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

 描述(申请人提供)：功能性腹痛(FAP)影响全球10%-15%的儿童和成人，以慢性间歇性腹痛为特征。症状从轻微到严重不等，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类似的症状。由于对它们的作用机制(生物学特征)以及对表型和随意定义的疾病的病理生理学缺乏了解，有效的治疗方法很少。此R21/R33应用程序建议研究薄荷油(PMO)的药效学/动力学(PKD)，这是一种植物药，有一些证据表明对患有肠易激综合征(一种类似于FAP的情况)的成年人有效。我们建议研究FAP儿童的PKD-胃肠(GI)功能关系，将胃肠道反应与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，最终有利于这种疾病的治疗和管理。无论结果如何，我们拟议的研究将提供一个创新和重要的机会，通过在同一个体中同时调查一些生物标志物，使用尖端方法来表征FAP的肠道微生物群组成和肠道功能，从而开发关于FAP病理生理学的新数据。我们的具体目标是：R21，目标1-测定FAP儿童PMO(薄荷醇)的PKD(n=30)。假设--腔内/全身薄荷醇暴露与胃肠道功能之间存在关系。亚假说-PMO后全身薄荷醇暴露反映了携带CYP2A6和/或UGT2B7等位基因变异的受试者的基因-表型关系。目的2-确定PMO给药对肠道微生物组组成(16S RNA测序)和收缩活动/肠道转运率(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转运。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，并对肠道微生物组组成和动力产生有益影响。假设：R21的发现将在更大的样本量中得到证实。治疗时间为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可以降低内脏过敏、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、心理社会苦恼/患者报告结果的影响，以及可接受性(通过有效的日记、儿科普罗米斯测量和副作用问卷检查腹痛和大便模式)。假设：PMO治疗将减少腹痛频率，患者报告的结果将反映这一改善。

 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.