Emerging pharmacotherapies for alcohol dependence: a systematic review focusing on reduction in consumption.

BACKGROUND: European Medicines Agency guidelines recognize two different treatment goals for alcohol dependence: abstinence and reduction in alcohol consumption. All currently approved agents are indicated for abstinence. This systematic review aimed to identify drugs in development for alcohol dependence treatment and to establish, based upon trial design, if any are seeking market authorization for reduction in consumption. METHODS: We searched PubMed and Embase (December 2001-November 2011) to identify agents in development for alcohol dependence treatment. Additional studies were identified by searching ClinicalTrials.gov and the R&D Insight and Clinical Trials Insight databases. Studies in which the primary focus was treatment of comorbidity, or n≤20, were excluded. Studies were then classified as 'abstinence' if they: described a detoxification/alcohol withdrawal period; enrolled patients who had undergone detoxification previously; or presented relapse/abstinence rates as the primary outcome. Studies in patients actively drinking at baseline were classified as 'reduction in consumption'. RESULTS: Of 602 abstracts identified, 45 full-text articles were eligible. Five monotherapies were in development for alcohol dependence treatment: topiramate, fluvoxamine, aripiprazole, flupenthixol and nalmefene. Nalmefene was the only agent whose sponsor was clearly seeking definitive approval for reduction in consumption. Development status was unclear for topiramate, fluvoxamine, aripiprazole and flupenthixol. Fifteen agents were examined in published exploratory investigator-initiated trials; the majority focused on abstinence. Ongoing (unpublished) trials tended to focus on reduction in consumption. CONCLUSIONS: While published studies generally focused on abstinence, ongoing trials focused on reduction in consumption, suggesting a change in emphasis in the approach to treating alcohol dependence.

Mapping the proteome of Leishmania Viannia parasites using two-dimensional polyacrylamide gel electrophoresis and associated technologies.

In this study we have demonstrated the potential of two-dimensional electrophoresis (2DE)-based technologies as tools for characterization of the Leishmania proteome (the expressed protein complement of the genome). Standardized neutral range (pH 5-7) proteome maps of Leishmania (Viannia) guyanensis and Leishmania (Viannia) panamensis promastigotes were reproducibly generated by 2DE of soluble parasite extracts, which were prepared using lysis buffer containing urea and nonidet P-40 detergent. The Coomassie blue and silver nitrate staining systems both yielded good resolution and representation of protein spots, enabling the detection of approximately 800 and 1,500 distinct proteins, respectively. Several reference protein spots common to the proteomes of all parasite species/strains studied were isolated and identified by peptide mass spectrometry (LC-ES-MS/MS), and bioinformatics approaches as members of the heat shock protein family, ribosomal protein S12, kinetoplast membrane protein 11 and a hypothetical Leishmania-specific 13 kDa protein of unknown function. Immunoblotting of Leishmania protein maps using a monoclonal antibody resulted in the specific detection of the 81.4 kDa and 77.5 kDa subunits of paraflagellar rod proteins 1 and 2, respectively. Moreover, differences in protein expression profiles between distinct parasite clones were reproducibly detected through comparative proteome analyses of paired maps using image analysis software. These data illustrate the resolving power of 2DE-based proteome analysis. The production and basic characterization of good quality Leishmania proteome maps provides an essential first step towards comparative protein expression studies aimed at identifying the molecular determinants of parasite drug resistance and virulence, as well as discovering new drug and vaccine targets.

The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the neuromodulation appropriateness consensus committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Enjeux éthiques des nouvelles technologies de la reproduction : une conception de la justice à l'interface de l'éthique du "care" et de l'approche des "capabilités"

L'émergence des nouvelles technologies de la reproduction (NTR) est allée de pair avec un certain nombre de discours. Un discours promettant d'une part une extension de la palette de choix reproductifs des individus, une extension de leur liberté et de leur autonomie reproductives, dont la forme la plus extrême peut se traduire par la formule : un enfant quand je veux et comme je veux. D'autre part, un discours annonçant une série de « catastrophes » à venir, telles que l'effondrement de l'institution de la famille et la modification de l'espèce humaine. En d'autres termes, une tension entre promesses et catastrophes qui place les sociétés contemporaines face à de nombreux défis sociaux, politiques et éthiques, notamment quant à la question de la régulation de la PMA (procréation médicalement assistée) : qui peut y avoir accès ? Quelles techniques doit-on autoriser ? Ou au contraire limiter ? Tant de questions auxquelles aucune réponse simple et évidente n'existe. La diversité des réponses législatives quant à ces questions illustre cette complexité. L'éthique peut, ici, jouer un rôle fondamental. Sans toutefois prétendre donner des réponses toutes faites et facilement applicables, elle offre un espace de réflexion, le privilège de prendre une certaine distance face à des enjeux contemporains. C'est dans cette perspective que nous avons ancré ce travail de recherche en questionnant les enjeux éthiques de la PMA à partir d'une perspective de justice. Toutefois, au sein des études en bioéthique, majoritairement issues de la tradition libérale, la tension énoncée précédemment mène la bioéthique à justifier un certain nombre d'inégalités plutôt que de veiller à les dépasser. Ainsi, une évaluation de la pratique de la PMA à partir d'une perspective de la justice, exige, au préalable, une réévaluation du concept même de justice. Ce faisant, par une articulation entre l'éthique du care de Joan Tronto et l'approche des capabilités de Martha Nussbaum qui placent la vulnérabilité au coeur de la personne, nous avons proposé une conception de la justice fondée sur une anthropologie de la vulnérabilité. Cette conception nous permet d'identifier, dans le cadre de la pratique de la PMA en Suisse et en partant de la loi sur la procréation assistée (LPMA), les constructions normatives qui mènent à la non-reconnaissance et, ce faisant, à la mise à l'écart, de certaines formes de vulnérabilité : une vulnérabilité générique et une vulnérabilité socio-économique. Traitant la question de la vulnérabilité générique principalement, nos analyses ont une incidence sur les conceptions de la famille, du bien de l'enfant, de la femme et de la nature, telles qu'elles sont actuellement véhiculées par une conception naturalisée de la PMA. Répondre aux vulnérabilités identifiées, en veillant à leur donner une place, signifie alors déplacer ces conceptions naturalisées, afin que les vulnérabilités soient intégrées aux pratiques sociales et que les exigences de justice soient ainsi remplies. - The emergence of assisted reproductive technologies (ART) came along with several discourses. On the one hand a discourse promising an extension of the individuals' reproductive choices, their procreative liberty and autonomy. On the other hand a discourse announced a series of disasters to come such as the collapse of the family institution and the modification of human kind. In other words, a growing tension appears between promises and disasters and contemporary societies are facing inevitable social, political and ethical challenges, in particular with regard to the issue of ART regulation: who has access? What procedures should be authorized? Which ones should be limited? These complex questions have no simple or obvious answers. The variety of legislative responses to these questions highlights complexity. Ethics can play a fundamental role, and without claiming to give simple answers, also offer a space for reflection as well as the privilege to distance itself with regard to contemporary issues. It is in this perspective that this study questions the ethical considerations of ART in a perspective of justice. However, in previous studies in bioethics mainly following a liberal tradition, previously mentioned tension has lead bioethics to justify some inequalities instead of trying to overcome them. As a consequence, evaluating practices of ART from a perspective of justice requires to first reevaluate the concept of justice itself. In doing so we offer a conception of justice founded on the anthropology of vulnerability. This conception draws on an articulation of the ethic of care of Joan Tronto and the capability approach of Martha Nussbaum, which places vulnerability at the center of the person. This conception allows us to identify, within the framework of ARTS in Switzerland and starting with the laws of medically assisted procreation (LPMA), some normative constructions. These constructions lead to the non-recognition and the disregard of some forms of vulnerability: a generic vulnerability as well as socio-economic counterpart. Focusing mainly on the issue of generic vulnerability, our analysis has implications for the conceptions of family, the best interests of the child, woman, and nature in the way they are defined in a naturalized conception of ART. Responding to such failures by taking into account these vulnerabilities thus means to move these conceptions in order for vulnerabilities to be integrated in social practices and requirements for justice to be fulfilled.

Vascular dysfunction in children conceived by assisted reproductive technologies: underlying mechanisms and future implications.

Epidemiological studies in humans have demonstrated a relationship between pathological events during fetal development and increased cardiovascular risk later in life and have led to the so called "Fetal programming of cardiovascular disease hypothesis". The recent observation of generalised vascular dysfunction in young apparently healthy children conceived by assisted reproductive technologies (ART) provides a novel and potentially very important example of this hypothesis. This review summarises recent data in ART children demonstrating premature subclinical atherosclerosis in the systemic circulation and pulmonary vascular dysfunction predisposing to exaggerated hypoxia-induced pulmonary hypertension. These problems appear to be related to the ART procedure per se. Studies in ART mice demonstrating premature vascular aging and arterial hypertension further demonstrate the potential of ART to increase cardiovascular risk and have allowed to unravel epigenetic alterations of the eNOS gene as an underpinning mechanism. The roughly 25% shortening of the life span in ART mice challenged with a western style high-fat-diet demonstrates the potential importance of these alterations for the long-term outcome. Given the young age of the ART population, data on cardiovascular endpoints will not be available before 20 to 30 years from now. However, already now cohort studies of the ART population are needed to early detect cardiovascular alterations with the aim to prevent or at least optimally treat cardiovascular complications. Finally, a debate needs to be engaged on the future of ART and the consequences of its exponential growth for public health.

Les adolescents, Internet et les nouvelles technologies: un nouveau pays des merveilles ? [Adolescents, Internet and new technologies: a new wonderland?]

Cet article passe en revue les côtés positifs et les risques liés à l'utilisation des nouvelles technologies. Parmi les aspects positifs, figurent l'accès rapide à des informations à caractère éducatif, la possibilité d'échanges à caractère social ou intellectuel, et l'ouverture à des renseignements dans le domaine de la santé, des drogues ou de la sexualité. Les menaces sont liées à l'inexpérience et à la difficulté à juger de la validité des informations, ou du risque que les jeunes prennent en diffusant des informations sur le web. La dépendance à internet et le risque de violence sont probablement surestimés. Un monitorage ouvert et interactif de la part des parents constitue une bonne prévention. L'investigation du rapport que chaque jeune patient entretient avec ces outils fait partie intégrante de tout bilan de santé. [Abstract] This reviews the use of new technologies with its benefits and pitfalls. Among the positive aspects are instant access to educational information, the possibility to connect with mates and to develop social exchanges, as well as an access to preventive contents in the field of health, substances or sexuality. The risks are linked with inexperience and the adolescent's inability to assess the validity of information collected on Internet, as well as a lack of insights of the consequences of launching information or images on the web. The menace of addiction or of violence induced by intemet is probably overestimated by many adults but should be taken into account. Parents should monitor their adolescents' activity in an open and interactive way. Moreover, any adolescent medical check-up should touch on the use of new technologies.

Antibiotic susceptibility of Estrella lausannensis, a potential emerging pathogen.

Estrella lausannensis is a new Chlamydia-related bacterium, belonging to the Criblamydiaceae family. As suggested by its species name, this bacterium harbors a peculiar star shape. E. lausannensis is able to infect a wide range of amoebal, fish and mammalian cell lines. Moreover, seroprevalence of 2.9% was reported in children and in women with tubal pathology, showing that humans are commonly exposed to this recently discovered strict intracellular bacteria considered as a potential pathogen. Antibiotic susceptibility was determined using two approaches: qPCR and cellular mortality assay. Antibiotics classically used against intracellular bacteria were tested, including β-lactams, fluoroquinolones, cyclines and macrolides. We showed that E. lausannensis is resistant to β-lactams and fluoroquinolones, and sensitive to cyclines. Interestingly, E. lausannensis is slightly resistant to azithromycin with a MIC of 2 μg/ml, which is 10 fold higher compared to Waddlia chondrophila and Parachlamydia acanthamoebae MIC's. A single A2059C mutation in 23S rRNA gene could be responsible for this unexpected resistance.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Ordonnance de sortie d'hôpital: un défi pour la continuité des soins et la collaboration interprofessionnelle [Hospital's discharge prescription: a challenge for continuity of care and the interprofessional collaboration].

The transition between hospital and community is an interface at high risk for medication. "The Association of Family Doctors" committee in the canton of Vaud (MFVaud), together with community pharmacists' and Homecare representatives, have begun to consider the following improvements: fast and co-ordinated care providers' information; arrangements for family doctors appointments as soon as possible; awareness and education for interprofessional collaboration; more secured preparation of pill boxes; development of interprofessional means such as medication use reviews and reconciliations. In the opinion of all the experts, there is an urgent public health need to act in an interprofessional manner, even if the solutions required (especially change in professional culture and technologies) are not immediate.