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

高达50%的肝硬化患者的精神状态受损，这可能表现为轻度障碍，但对他们的生活质量，驾驶能力和日常功能产生重大影响。另一方面，这种精神障碍可能导致严重的混乱，昏迷，脑疝最终死亡。一百多年来，人们一直认为有毒气体？氨水？由于患病的肝脏无法解毒这种气体，因此这种气体会积聚在肝硬化患者的血液和大脑中。氨对大脑的代谢功能产生有害影响。因此，降低氨是治疗肝病脑功能障碍的重要靶点。目前，对于这种危及生命的肝硬化并发症还没有有效的治疗方法。值得注意的是，当面临肝功能障碍的情况时，肌肉成为氨解毒的辅助部位，并且调节该过程的机制被上调。它已被证明，提供的基板？谷氨酸盐？暂时将氨解毒吗安全吗分子？谷氨酰胺？我们和其他人已经表明，这种暂时的解毒产品，？谷氨酰胺？有可能在肠道中再生氨。我们的发明通过集中于从这些概念得到的知识提供了控制氨的潜在的新方法。使用我们新化合物的初步研究？L-鸟氨酸苯乙酸盐？这说明了什么鸟氨酸？在肌肉中转化为谷氨酸盐，谷氨酸盐为谷氨酰胺的形成提供底物。这种谷氨酰胺结合了一个氨分子，它与？苯乙酸？在尿液中的成分苯乙酰谷氨酰胺？。对动物模型施用鸟氨酸加苯乙酸盐证实了这种治疗显著降低了氨浓度并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2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可供主要研究者和共同申请人使用。目前，该新化合物正在进行严格的毒性测试，将在伦理批准和开始这项研究之前完成。本研究结果的转化可在5 - 7年内用于肝病脑功能障碍患者。

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.