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Treatment for alcoholic liver disease

酒精性肝病的治疗

基本信息

批准号：
8331465
负责人：
Bert J. W. M. Oehlen
金额：
$ 122.33万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8331465
关键词：
Adverse event Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic liver damage Apoptosis CCL4 gene Canis familiaris Cardiovascular system Cause of Death Cell Proliferation Chromosome abnormality Chronic Cicatrix Cirrhosis Clinical Country Cytochrome P450 Data Development Disease Dose Drug Exposure Drug Interactions Enzymes Excretory function Female Grant Hepatocyte In Vitro Injury to Liver Ion Channel Kilogram Lead Liver Liver Cirrhosis Liver Fibrosis Lymphoma Medical Messenger RNA Metabolism Microsomes Modeling Molecular Mus Neurologic Oral P-Glycoprotein Patients Pharmaceutical Preparations Property Rattus Recombinants Research Rodent Safety Sampling Series Serum Signal Transduction Staging Techniques Testing Therapeutic Therapeutic Index Time Tissue Sample Toxicology Transcript Tretinoin United States Western Blotting Work absorption analytical method drug candidate effective therapy in vivo in vivo Model inhibitor/antagonist male method development micronucleus novel pre-clinical preclinical efficacy problem drinker receptor respiratory

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice. We have identified a novel series of ATRA modulators with excellent in vitro and in vivo pharmacological properties and demonstrate its anti-fibrotic activity in vivo. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease.

描述（由申请人提供）：肝纤维化是一种瘢痕形成形式，几乎在所有肝脏慢性损伤患者中都有发现。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死亡原因，折磨着全世界数亿人。在西方国家，酒精摄入仍然是导致肝硬化的最重要原因。酒精性肝病可分为不同的发展阶段：(1)轻度酒精性肝损伤，(2)脂肪变性，(3)酒精性肝炎，(4)酒精性肝纤维化和(5)肝硬化。尽管已经在酒精性肝病患者中尝试了几种药物治疗方法，但迄今为止，没有一种治疗方法在酒精性肝损伤的过程中显示出持续的改善，对有效治疗的医学需求仍未得到满足。在我们的初步数据中，我们表明内源性ATRA水平的调节剂在小鼠中具有抗纤维化活性。我们已经鉴定了一系列具有良好体外和体内药理特性的ATRA调节剂，并在体内证明了其抗纤维化活性。我们建议将该系列的先导化合物作为酒精性肝病的潜在治疗药物进行IND提名。