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:10463682
- 负责人:
- 金额:$ 19.3万
- 依托单位:
- 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:
- 关键词:AnimalsAntidiarrhealsAntineoplastic AgentsAtrophicAttenuatedBacteriaBeta-glucuronidaseBiliaryBiological ProductsCessation of lifeChai HuChineseChinese Traditional MedicineClinicalClinical ResearchClinical TrialsCyclosporineDiarrheaDoseDouble-Blind MethodDown-RegulationDrug ExposureDrug KineticsDrug Metabolic DetoxicationDrug resistanceEnzyme ActivationEnzymesExcretory functionGTP-Binding Protein alpha Subunits, GsGlucuronidesGlucuronosyltransferaseGoalsHospitalizationHumanIn VitroIncidenceInflammationInflammatoryIntestinesInvestigational TherapiesLeadLifeMalignant NeoplasmsMalignant neoplasm of pancreasMedicalMethodsModelingMucositisMusNatural ProductsPathway interactionsPatientsPharmaceutical PreparationsPhase II Clinical TrialsPhytochemicalPlasmaPreventionProdrugsQuality ControlQuality of lifeRaloxifeneRandomizedRecoveryResearchResortRunningSN-38SN-38GSafetySignal TransductionTestingTherapeuticTight JunctionsTissuesToll-like receptorsToxic effectTreatment EfficacyTreatment outcomeVillusattenuationcancer carecancer therapychemotherapeutic agentchemotherapycytokinedesigndietary supplementsexperiencefunctional restorationimprovedin vivo Modelirinotecanmalignant stomach neoplasmmetastatic colorectalnovelnovel strategiespharmacokinetics and pharmacodynamicspreservationpreventprimary outcomereceptorrefractory cancerresponsesecondary endpointside effectsuccesstargeted 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.
摘要
伊立替康是SN-38的前药,用于治疗多种类型的转移性和耐药癌症,通常
代表了最后一招的疗法。不幸的是,这些患者中有很大一部分(高达40%)将
经历严重(2级)和严重(3-4级)延迟性腹泻(SDOD),这确实降低了级别
患者的生活质量。在某些情况下,SDOD可能会导致延长住院时间,甚至死亡。这个
我们研究的长期目标是开发实验性疗法和/或营养补充方法。
以减少SDOD,这样患者就可以继续进行化疗。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(UGTS)的作用是SN-38致病的新机制
而中药小柴胡汤(XCHT)可减轻小鼠脑组织中HSP70的失活
小鼠肠道UGT。因此,当前提案的中心假设是,因此,我们假设
XCHT将通过减弱UGT活性的下降,减少伊立替康诱导的SDOD,从而预防或减少伊立替康诱导的SDOD
肠道SN-38暴露,促进肠道UGT活性恢复。我们计划用四个实验来检验这一假设
具体目标:(1)进行XCHT的植物化学、生物制药和药代动力学表征
支持质量控制、全身和肠道药物暴露测定,并提供生物分析
临床研究和PK/PD模型所需的方法和药代动力学参数;(2)验证血浆
以雷洛昔芬-4‘-葡萄糖醛酸苷水平作为肠道UGT/UGT活性变化的探针;
支持人体机械性试验并确定XCHT抗肿瘤作用机制的研究
使用体外和体内模型进行伊立替康诱导的SDOD;以及(4)使用
一项安全“磨合”的随机双盲设计,以确定XCHT是否可以弱化人体肠道
UGT减少和降低伊立替康化疗引起的3级或更高程度腹泻的发生率。搁置一边
根据这些初步结果,我们还将确定肠道UGT活动的探针al-4‘-G的水平是否
与全身炎症细胞因子水平呈负相关。通过这项研究取得的成功将
为我们靶向治疗伊立替康化疗所致的SDOD提供了新的机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MING HU其他文献
MING HU的其他文献
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{{ truncateString('MING HU', 18)}}的其他基金
Elucidating High Oral Fluid Exposure Mechanisms of Buprenorphine to Reduce Dental Caries
阐明丁丙诺啡的高口腔液暴露机制以减少龋齿
- 批准号:
10765181 - 财政年份:2023
- 资助金额:
$ 19.3万 - 项目类别:
Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury
开发用于化疗引起的肠道损伤的药物解毒细菌
- 批准号:
10560782 - 财政年份:2021
- 资助金额:
$ 19.3万 - 项目类别:
Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury
开发用于化疗引起的肠道损伤的药物解毒细菌
- 批准号:
10252721 - 财政年份:2021
- 资助金额:
$ 19.3万 - 项目类别:
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:
10262912 - 财政年份:2020
- 资助金额:
$ 19.3万 - 项目类别:
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:
10686830 - 财政年份:2020
- 资助金额:
$ 19.3万 - 项目类别:
Inhibition of Oral Tumorigenesis by Antitumor B
抗肿瘤 B 抑制口腔肿瘤发生
- 批准号:
10516360 - 财政年份:2016
- 资助金额:
$ 19.3万 - 项目类别:
Inhibition of Oral Tumorigenesis by Antitumor B
抗肿瘤 B 抑制口腔肿瘤发生
- 批准号:
10170283 - 财政年份:2016
- 资助金额:
$ 19.3万 - 项目类别:
Disposition of Flavonoids via Glucuronidation, Critical Role of Efflux Transporte
通过葡萄糖醛酸化处理黄酮类化合物,外排转运的关键作用
- 批准号:
8870372 - 财政年份:2006
- 资助金额:
$ 19.3万 - 项目类别:
Disposition of Flavonoids via Metabolic Interplay
通过代谢相互作用处理黄酮类化合物
- 批准号:
7784367 - 财政年份:2006
- 资助金额:
$ 19.3万 - 项目类别:
Disposition of Flavonoids via Glucuronidation, Critical Role of Efflux Transporte
通过葡萄糖醛酸化处理黄酮类化合物,外排转运的关键作用
- 批准号:
9267482 - 财政年份:2006
- 资助金额:
$ 19.3万 - 项目类别: