Prevention of what?
Prevention of what?
复制标题
DOI：
--
复制
发表时间：
1983-04
期刊：
影响因子：
--
通讯作者：
H. Hendrickson
中科院分区：
文献类型：
--
作者：
H. Hendrickson
背景。在酒精依赖患者的治疗中，保持戒酒是最重要的，但也是最具挑战性的目标。我们的目的是研究长期治疗最近解毒的酒精依赖患者的长期安全性和有效性。方法：根据DSM-IV标准诊断为酒精依赖的314例患者从11个欧洲站点随机入组，分为两个治疗组：氢氧化钠（n = 154）和安慰剂（n = 160）。研究时间为12个月（6个月双盲治疗期和6个月未治疗随访）。主要终点是累积戒断时间（CAD）。发现。24名健康志愿者参加了一项双盲交叉试验。客观和主观镇静165分钟后给药。SMO与SMO之间存在显著的交互作用。IR和酒精，在15分钟，警觉性和刺激的增加和镇静的减少。在联合用药165分钟后，观察到单独的手指警戒准确性轻度下降。联合用药增加了治疗后出现的不良事件的数量：而SMO组为30。IR和34加酒精生命体征、血氧饱和度和实验室检查均未见明显变化。药物对预防复发、治疗中途退出率的影响；而次要结果是：药物副作用和不良反应，食欲行为（“滥用”），药物滥用和过量，中毒和戒断发作。最后，该研究首次在意大利大量酗酒者中评估了传染病（如丙型肝炎、艾滋病毒等）和普遍精神疾病（包括人格障碍）的流行情况。发现。该研究证实了氧酸钠在抗压戒断综合征（81%的治疗对象成功康复）和维持戒断方面的有效性（76%和78%的患者在开始治疗后6个月和12个月戒酒）。研究表明，该药也是安全可控的，特别是在剂量为50至100毫克/公斤/例（平均剂量为78.11 + 22.30毫克/公斤/例）的情况下使用。误用和滥用是有限的（12%的治疗），中毒和过量的情况极为罕见。在意大利，该研究首次帮助确定了接受氧酸钠治疗的大量酗酒者样本的主要人口统计学和临床特征，以及流行传染病的患病率（31%为HBcAb+ HBsAg阳性，15%为HCV阳性，4%为HIV阳性）和精神疾病（轴I为12%，轴II为4%）。解释。GUM研究证实了在意大利酒精治疗中心接受康复治疗的受试者中使用氧酸钠的有效性和安全性。资助：Laboratorio Farmaceutico CT S.r.l.到20mM上调miR-9在神经元切片。这些观察结果促使我们使用乙醇暴露和停药方案来执行更详细的miR-9对乙醇反应的时间特征和剂量依赖性。我们使用两种生理相关的乙醇浓度分别为20 mM和50 mM。暴露和/或退出时间为15分钟至24小时。我们在出生后提取小RNA片段（< 200nt），用DNase处理。通过qRT-PCR检测成熟的mmu-miR-9、miR-9*和miR-9前体pre-miR-9-1、-9-2和-9-3的浓度。初步结果表明，暴露于20 mM而不是50 mM乙醇中15分钟导致miR-9表达增加近2倍。有趣的是，pre-mir-9-1的表达也在乙醇的作用下增加。我们目前正在测试乙醇对pre-miR-9-2和-9-3前体表达的影响。我们还试图了解遗传（snp）和表观遗传（DNA甲基化）机制对乙醇调控mir-9基因表达的相互作用。我们使用人类样本对mir-9基因启动子进行测序，并观察到这些区域存在几个snp。其中一些snp可以改变转录因子的结合和/或促子甲基化。总之，这些结果可以为酒精成瘾的发展提供新的认识。慢性酒精中毒是世界范围内脑/突触损伤和轻度至中度认知障碍的重要原因，但其机制尚未解决。在这方面，成年大鼠和大鼠器官型脑培养物反复、亚慢性暴饮乙醇会触发神经炎症途径，导致氧化应激和局部神经变性。我们的研究结果表明，由于磷脂酶A2 （PLA2）水平/活性增加，花生四烯酸（AA）过度动员，这似乎与星形胶质水通道蛋白-4 （AQP4）和脑水肿的升高有关。此外，抑制AQP4具有神经保护作用。一种很有前途的传感器是核聚（adp -核糖）聚合酶-1 (PARP1)，它也被乙醇增强，可能会触发下游AQP4和PLA2的升高。事实上，用PJ34阻断PARP1活性可以减少暴饮乙醇诱导的神经毒性，这意味着该过程的一个组成部分本质上是坏死性死亡或“旁咽炎”。此外，omega-3二十二碳六烯酸（DHA 22:6）可显著抑制PARP1、AQP4和PLA2升高、AA释放和神经损伤。有关PLA2亚型的细节和DHA的神经保护机制的见解将被提出。其他实验室报道，慢性乙醇治疗增加toll样受体/配体、促炎细胞因子和NADPH氧化酶；我们认为这些神经免疫通路通过与PARP1-AQP4-PLA2-AA级联的串扰相互作用，从而增加氧化应激。本文介绍了一种新的饮酒实验方法，可以促进撒丁岛嗜酒大鼠（世界上为数不多的因过量饮酒而选择性繁殖的大鼠系之一）的异常高酒精摄入量。在每日光/暗循环的黑暗阶段的12小时之一中，将sP大鼠暴露于4瓶“酒精（10%，20%和30%，v/v） vs水”选择方案中；在半随机顺序下，每天改变酒精暴露时间，对大鼠来说是不可预测的。酒精摄入量与酒精暴露时间呈高度正相关（n = 24, r = 0.984, P < 0.0001），范围从平均0.86±0.06 g/kg（在黑暗期的第1小时饮酒）到平均2.00±0.07 g/kg（在黑暗期的第12小时饮酒）。在黑暗阶段的第12小时饮酒导致(a)血液酒精水平平均为101.1±8.1 mg%, (b)严重的酒精中毒迹象（例如，旋转杆任务的表现明显受损）。这些结果表明，不可预测的，有限的获取多种酒精浓度可能导致sP大鼠异常高的酒精摄入量。与大鼠对酒精的预期相关的逐渐增加的情绪“痛苦”可能是这种行为的神经生物学基础。PD30-42，其次是车轮运行后暴露于EC （PD42-72）。研究人员对动物的学习行为进行了测试，并收集了它们的大脑进行神经解剖。我们的数据表明：1)运动本身不足以挽救酒精引起的缺陷；2)运动后EC的“超级”组合在促进新细胞存活和树突重组方面更有效；3)行为（学习）缺陷可以通过“超级”疗法逆转。
Background. Maintenance of abstinence from alcohol represents the most im- portant, but also the most challenging objective in the treatment of alcohol dependent patients. We aimed to investigate the long-term safety and efficacy of sodium oxybate in the long-term treatment of recently detoxified alcohol-dependent patients. Method. 314 patients with a diagnosis of alcohol dependence according to DSM-IV criteria were randomly enrolled from 11 European sites and allocated to two treatment groups: sodium oxybate (n = 154) and placebo (n = 160). Study duration was of 12 months (6 months of double-blind treatment period and 6 months of untreated follow-up). The primary outcome was the Cumulative Abstinence Duration (CAD). Findings. Sodium oxybate was superior to placebo in achieving potentiation antagonism of and 24 healthy volunteers participated in a double-blind crossover trial. objective and subjective sedation 165 min post dose. There was a significant interaction between SMO.IR and alcohol, at 15 min, with an increase in alertness and stimulation and a decrease in sedation. An isolated mild decrease in digit vigi-lance accuracy was observed at 165 minutes post dose with the combination. The combination increased the number of treatment-emergent adverse events: vs 30 with SMO.IR and 34 with alcohol. No significant changes in vital signs, oxygen saturation, and laboratory tests were observed. drug effects on relapse prevention, the treatment drop out rate; while the secondary outcomes were: the drug side effects and adverse reactions, the appetive behavour ( “ misuse ” ), the drug abuse and the overdose, intoxication and withdrawal episodes. Finally, the study evaluated, for the first time, in a large cohort of Italian alcoholics, the prevalence of both infection diseases (e.g. hepatitis C, HIV, ect.) and prevalent psychiatric illness (includ- ing personalities disorders). Findings. The study confirmed the effectiveness of Sodium Oxybate in sup- pressing withdrawal syndrome (81% of the subjects treated were successfully rehabilitated) and in maintaining abstinence (76% and 78% of patients were abstinent at six and twelve months after starting treatment). The study showed that the drug is also safe and manageable, especially if used in doses between 50 and 100 mg/kg/die (the average dose was between 78.11 + 22.30 mg/kg/ die). Misuse and abuse were limited (12% of treatments), cases of intoxication an overdose extremely rare. For the first time in Italy, the study helped to iden-tify the main demographics and clinical features of a significant sample of alcoholics subjects treated with Sodium Oxybate and the prevalence of prevalent infections diseases (31 % were HBcAb+ HBsAg positive, 15% were HCV positive and 4% were HIV positive) and psychiatric illnesses (12% in Axis I and 4% in Axis II). Interpretation. The GUM study confirms the effectiveness and the safety of Sodium Oxybate in the treatment of subjects undergoing rehabilitation in Italian alcohol treatment centers. Funding: Laboratorio Farmaceutico CT S.r.l. to 20mM upregulated miR-9 in neuronal slices. These observations prompted us to perform more detailed temporal characteristics and dose-dependence of miR-9 response to ethanol using a regimen of ethanol exposures and withdrawals. We used two physiologically-relevent ethanol concentrations 20 mM and 50 mM. Exposure and/or withdrawal ranged from 15 minutes to 24 hours. We used postnatal day and small RNA fraction (<200 nt) were isolated and treated with DNase. Concentrations of mature mmu-miR-9, miR-9* and miR-9 precursors: pre-miR-9-1, -9-2, and -9-3 were determined by qRT-PCR. Preliminary results indicate that exposure to 20 mM but not 50 mM ethanol for 15 min caused an almost 2-fold increase in miR-9 expression. Interestingly, the ex- pression of pre-mir-9-1 was also increased in response to ethanol. We are cur-rently testing ethanol effect on expression of pre-miR-9-2 and -9-3 precursors. We are also trying to understand interplay between genetic (SNPs) and epigen-etic (DNA methylation) mechanisms on regulation of expression of mir-9 genes by ethanol. We performed sequencing of promoters of mir-9 genes using human samples and observed presence of several SNPs in these regions. Some of these SNPs could alter binding of transcription factors and/or pro-moter methylation. Together, these results can provide new understanding of development of alcohol addiction. Chronic alcoholism is a significant worldwide reason for brain/synaptic damage and mild-to-moderate cognitive impairment, but the mechanisms are unresolved. In that regard, repetitive, subchronic binge ethanol exposure with adult rats and rat organotypic brain cultures triggers neuroinflammatory routes leading to oxidative stress and regional neurodegeneration. Our results indicate excessive arachidonic acid (AA) mobilization due to increased phospholipase A2 (PLA2) levels/activity, and this appears related to elevations in astroglial aquaporin-4 (AQP4) and brain edema. Furthermore, inhibiting AQP4 is neuro-protective. A promising sensor for the binge ethanol which could be triggering downstream AQP4 and PLA2 elevations is nuclear poly(ADP-ribose) polymerase-1 (PARP1), also potentiated by ethanol. Indeed, blocking PARP1 activity with PJ34 reduces binge ethanol-induced neurotoxicity, which implies that a component of the process is necroptotic or “ parthanatotic ” in nature. Furthermore, omega-3 docosahexaenoic acid (DHA 22:6) administration significantly suppresses PARP1, AQP4 and PLA2 elevations, AA release, and neurodamage. Details regarding the PLA2 isoforms involved and insights into DHA ’ s mechanism of neuroprotection will be presented. Other laboratories have reported that chronic ethanol treatments increase toll-like receptors/ ligands, proinflammatory cytokines and NADPH oxidase; we suggest that those neuroimmune pathways interact via cross-talk with PARP1-AQP4-PLA2-AA cascades in order to augment oxidative stress as well. This paper describes a new experimental procedure of alcohol drinking pro- moting exceptionally high intakes of alcohol in Sardinian alcohol-preferring (sP) rats (one of the few rat lines selectively bred worldwide for excessive alcohol consumption). sP rats were exposed to the 4-bottle “ alcohol (10%, 20%, and 30%, v/v) vs water ” choice regimen during one of the 12 hours of the dark phase of the daily light/dark cycle; the time of alcohol exposure was changed daily under a semi-random order and was unpredictable to rats. Alcohol intake was found to be highly positively correlated (n = 24, r = 0.984, P < 0.0001) with the time of alcohol exposure and ranged from an average of 0.86 ± 0.06 g/kg (drinking session occurring during the 1st hour of the dark phase) to an average of 2.00 ± 0.07 g/kg (drinking session occurring during the 12th hour of the dark phase). Alcohol drinking during the 12th hour of the dark phase resulted in (a) blood alcohol levels averaging 101.1 ± 8.1 mg% and (b) severe signs of alcohol intoxication (e.g., markedly impaired performance at a Rota-Rod task). These results demonstrate that unpredictable, limited access to multiple alcohol concentrations may result in exceptionally high intakes of alcohol in sP rats. A progressively increasing emotional “ distress ” associated to the rats ’ expectation of alcohol might be the neurobiological basis of this behavior. PD30-42, followed by exposure to EC (PD42-72) after wheel-running. Animals were tested on learning behavior and brains were col- lected for neuroanatomy. Our data indicates that 1) exercise alone is not suffi-cient to rescue the alcohol-induced deficits; 2) a “ super ” combination of exercise followed by EC is more effective in promoting new cell survival and dendritic reorganization; and 3) behavioral (learning) deficits could be reversed by the “ super ” therapy.