A Histamine Pharmacodynamic Biomarker to Guide Treatment in Pediatric Asthma

指导小儿哮喘治疗的组胺药效生物标志物

• 批准号: 10178069
• 负责人: BRIDGETTE L. JONES
• 金额: $ 52.07万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178069
• 关键词: Adrenal Glands; Adverse effects; African American; Allergens; Allergic; Antibody Therapy; Antihistamines; Asthma; Biological; Biological Markers; Biological Response Modifiers; Blood; Bronchoconstriction; Caucasians; Cell Adhesion Molecules; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Childhood; Childhood Asthma; Chronic Disease; Clinical; Clinical Markers; Data; Decision Making; Disease; Effectiveness; Emergency department visit; Enzymes; Exhalation; Exhibits; Exposure to; Extrinsic asthma; Functional disorder; Generations; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Guidelines; Histamine; Histamine Receptor; Hypersensitivity; IgE; Immune; Immunologic Markers; Immunologics; Individual; Inhalation; Iontophoresis; Knowledge; Lasers; Lead; Leukotrienes; Link; Literature; Modeling; Monitor; Monoclonal Antibodies; Moods; Morbidity - disease rate; Mucous body substance; Nitric Oxide; Nucleotides; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Prediction of Response to Therapy; Production; Race; Regimen; Reproducibility; Research; Safety; Single Nucleotide Polymorphism; Steroids; Techniques; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; United States; Weight Gain; Work; base; chemokine; clinical biomarkers; cost; cytokine; efficacy outcomes; eosinophil; experience; improved; innovation; mortality risk; neutrophil; novel; omalizumab; pediatric patients; pharmacodynamic biomarker; predicting response; predictive marker; predictive modeling; pulmonary function; response; side effect; skin prick test; success; treatment response

Abstract There is a critical need for validated objective biomarkers that predict therapeutic response for asthma therapies in children. Children who require daily asthma treatment with a controller medication such as an inhaled steroid are defined to have persistent asthma. Approximately 60% of children with asthma in the United States have persistent disease. Variability in treatment response to standard guideline supported medications (e.g. inhaled steroids, leukotriene modifiers, mono-clonal antibodies) exist among children with persistent asthma. Clinical markers such as IgE level, exhaled nitric oxide level, eosinophil and neutrophil counts have not been validated to predict treatment response to asthma medications in children. It is not possible to optimize currently available treatments for asthma in achieving therapeutic efficacy and limiting exposure to adverse effects from non-efficacious medications without robust non-invasive biomarkers that can drive therapeutic decision making. The long-term goal is to advances and improve therapeutic intervention for pediatric patients with asthma. The objective in this particular application is to establish the utility of Histamine Iontophoresis with Laser Doppler monitoring (HILD) as biomarker for accurate prediction of therapeutic response to low cost and low side-effect antihistamine treatment in children with allergic asthma. The central hypothesis is that “HILD is predictive of treatment response to an antihistamine in children with asthma”. This hypothesis has been formulated by the applicant's strong preliminary data and supporting literature. The rationale for the proposed research is that HILD is able to identify distinct histamine pharmacodynamic response types that predict treatment response to antihistamine medications in asthma. Guided by strong preliminary data, this hypothesis will be tested by two specific aims: 1) to determine HILD prediction of therapeutic response to an antihistamine among children with allergic asthma; 2) to develop a robust predictive model of therapeutic response to an antihistamine among children with allergic asthma. The first aim will compare change in Asthma Control Test (ACT®) scores by histamine response type in a six week, 2x2 cross-over, add-on trial of Levocetirizine (LTZ) among children with uncontrolled allergic asthma. The second aim will determine the best predictive model (incorporating HILD and clinical variables) for change in ACT® scores after LTZ treatment among children with allergic asthma. The proposed research is significant because it has the potential to alter the current treatment paradigms for children with asthma where response to treatment is predicted a priori; and is innovative in testing and validating a first biomarker accurately predicting response to an asthma treatment in children. The knowledge gained will make available the first validated biomarker to predict treatment response in children with asthma and will improve therapeutic efficacy and outcomes in these children.

摘要 迫切需要有效的客观生物标志物来预测哮喘的治疗反应 治疗儿童。需要每天使用控制性药物（如 吸入类固醇被定义为患有持续性哮喘。在美国，大约60%的哮喘儿童 国家有持续的疾病。对标准指南支持药物治疗反应的变异性 (e.g.吸入类固醇，白三烯调节剂，单克隆抗体）存在于持续性 哮喘临床标记物如IgE水平、呼出气一氧化氮水平、嗜酸性粒细胞和中性粒细胞计数没有 已被验证用于预测儿童哮喘药物的治疗反应。无法优化 目前可用的哮喘治疗方法在实现治疗功效和限制暴露于不良反应方面的作用 非有效药物的影响，没有强大的非侵入性生物标志物，可以驱动治疗 决策。长期目标是推进和改善儿科患者的治疗干预 哮喘本特定应用的目的是建立组胺离子电渗疗法的效用， 激光多普勒监测（HILD）作为生物标志物，用于准确预测低成本和低成本的治疗反应， 低副作用抗组胺药治疗儿童过敏性哮喘核心假设是“HILD是 预测哮喘儿童对抗组胺药的治疗反应”。这一假设一直被 由申请人强有力的初步数据和支持文献制定。建议的理由 研究表明，HILD能够识别不同的组胺药效学反应类型， 抗组胺药物治疗哮喘的反应。在强有力的初步数据的指导下， 将通过两个特定目的进行测试：1）确定HILD对抗组胺药治疗反应的预测 在儿童过敏性哮喘; 2）开发一个强大的预测模型的治疗反应， 过敏性哮喘儿童的抗组胺药。第一个目标是比较哮喘控制测试的变化 (ACT·）在左西替利嗪（LTZ）的6周、2x2交叉、添加试验中按组胺反应类型评分 儿童过敏性哮喘的发病率第二个目标将确定最佳预测模型 （合并HILD和临床变量），以了解LTZ治疗后ACT®评分的变化， 过敏性哮喘这项拟议中的研究意义重大，因为它有可能改变目前的治疗方法 哮喘儿童的范例，其中对治疗的反应是先验预测的;并且在测试中是创新的 以及验证第一生物标志物，所述第一生物标志物准确地预测对儿童哮喘治疗的反应。的 获得的知识将使第一个经验证的生物标志物可用于预测儿童的治疗反应， 并将改善这些儿童的治疗效果和结果。