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）： 哮喘是气道的一种慢性炎症性疾病，是由于遗传和环境因素之间复杂的相互作用引起的。在美国，超过1100万人报告说，2002年至少有一次哮喘发作，预计到2020年，哮喘患者的数量预计将增加到2900万。鉴于哮喘的死亡率，发病率和经济影响很大，重要的是改善对疾病的治疗，并开发新的策略和药物进行干预。用于控制哮喘症状的大多数药物属于3种药理学类别：吸入的皮质类固醇（ICS），白细胞受体拮抗剂（LTRA）和长效β肾上腺素能受体激动剂（LABA）。临床试验已经建立了这些药物的疗效和安全性，或者结合使用以治疗哮喘。然而，对每种药物的响应响应响应的标志性变异性限制了其安全性，功效和成本效益。最近的研究表明，响应哮喘药物的患者间变异性的多达80％是由于遗传变异所致。美国肺协会哮喘临床研究中心正在进行一项临床试验，标题为：白细胞化剂或皮质类固醇（LOC）试验。患有哮喘的6岁以上的患者吸入哮喘 氟替卡松（FP）单一疗法4至6周，将随机分配以继续吸入FP，每天两次100 ug或Montelukast，10毫克睡前或吸入的Salmeterol，每天两次两次UG，持续16周。 165名患者将参加每个治疗部门（共495例）。 LOCS试验旨在确定Montelukast单一疗法和Salmeterol单药治疗是否可以代替吸入FP而不会损失哮喘。与吸入FP相比，主要结果是由Montelukast单一疗法和Salmeterol单药治疗率确定的哮喘控制。次要结局包括肺功能，包括药物使用在内的哮喘症状，与患者相关的措施，炎症标志物以及200名患者的标志，气道对甲基苯胺的反应。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SNP，以预测哪些患者可以用Montelukast或Salmeterol单药治疗，而不会损失吸入FP的控制。这项药物遗传学研究的结果可能有助于最佳选择哮喘中的单一疗法。