Pharmacodynamics, Pharmacogenetics, Clinical Efficacy and Safety of Cannabidiol for Gastroparesis and Functional Dyspepsia

摘要 胃轻瘫是指胃肠道动力障碍，客观上伴有胃排空延迟， 无机械性阻塞。胃轻瘫与上消化道症状有关 包括早饱、餐后饱胀、恶心、呕吐、腹胀和上腹部疼痛。的 胃轻瘫的诊断是基于胃轻瘫的症状、胃出口缺失 阻塞或溃疡，以及胃排空延迟（4小时胃排空试验）。类似的症状可能 还伴随胃功能障碍的其他机制，包括胃适应性降低， 胃过敏总之，这些胃运动和感觉异常可能导致功能性 消化不良功能性消化不良是一个非常常见的原因，大量的发病率，估计影响10% 在人群中，每周至少有三天在进食后表现为腹痛/不适。它 据估计，有40%的这种症状的患者咨询他们的医生， 他们的工作场所出勤率和生产力以及2009年超过180亿美元的经济影响。 鉴于显著未满足的医疗需求，开发这些病症的有效治疗是期望的。的 唯一被批准用于胃轻瘫的药物是甲氧氯普胺，一种多巴胺D2拮抗剂和5-HT 4激动剂;它可以 由于内分泌、心脏和神经方面的原因，少数患者可开具长达3个月的处方 方面的影响.目前尚无获批的功能性消化不良治疗方法。非选择性大麻素 受体激动剂屈大麻酚以前被证明可以延缓胃排空， 住宿.Δ 9THC和非药用级大麻二酚用于各种疼痛相关疾病; 这些药物的作用和获益风险比尚不清楚。随着最近FDA批准大麻二酚，我们的 一般的假设是大麻二酚缓解胃轻瘫患者的症状， 对胃排空、调节、饱食或饱腹感没有有害影响的消化不良。我们的目标是： 1.比较大麻二酚与安慰剂对饱食、空腹 以下患者的胃容量、胃调节、胃排空和症状： 1a.胃轻瘫（基于胃轻瘫主要症状指数-每日日记（GCSI-DD）的症状）;以及 1b.功能性消化不良（+非胃排空延迟）和基于Nehru消化不良指数的症状 2.评估FAAH和CNR1基因变异体对药效学的药物遗传学影响 与安慰剂相比，大麻二酚对空腹和调节胃容量、胃排空 和饱足感。 预期的结果和意义：我们希望这些研究将有助于了解机制 大麻二酚在改善胃肠道功能和患者报告的结局（包括疼痛）方面的作用， 胃轻瘫或功能性消化不良患者，解决数百万美国公民未满足的需求。

ABSTRACT Gastroparesis is defined as a gastrointestinal motility disorder with objectively delayed gastric emptying in the absence of mechanical obstruction. Gastroparesis is associated with upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain. The diagnosis of gastroparesis is based on the combination of symptoms of gastroparesis, absence of gastric outlet obstruction or ulceration, and delay in gastric emptying (4 hour gastric emptying test). Similar symptoms may also accompany other mechanisms of gastric dysfunction including reduced gastric accommodation and gastric hypersensitivity. Together, these gastric motor and sensory abnormalities may cause functional dyspepsia. Functional dyspepsia is a very common cause of substantial morbidity; it is estimated to affect 10% of the population and manifests as abdominal pain/discomfort after eating for at least three days per week. It has been estimated that 40% of patients with this symptom complex consult their physicians, with impact on their workplace attendance and productivity and an economic impact in excess of $18 billion in 2009. Development of effective treatments of these disorders is desirable, given significant unmet medical need. The only approved drug for gastroparesis is metoclopramide, a dopamine D2 antagonist and 5-HT4 agonist; it can be prescribed for a minority of patients for up to 3 months because of endocrine, cardiac and neurological side effects. There is no currently approved treatment for functional dyspepsia. The non-selective cannabinoid receptor agonist, dronabinol, was previously shown to retard gastric emptying and enhance gastric accommodation. Δ9THC and non-pharmaceutical grade cannabidiol are used for diverse pain-related disorders; the effects and benefit-risk ratio of these agents are unclear. With recent FDA approval of cannabidiol, our general hypothesis is that cannabidiol relieves symptoms in patients with gastroparesis and functional dyspepsia without deleterious effects on gastric emptying, accommodation, satiation or satiety. Our aims are: 1. To compare the pharmacodynamics and clinical effects of cannabidiol vs. placebo on satiation, fasting gastric volume, gastric accommodation, gastric emptying, and symptoms in patients with: 1A. gastroparesis (symptoms based on Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD); and 1B. functional dyspepsia (+ non-delayed gastric emptying) and symptoms based on Nepean Dyspepsia Index 2. To assess pharmacogenetics effects of variants in FAAH and CNR1 genes on the pharmacodynamics effects of cannabidiol compared to placebo on fasting and accommodation gastric volumes, gastric emptying and satiation. Anticipated Results and Significance: We expect these studies will lead to understanding the mechanisms of action of cannabidiol in improving gastrointestinal functions and patient reported outcomes, including pain, in patients with gastroparesis or functional dyspepsia, addressing unmet needs of millions of American citizens.