Human Lactoferrin in Acetaminophen Overdose-Induced Liver Failure

人乳铁蛋白在对乙酰氨基酚过量引起的肝衰竭中的作用

基本信息

批准号：
8390973
负责人：
Cynthia Ju
金额：
$ 20.19万
依托单位：
VENTRIA BIOSCIENCE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390973
关键词：
Accident and Emergency department Accounting Acetaminophen Acetylcysteine Acute Acute Liver Failure Adult Alanine Transaminase Animals Antibiotics Antidotes Attenuated Biological Assay Canis familiaris Cereals Cessation of life Characteristics Charge Clinic Clinical Clinical Research Data Diarrhea Discontinuous Capillary Disease Dose Effectiveness Endothelial Cells Evans blue stain FDA approved Functional disorder Hemorrhage Hepatic Histopathology Hospitalization Human Infant Ingestion Injectable Injury Investigation Laboratories Lactoferrin Life Liver Liver Failure Measures Microcirculation Milk Modeling Mus Oral Administration Overdose Pathogenesis Patients Pharmaceutical Preparations Phase Preparation Procedures Proteins Rattus Recombinants Research Personnel Rice Rosa Safety Scientist Seasons Sepharose Serum Simulate Small Business Technology Transfer Research Solutions Suicide attempt Symptoms Testing Therapeutic Time Visit acetaminophen overdose base intravenous administration novel novel therapeutics phase 2 study protective effect

项目摘要

DESCRIPTION (provided by applicant): An acute or cumulative overdose of acetaminophen (APAP), following either therapeutic overdose or suicide attempts, can cause severe liver damage with the potential to progress to liver failure. APAP overdose accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year, making APAP the most frequent cause of drug-induced liver failure in the U.S. Currently, N- acetylcysteine (NAC) is the only antidote used clinically to ameliorate APAP-induced liver injury (AILI). However, the effectiveness of NAC declines rapidly after APAP ingestion. Therefore, developing new life-saving treatment is critically needed. In our preliminary study with milk- derived lactoferrin, we demonstrate that the lactoferrin has a profound hepato-protective effect in a murine model of AILI. In the present proposal, we will team up with scientists from Ventria Bioscience to investigate the feasibility of developing a novel treatment o AILI with recombinant human lactoferrin (rhLF) produced by Ventria. There are two aims in the present proposal. Aim 1. Purification of rhLF from rice suitable for intravenous (i.v.) administration. We will purify sufficient amount of rhLF from rice grain and formulate it for systemic administration to mice. Aim 2. Investigation of the feasibility of the rhLF in attenuating AILI in mice. We will determine the condition in which rhLF can exert maximal/optimal effect on AILI. We expect that the study will prove that the rhLF is able to protect mice from liver injury due to overdose of APAP and establish a base for further study in phase II STTR to develop a novel therapy for AILI. PUBLIC HEALTH RELEVANCE: Acetaminophen overdose cause severe liver damage and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths each year in the U.S. Based on our preliminary study, we propose to develop a novel therapeutic treatment with recombinant human lactoferrin.

描述（由申请人提供）：治疗过量或自杀企图后，急性或累积过量服用对乙酰氨基酚（APAP）可导致严重的肝损伤，并有可能发展为肝衰竭。 APAP 过量每年导致超过 56,000 例急诊就诊、2,600 例住院治疗，估计有 458 例因急性肝衰竭死亡，使 APAP 成为美国药物性肝衰竭的最常见原因。目前，N-乙酰半胱氨酸 (NAC)是临床上唯一用于改善 APAP 引起的肝损伤 (AILI) 的解毒剂。然而，摄入 APAP 后，NAC 的有效性迅速下降。因此，迫切需要开发新的挽救生命的治疗方法。在我们的初步通过对牛奶源乳铁蛋白的研究，我们证明乳铁蛋白在 AILI 小鼠模型中具有深远的肝保护作用。在目前的提案中，我们将与 Ventria Bioscience 的科学家合作，研究利用 Ventria 生产的重组人乳铁蛋白（rhLF）开发一种新的 AILI 治疗方法的可行性。本提案有两个目标。目标 1. 从大米中纯化适合静脉 (i.v.) 给药的 rhLF。我们将从米粒中纯化足量的rhLF，并将其配制用于小鼠全身给药。目标 2. 研究 rhLF 衰减的可行性小鼠的 AILI。我们将确定 rhLF 对 AILI 发挥最大/最佳效果的条件。我们期望该研究将证明rhLF能够保护小鼠免受过量APAP引起的肝损伤，并为STTR II期进一步研究开发治疗AILI的新疗法奠定基础。公共卫生相关性：对乙酰氨基酚过量服用会导致严重的肝损伤，导致美国每年有超过 56,000 例急诊室就诊、2,600 例住院治疗，估计有 458 例死亡。根据我们的初步研究，我们建议开发一种使用重组人的新型治疗方法乳铁蛋白。