveness to the association of this antidepressant treatment with pindolol. In fact, the open label studies who demonstrated efficacy of the association between pindolol and serotoninergic therapy in major resistant depression were realized with new antidepressant molecule for the episode. Other controlled trials could confirm these facts. Most of the studies failed to retrace clearly the historicity of depression, and it may be interesting in future investigations to analyze the response of the association -compared to the status of the patient with the antidepressant therapy. Further perspective could be envisaged especially in the utilization of pindolol for the treatment of pathologies which are usually treated with a serotoninergic antidepressant -therapy. For example, the antagonist 5HT(1A) Way 100635 was experimented with success in animals in order to augment the efficacy of clomipramine in the treatment of chronic pain. In other respects several psychopharmacogenetics studies could be investigated to examine, for instance, the role of the 5-HT transporter and its implication in the response to pindolol and antidepressant association. In summary, pindolol accele-rates, and in some cases enhances the clinical action of antidepressant drugs. It appears that this augmentation strategy has more limited effect on treatment resistant patient but there is experimental evidence for using higher doses in future augmentation trial.

To date, biomedical research using nominal data files for the data collection, data acquisition or data processing has had to comply with 2 French laws (Law of December, 20, 1988, modified, relating to the protection of patients participating in biomedical research, and the Law of January, 6, 1978, completed by the Law of July 1, 1994 n degrees 94-548, chapter V bis). This later law dictates rules not only for the establishment of nominal data files, but also confer individual rights to filed persons. These regulations concern epidemiological research, clinical trials, drug watch studies and economic health research. In this note, we describe the obligations and specific general and simplified procedure required for conducting biomedical research. Included in the requirements are an information and authorization procedure with the local and national consultative committees on data processing in biomedical research (CCTIRS, Comité Consultatif sur le Traitement de l'Information en Recherche Biomédicale, and CNIL, Commission Nationale Informatique et Libertés).

1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.

INFLUENCE OF AGING ON PAIN: Although pain affects a large majority of the elderly population living in the community and in institutions, our knowledge of the evolution of pain experience with age is poor. Results of clinical surveys and experimental pain studies are contradictory, showing no change, an increase, or a decrease of pain with age. Many results suggest a decrease of pain perception with age that could be explained by peripheral and central neuroanatomical aging and psychological changes of the aging patient towards pain.Biological aging added to multiple pathologies and polymedication explains the pharmacological changes of analgesics. Among pharmacokinetic changes that are globally well known, vigilance must focus on renal excretion of analgesics and their metabolites and on the increased risk of side-effects and drug interactions. Information on pharmacodynamic changes of analgesics are scarce in aging patients who are susceptible to drugs and which demographical trend increases.A better fundamental knowledge of the evolution of pain with age could help to improve care in the elderly with pain, especially in very old subjects with cognitive impairment and loss of communication skills, where pain evaluation is particularly difficult. Also, more research is needed on the pharmacodynamics of analgesics in older subjects, with a view of a decreased iatrogenic risk, a better pain treatment and quality of life of the elderly.

The assessment of the clinical properties of analgesics is not easy. Some of the difficulties are due to the multiplicity of the aetiologies involved in the pain process, to the complexity of pathophysiological mechanisms modulating the nociception and to the subjectivity of painful sensation. All of these explain the fairly high variability of the criteria available for assessing pain level or pain relief. As a consequence, that variability directly interferes with the pharmacological effect of analgesics to be assessed in clinical trials. Furthermore, the lack of consensus concerning the evaluation criteria does not facilitate the choice of a study design or the comparison of data collected from different clinical trials. Clinicians have to choose between testing the analgesics in healthy volunteers (experimental pain) or in patients suffering from painful disease (spontaneous pain). These two approaches are often complementary for assessing the pharmacological profile of new analgesic compounds. Whatever the choice, the investigators have to pay attention to the methodological aspects to avoid pitfalls and bias in this difficult field of therapeutic research.

The relationships between inflammation and pain were known for a long time, even by antique civilizations. However most of the fundamental knowledge about biological mechanisms explaining some of the links between inflammation and nociception processes have been discovered over the last three decades. Peripheral infection or injury can induce an inflammation and related pain but also some nerves, especially C fibers which are mainly involved in nociception transmission, can generate a so called “neurogenic inflammation”. New findings rise some questions about the role of magnesium (Mg) in these two phenomena.

Rats (Sprague-Dawley), submitted to a mechanical noxious stimulus (paw pressure), were tested to determine 1) the antinociceptive effects of p.o. (200, 400 and 800 mg/kg), i.v. (50, 100, 200 and 300 mg/kg) and intrathecal (i.t.) (100 and 200 micrograms/rat) administrations of paracetamol; 2) the influence of i.t. administered tropisetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist (0.5, 1 or 10 micrograms/rat) on paracetamol-induced antinociception; 3) the influence of indomethacin (25 mg/kg s.c.), naloxone (10 micrograms/rat i.t.) and yohimbine (1 mg/kg i.v.) on the effect of paracetamol (200 mg/kg i.v.) to determine the involvement of prostaglandins, opioids and alpha-2 adrenoceptors. The displacement by paracetamol of radioligand binding to various receptors was also investigated. Paracetamol induced a significant antinociceptive effect after p.o., i.v. and i.t. administration. A total inhibition of the effect of paracetamol, administered p.o. or i.t., occurred at the dose of 0.5 microgram/rat of tropisetron, whereas 10 micrograms/rat of this antagonist was needed to totally inhibit the action of i.v. administered paracetamol. Indomethacin, naloxone and yohimbine failed to modify paracetamol antinociceptive action. In vitro studies failed to show any binding of paracetamol to 5-HT3 and several other receptors and to 5-HT uptake sites. It is concluded that paracetamol has a central antinociceptive effect, based on an indirect involvement of spinal 5-HT3 receptors.

The ciliary beat frequency (CBF) of the tracheal epithelial cells controls in part the respiratory tract mucociliary transport efficiency. We investigated the effects on CBF of PAF-acether (PAF) and its metabolite/precursor lyso-PAF. Guinea-pig tracheal rings were incubated for 3 to 6h with 1 microM PAF (C16, C18, C16/C18: 80/20%), lyso-PAF C16 or lyso-phosphatidylcholine (LPC). CBF changes were assessed by microphotooscillography (mean number of measures per ring = 14). We also examined the effect on PAF-induced CBF changes of the PAF receptor-antagonist WEB 2086, the anti-asthmatic/anti-anaphylactic drug ketotifen and the anti-histamine H1 pyribenzamine. CBF of control rings exposed to vehicle only from 0 to 6h showed no significant statistical variations (hertz, mean +/- SEM): 10.8 +/- 0.1 (n of measures = 890). By contrast, 1 microM C16, C18, and C16/C18 PAF significantly inhibited CBF after 3 to 6h incubation. C16 and C16/C18 PAF were more potent than C18 PAF (8.8 +/- 0.2, n = 112, 8.7 +/- 0.2, n = 64, and 9.6 +/- 0.1, n = 537 respectively; ANOVA analysis, p0.001 from control). At the same concentration, lyso-PAF also inhibited CBF, 9.5 +/- 0.1 (n = 197, p0.001) but not LPC, 10.5 +/- 0.2 (n = 127). WEB 2086 inhibited lyso-PAF and C16/18 PAF-induced CBF decrease. Preincubation (20 min) with ketotifen but not with pyribenzamine (1 microM) also suppressed the CBF inhibitory effect of PAF and lyso-PAF. Incubation of [3H]PAF with tracheal rings from 10 min to 6h resulted in its partial metabolism (25%) into [3H]lyso-PAF and a compound with a short retention time (10 min). [3H]lyso-PAF incubated for 3h with tracheal rings was partially metabolized (10%) into [3H]PAF and a compound with a short retention time. The PAF-induced decrease of CBF is congruent with its influence on pulmonary clearance, possibly via a specific receptor, since WEB 2086 abolished the effect of PAF. The inhibition of the PAF-induced CBF decrease by ketotifen may contribute to the therapeutic properties of this antiallergic drug.

Postoperative pain has rarely been assessed after ENT surgery for cancer. Its evaluation is difficult because of the frequent lack of speech after this type of surgery.to assess postoperative pain after pharyngeal and laryngeal surgery for cancer.prospective study in 13 men (38-71 ans) operated on by total laryngectomy with or without partial pharyngectomy. A standardised treatment using propacetamol and nalbuphine was systematically prescribed. Pain, anxiety and relief were assessed with the help of visual analogue scales (VAS). Heart rate, mean blood pressure and respiratory rate were evaluated too.mean postoperative pain was maximal just after recovery (6,64 +/- 2,14 cm) then decreased regularly. Initial mean score of anxiety was 3,14 +/- 3 cm and then was decreasing too. Anxiety and pain did not correlate except in 2 cases. None of the 3 objective parameters correlated with pain.postoperative pain can be assessed reliably after pharyngolaryngeal cancer surgery and is probably underrated. Its high initial score indicates that efforts must be focused on pre-emotive analgesia. Its high individual variability let us hypothesise that PCA systems should be effective.

The mechanism of proteinuria at high altitude is unclear. Renal function and urinary excretion rate of albumin (Ualb) at rest and during submaximal exercise and transcapillary escape rate of 125I-labeled albumin (TERalb) were investigated in 12 normal volunteers at sea level and after rapid and passive ascent to 4,350 m. The calcium antagonist isradipine (5 mg/day; n = 6) or placebo (n = 6) was administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and urinary excretion of beta 2-microglobulin were used to evaluate renal tubular function. High altitude increased Ualb from 2.8 to > 5.0 micrograms/min in both groups (P < 0.05). In the placebo group, high altitude significantly increased filtration fraction (P < 0.05), but this response was abolished by isradipine. Lithium clearance and urinary excretion of beta 2-microglobulin remained unchanged by hypoxia in both groups. Exercise did not reveal any further renal dysfunction. In both groups, high altitude increased TERalb from 4.8 to > 6.7%/h (P < 0.05). In conclusion, acute altitude hypoxia increases Ualb despite unchanged tubular function and independent of effects of isradipine on filtration fraction. The elevated TERalb suggests an overall increase in capillary permeability, including the glomerular endothelium, as the critical factor in high-altitude induced albuminuria.

Introduction L’utilisation de traitements par voie topique pour soulager des douleurs articulaires ou musculaires est largement repandue. Ce mode d’administration qui concerne particulierement les AINS permet d’obtenir localement des concentrations efficaces avec des concentrations plasmatiques faibles et donc des effets indesirables reduits par rapport a une administration orale. Le menthol en formulation topique a trouve des bases d’utilisation rationnelles avec la mise en evidence de recepteurs impliques dans les processus nociceptifs sur lesquels il agirait. Objectif Le present travail est destine a evaluer l’action antalgique d’une association ibuprofene/menthol en application topique, comparativement a l’ibuprofene seul, par voie topique et orale. Materiel et methode Cette etude croisee, randomisee, a ete realisee chez des volontaires sains chez lesquels est induite une hyperalgesie au froid qui presente de facon concentrique deux zones d’hyperalgie (hyperalgie primaire, centrale (Z1) et hyperalgie secondaire, peripherique (Z2). Les seuils de douleur en reponse a un stimulus mecanique (von Frey) sont mesures dans ces 2 zones d’hyperalgesie, pendant 4 heures apres l’administration des traitements : (1) ibuprofene (5 %)/levomenthol (3), (2) ibuprofene 5 % (gel commercialise) (3) gel neutre (sans ibuprofene ni menthol) par voies topique ou (4) ibuprofene, 400 mg par voie orale. Le protocole de l’etude a ete soumis a l’avis du CCPPRB de la Region Auvergne. Resultats Le gel ibuprofene/menthol entraine des 15 minutes, une augmentation significative (20 % (p = 0,019) en Z1 et 13,5 % (p = 0,005) en Z2) et durable, des seuils de douleur. Le gel ibuprofene, au contraire, est efficace seulement en Z1. Une augmentation de 50 % du seuil de douleur est observe chez 58 % (Z1) et 33 % (Z2) des sujets traites par ibuprofene/menthol. Les effets de ce traitement sont d’amplitude comparable a ceux de l’ibuprofene par voie orale. Conclusion L’ensemble des resultats montrent que vis a vis de l’hyperalgesie induite, le gel ibuprofene/menthol est plus efficace que le gel ibuprofene seul. Cette difference pourrait etre mise en relation avec un effet analgesique propre du menthol et/ou une absorption cutanee de l’ibuprofene facilitee par le menthol.

Extension to the unanesthetized dog with chronic A-V block of the method of determination of the atrial effective refractory period described in vitro by Dawes provides a useful model for the study in atria of potential antiarrhythmic agents. This model, which comes fairly close to physiological conditions, is capable of furnishing reproducible results which correlate well with those obtained by other techniques, as shown by a study of quinidine chosen as reference. It also makes possible long-term studies of the effects of prolonged administration of antiarrhythmic agents on atrial effective refractory period, under conditions close to those of therapeutic practice, and so is likely to have predictive value.

The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%). There was no relationship between the absorption of nicardipine and water movement or bile salt concentration in the jejunum. Nicardipine was already present in the first plasma sample taken after 15 min and the peak level was found at the end of the perfusion. The areas under the curves differed widely between subjects, because of interindividual variation in the first pass effect, but they were similar in Experiments A, B and C. The experimental data showed a good fit to a mode involving a two-phase absorption process. The first phase was associated with intestinal perfusion (zero order process) and the second with passage across the intestinal wall (1st order process). In three further healthy subjects, nicardipine in saline was perfused in the jejunum and then in the ileum on consecutive days. Mean plasma levels over time were similar. The study showed that absorption of nicardipine both from the jejunum and the ileum was complete and was especially rapid. The food-induced change in the kinetics of absorption from the jejunum was too small to affect the pharmacokinetic parameters of nicardipine.

The renin-aldosterone system may be depressed in subjects exercising at high altitude, thereby preventing excessive angiotensin I (ANG I) and aldosterone levels, which could favor the onset of acute mountain sickness. The role of beta-adrenoceptors in hormonal responses to hypoxia was investigated in 12 subjects treated with a nonselective beta-blocker, pindolol. The subjects performed a standardized maximal bicycle ergometer exercise with (P) and without (C) acute pindolol treatment (15 mg/day) at sea level, as well as during a 5-day period at high altitude (4,350 m, barometric pressure 450 mmHg). During sea-level exercise, pindolol caused a reduction in plasma renin activity (PRA, 2.83 +/- 0.35 vs. 5.13 +/- 0.7 ng ANG I.ml-1.h-1, P less than 0.01), an increase in plasma alpha-atrial natriuretic factor (alpha-ANF) level (23.1 +/- 2.9 (P) vs. 10.4 +/- 1.5 (C) pmol/1, P less than 0.01), and no change in plasma aldosterone concentration [0.50 +/- 0.04 (P) vs. 0.53 +/- 0.03 (C) nmol/1]. Compared with sea-level values, PRA (3.45 +/- 0.7 ng ANG I.ml-1.h-1) and PA (0.39 +/- 0.03 nmol/1) were significantly lower (P less than 0.05) during exercise at high altitude. alpha-ANF was not affected by hypoxia. When beta-blockade was achieved at high altitude, exercise-induced elevation in PRA was completely abolished, but no additional decline in PA occurred. Plasma norepinephrine and epinephrine concentrations tended to be lower during maximal exercise at altitude; however, these differences were not statistically significant. Our results provide further evidence that hypoxia has a suppressive effect on the renin-aldosterone system. However, beta-adrenergic mechanisms do not appear to be responsible for inhibition of renin secretion at high altitude.

A three-year-old girl who had for two months suffered bruising after minimal injury was admitted because of diffuse ecchymoses and a large haematoma hindering elbow movement. These symptoms were attributable to the development of antifactor VIII inhibitor. No definite etiology was evident despite repeated immunological investigation. Although the inhibitor still persisted at high levels after two years, no further haemorrhage occurred, excepted haematomas three months after the onset of symptoms, in association with mumps.

The authors report the case of a 15-year old boy with Tangier disease characterized clinically by grossly enlarged tonsils, liver and spleen. Blood counts showed signs of hypersplenism, and blood lipid assays disclosed hypercholesterolaemia with moderate hypertriglyceridaemia and very low levels of high density lipoproteins. The diagnosis was confirmed by biopsies of the liver, spleen, rectal mucosa, tonsils and bone marrow, all tissues which contained foamy histiocytic cells staining like adipose cells. Following splenectomy, the child developed an unexplained, persistent (6 months) fever, then died suddenly of digestive haemorrhage. A genetic study showed a high degree of inbreeding, with 2 deaths probably due to Tangier disease. The authors contrast the surprising severity of this case with the apparent benignity of the disease as described in other publications.