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

 描述（由申请人提供）：功能性腹痛（FAP）影响全球10-15%的儿童和成人，其特征是慢性间歇性腹痛。症状从轻微到严重，使人虚弱，并导致生活质量下降。高达66%的儿童会出现与成人相似的症状。由于对其作用机制（生物学特征）以及表型和任意定义的疾病的病理生理学的理解不足，几乎没有有效的治疗方法。这项R21/R33申请旨在研究薄荷油（PMO）的药效学/动力学（PKD），PMO是一种植物药，在成人肠易激综合征（一种类似于FAP的疾病）中具有一定的疗效。我们建议研究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，用于优化特定生物特征反应的剂量，最终有利于治疗和管理这种疾病。无论结果如何，我们提出的研究将提供一个创新和重要的机会，通过使用尖端方法同时研究同一个体中的许多生物标志物来开发有关FAP病理生理学的新数据，以表征FAP中的肠道微生物组组成和肠道功能。我们的具体目标是：R21，目标1 -确定PMO（薄荷醇）在FAP儿童中的PKD（n=30）。假设-管腔内/全身薄荷醇暴露与GI功能之间存在关系。 亚假设-PMO后的全身薄荷醇暴露反映了CYP 2A 6和/或UGT 2B 7等位基因变体受试者的基因型-表型关系。目的2 -确定PMO施用对肠道微生物组组成（16 S RNA测序）和收缩活性/肠道通过率（使用SmartPill®）的影响。假设- PMO将增加肠道多样性，减少收缩活动和肠道运输。R33，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作用。假设：R21的结果将在较大样本量中得到证实。治疗将持续1周。目的2 -评估PMO对疼痛处理（条件性疼痛调制）、肠道炎症（粪便β防御素和嗜铬粒蛋白浓度）和屏障功能（通透性）的影响。假设：PMO将降低内脏高敏感性、肠道炎症和/或改善肠道屏障功能。目的3 -评价PMO对临床症状、社会心理困扰/患者报告结局和可接受性（通过经验证的日记、儿科PROMIS测量、副作用问卷评估腹痛和排便模式）的影响。假设：PMO治疗将减少腹痛频率，患者报告的结局将反映这种改善。

 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.