ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
Adv Drug Deliv Rev. 2015 Aug 1;90:55-68. doi: 10.1016/j.addr.2015.04.009. Epub 2015 Apr 17.
Ammonia is a neurotoxic agent that is primarily generated in the intestine and detoxified in the liver. Toxic increases in systemic ammonia levels predominantly result from an inherited or acquired impairment in hepatic detoxification and lead to potentially life-threatening neuropsychiatric symptoms. Inborn deficiencies in ammonia detoxification mainly affect the urea cycle, an endogenous metabolic removal system in the liver. Hepatic encephalopathy, on the other hand, is a hyperammonemia-related complication secondary to acquired liver function impairment. A range of therapeutic options is available to target either ammonia generation and absorption or ammonia removal. Therapies for hepatic encephalopathy decrease intestinal ammonia production and uptake. Treatments for urea cycle disorders eliminate ammoniagenic amino acids through metabolic transformation, preventing ammonia generation. Therapeutic approaches removing ammonia activate the urea cycle or the second essential endogenous ammonia detoxification system, glutamine synthesis. Recent advances in treating hyperammonemia include using synergistic combination treatments, broadening the indication of orphan drugs, and developing novel approaches to regenerate functional liver tissue. This manuscript reviews the various pharmacological treatments of hyperammonemia and focuses on biopharmaceutical and drug delivery issues.
氨是一种神经毒性物质，主要在肠道中产生，并在肝脏中解毒。全身氨水平的毒性增加主要是由于肝脏解毒功能的遗传或获得性损害引起的，并导致潜在的危及生命的神经精神症状。氨解毒的先天性缺陷主要影响尿素循环，这是肝脏内的一种内源性代谢清除系统。另一方面，肝性脑病是一种与获得性肝功能损害相关的高氨血症相关并发症。有一系列针对氨生成和吸收或氨去除的治疗选择。肝性脑病的治疗方法可减少肠道氨的产生和吸收。尿素循环障碍的治疗方法通过代谢转化消除产氨氨基酸，从而防止氨的生成。去除氨的治疗方法通过激活尿素循环或第二种必需的内源性氨解毒系统——谷氨酰胺合成来发挥作用。治疗高氨血症的最新进展包括使用协同联合治疗、扩大孤儿药的适应证以及开发新方法来再生功能性肝组织。本文综述了高氨血症的各种药物治疗方法，并重点介绍了生物制药和药物传递问题。
