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

大麻二酚治疗胃轻瘫和功能性消化不良的药效学、药物遗传学、临床疗效和安全性

基本信息

批准号：
10404023
负责人：
MICHAEL L. CAMILLERI
金额：
$ 37.32万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-08-31
项目状态：
已结题

项目摘要

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.

抽象的胃轻瘫被定义为胃肠动力障碍，客观上胃排空延迟。无机械阻塞。胃轻瘫与上消化道症状有关包括早饱、餐后饱胀、恶心、呕吐、腹胀和上腹痛。这胃轻瘫的诊断基于胃轻瘫症状、胃出口缺失的组合梗阻或溃疡，以及胃排空延迟（4小时胃排空测试）。类似症状可能还伴随胃功能障碍的其他机制，包括胃调节减少和胃过敏。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高发病率的一个非常常见的原因。估计影响10% 每周至少三天进食后出现腹痛/不适。它据估计，40% 患有这种症状的患者会咨询医生，这对 2009 年，他们的工作场所出勤率和生产力以及经济影响超过 180 亿美元。鉴于显着的未满足的医疗需求，开发这些疾病的有效治疗方法是令人期望的。这唯一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-HT4 激动剂；它可以由于内分泌、心脏和神经方面的原因，少数患者需要服用长达 3 个月的处方影响。目前尚无批准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先前被证明可以延迟胃排空并增强胃功能住宿。 Δ9THC 和非药物级大麻二酚用于治疗多种疼痛相关疾病；这些药物的效果和获益风险比尚不清楚。随着 FDA 最近批准大麻二酚，我们的一般假设是大麻二酚可以缓解胃轻瘫和功能障碍患者的症状消化不良，但对胃排空、调节、饱腹感或饱腹感没有有害影响。我们的目标是： 1. 比较大麻二酚与安慰剂对饱腹感、禁食的药效学和临床效果胃容量、胃调节、胃排空和以下患者的症状： 1A。胃轻瘫（基于胃轻瘫主要症状指数-每日日记（GCSI-DD）的症状；和 1B.功能性消化不良（+非延迟胃排空）和基于 Nepean 消化不良指数的症状 2. 评估FAAH和CNR1基因变异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、胃排空的影响和饱腹感。预期结果和意义：我们期望这些研究将有助于理解其机制大麻二酚在改善胃肠功能和患者报告的结果（包括疼痛）方面的作用胃轻瘫或功能性消化不良患者，解决数百万美国公民未得到满足的需求。