Évaluation de la prescription et de la balance bénéfice/risque du baclofène dans l'alcoolo-dépendance (étude transversale sur 28 patients en échec thérapeutique)

Introduction : Le baclofène a montré des résultats prometteurs dans le maintien de l abstinence ou la réduction de la consommation chez des patients alcoolo-dépendants. Objectifs : Evaluer la balance bénéfice/risque du baclofène dans cette indication. Les objectifs secondaires sont de caractériser la prescription de ce médicament, ainsi que de déterminer les éléments prédictifs de bonne ou de mauvaise réponse au baclofène. Matériel et Méthode : 28 patients alcoolo-dépendants traités par baclofène depuis au moins trois mois ont répondu à un questionnaire collectant des informations liées au patient, à la prescription de baclofène, aux effets indésirables, et recueillant les variations, avant et durant le traitement par baclofène, de la consommation d alcool, du craving pour l alcool, de l anxiété, la dépression, la recherche de sensation, l impulsivité, la qualité de vie et le sommeil. Résultats: La prescription de baclofène a été effectuée à une dose médiane de 145 mg/j pendant une durée médiane de 293 jours. La consommation d alcool a réduit de façon significative après traitement par baclofène, ainsi que la majorité des paramètres secondaires (craving, anxiété, ). Des effets indésirables principalement bénins ont été détectés : somnolence, fatigue, bouche sèche... Un haut niveau de craving semble être un élément prédictif de moindre réponse au baclofène. Conclusion : Cette étude montre une balance bénéfice/risque favorable du baclofène : malgré des doses importantes, les effets indésirables sont principalement bénins et 75% des patients ont une consommation nulle ou à faible risque. Le baclofène est un outil qui doit s intégrer dans une prise en charge biopsycho-sociale.Introduction: Baclofen has shown promising results in abstinence maintenance or consumption reduction in alcohol-dependent patients. Aims: To assess the baclofen risk-benefit balance in this indication. Secondary aims are to characterize the prescription of this drug and to determine predictive factors of good or bad response to baclofen. Method: 28 alcohol-dependent patients treated with baclofen for at least three months answered to a questionnaire collecting informations related to the patients, the prescription and side effects of baclofen, and collecting changes before and during treatment with baclofen, of alcohol consumption, craving, anxiety, depression, sensation seeking, impulsivity, quality of life and sleep. Results: Baclofen was prescribed at a medial dose of 145mg/d during a medial duration of 293 days. Alcohol consumption significantly decreased with baclofen, as well as most of secondary parameters (craving, anxiety ). Mainly benign side effects were notified: drowsiness, tiredness, dried mouth Very high level of craving seems to be a predictive factor of bad response to baclofen. Conclusion: This study shows a favourable baclofen risk-benefit balance: in spite of high dose, side effects are mainly benign and 75% of patients are abstinent or have low risk consumption. Baclofen is a tool which has to be proposed with psycho-social management.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Opioid-related deaths in Europe: Strategies for a comprehensive approach to address a major public health concern

Abstract Use of illicit opioids and misuse of prescription opioids are the main causes of drug-related deaths across the world, and the continuing rise in opioid-related mortality, especially affecting North America, Australia and Europe, is a public health challenge. Strategies that may help to decrease the high levels of opioid-related mortality and morbidity and improve care across Europe include risk assessment and interventions to improve the use of opioid analgesics, e.g. prescription drug-monitoring programmes, education on pain management to reduce opioid prescribing, and the implementation of evidence-based primary prevention programmes to reduce the demand for opioids. For patients who develop opioid use disorder (a chronic and relapsing problematic use of opioids that causes clinical impairment or distress), treatment combining opiate receptor full or partial agonist medications for opioid-use disorder (MOUD) with psychosocial interventions is essential. However, in Europe a substantial proportion of the 1.3 million high-risk opioid users (defined as injecting drug use or regular use of opioids, mainly heroin) remain outside of dedicated treatment programmes. More widespread and easier access to MOUD could reduce mortality levels; via approaches such as primary care-led treatment models, and efforts to improve patient retention and adherence to treatment programmes. Other harm-reduction strategies, such as the use of MOUD at optimal doses, the provision of take-home naloxone, the introduction of supervised drug-consumption facilities, and patient education to reduce the risk of overdose may also be beneficial

Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60–120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34–2), clearance (Cl/F) 11.6 L/h (10.8–12.3) and volume of distribution (Vd/F) 72.8 L (66.5–80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19–65), 21% (16–27), and 22% (11–36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21–26). No serious adverse event was reported.Registration: EudraCT #2013-003412-4

Toll-Like Receptor-4 Mediated Inflammation Is Involved in the Cardiometabolic Alterations Induced by Intermittent Hypoxia

Objective. Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH. Methods. Lean adult male TLR4-deficient (TLR4−/−) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta. Results. IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion. Conclusion. IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients

Intracerebral adenosine during sleep deprivation : A meta-analysis and new experimental data

Funding Information: The systematic review was funded by The Netherlands Organisation for Health Research and Development (ZonMW; 114024101); R2N, Federal State of Lower Saxony; and the DFG (FOR2591, BL 953/11-1). The microdialysis experiment was funded by Netherlands Organization for Scientific Research (NWO; 051-04-010, to Eus van Some-ren). The HPLC adenosine measurements were funded by the University of Helsinki sleep team and a travel grant from the European Sleep Research Society. Publisher Copyright: © 2018 Ubiquity Press. All rights reserved.The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of washout, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.Peer reviewe

Implications du système nerveux périphérique dans le syndrome d'apnées du sommeil (le nerf périphérique, un marqueur tissulaire de l'hypoxie intermittente, la neuropathie pharyngée, une cause d'apnées du sommeil, un nouvel outil pour diagnostiquer la neuropathie pharyngée)

La neuropathie pharyngée serait l'une des composantes majeures de la physiopathologie du syndrome d'apnées obstructives du sommeil (SAOS). Une atteinte des afférences sensorielles et/ou des efférences motrices pourrait compromettre au cours du sommeil le réflexe dilatateur protecteur du pharynx causant ainsi l'occlusion des voies aériennes supérieures. La cause de cette neuropathie est classiquement attribuée au traumatisme induit par le ronflement et les apnées. La contribution de l'hypoxie intermittente associée au SAOS n'est pas connue. D'autre part, l'évaluation de cette neuropathie, notamment dans son versant sensoriel, est actuellement difficilement réalisable (...) La sévérité des deux pathologies était corrélée. En l'absence des facteurs de risque classiques du SAS, l'hypothèse permettant de relier les deux pathologies était l'existence d'une neuropathie pharyngée s'intégrant dans la neuropathie héréditaire. Pour valider cette hypothèse et étudier en routine l'implication de la sensibilité pharyngée dans la physiopathologie du SAOS, nous avons développé un test très simple permettant de mesurer cette sensibilité (seuil de perception pharyngée), en administrant à travers un dispositif intra-buccal un flux d'air sur la muqueuse pharyngée. Les apnéiques avaient un seuil de perception plus élevé. Cette sensibilité était d'autant plus altérée que la proportion d'apnées-hypopnées était élevée. De plus, ce test permis de dépister un SAS chez des sujets asymptomatiques. Il ouvre ainsi de nouvelles perspectives d'études qui permettront d'améliorer la compréhension et le diagnostic des apnées du sommeil.Pharyngeal neuropathy may play a major role in the pathophysiology of obstructive sleep apnea syndrome (OSAS). Impairment of sensory input and/or motor output may compromise the protective dilating pharyngeal reflex leading to upper airway collapse during sleep. Pharyngeal neuropathy is classically attributed to vibrations and soft tissue stretching related to snoring and apnea respectively (...) Compared to controls, apneic patients had an increased sensory threshold. The higher the proportion of hypopneas and apneas, the higher the pharyngeal sensory threshold. Furthermore, this test enabled to detect sleep apnea in asymptomatic patients. This test supports new perspectives for understanding and diagnosing sleep apnea.Hypoxie intermittenteGRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Les médicaments dopaminergiques (de la maladie de Parkinson aux traitements des addictions)

La maladie de Parkinson peut être associée à une longue liste de complications thymiques et comportementales. Ces modifications psychiques semblent dépendre du traitement dopaminergique du patient, et plus exactement de son état d'hyper- ou d'hypodopaminergie cérébral. La reconnaissance de l'impact neuropsychiatrique du traitement dopaminergique substitutif chez les malades Parkinsoniens apporte un éclairage nouveau sur la compréhension des troubles de l'addiction. La dopamine cérébrale constitue l élément central de la physiopathologie de l'addiction. Les troubles de l'addiction sont asservis aux fluctuations dopaminergiques du système mésocorticolimbique. Tout comme les patients parkinsoniens, les patients souffrants d'addiction passent par des états d'hypo- et d'hyperdopaminergie, en fonction de la stimulation des systèmes dopaminergiques cérébraux par les drogues d'abus. La labilité des systèmes dopaminergiques cérébraux, sous l'influence d'une substance psychoactive, conditionne les troubles du comportement rencontrés chez les patients toxicomanes et précipite les sujets dans l'addiction. A la lumière des récentes découvertes concernant la gestion des troubles du comportement chez les patients parkinsoniens, nous verrons que les traitements (médicaments, stimulation cérébrale) agissant, directement ou indirectement, sur le système dopaminergique mésocorticolimbique ainsi que les tests pharmacologiques de labilité du système dopaminergique et l'imagerie médicale sont autant de pistes thérapeutiques sérieusement envisagées pour la stabilisation de l'équilibre dopaminergique des patients souffrants d'addiction et la résolution de leurs troubles neuropsychiatriques.Degeneration of the dopaminergic system in Parkinson's disease and longstanding exposure to dopaminergic drugs may cause reward system dysfunction. This may manifest as addiction to dopaminergic drugs and behavorial disturbances associated with the impulse control system. Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. Activation of the mesocorticolimbic dopaminergic system by drugs of abuse plays a key role in the development and maintenance of addictive behavior. Chronic exposure to drugs of abuse results in neurobiological dysfunctions and neuropsychiatric disorders. The classification of mood disorders based on the dopaminergic status of each patient can be applied to addictions. The use of pharmacological agents has become a standard approach to attempt to ameliorate aspects of drug addiction in combination with social and behavioral treatment. While pharmacotherapy may be an effective approach to the treatment of drug addiction for individuals, the prevalence of this disorder remains unacceptably high. The characterization of the central dopaminergic sensitivity could be a promising approach for the development of novel treatments for addictions. Such as the exploitation of cerebral stimulation or imaging techniques. Those one provide new insights on the role of dopamine in drug abuse and addiction in the human brain.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Caractérisation de la prescription et des effets du Baclofène (Liorésal®) dans le traitement des dépendances de type alcool ou autres

Introduction : L espoir né du livre du Docteur Ameisen sur le baclofène dans l alcoolodépendance a entraîné de nombreuses questions. Suite à une revue de la littérature, il apparaît comme l un des seuls médicaments pouvant entraîner une suppression complète et prolongée du craving à hautes doses. Cependant les données restent rares. Méthode : Une étude de prévalence a été réalisée auprès de 3 catégories de médecins. Des questionnaires destinés respectivement aux prescripteurs et aux patients ont été conçus et envoyés aux prescripteurs recensés. Ils visent à caractériser les médecins et leurs patients, à confirmer ou infirmer l efficacité du baclofène, à définir son profil de tolérance, les posologies à utiliser et la durée du traitement. Résultats : Toutes spécialités confondues, 6,7% de ces médecins déclarent utiliser le baclofène dans les addictions dont 16,7% des médecins addictologues et 5,9% des médecins psychiatres. Les hépato-gastro-entérologues ne l utilisent pas. De gros foyers de prescription ont été mis en évidence. 23 questionnaires-prescripteurs et 125 questionnaires patients ont été envoyés. Les résultats préliminaires de 2 questionnaires sont présentés. Discussion : Malgré l engouement général, les médecins restent prudents vis-à-vis du baclofène. Les principales raisons étant l absence d AMM, le manque d informations et d études. Les résultats préliminaires paraissent prometteurs mais devront être confirmés. Conclusion : Le nombre important de questionnaires envoyés, qui fera l objet d une analyse statistique dans un travail ultérieur, devrait permettre d obtenir rapidement des données régionales significatives pouvant servir de base à une prescription encadrée.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice.: Intermittent hypoxia-induced atherosclerosis

International audienceRATIONALE: Obstructive sleep apnea results in nocturnal intermittent hypoxia (IH) as a main trigger for cardiovascular morbidity, including atherosclerosis. IH induces hemodynamic, hormono-metabolic and also immuno-inflammatory alterations that could differentially contribute to atherosclerosis. Our study aimed at examining their respective contribution to the proatherogenic role of IH in atherosclerosis-prone mice. METHODS: Fifteen-week-old male apolipoprotein E-deficient (ApoE(-/-)) mice fed on a high-cholesterol diet (HCD) for 6 weeks and exposed for the last 14 days to IH (21-5% FiO(2), 60s cycle, 8h/day) or air, were investigated for aortic atherosclerosis and lipid alterations. Then IH proatherogenicity was assessed in 15- and 20-week-old ApoE(-/-) mice fed on a standard-chow diet (SCD) exposed to IH or air for 14 days and assessed for atherosclerosis, lipid, hemodynamic and inflammation alterations. RESULTS: IH aggravated atherosclerosis in HCD-fed mice, whereas the extremely high cholesterol levels due to HCD were not different between normoxic and hypoxic animals. In SCD-fed mice, IH also aggravated atherosclerosis, more severely in 20 compared to 15-week-old animals. However, cholesterol levels that increased with IH were not different in the two SCD-fed groups. IH slightly elevated arterial blood pressure in 20-week-old animals only, and induced systemic and vascular inflammation, including increased splenocyte proliferation with decreased IL-10 secretion, and increased T-lymphocytes within atherosclerotic plaques. CONCLUSIONS: A short IH exposure without HCD has proatherogenic effects. In contrast to blood pressure or plasma lipids which were slightly or inconstantly affected by IH, inflammation at systemic and vascular levels appears as a potential contributing factor to IH atherogenicity

Is suicide under the influence of alcohol a deliberate self-harm syndrome? An autopsy study of lethality

International audienc