Ribavirin depletes endogenous nucleotide pools

利巴韦林消耗内源核苷酸库

• 批准号: 8358717
• 负责人: JENNIFER JUSTICE KISER
• 金额: $ 8.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358717
• 关键词: Address; Adenosine Triphosphate; Adverse effects; Anemia; Antiviral Agents; Biological Assay; Blood; Blood Cells; Cells; Chronic Hepatitis C; Cirrhosis; Clinic; Clinical; Clinical Trials; Coupled; Cytolysis; Dose; Dose-Limiting; Drug usage; Enrollment; Enzymes; Erythrocytes; Failure; Future; Genes; Genetic; Genotype; Grant; Guanosine Triphosphate; HIV; Health; Hemolytic Anemia; Hepatic; Hepatitis B; Hepatitis C virus; Hepatology; Human; Human Volunteers; Immune; Immunologics; In Vitro; Incidence; Investigation; Knowledge; Life; Light; Liquid Chromatography; Malignant Neoplasms; Measures; Mediating; Mononuclear; Nucleosides; Nucleotides; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Polymerase; Primary carcinoma of the liver cells; Purine Nucleotides; Purines; RNA Viruses; Regimen; Ribavirin; Role; Single Nucleotide Polymorphism; Technology; Therapeutic Effect; Toxic effect; Variant; Viral; Virus Diseases; Virus Replication; Work; analog; base; enzyme activity; improved; in vivo; inhibitor/antagonist; inosine triphosphatase; liquid chromatography mass spectrometry; nucleoside analog; peripheral blood; purine; response; tandem mass spectrometry; therapy development; treatment response; tripolyphosphate

DESCRIPTION (provided by applicant): Ribavirin, a nucleoside analog, is one of the only broad-spectrum antiviral drugs available in the world, and it is a fundamental component of treatment for chronic Hepatitis C virus (HCV). Despite decades of clinical use, the exact mechanisms by which ribavirin inhibits HCV replication and causes its major dose limiting toxicity, anemia are unclear. Our lack of understanding of how ribavirin works and causes anemia represent fundamental gaps in our knowledge of the treatment of HCV. To optimize HCV cure rates and minimize anemia from ribavirin-based treatment, we need to understand this drug's pharmacology. In vitro, ribavirin depletes endogenous purines which likely explains its toxic and therapeutic effects, but this has not been investigated in humans. Through this application, Dr. Kiser will extend efforts on her K23 and explore the effects of ribavirin on endogenous purines. The specific aims for the study are to (1) compare the change in endogenous purine concentrations in the red blood and peripheral blood mononuclear cells of HCV-infected patients on ribavirin-based treatment across ITPA activity phenotype groups and (2) to determine associations between endogenous purine depletion and virologic response and anemia and the degree to which ITPA activity phenotype moderates these effects. To address these aims, we will measure endogenous purine concentrations before starting ribavirin-based HCV treatment and 4- and 12-weeks after initiating treatment and ribavirin triphosphate concentrations 4- and 12-weeks after initiating treatment in the peripheral blood mononuclear and red blood cells of 40 subjects in Dr. Kiser's K23 study and 170 subjects prospectively enrolled (and stratified by ITPA activity phenotype) through our Hepatology clinic. This study will increase our understanding of how ribavirin inhibits HCV replication and causes anemia and determine if there are differences in effect based on ITPA genetics. Additionally, while the LC/MS/MS assay developed through this grant will be immediately used to address the aims of this application, the technology can also be applied to investigations of the effects of HCV nucleoside polymerase inhibitors and nucleos(t)ide analogs used in the treatment of HIV, Hepatitis B, and cancer on endogenous nucleotide pools. PUBLIC HEALTH RELEVANCE: Millions of people around the world will develop hepatic complications from chronic HCV infection and our current therapies are inadequate because of their high incidence of adverse effects and suboptimal chances for viral cure. The work proposed in this application has high human health relevance since findings will shed light on the mechanism of action and toxicity for ribavirin. Ribavirin is an essential agent in the treatmen of HCV and many other life-threatening viral infections.

描述（由申请人提供）：利巴韦林是一种核苷类似物，是世界上仅有的广谱抗病毒药物之一，是治疗慢性丙型肝炎病毒（HCV）的基本成分。尽管临床使用了几十年，但利巴韦林抑制HCV复制并导致其主要剂量限制性毒性贫血的确切机制尚不清楚。我们缺乏对利巴韦林如何起作用和引起贫血的了解，这代表了我们对HCV治疗知识的根本空白。为了优化HCV治愈率并最大限度地减少基于利巴韦林的治疗引起的贫血，我们需要了解这种药物的药理学。在体外，利巴韦林消耗内源性嘌呤，这可能解释了其毒性和治疗作用，但这尚未在人体中进行研究。通过这项应用，Kiser博士将在她的K23上继续努力，并探索利巴韦林对内源性嘌呤的影响。本研究的具体目的是（1）比较ITPA活性表型组间接受利巴韦林治疗的HCV感染患者的红细胞和外周血单核细胞中内源性嘌呤浓度的变化，（2）确定内源性嘌呤耗竭与病毒学应答和贫血之间的相关性，以及ITPA活性表型对这些效应的调节程度。为了实现这些目标，我们将在Kiser博士的K23研究中的40名受试者和前瞻性入选的170名受试者的外周血单核细胞和红细胞中，测量开始基于利巴韦林的HCV治疗前和开始治疗后4周和12周的内源性嘌呤浓度以及开始治疗后4周和12周的三磷酸利巴韦林浓度（并按ITPA活性表型分层）通过我们的肝病诊所。本研究将 增加我们对利巴韦林如何抑制HCV复制和导致贫血的理解，并确定是否存在基于ITPA遗传学的效应差异。此外，虽然通过该授权开发的LC/MS/MS检测将立即用于解决本申请的目的，但该技术也可应用于研究用于治疗HIV、B型肝炎和癌症的HCV核苷聚合酶抑制剂和核苷（酸）类似物对内源性核苷酸库的影响。 公共卫生关系：全世界有数百万人将因慢性HCV感染而发生肝脏并发症，而我们目前的治疗方法是不够的，因为它们的不良反应发生率很高，而且病毒治愈的机会不理想。本申请中提出的工作具有高度的人类健康相关性，因为这些发现将阐明利巴韦林的作用机制和毒性。利巴韦林是治疗HCV和许多其他危及生命的病毒感染的重要药物。