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.

摘要