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

摘要 胃轻瘫是一种胃肠动力障碍，客观上表现为胃排空障碍。 无机械阻塞。胃轻瘫与上消化道症状有关 包括早饱、餐后饱腹感、恶心、呕吐、腹胀和上腹部疼痛。这个 胃瘫的诊断是基于胃瘫的症状，胃出口的缺失 肠梗阻或溃疡，胃排空延迟(4小时胃排空试验)。类似的症状可能 也伴随着胃功能障碍的其他机制，包括胃适应能力下降和 胃过敏。总之，这些胃运动和感觉异常可能会导致功能性 消化不良。功能性消化不良是导致严重发病率的一种非常常见的原因；据估计，它会影响10% 每周至少三天进食后表现为腹痛/不适。它 据估计，40%的有这种症状的患者会咨询他们的医生，对 他们的工作场所出勤率和生产率，以及2009年超过180亿美元的经济影响。 考虑到大量未得到满足的医疗需求，开发有效的治疗这些疾病是可取的。这个 唯一被批准用于胃瘫的药物是胃复安，一种多巴胺D2拮抗剂和5-HT4激动剂；它可以 由于内分泌、心脏和神经方面的原因，为少数患者开了长达3个月的处方 效果。目前还没有被批准的治疗功能性消化不良的方法。非选择性大麻素 受体激动剂屈诺比诺先前被证明可以延缓胃排空和促进胃功能。 住宿。Δ9THC和非药用级别的大麻二醇用于治疗各种疼痛相关疾病； 这些药物的效果和益处-风险比尚不清楚。随着FDA最近批准大麻二醇，我们的 一般假设是大麻二醇可以缓解胃瘫和功能性胃轻瘫患者的症状。 消化不良对胃排空、调节、饱腹感或饱腹感无不良影响。我们的目标是： 1.比较大麻二醇与安慰剂对饱腹感、空腹症状的药效学及临床疗效。 患有以下疾病的患者的胃容量、胃调节、胃排空和症状： 1A.胃瘫(以胃瘫基本症状指数-日常日记为基础的症状(GCSI-DD)；以及 1B.功能性消化不良(+非胃排空延迟)和基于Nepean消化不良指数的症状 2.评价FAAH和CNR1基因变异对药效学的影响 大麻二醇与安慰剂对空腹调节胃容量、胃排空的影响 和满足感。 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 大麻二醇在改善胃肠功能和患者报告的结果(包括疼痛)方面的作用 胃瘫或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 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.