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

• 批准号: 9983012
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983012
• 关键词: 2-arachidonylglycerol; Abdominal Pain; Acids; Address; Adverse effects; Affect; Agonist; Alternative Therapies; American; Antidepressive Agents; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cardiac; Complex; Consult; Descending colon; Development; Devices; Diabetes Mellitus; Diagnosis; Diarrhea; Diet; Disease; Dopamine; Dronabinol; Dyspepsia; Eating; Electric Stimulation; Electrolytes; Endocannabinoids; Endocrine; Enzymes; Etiology; FDA approved; Fasting; Female; Food; Functional disorder; Gases; Gastric Emptying; Gastric outlet obstruction; Gastrointestinal Motility; Gastroparesis; Genes; Genotype; Helicobacter pylori; Hour; Hydrolase; Hypersensitivity; Iatrogenesis; Intestines; Ligands; Liquid substance; Mechanics; Medical; Methods; Metoclopramide; Minority; Monoacylglycerol Lipases; Morbidity - disease rate; Motor; Nausea and Vomiting; Neurologic; Neurons; Nutritional Support; Obstruction; Operative Surgical Procedures; Oral; Pain; Parkinsonian Disorders; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacologic Substance; Pharmacology; Phase; Physicians; Placebos; Population; Productivity; Pylorus; Refractory; Research; Safety; Satiation; Scleroderma; Sensory; Societies; Solid; Stents; Stomach; Stomach Diseases; Subgroup; Symptoms; Testing; Ulcer; United States National Institutes of Health; Variant; Vision; Workplace; anandamide; base; cannabinoid receptor; cell motility; clinical effect; clinical efficacy; diabetic; diaries; disabling symptom; early satiety; economic impact; effective therapy; endogenous cannabinoid system; experience; fatty acid amide hydrolase; gastrointestinal function; gastrointestinal symptom; glycemic control; improved; indexing; male; motility disorder; pain sensation; pressure; psychologic; receptor; reduce symptoms; response; restoration; risk benefit ratio; side effect

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 胃轻瘫定义为一种胃肠道运动障碍，客观地延迟了胃排空 没有机械异议。胃轻瘫与上胃肠道症状有关 包括早期饱腹感，餐后饱满，恶心，呕吐，腹胀和上腹痛。 胃轻瘫的诊断是基于胃轻瘫症状的组合，缺乏胃出口 阻塞或溃疡，并延迟胃排空（4小时胃排空测试）。类似的症状可能 还适合其他胃功能障碍的机制，包括减少胃的住宿和 胃超敏反应。这些胃电动机和感觉异常可能会引起功能 消化不良。功能性消化不良是造成大量发病率的非常普遍的原因。估计会影响10％ 人口和表现为腹部疼痛/不适，每周至少三天。它 据估计，有40％的患有此符号综合体的患者会咨询其医生，并影响 他们的工作场所出勤率和生产力以及2009年的经济影响超过180亿美元。 鉴于巨大的未满足医疗需求，需要开发这些疾病的有效治疗方法。这 仅批准的胃轻瘫药物是甲氧氯普胺，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，要为少数患者开处方长达3个月 效果。目前尚无批准的功能性消化治疗方法。非选择性大麻素 受体激动剂Dronabinol先前被证明会阻碍胃排空并增强胃 住宿。 δ9THC和非药物级大麻二酚用于潜水疼痛相关的疾病； 这些药物的效果和利益风险比率尚不清楚。随着FDA的最近批准大麻二酚，我们的 一般假设是，大麻二醇可挽救胃轻瘫和功能性的患者的症状 消化不良对胃排空，住宿，满意度或满意度没有有害影响。我们的目标是： 1。比较大麻二酚与安慰剂对饱食的药效学和临床作用 患者患者的胃体积，胃排空，胃排空和症状： 1a。胃轻瘫（基于胃轻瘫的基本症状指数日记（GCSI-DD）和 1B。功能性消化不良（+基于Nepean DeSpepsia指数 2。评估FAAH和CNR1基因中变体对药效学的药物遗传学作用 与安慰剂相比，大麻二酚对禁食和容纳胃量，胃排空的影响 和满足。 预期的结果和意义：我们希望这些研究将导致理解机制 大麻二酚在改善胃肠道功能和患者报告的结果（包括疼痛）中的作用 胃轻瘫或功能性消化不良的患者满足了数百万美国公民的需求。