Treatment of Hyperammonemia and Hepatic Encephalopathy in Liver Failure with L-Ornithine Phenylacetate

高达50%的肝硬化患者精神状态受损，表现为轻度紊乱，但对其生活质量、驾驶能力和日常生活功能产生重大影响。另一方面，这种精神损伤可能导致严重的神志不清、昏迷、脑疝，最终导致死亡。一百多年来，人们已经认识到一种有毒气体？氨吗?在肝硬化患者的血液和大脑中积累，因为患病的肝脏不能解毒。氨对大脑的代谢功能产生有害影响。因此，氨还原是治疗肝病脑功能障碍的重要靶点。目前尚无证实有效的治疗方法来治疗这种危及生命的肝硬化并发症。值得注意的是，当面临肝功能障碍时，肌肉成为氨解毒的辅助部位，调节这一过程的机制被上调。研究表明，提供底物？谷氨酸？将氨解毒到暂时？安全？分子谷氨酰胺?。我们和其他人已经证明，这种暂时解毒的产品，谷氨酰胺？有可能在肠道中再生氨。我们的发明提供了一种潜在的新方法来控制氨，通过关注从这些概念中获得的知识。使用我们的新化合物的初步研究？L-Ornithine苯乙酸盐吗?这意味着什么？鸟氨酸吗?在肌肉中转化为谷氨酸，为谷氨酰胺的形成提供底物。这种谷氨酰胺含有一种氨分子，与？乙酸苯酯?尿液中的苯乙酰谷氨酰胺。鸟氨酸加苯乙酸对动物模型的治疗证实，这种治疗可显著降低氨浓度，使脑肿胀的严重程度正常化。我们的研究计划将在严重肝病患者中测试这种新型化合物，并关注其对临床相关终点的影响。这些研究将由英国两家领先机构的肝病专家和重症监护医生进行。我们在提案中描述的所有技术都适用于主要研究者和共同申请人。目前，新化合物正在进行严格的毒性测试，将在伦理批准和本研究开始之前完成。将本研究结果转化为肝脏疾病脑功能障碍患者的获益可能发生在5-7年内。

Up to 50% of patients with liver cirrhosis have impairment in their mental state, which can manifest as mild disturbances but produce major effect on their quality of life, ability to drive and in daily functioning. On the other hand, this mental impairment may lead to severe confusion, coma, brain herniation culminating in death. For over a hundred years it has been recognised that a toxic gas ?Ammonia? accumulates in the blood and brain of patients with cirrhosis because the diseased liver cannot detoxify this gas. Ammonia produces deleterious effects on the metabolic functioning of the brain. Therefore, ammonia reduction is an important target for the treatment of the brain dysfunction of liver disease. At present there is no proven effective treatment for this life-threatening complication of cirrhosis. It is remarkable that when faced with the situation of liver dysfunction, the muscle becomes an accessory site of ammonia detoxification and the machinery that regulates this process is up-regulated. It has been shown that the provision of the substrate ?glutamate? detoxifies ammonia to a temporary ?safe? molecule ?glutamine?. We and others have shown that this temporary detoxification product, ?glutamine? has the potential to regenerate ammonia in the gut. Our invention provides a potential new approach to controlling ammonia by focussing on the knowledge derived from these concepts. Preliminary studies using our novel compound ?L-Ornithine Phenylacetate? suggests that ?Ornithine? is converted to glutamate in the muscle which provides the substrate for the formation of glutamine. This glutamine incorporates a molecule of ammonia which is excreted in combination with ?Phenylacetate? in the urine, as the compound ?Phenylacetylglutamine?. The administration of ornithine plus phenylacetate to animal models confirms that this treatment reduces ammonia concentration markedly and normalises the severity of brain swelling. Our research proposal will test this novel compound in patients with severe liver disease and focus on its effects on clinically relevant end-points. The studies will be performed by expert hepatologists and intensive care doctors in 2 leading institutions in the UK. All the techniques we describe in the proposal are available to the principle investigator and co-applicants. At present, the novel compound is undergoing strict toxicity testing which will be completed before ethical approval and start of this study. The translation of the results of this study to use for benefit of patients with brain dysfunction of liver disease can occur within 5-7 years.