Interventions to Test the alpha 7 Nicotinic Receptor Model in Schizophrenia

测试精神分裂症 α7 烟碱受体模型的干预措施

• 批准号: 7591196
• 负责人: STEPHEN I DEUTSCH
• 金额: $ 20.95万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591196
• 关键词: Address; Adverse effects; Adverse event; Agonist; Attention; Autopsy; Brain; Choline; Clinical; Clinical Trials; Cognition; Cognitive deficits; Cytidine Diphosphate Choline; DSM-IV; Data; Development; Dose; Galantamine; Genetic; Goals; Human; Intervention; Measures; Memory; Modeling; Monitor; Motivation; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Outcome Measure; Patients; Pharmaceutical Preparations; Placebos; Prevention; Property; Randomized; Recovery of Function; Research Project Grants; Residual state; Risperidone; Schizoaffective Disorders; Schizophrenia; Secondary to; Services; Signs and Symptoms; Symptoms; Testing; Treatment Protocols; Wit; acetylcholine receptor agonist; atypical antipsychotic; base; desensitization; improved; novel; pilot trial; pre-clinical; prevent; primary outcome; receptor; receptor binding; receptor function; secondary outcome; single molecule; smoking prevalence; therapy development; week trial

DESCRIPTION (provided by applicant): Atypical antipsychotic medications reduce extrapyramidal side effects and improve prevention compared to older agents. However, in spite of their use many patients with schizophrenia do not achieve functional recovery. Residual symptoms, lack of motivation and cognitive deficits persist. Thus, development of novel pharmacological strategies to address residual signs and symptoms are urgent. The hypothesis of alpha-7 nicotinic acetylcholine receptor (a7 nAChR) hypofunction is based on the prevalence of smoking in schizophrenia, receptor binding data on autopsied brain, pathophysiological and familial and genetic studies. This hypothesis has stimulated both preclinical and clinical exploration of nicotinic agonists to enhance functioning of the receptor. However, the limited availability of safe and selective a7 nAChR agonists for human administration and rapid desensitization of these receptors has made clinical trials problematic. Long term administration of an agonist could have the unintended pharmacological consequence of functional "antagonism" of the receptor, whose expression is already reduced. The aim of this R34 proposal is to conduct a "proof of concept" clinical trial combining galantamine and CDP-choline. We hypothesize that galantamine will prevent desensitization, allowing choline to serve as a selective agonist, rather than becoming a functional antagonist secondary to receptor desensitization. We predict that co-administration of these agents will reduce symptoms and improve memory and attention. Fifty patients with DSM-IV schizophrenia or schizoaffective disorder will be randomly assigned to either combination treatment or placebos for both in a16 week trial. All patients will be maintained on a stable regimen of risperidone for the trial duration. The dose of galantamine will be 24 mg/day; the dose of CDP-choline will be 2000 mg/day. The PANSS, CGI and nicotine will be assessed at baseline, week 4, 8, 12 and 16. Cognition will be assessed at baseline, week 8 and 16. Adverse events will be monitored weekly. The primary outcome measure is negative symptoms, all other measures are secondary outcomes. The goals of this application fit well wit the aims of the "From Intervention Development to Services; Exploratory Research Grants" announcement. If the results of this pilot trial are positive, the next steps will be a definitive trial and efforts to develop medications that combine the allosteric modulatory and agonist properties of the combination in a single molecule.

描述（由申请人提供）：与老年人相比，非典型抗精神病药可减少锥体外副作用并改善预防。但是，尽管使用了许多精神分裂症患者，但仍无法实现功能恢复。残留症状，缺乏动力和认知缺陷持续存在。因此，紧急解决残留体征和症状的新型药理策略的发展是紧迫的。 α-7烟碱乙酰胆碱受体（A7 NACHR）的假设是基于精神分裂症中吸烟的患病率，在尸体生理学和家族性和家族性研究中的受体结合数据。该假设刺激了烟碱激动剂的临床前和临床探索，以增强受体的功能。但是，安全和选择性的A7 NACHR激动剂的可用性有限，这些受体对这些受体的快速脱敏，这使临床试验有问题。激动剂的长期给药可能会产生受体功能“拮抗”的意外药理学后果，其表达已经降低。该R34提案的目的是进行“概念证明”临床试验，该试验结合了甘氨酸和CDP-胆碱。我们假设甘氨酸将防止脱敏，从而使胆碱可以作为选择性激动剂，而不是成为继发受体脱敏的功能拮抗剂。我们预测，这些药物的共同给药将减轻症状并改善记忆力和注意力。 在A16周试验中，将有50例DSM-IV精神分裂症或精神分裂症患者随机分配给组合治疗或安慰剂。在试验期间，所有患者将维持在利培酮的稳定方案上。甘氨酸的剂量为24毫克/天； CDP-胆碱的剂量为2000 mg/天。 panss，CGI和尼古丁将在基线第4、8、12和16周进行评估。将在基线，第8和第16周评估认知。不良事件将每周监控。主要结局指标是负症状，所有其他措施都是次要结果。 该应用程序的目标非常适合“从干预开发到服务；探索性研究赠款”的目标。如果该试验试验的结果是积极的，那么下一步将是一项确切的试验，并努力开发将组合的变构调节性和激动剂特性结合在单个分子中的药物。