Human Lactoferrin in Acetaminophen Overdose-Induced Liver Failure

描述（由申请人提供）：急性或累积过量服用对乙酰氨基酚（APAP），在治疗过量或自杀未遂之后，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，估计458例因急性肝衰竭死亡，使APAP成为美国药物性肝衰竭最常见的原因。目前，N-乙酰半胱氨酸（NAC）是临床用于改善APAP诱导的肝损伤（AILI）的唯一解毒剂。然而，摄取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。在我们的初步研究中

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.