Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities

中药方剂小柴胡汤抗伊立替康肠道毒性的机制和药代动力学研究

• 批准号: 10463682
• 负责人: MING HU
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463682
• 关键词: Animals; Antidiarrheals; Antineoplastic Agents; Atrophic; Attenuated; Bacteria; Beta-glucuronidase; Biliary; Biological Products; Cessation of life; Chai Hu; Chinese; Chinese Traditional Medicine; Clinical; Clinical Research; Clinical Trials; Cyclosporine; Diarrhea; Dose; Double-Blind Method; Down-Regulation; Drug Exposure; Drug Kinetics; Drug Metabolic Detoxication; Drug resistance; Enzyme Activation; Enzymes; Excretory function; GTP-Binding Protein alpha Subunits, Gs; Glucuronides; Glucuronosyltransferase; Goals; Hospitalization; Human; In Vitro; Incidence; Inflammation; Inflammatory; Intestines; Investigational Therapies; Lead; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical; Methods; Modeling; Mucositis; Mus; Natural Products; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phytochemical; Plasma; Prevention; Prodrugs; Quality Control; Quality of life; Raloxifene; Randomized; Recovery; Research; Resort; Running; SN-38; SN-38G; Safety; Signal Transduction; Testing; Therapeutic; Tight Junctions; Tissues; Toll-like receptors; Toxic effect; Treatment Efficacy; Treatment outcome; Villus; attenuation; cancer care; cancer therapy; chemotherapeutic agent; chemotherapy; cytokine; design; dietary supplements; experience; functional restoration; improved; in vivo Model; irinotecan; malignant stomach neoplasm; metastatic colorectal; novel; novel strategies; pharmacokinetics and pharmacodynamics; preservation; prevent; primary outcome; receptor; refractory cancer; response; secondary endpoint; side effect; success; targeted agent

Abstract Irinotecan, a prodrug of SN-38, is used to treat many types of metastatic and drug-resistant cancers, and often represents the therapy of the last resort. Unfortunately, a large percentage (up to 40%) of these patients will experience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD), which really downgrade patient’s quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. The long-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approach to reduce SDOD, so patients can sustain their chemotherapy. Our recent studies have shown that inactivation of intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causes SDOD, and that a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (XCHT), could attenuate the inactivation of intestinal UGTs in mice. Therefore, the central hypothesis of this current proposal is Therefore, we hypothesize that XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities, reducing gut SN-38 exposure, and promoting the recovery of gut UGT activities. We plan to test this hypothesis using four Specific Aims: (1) perform phytochemical, biopharmaceutical and pharmacokinetic characterization of XCHT to enable quality control, systemic and intestinal drug exposure determinations, and to provide bioanalytical methods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasma raloxifene-4′-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse “co- trial” studies to support human mechanistic trials and to determine the mechanisms of action of XCHT against irinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial using a randomized double-blind design with a safety “Run-In” to determine if XCHT can attenuate human intestinal UGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Aside from these primary outcomes, we will also determine if levels of Ral-4’-G, a probe of intestinal UGT activities is (negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research will provide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy.

抽象的 伊立替康是 SN-38 的前药，用于治疗多种类型的转移性癌症和耐药性癌症，并且经常用于治疗多种类型的转移性癌症和耐药性癌症。 不幸的是，这些患者中很大一部分（高达 40%）会采取这种治疗。 经历严重（2 级）和严重（3-4 级）迟发性腹泻 (SDOD)，这确实会降级 患者的生活质量可能会导致住院时间延长，甚至在某些情况下死亡。 我们研究的长期目标是开发实验疗法和/或营养补充方法 减少 SDOD，使患者能够维持化疗。我们最近的研究表明，灭活。 SN-38 对肠道 UDP-葡萄糖醛酸基转移酶 (UGT) 的影响是 SN-38 引起的一种新机制 SDOD 以及中药小柴胡汤 (XCHT) 可以减轻 因此，当前提案的中心假设是因此，我们陷入了困境。 XCHT 将通过减弱 UGT 活性的下降来预防或减少伊立替康诱导的 SDOD，减少 肠道 SN-38 暴露，并促进肠道 UGT 活性的恢复 我们计划使用四种方法来检验这一假设。 具体目标：(1) 对 XCHT 进行植物化学、生物制药和药代动力学表征，以 实现质量控制、全身和肠道药物暴露测定，并提供生物分析 (2) 验证临床研究和 PK/PD 建模所需的血浆方法和药代动力学参数； 雷洛昔芬-4′-葡萄糖苷酸水平作为肠道 Ugt/UGT 活性变化的探针；(3) 进行小鼠“共- “试验”研究支持人体机械试验并确定 XCHT 的作用机制 使用体外和体内模型进行伊立替康诱导的 SDOD；以及 (4) 使用 具有安全“磨合”的随机双盲设计，以确定 XCHT 是否可以减弱人体肠道 除伊立替康化疗外，UGT 减少并减少 3 级或以上腹泻的发生率。 根据这些主要结果，我们还将确定 Ral-4'-G（肠道 UGT 活性探针）的水平是否 通过这项研究获得的成功与炎症细胞因子的全身水平（负）相关。 为我们靶向治疗伊立替康化疗引起的SDOD提供了一种新机制。