L-arginine as a therapy in severe asthma

L-精氨酸治疗严重哮喘

• 批准号: 8780667
• 负责人: Nicholas J. KENYON
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780667
• 关键词: Address; Adrenal Cortex Hormones; Adult; Affect; Animal Model; Animals; Arginine; Asthma; Biology; Blinded; Blood; Breathing; Bronchodilator Agents; Bronchoscopy; Caring; Cell Culture Techniques; Cells; Clinical; Clinical Research; Clinical Trials; Crossover Design; Disease; Dosage Forms; Dose; Drug Formulations; Effectiveness; Enrollment; Enzymes; Epithelial Cells; Exhalation; Fibrosis; Goals; Harvest; Human; Inflammatory; Intervention; Knowledge; Life; Lung; Measurable; Measures; Messenger RNA; Metabolism; Mus; NOS2A gene; Nitric Oxide; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebo Control; Placebos; Proteins; Quality of life; Randomized; Recruitment Activity; Regulation; Series; Steroids; Supplementation; Symptoms; Testing; Therapeutic Agents; Toxic effect; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; arginase; arginine treatment; asthmatic; asthmatic airway; asthmatic patient; cohort; design; improved; inhibitor/antagonist; metabolomics; mouse model; nanoparticle; novel therapeutic intervention; novel therapeutics; preclinical study; respiratory; standard of care

DESCRIPTION (provided by applicant): Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. We need novel therapeutic agents that are affordable, can decrease the reliance on steroids, and can improve quality of life. This clinical and mechanistic study has the potential to impact treatment of a subset of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and NO biology in the airways of asthmatics. We will pursue a clinical trial in subjects not well controlled on standard drug therapy; this strategy will address whether L-arginine is efficacious in patients receiving standard of care medications. In studies using animal models, we and others have shown that interventions that augment NO levels, through either supplementation of L-arginine or inhibition of arginase, decrease allergic airway inflammation and hyperresponsiveness-the two hallmarks of asthma. Overall, we hypothesize that a "responder" subset of adult severe asthma patients will derive clinical benefit from supplemental L-arginine therapy and that these patients will have a lower exhaled NO concentrations (<20 ppb) and a higher NOS2/Arg1 mRNA and protein ratio in their airway epithelial cells than "non-responders." We aim to: 1) test the hypothesis that uncontrolled, adult severe asthma patients with exhaled breath NO concentrations <20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO > 25, 2) determine the mechanisms by which L-arginine affects the regulation of NOS and arginase enzymes in primary airway epithelial cell cultures from severe asthmatic subjects, and 3) test the hypothesis that inhaled nanoparticle carrier formulations of L-arginine will decrease airway inflammation, airway hyperresponsiveness, and airway fibrosis at lower doses than systemically administered L-arginine. The major impact of our study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. Our ultimate goal is to develop novel therapeutic agents to treat adult severe asthma patients better.

描述（由申请人提供）：哮喘是一种进行性炎症性气道疾病，在许多严重受累的成人中导致气道结构变化和衰弱症状。我们需要新的治疗药物，价格合理，可以减少对类固醇的依赖，并可以提高生活质量。这项临床和机制研究有可能影响成人重度哮喘患者的治疗，并进一步了解哮喘患者气道中L-精氨酸代谢和NO生物学机制。我们将在标准药物治疗控制不佳的受试者中进行临床试验;该策略将解决L-精氨酸在接受标准治疗药物的患者中是否有效。在使用动物模型的研究中，我们和其他人已经表明，通过补充L-精氨酸或抑制精氨酸酶来增加NO水平的干预措施可以减少过敏性气道炎症和高反应性-哮喘的两个标志。总的来说，我们假设成人重度哮喘患者中的"应答者"亚组将从补充L-精氨酸治疗中获得临床益处，并且这些患者的呼出气NO浓度（<20 ppb）和气道上皮细胞中的NOS 2/Arg 1 mRNA和蛋白比高于"无应答者"。“我们的目标是：1）测试不受控制的成年重度哮喘患者呼出气NO浓度25的假设，2）确定L-精氨酸影响严重哮喘受试者原代气道上皮细胞培养物中NOS和NOS酶调节的机制，3）测试吸入L-精氨酸纳米颗粒载体制剂的假设，即在低于全身给予L-精氨酸的剂量下，可以减少气道炎症，气道高反应性和气道纤维化。<20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO >我们研究的主要影响是确定成人重度哮喘队列将受益于补充L-精氨酸治疗。我们的最终目标是开发新的治疗药物，以更好地治疗成人重度哮喘患者。