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

基本信息

批准号：
10888576
负责人：
BRIDGETTE L. JONES
金额：
$ 4.93万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
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/10888576
关键词：
Adrenal Glands Adverse effects African American Allergens Allergic Antibody Therapy Antihistamines Asthma Biological Markers Biological Response Modifiers Blood Bronchoconstriction Caucasians Cell Adhesion Molecules Cessation of life Chemotaxis 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 Immunologic Markers Immunologics Individual Inhalation Iontophoresis Knowledge Lasers Leukotrienes Link Literature Modeling Monitor Monoclonal Antibodies Moods Morbidity - disease rate Mucous body substance Nitric Oxide Nucleotides Outcome Pathway interactions Patient Selection 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 biomarker validation chemokine clinical biomarkers cost cytokine disease phenotype eosinophil experience immunoregulation improved innovation mortality risk neutrophil novel omalizumab pediatric patients pharmacodynamic biomarker predicting response predictive marker predictive modeling pulmonary function racial population response side effect skin prick test success therapy outcome treatment response

项目摘要

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.

抽象的迫切需要经过验证的客观生物标志物来预测哮喘治疗反应儿童的疗法。需要每天使用控制器药物（例如吸入的立体定义为具有持续的哮喘。美国大约60％的哮喘儿童国家患有持续性疾病。治疗响应对标准指南支持药物的差异（例如吸入的立体素，白三烯修饰剂，单旋抗体）存在于患有持续的儿童中哮喘。临床标记，例如IgE水平，呼出的一氧化氮水平，嗜酸性粒细胞和中性粒细胞计数经过验证以预测儿童哮喘药物的治疗反应。不可能优化目前可用于达到治疗效率和限制不良暴露的哮喘治疗方法无效的无侵入性生物标志物的非有效药物的影响可以驱动治疗决策。长期目标是进步并改善儿科患者的治疗干预措施哮喘。该特定应用的目的是建立组胺离子噬菌体的实用性激光多普勒监测（HILD）作为生物标志物，以准确预测低成本的治疗反应过敏性哮喘儿童的低副作用抗组胺药治疗。中心假设是“ hild是预测哮喘儿童中对抗组胺药的治疗反应”。这种假设一直是由申请人强大的初步数据和支持文献制定。提议的理由研究是，希尔德能够识别出不同的组胺药效反应类型对哮喘抗组胺药的治疗反应。在强大的初步数据的指导下，该假设将通过两个具体目的测试：1）确定对抗组胺药的治疗反应预测在过敏性哮喘的儿童中； 2）开发一种对治疗反应的强大预测模型过敏性哮喘儿童中的抗组胺药。第一个目标将比较哮喘控制测试的变化（ACT®）组胺反应类型在六个星期，2x2横击，左旋塞提嗪附加试验（LTZ）中得分在患有不受控制的过敏性哮喘的儿童中。第二个目标将决定最佳预测模型（合并HILD和临床变量）在LTZ治疗后的ACT®分数变化中过敏性哮喘。拟议的研究很重要，因为它有可能改变当前治疗哮喘儿童的范例预测对治疗的反应是先验的；并且在测试方面具有创新性并验证第一个生物标志物可以准确预测儿童哮喘治疗的反应。获得的知识将提供第一个经过验证的生物标志物，以预测患有儿童的治疗反应哮喘并将提高这些儿童的治疗效率和结果。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

DOI：
10.1016/j.jaci.2021.02.037
发表时间：
2021-06
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Chambers CD;Krishnan JA;Alba L;Albano JD;Bryant AS;Carver M;Cohen LS;Gorodetsky E;Hernandez-Diaz S;Honein MA;Jones BL;Murray RK;Namazy JA;Sahin L;Spong CY;Vasisht KP;Watt K;Wurst KE;Yao L;Schatz M
通讯作者：
Schatz M

Reducing Health Disparities in Asthma: How Can Progress Be Made.