Pharmacodynamics, Pharmacogenetics, Clinical Efficacy and Safety of Tradipitant for Functional Dyspepsia

摘要 30行(当前为30行) 上消化道症状可能是由胃功能障碍引起的，包括胃适应能力降低 和胃过敏，并可能导致功能性消化不良(FD)，这是一种非常常见的原因 发病率估计影响10%的人口。FD至少表现为腹痛/不适 每周三天，这可能与进食有关。据估计，40%的有这种症状的患者 Complex咨询他们的医生，对他们的工作场所出勤率和工作效率产生负面影响 2009年的总体经济影响超过180亿美元。这些疾病的有效治疗方法的发展 考虑到巨大的未得到满足的医疗需求，紊乱是可取的。系统评价和荟萃分析 文献表明，目前包括质子泵抑制剂H在内的治疗方法的疗效很低 幽门螺杆菌根除、促动力和中枢神经调节剂。目前还没有批准的治疗方法 功能性消化不良。我们开发了一种非侵入性的成像方法来同时测量胃 调节和胃排空，据报道，高达75%的患者其中一项或两项都有改变 患有功能性消化不良。已批准的NK 1受体(NK1R)拮抗剂已被证明是 增加健康受试者的空腹胃容量和餐后调节，而不是有害的 影响胃排空的。新的NK1R拮抗剂TRANSPANT先前被证明可以减轻症状 在胃瘫患者中，尽管这种疗法的确切机制、总体效果和受益风险比 药物治疗尚不清楚。我们的一般假设是，传统疗法可以缓解功能性精神分裂症患者的症状。 消化不良，增强餐后胃适应能力，对胃无不良影响 正在清空。我们的目标是： 1.比较传统抗炎药与安慰剂的药效学和临床疗效。 功能性胃病患者的进食量、胃调节、胃排空和症状 基于鲁汶消化不良分级和Nepean的消化不良(和基线时无延迟的胃排空) 消化不良指数 2.评估NKR-SNP rs881基因变异的患病率及该变异的药物遗传学效应。 NK1基因对传统降糖药与安慰剂空腹调节胃的药效学比较 容量、胃排空和饱腹感。 在探索性分析中，我们将评估胃调节和胃排空之间的相关性。 功能性消化不良，并与以前在健康志愿者中报告的关系进行比较。 预期结果和意义：我们希望这些研究将有助于理解这些机制 传统药物在改善胃肠功能和患者报告结果(包括疼痛)方面的作用 功能性消化不良患者，满足数百万美国公民未得到满足的需求。

ABSTRACT 30 lines (currently 30) Upper gastrointestinal symptoms may result from gastric dysfunction including reduced gastric accommodation and gastric hypersensitivity, and may cause functional dyspepsia (FD), a very common cause of substantial morbidity estimated to affect 10% of the population. FD manifests as abdominal pain/discomfort for at least three days per week which may be associated with eating. An estimated 40% of patients with this symptom complex consult their physicians, negatively influencing their workplace attendance and productivity with overall economic impact of more than $18 billion in 2009. Development of effective treatments of these disorders is desirable, given significant unmet medical need. Systematic reviews and meta-analyses of the literature have shown low levels of efficacy with current treatments which include proton pump inhibitors, H pylori eradication, prokinetics, and central neuromodulators. There is currently no approved treatment for functional dyspepsia. We have developed a noninvasive imaging method to simultaneously measure gastric accommodation and gastric emptying, one or both of which are reported to be altered in up to 75% of patients with functional dyspepsia. The approved NK 1 receptor (NK1R) antagonist aprepitant has been shown to increase fasting gastric volume and postprandial accommodation in healthy participants without deleteriously affecting gastric emptying. The novel NK1R antagonist, tradipitant, was previously shown to reduce symptoms in patients with gastroparesis although the precise mechanism, overall effects, and benefit-risk ratio of this medication unclear. Our general hypothesis is that tradipitant relieves symptoms in patients with functional dyspepsia as well as enhances postprandial gastric accommodation without deleterious effects on gastric emptying. Our aims are: 1. To compare the pharmacodynamics and clinical effects of tradipitant vs. placebo on satiation, fasting and fed gastric volume, gastric accommodation, gastric emptying, and symptoms in patients with functional dyspepsia (and non-delayed gastric emptying at baseline) based on Leuven Dyspepsia scale and Nepean Dyspepsia Index 2. To assess prevalence of NKR-SNP rs881 genetic variant and the pharmacogenetics effects of this variant in NK1 gene on the pharmacodynamics of tradipitant compared to placebo on fasting and accommodation gastric volumes, gastric emptying and satiation. In an exploratory analysis, we shall assess the correlation between gastric accommodation and emptying in functional dyspepsia and to compare the relationship with those previously reported in health volunteers. Anticipated Results and Significance: We expect these studies will lead to understanding the mechanisms of action of tradipitant in improving gastrointestinal functions and patient reported outcomes, including pain, in patients with functional dyspepsia, addressing unmet needs of millions of American citizens.