Peppermint Oil Pharmacokinetics/Dynamics and Novel Biological Signatures in Children with Functional Abdominal Pain

功能性腹痛儿童的薄荷油药代动力学/动力学和新的生物特征

• 批准号: 9096507
• 负责人: Robert J Shulman
• 金额: $ 21.82万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096507
• 关键词: Abdomen; Abdominal Pain; Address; Adult; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Bacteria; Biological; Biological Availability; Biological Markers; Botanicals; Child; Childhood; Chromogranins; Chronic; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Communities; Data; Development; Dietary Carbohydrates; Disease; Disease Management; Distress; Dose; Drug Kinetics; Economic Burden; Economics; Effectiveness; Emotional; Feces; Frequencies; Functional disorder; Generations; Genotype; Genus Mentha; Goals; Health; Health Benefit; Human; Hypersensitivity; Immune; Immunologic Markers; In Vitro; Individual; Inflammatory disease of the intestine; International; Irritable Bowel Syndrome; Irritants; Kinetics; Link; Lymphocyte; Measures; Menthol; Methodology; Mucositis; Muscle relaxation phase; Natural Products; Neuraxis; Outcome; Pain; Patient Outcomes Assessments; Patients; Pattern; Peppermint oil; Permeability; Phased Innovation Awards; Phenotype; Physiological Processes; Physiology; Play; Process; Quality of life; Questionnaires; Research Priority; Role; Safety; Sample Size; School-Age Population; Serum; Smooth Muscle; Symptoms; Time; UGT2B7 UDP-glucuronosyltransferase; Visceral; Vulnerable Populations; base; beta-Defensins; cell motility; cytokine; design; diaries; effective therapy; gastrointestinal; gastrointestinal function; genetic variant; gut microbiome; improved; innovation; insight; multidisciplinary; novel; pain symptom; pre-clinical; psychosocial; research clinical testing; response; social; transcriptome sequencing; treatment strategy

 DESCRIPTION (provided by applicant): Functional abdominal pain (FAP) affects 10-15% of children and adults worldwide and is characterized by chronic, intermittent abdominal pain. Symptoms range from mild to severe and debilitating and result in reduced quality of life. Up to 66% of children go on to have similar symptoms as adults. There are few effective treatments because of poor understanding of their mechanism of action (biological signatures) and of the pathophysiology of what are phenotypically and arbitrarily defined disorders. This R21/R33 application proposes to investigate the pharmaco-dynamic/kinetics (PKD) of peppermint oil (PMO), a botanical with some evidence of efficacy in adults with irritable bowel syndrome – a condition similar to FAP. We propose to study the PKD-gastrointestinal (GI) function relationships in children with FAP to link GI responses to PMO PKD, providing bioavailability data to be used to optimize dosing for a particular biological signature response, ultimately benefiting treatment and management of this disorder. No matter the outcome, our proposed study will provide an innovative and significant opportunity to develop novel data about the pathophysiology of FAP by investigating a number of biomarkers simultaneously in the same individual using cutting edge methodology to characterize gut microbiome composition and gut function in FAP. Our Specific Aims are to: R21, Aim 1 - Determine the PKD of PMO (menthol) in children with FAP (n=30). Hypothesis - a relationship exists between intraluminal/systemic menthol exposure and GI function. Sub-Hypothesis – Systemic menthol exposure after PMO reflects a genotype-phenotype relationship in subjects with allelic variants of CYP2A6 and/or UGT2B7. Aim 2 – Determine effect of PMO administration on gut microbiome composition (16S RNA sequencing) and contractile activity/gut transit rate (using the SmartPill®). Hypothesis – PMO will increase gut diversity and decrease contractile activity and gut transit. R33, Aim 1 - Confirm the findings of the R21 in a larger sample size and adjust dosing if necessary to optimize tolerability/safety and beneficial effects on gut microbiome composition and motility. Hypothesis: The findings of the R21 will be confirmed in the larger sample size. Treatment will be given for 1 week. Aim 2 – Assess the effect of PMO on pain processing (conditioned pain modulation), gut inflammation (stool beta defensin and chromogranin concentrations), and barrier function (permeability). Hypothesis: PMO will reduce visceral hypersensitivity, gut inflammation, and/or improve gut barrier function. Aim 3 - Evaluate the effect of PMO on clinical symptoms, psychosocial distress/patient reported outcomes, and acceptability (abdominal pain and stooling pattern via validated diary, pediatric PROMIS measures, side effects questionnaire). Hypothesis: PMO treatment will reduce abdominal pain frequency and patient reported outcomes will reflect this improvement.

 描述（由申请人提供）：功能性腹痛 (FAP) 影响全世界 10-15% 的儿童和成人，其特点是慢性、间歇性腹痛，症状从轻微到严重，使人衰弱，导致生活质量下降。 66% 的儿童会出现与成人相似的症状，因为对其作用机制（生物特征）和表型的病理生理学了解甚少。该 R21/R33 申请旨在研究薄荷油 (PMO) 的药效/动力学 (PKD)，薄荷油是一种植物药，有一些证据表明对患有肠易激综合征（类似于 FAP 的病症）的成人有效。提议研究 FAP 儿童的 PKD-胃肠道 (GI) 功能关系，将 GI 反应与 PMO PKD 联系起来，提供生物利用度数据，用于优化治疗剂量特定的生物特征反应，最终有利于这种疾病的治疗和管理，无论结果如何，我们提出的研究都将提供一个创新和重要的机会，通过使用同一个体同时研究多种生物标志物来开发有关 FAP 病理生理学的新数据。表征 FAP 肠道微生物组成和肠道功能的前沿方法 我们的具体目标是： R21，目标 1 - 确定 FAP 儿童 (n=30) 的 PMO（薄荷醇）的 PKD。假设 - 腔内/全身薄荷醇暴露与胃肠道功能之间存在关系 子假设 - PMO 后的全身薄荷醇暴露反映了具有 CYP2A6 和/或 UGT2B7 等位基因变异的受试者的基因型-表型关系 目标 2 - 确定 PMO 给药的效果。肠道微生物组成（16S RNA 测序）和收缩活动/肠道转运率（使用 SmartPill®）。 PMO 将增加肠道多样性并减少收缩活动和肠道运输，目标 1 - 在更大的样本量中确认 R21 的发现，并在必要时调整剂量，以优化耐受性/安全性以及对肠道微生物组组成和运动性的有益影响。 ：R21 的结果将在更大的样本量中得到证实，治疗将持续 1 周——评估 PMO 对疼痛处理（条件性疼痛）的影响。调节）、肠道炎症（粪便 β 防御素和嗜铬粒蛋白浓度）和屏障功能（渗透性） 假设：PMO 将减少内脏过敏、肠道炎症和/或改善肠道屏障功能 目标 3 - 评估 PMO 对临床的影响。症状、社会心理困扰/患者报告的结果和可接受性（通过验证日记显示的腹痛和排便模式、儿科 PROMIS 测量、副作用问卷）。假设：PMO 治疗将减少腹痛频率，患者报告的结果将反映这种改善。