PHARMACOGENETICS OF ASTHMA MONOTHERAPY

哮喘单一疗法的药物遗传学

• 批准号: 6698911
• 负责人: JOHN J LIMA
• 金额: $ 66.4万
• 依托单位: NEMOURS CHILDREN'S CLINIC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698911
• 关键词: asthma; beta adrenergic receptor; bronchodilators; clinical research; corticosteroid receptors; genetic polymorphism; genotype; high throughput technology; human subject; human therapy evaluation; inflammation; methacholine; patient oriented research; pharmacogenetics; phenotype; questionnaires; respiratory disorder chemotherapy; respiratory function; sign /symptom

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways that is caused by a complex interaction between genetic and environmental factors. In the US, more than 11 million individuals reported having at least one attack of asthma in 2002, and the number of people with asthma is expected rise to 29 million by 2020. Given the significant mortality, morbidity and economic impact of asthma, it is important to improve treatment of the disease and to develop new strategies and drugs for intervention. Most of the drugs used to control asthma symptoms fall into 3 pharmacological classes: inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA) and long-acting beta adrenergic receptor agonists (LABA). Clinical trials have established the efficacy and safety of these drugs alone or in combination to treat asthma. However, marked inter-patient variability in response to each of the drugs limit their safety, efficacy and cost-effectiveness. Recent studies suggest that up to 80% of the inter-patient variability in response to asthma drugs is due to genetic variation. The American Lung Association Asthma Clinical Research Centers are performing a clinical trial entitled: LeukotrieneModifier or Corticosteroids (LOCS) trial. Patients 6 years or older with asthma who are stable on inhaled fluticasone (FP) monotherapy for 4 to 6 weeks, will be randomly assigned to continue taking inhaled FP, 100 ug twice a day, OR montelukast, 10 mg at bedtime, OR inhaled salmeterol, 50 ug twice a day, for 16 weeks. 165 patients will participate in each treatment arm (495 total). The LOCS trial was designed to determine if montelukast monotherapy and salmeterol monotherapy can be substituted for inhaled FP without loss of asthma control. The primary outcome is asthma control as determined by the rate of treatment failures with montelukast monotherapy and salmeterol monotherapy compared to inhaled FP. Secondary outcomes include pulmonary function, asthma symptoms including medication use, patient related measures, markers of inflammation and in 200 patients, airway responsiveness to methacholine. The goals of the present ancillary pharmacogenetic study are to identify SNPs in one or multiple genes that predict which patients can be treated with either montelukast or salmeterol monotherapy without loss of control conferred by inhaled FP. The results of this pharmacogenetic study may facilitate the optimal selection of monotherapy in asthma.

描述（由申请人提供）： 哮喘是一种慢性气道炎症性疾病，是由遗传和环境因素之间复杂的相互作用引起的。在美国，2002 年有超过 1100 万人报告至少患有一次哮喘，预计到 2020 年，哮喘患者人数将增加到 2900 万。鉴于哮喘的显着死亡率、发病率和经济影响，对于改善该疾病的治疗以及开发新的干预策略和药物非常重要。大多数用于控制哮喘症状的药物分为 3 个药理学类别：吸入皮质类固醇 (ICS)、白三烯受体拮抗剂 (LTRA) 和长效 β 肾上腺素能受体激动剂 (LABA)。临床试验已经确定了这些药物单独或联合治疗哮喘的有效性和安全性。然而，患者对每种药物反应的显着差异限制了它们的安全性、有效性和成本效益。最近的研究表明，高达 80% 的患者对哮喘药物反应的差异是由于遗传变异造成的。美国肺脏协会哮喘临床研究中心正在进行一项名为：白三烯调节剂或皮质类固醇 (LOCS) 试验的临床试验。吸入后病情稳定的 6 岁或以上哮喘患者 氟替卡松 (FP) 单药治疗 4 至 6 周，将被随机分配继续服用吸入 FP，100 ug，每天两次，或孟鲁司特，睡前 10 mg，或吸入沙美特罗，50 ug，每天两次，持续 16 周。每个治疗组将有 165 名患者参与（总共 495 名患者）。 LOCS 试验旨在确定孟鲁司特单药疗法和沙美特罗单药疗法是否可以替代吸入性 FP，而不会导致哮喘失控。主要结局是哮喘控制，由孟鲁司特单一疗法和沙美特罗单一疗法与吸入FP相比的治疗失败率决定。次要结局包括肺功能、哮喘症状（包括药物使用）、患者相关措施、炎症标志物以及 200 名患者的气道对乙酰甲胆碱的反应性。本辅助药物遗传学研究的目标是鉴定一个或多个基因中的 S​​NP，预测哪些患者可以接受孟鲁司特或沙美特罗单一疗法治疗，而不会失去吸入 FP 带来的控制。这项药物遗传学研究的结果可能有助于哮喘单一疗法的最佳选择。