Human Lactoferrin in Acetaminophen Overdose-Induced Liver Failure

描述（由申请方提供）：治疗性过量或自杀企图后，急性或累积过量的对乙酰氨基酚（APAP）可导致重度肝损伤，并有可能进展为肝衰竭。APAP过量导致每年超过56，000次急诊室就诊、2，600次住院治疗和估计458例急性肝衰竭死亡，使APAP成为美国药物诱导的肝衰竭的最常见原因。目前，N-乙酰半胱氨酸（NAC）是临床上用于改善APAP诱导的肝损伤（AILI）的唯一解毒剂。然而，NAC的有效性在摄入APAP后迅速下降。因此，迫切需要开发新的拯救生命的治疗方法。在我们的初步调查中 通过对乳源性乳铁蛋白的研究，我们证明了乳铁蛋白在AILI的鼠模型中具有显著的肝保护作用。在本提案中，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）开发新型AILI治疗方法的可行性。本建议有两个目的。目标1.从大米中纯化适于静脉内（i. v.）局我们将从稻米中纯化足够量的rhLF，并将其配制用于小鼠的全身给药。目标2.重组人肝细胞因子减毒的可行性研究 小鼠AILI。我们将确定rhLF对AILI发挥最大/最佳作用的条件。我们期望本研究能证明rhLF对APAP过量致小鼠肝损伤具有保护作用，并为进一步开展II期STTR研究开发AILI的新疗法奠定基础。 公共卫生相关性：对乙酰氨基酚过量导致严重的肝损伤，并占超过56，000急诊室就诊，2，600住院治疗，估计每年有458人死亡在美国根据我们的初步研究，我们建议开发一种新的重组人乳铁蛋白治疗方法。

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.