LEUKOTRIENE POLYMORPHISMS & MONTELUKAST RESPONSE

白三烯多态性

• 批准号: 6552899
• 负责人: JOHN J LIMA
• 金额: $ 17.95万
• 依托单位: NEMOURS CHILDREN'S CLINIC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6552899
• 关键词: asthma; clinical research; clinical trials; genetic polymorphism; human genetic material tag; human subject; human therapy evaluation; inhibitor /antagonist; leukotrienes; lipoxygenase; patient oriented research; pharmacogenetics; quinoline; respiratory disorder chemotherapy; respiratory pharmacology; theophylline; asthma; clinical research; clinical trials; genetic polymorphism; human genetic material tag; human subject; human therapy evaluation; inhibitor /antagonist; leukotrienes; lipoxygenase; patient oriented research; pharmacogenetics; quinoline; respiratory disorder chemotherapy; respiratory pharmacology; theophylline

DESCRIPTION (provided by applicant): Asthma is a common disease caused by a complex interaction between genetic and environmental factors. Asthma afflicts 17 million Americans. In 1999, > 5000 persons died from asthma. Given the significant mortality and morbidity associated with asthma, it is important to continue to develop new strategies for intervention. Leukotriene antagonists are thought to be the most innovative approach to asthma therapy in 20 years. Despite their demonstrated efficacy, safety and popularity, the leukotriene antagonists are associated with a significant degree of inter-patient variability in response, which can limit their safety, efficacy and cost-effectiveness. The overall objective of this ancillary study is to elucidate the mechanisms underlying inter-patient variation in response to montelukast. Up to 80% of the variation in response to asthma drugs may be due to genetic variation. Several polymorphisms in leukotriene pathway genes can contribute to variability in response. The specific aim of this project is to determine if polymorphisms in genes encoding 5-lipoxygenase, leukotriene A4hydrolase, LTC4 synthase, multi-drug resistance protein 1 (MRP1) and LT1 receptor proteins are determinants of response to montelukast treatment. We will collect DNA from patients participating in a parent clinical trial entitled: Effectiveness of Low Dose Theophylline as Add-On Therapy in the Treatment of Asthma (LoDo Trial). 627 patients from 19 Asthma Clinical Research Centers will be randomly assigned to receive placebo, or low dose theophylline (300 mg/day) or montelukast, 10 mg daily, for 6 months. Stepwise Linear and Poisson regressions will be performed on outcomes including treatment and genetic covariates, and interaction terms between treatment arm and genetic makeup. Polymorphisms that are highly associated with response can lead to the development of genetic tests that will identify patients most likely to benefit from montelukast treatment. This information may lead to individualization of asthma medications based on the genetic make-up of the patient.

描述（由申请人提供）： 哮喘是遗传因素和环境因素之间复杂的相互作用引起的一种常见疾病。哮喘折磨了1700万美国人。 1999年，> 5000人死于哮喘。鉴于与哮喘有关的死亡率和发病率很高，重要的是要继续制定新的干预策略。白细胞拮抗剂被认为是20年来最具创新性的哮喘治疗方法。尽管表现出了功效，安全性和受欢迎程度，但白三烯拮抗剂仍与重大的患者间差异相关，这可能会限制其安全性，功效和成本效益。这项辅助研究的总体目的是阐明响应于蒙特鲁卡斯特的患者间变化的机制。对哮喘药物的响应量的多达80％可能是由于遗传变异所致。白三烯途径基因中的几种多态性可能导致反应的变异性。该项目的具体目的是确定编码5-脂氧酶，白三氢酶，LTC4合酶，多药耐药蛋白1（MRP1）和LT1受体蛋白的基因中的多态性是否是对Montelukast治疗反应的决定性的。我们将从参加母亲临床试验的患者中收集DNA：低剂量茶碱作为哮喘治疗中的附加疗法的有效性（Lodo试验）。来自19个哮喘临床研究中心的627例患者将随机分配接受安慰剂或低剂量的茶碱（300 mg/day）或蒙特鲁卡斯特（Montelukast），每天10 mg，持续6个月。将在包括治疗和遗传协变量在内的结果以及治疗组和遗传组成之间的相互作用项上进行逐步线性和泊松回归。与反应高度相关的多态性可以导致基因检测的发展，这些基因检测将确定最有可能受益于蒙特鲁卡斯特治疗的患者。这些信息可能会导致基于患者的遗传组成的哮喘药物个性化。