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

基本信息

批准号：
10686830
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
项目类别：
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/10686830
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 Glucuronides Glucuronosyltransferase Goals Hospitalization Human In Vitro Incidence Inflammation Inflammatory Intestines Investigational Therapies 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 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

项目摘要

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 Irinotecan是SN-38的前药，用于治疗多种类型的转移性和耐药性癌症，并且经常代表了最后一个度假胜地的治疗。不幸的是，这些患者中有很大一部分（多达40％）将体验严重（2级）和严重（3-4级）延迟发作的腹泻（SDOD），这确实降级病人的生活质量。在某些情况下，SDOD可能导致长期住院甚至死亡。这我们研究的长期目标是开发实验疗法和/或营养补充方法为了减少SDOD，因此患者可以维持其化学疗法。我们最近的研究表明，失活 SN-38的肠UDP UDP-葡萄糖基转移酶（UGT）是SN-38的新机制 SDOD和传统的中药，小chai-hu-tang（XCHT），可能会衰减小鼠肠道UGT。因此，当前建议的核心假设是我们假设的 XCHT将通过减少UGT活动的下降，减少iNotecan诱导的SDOD或减少帝Irinotecan诱导的SDOD 肠道SN-38暴露，并促进肠道UGT活动的恢复。我们计划使用四个具体目的：（1）执行XCHT的物理，生物制药和药代动力学表征实现质量控制，系统性和肠道药物暴露确定，并提供生物分析临床研究和PK/PD建模所需的方法和药代动力学参数；（2）验证血浆 rAxifene-4'-葡萄糖醛酸水平作为改变肠道UGT/UGT活性的探针；（3）执行鼠标“共同试验”研究以支持人类机械试验并确定XCHT对使用体外和体内模型都使用Irinotecan诱导的SDOD；（4）使用带有安全性“磨合”的随机双盲设计，以确定XCHT是否可以减轻人类肠道 UGT降低并降低由伊立替康化疗引起的3级或更高腹泻的发病率。旁边从这些主要结果中，我们还将确定RAL-4'-G的水平是否是肠道UGT活动的探测（负）与全身性炎症细胞因子水平相关。通过这项研究获得的成功将提供一种新的机制，我们可以通过该机制来靶向以伊立替康化学疗法引起的SDOD。