PHARMACOLOGICAL TREATMENT OF ETHANOL WITHDRAWAL

乙醇戒断的药理学治疗

• 批准号: 2389897
• 负责人: LARRY P GONZALEZ
• 金额: $ 12.76万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2389897
• 关键词: NMDA receptors; anticonvulsants; behavior test; brain electrical activity; calcium channel blockers; carbamazepine; convulsions; diazepam; dizocilpine; dosage; drug administration rate /duration; drug withdrawal; electroencephalography; ethanol; inhalation drug administration; inhibitor /antagonist; laboratory rat; mental disorder chemotherapy; neuropharmacology; nitrendipine; nonhuman therapy evaluation; reflex epilepsy; verapamil

Chronic exposure to ethanol produces a latent state of CNS hyperexcitability which becomes evident upon removal from ethanol exposure. The occurrence of some of the symptoms of this hyperexcitability are serious enough medically to warrant pharmacological intervention. Benzodiazepines have for some time been the drugs of choice in the treatment of ethanol withdrawal, but the use of these drugs is not without controversy. Benzodiazepines are most effective in reducing the incidence of motor convulsions following ethanol withdrawal, but evidence relating to their ability to reduce or prevent electrophysiological signs of central seizure activity is incomplete. Investigations of withdrawing alcoholics indicate that some individuals may be resistant to the anticonvulsant effects of benzodiazepines, and some investigators have suggested that these drugs may actually increase the probability of withdrawal seizures during subsequent withdrawals from ethanol. Data are also available indicating a possible dissociation between the effects of benzodiazepines on motor convulsions and their effects on abnormal neuronal electrical discharge. Since electrical seizure discharge is sometimes associated with neuropathological changes and may result in a kindling-like increase in the severity of subsequent withdrawal episodes, it is of clinical relevance to determine the extent to which pharmacological agents suppress both motor convulsions and electrical discharge following withdrawal from chronic ethanol exposure. Studies proposed in this application will examine and compare the effects of several drug treatments on measurements of the ethanol withdrawal syndrome in rats chronicallY exposed to ethanol. These studies will include two drugs commonly used in the treatment of the ethanol withdrawal syndrome, the benzodiazepine diazepam and the anticonvulsant carbamazepine, and will also include four additional drugs representative of two drug classes of recent clinical interest, the voltage-dependent calcium channel inhibitors and the NMDA receptor antagonists. Measurements of convulsant withdrawal symptoms will be made along with observations of electrophysiological measures of CNS function. Drug treatment will include both single and multiple dosing schedules and the effects on subsequent withdrawal symptomatology will be evaluated. Since recent evidence suggests that the severity of ethanol withdrawal symptoms may depend more upon the history of withdrawal experiences than upon the actual length of ethanol exposure, studies are also proposed to examine the effectiveness of these drugs in suppressing withdrawal symptoms after multiple withdrawal episodes, as well as after a single period of ethanol exposure and withdrawal. These studies should provide important information about the effectiveness of these treatments for the ethanol withdrawal syndrome under different conditions of ethanol exposure and drug administration, and will permit an examination of effects on central neuronal functioning as well as on motor convulsions and behavioral measures of CNS hyperexcitability.

长期暴露于乙醇会产生中枢神经系统的潜在状态 从乙醇中取出后，过度兴奋的性能很明显 接触。某些症状的发生 过度兴奋性在医学上足够严重，可以保证药理 干涉。苯二氮卓类药物已经有一段时间了 在治疗乙醇提取时，但是这些药物的使用不是 没有争议。苯二氮卓类药物最有效地减少 退出乙醇后运动抽搐的发生率，但证据 与他们减少或预防电生理体征的能力有关 中央癫痫发作的活动不完整。撤回的调查 酗酒者表明，有些人可能对 苯二氮卓类药物和一些研究人员的抗惊厥作用具有 建议这些药物实际上可能增加 随后从乙醇提取期间的戒断癫痫发作。数据是 也可用，表明 苯二氮卓运动有关运动抽搐及其对异常的影响 神经元电气放电。 由于癫痫发作的排放是 有时与神经病理学变化有关，可能导致 在随后的撤回发作的严重程度上类似点燃的增加， 确定在多大程度上是临床相关性 药理学剂抑制运动抽搐和电气 退出慢性乙醇暴露后。 研究 在本应用程序中提出的将检查和比较 关于乙醇提取的测量的几种药物治疗 长期暴露于乙醇的大鼠中的综合征。这些研究会 包括两种通常用于治疗乙醇的药物 戒断综合征，苯二氮卓地西ep和抗惊厥药 卡马西平，还将包括四个其他药物代表 在最近临床兴趣的两个药物类别中，电压依赖性 钙通道抑制剂和NMDA受体拮抗剂。 将对抽搐戒断症状进行测量 观察中枢神经系统功能的电生理测量值。药品 治疗将包括单一和多种给药时间表以及 将评估对随后的戒断症状学的影响。自从 最近的证据表明乙醇戒断症状的严重程度 可能更多地取决于退出经历的历史，而不是 乙醇暴露的实际长度，还提出了研究 这些药物在抑制戒断症状后的有效性 多次提取发作以及单个乙醇之后 暴露和退出。这些研究应该提供重要的 这些治疗方法对乙醇的有效性的信息 在乙醇暴露的不同条件下戒断综合征和 药物管理局，并将允许检查中央的影响 神经元功能以及运动抽搐和行为 中枢神经系统过时的度量。