MECHANISMS OF CANNABINOID'S ANTIEMETIC ACTIONS

大麻素的止吐作用机制

• 批准号: 6818748
• 负责人: NISSAR A DARMANI
• 金额: $ 7.6万
• 依托单位: A.T. STILL UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818748
• 关键词: Mammalia; anandamide; antiemetics; cannabinoid receptor; cannabinoids; chemosensitizing agent; cis platinum compound; dexamethasone; dopamine agonists; dopamine receptor; drug adverse effect; drug interactions; drug screening /evaluation; drug tolerance; emesis; gastrointestinal disorder chemotherapy; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pharmacokinetics; serotonin inhibitor; serotonin receptor; therapy adverse effect

DESCRIPTION (provided by applicant): Chemotherapy induces emesis in two phases, immediate and delayed. The immediate phase of vomiting induced by chemo- or radiotherapy can be treated with serotonin 5-HT3 receptor antagonists, however, there is currently no clinically available antiemetic or antiemetic combination therapy that is effective in all patients either for the immediate or the delayed phase. Moreover, although clinical trials indicate that addition of dexamethasone and/or substance P receptor antagonists improve the antiemetic activity of 5-HT3 antagonists in both acute and delayed emesis, these agents are not effective in all patients. (9- Tetrahydrocannabinol ((9-THC) and its synthetic analog, nabilone, are effective antiemetics against chemo- and radiotherapy, and patients who are protected during the immediate phase also respond well during the delayed phase. Recent animal studies have shown that xenobiotic cannabinoids of diverse structure and activity ((9-THC, CP 55, 940 and WIN 55, 212-2) have broadspectrum antiemetic efficacy via cannabinoid CB1 receptors. Indeed, (9-THC and its analogs prevent the acute phase of cisplatin-induced emesis at doses which do not significantly suppress spontaneous motor activity in the least shrew (Cryptotis parva). The goals of this proposal are to define the broadspectrum antiemetic nature of cannabinoids against both the immediate and delayed phases of emesis produced by chemo and radiotherapy as well as revealing by behavioral and biochemical means whether tolerance develop to the antiemetic capacity of xenobiotic cannabinoids. The specific aims are: 1) Further characterization and mechanistic evaluation of broadspectrum antiemetic potential of xenobiotic cannabinoids ((9-THC, WIN 55, 212-2, CP 55, 940) in the least shrew against diverse emetic stimuli such as radiation, substance P and cisplatin-induced delayed emesis; 2) To show whether co-administration of (9-THC can potentiate the antivomiting efficacy of established antiemetics (serotonin 5-HT3-, dopamine D2- and neurokinin NK1-receptor antagonists and dexamethasone) against chemo- and radiotherapy-induced vomiting; 3) Determination of relative development of tolerance to antiemetic and motor suppressive effects of (9-THC by means of behavioral studies, radioligand binding and G-protein assays. The results will have important implications for the therapeutic utility of these "agonist antiemetics".

描述（由申请人提供）：化疗分两个阶段引起呕吐，即立即呕吐和延迟呕吐。化疗或放疗引起的呕吐的即刻期可用5-羟色胺5-HT3受体拮抗剂治疗，然而，目前临床上尚无对所有患者即刻或延迟期有效的止吐或止吐联合疗法。此外，尽管临床试验表明添加地塞米松和/或 P 物质受体拮抗剂可改善 5-HT3 拮抗剂在急性和延迟性呕吐中的止吐活性，但这些药物并非对所有患者都有效。 (9-四氢大麻酚 ((9-THC)) 及其合成类似物大麻隆是针对化疗和放疗的有效止吐剂，在即刻阶段受到保护的患者在延迟阶段也有良好反应。最近的动物研究表明，具有不同结构和活性的异生大麻素 ((9-THC、CP 55、940 和 WIN 55、212-2) 通过大麻素 CB1 受体发挥广谱止吐功效。事实上，（9-THC 及其类似物在不显着抑制最小鼩鼱（Cryptotis parva）自发运动活动的剂量下，可以预防顺铂引起的呕吐的急性期。该提案的目标是确定大麻素针对立即和延迟的广谱止吐性质。 化疗和放疗产生的呕吐阶段以及通过行为和生化手段揭示是否对异生大麻素的止吐能力产生耐受性。具体目标是： 1) 进一步表征和评估异生大麻素 ((9-THC, WIN 55, 212-2, CP 55, 940) 的广谱止吐潜力。 对各种催吐刺激（如辐射、P 物质和顺铂引起的延迟性呕吐）的抵抗力最少； 2) 证明联合使用（9-THC）是否可以增强现有止吐药（5-羟色胺 5-HT3-、多巴胺 D2- 和神经激肽 NK1-受体拮抗剂和地塞米松）对化疗和化疗的抗呕吐功效。 放射治疗引起的呕吐； 3)通过行为研究、放射性配体结合和G蛋白测定来确定(9-THC)止吐和运动抑制作用耐受性的相对发展。结果将对这些“激动剂止吐药”的治疗效用具有重要意义。