Medication Development for Cocaine Dependence

可卡因依赖的药物开发

• 批准号: 6827173
• 负责人: Bankole A Johnson
• 金额: $ 62.4万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827173
• 关键词: anticonvulsants; behavioral /social science research tag; clinical research; clinical trials; cocaine; cognitive behavior therapy; craving; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug adverse effect; drug design /synthesis /production; drug detection; drug screening /evaluation; gamma aminobutyrate; human subject; human therapy evaluation; interview; patient oriented research; psychosocial rehabilitation; reinforcer; urinalysis

DESCRIPTION (provided by applicant): Despite considerable scientific effort in the last two decades, no medication has proved to be an effective treatment for cocaine dependence. Cocaine's rewarding effects are mediated primarily through mesolimbic dopamine (DA) pathways. Yet, experiments that have focused on developing medications that either inhibit midbrain DA release or produce post-synaptic DA receptor blockade have shown that these are not effective treatments for cocaine dependence. Therefore, we propose to test a different strategy to developing a medication for treating cocaine dependence: Is opposition of midbrain DA release alone sufficient, or can we more reliably control DA effects by contemporaneously modulating DA functional expression? Expression of midbrain DA-associated reward may be mediated through inhibition of gamma-aminobutyric acid (GABA), via efferents that project from the nucleus accumbens to the cortex and that are themselves under the tonic control of excitatory amino acid (EAA) pathways. Thus, it is reasonable to hypothesize that a pharmacological agent that facilitates mesocortical GABAergic function and inhibits the action of EAAs should more reliably diminish cocaine's rewarding effects by inhibiting the expression of midbrain DA function in addition to decreasing midbrain DA release. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate (a fructo-pyranose derivative that diminishes DA functional expression) is effective at reducing craving and alcohol consumption among alcohol-dependent individuals. Next, we will expand the test of our hypothesis by determining in a randomized clinical trial (RCT) whether topiramate significantly reduces cocaine's rewarding effects associated with abuse liability. In this RCT, male and female cocaine dependent individuals will be randomized to receive either topiramate (up to 300 mg/day) or placebo (N = 90 subjects/group x 2 groups = 180) as an adjunct to standardized weekly Cognitive Behavioral Therapy for 12 weeks. Participants also will be followed up at 2 weeks and at 1,2, and 3 months after the end of the 12-week treatment period. The primary specific aims of this study are to test two predictions of our hypothesis: 1) Topiramate will be superior to placebo at increasing the maximum number of cocaine-free (abstinent) days (assessed by self-report of use and urine assays for benzoylecgonine, the major metabolite of cocaine), and 2) Topiramate will be superior to placebo at decreasing cocaine craving, and these reductions in cocaine craving will be associated with decreased cocaine intake. We also will test the additional secondary predictions that: 3) Topiramate, compared with placebo, will be associated with an improvement in psychosocial functioning as exemplified by: a) Improved general well-being; b) Social Functioning, and c) Enhanced Quality of Life, and d) that these improvements in psychosocial functioning will be correlated with decreased cocaine intake. This study supports NIDA's mission to develop effective medications for the treatment of cocaine dependence. It also will provide evidence for or against the above hypothesis, and thus will improve our understanding of the fundamental neurobiological mechanisms that control and modulate cocaine dependence.

描述（由申请人提供）：尽管在过去的二十年中进行了相当大的科学努力，但事实证明，没有药物是可卡因依赖性的有效治疗方法。可卡因的奖励作用主要是通过中唇多巴胺（DA）途径介导的。然而，重点是开发抑制中脑DA释放或产生突触后DA受体阻滞的药物的实验表明，这些不是可卡因依赖性的有效治疗方法。因此，我们建议测试一种不同的策略来开发一种用于治疗可卡因依赖性的药物：单独的中脑DA释放的对立是否足够，还是我们可以通过同时调节DA功能表达来更可靠地控制DA效应？中脑DA相关奖励的表达可以通过抑制γ-氨基丁酸（GABA），通过从伏隔核向皮层投射的传出来介导，并且本身在兴奋性氨基酸（EAA）途径的强度控制下。因此，可以合理地假设，促进中皮质GABA能功能并抑制EAA的作用的药理学剂应通过抑制中脑DA功能的表达在中脑DA释放的情况下抑制中脑DA功能的表达，从而更可靠地减少可卡因的奖励作用。我们最近的概念概念证明（一种降低DA功能表达）的托吡酯（一种质丙糖衍生物）可以有效地减少依赖酒精依赖性的个体的渴望和酒精消耗，这是一种新颖方法的希望。接下来，我们将通过在一项随机临床试验（RCT）中确定托吡酯是否显着降低可卡因与虐待责任相关的奖励效果，从而扩展假设的检验。在此RCT中，将随机分配男性和女性可卡因依赖性个体，以接受托吡酯（最多300 mg/天）或安慰剂（n = 90名受试者/x 2组= 180），作为标准化每周认知行为疗法的辅助手段12周。 参与者还将在12周的治疗期结束后的2周和1,2和1,2和3个月后进行跟进。 The primary specific aims of this study are to test two predictions of our hypothesis: 1) Topiramate will be superior to placebo at increasing the maximum number of cocaine-free (abstinent) days (assessed by self-report of use and urine assays for benzoylecgonine, the major metabolite of cocaine), and 2) Topiramate will be superior to placebo at decreasing cocaine craving, and these reductions在可卡因中，渴望将与可卡因摄入量减少有关。我们还将测试其他二次预测：3）托吡酯与安慰剂相比，将与以下示例的社会心理功能相关的改善：a）改善一般福祉； b）社会功能，c）增强的生活质量，d）这些改善的社会心理功能将与可卡因摄入量减少相关。这项研究支持NIDA开发有效治疗可卡因依赖性药物的使命。它还将为上述假设提供证据，因此将提高我们对控制和调节可卡因依赖性的基本神经生物学机制的理解。