title: Recent advances in the treatment of hyperammonemia.
abstract: 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.
authors.affiliation: ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Matoori
authors.affiliation: ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland. Electronic address: jleroux@ethz.ch.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000641:Ammonia / Q000378:metabolism; D000818:Animals; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism / Q000628:therapy*; D008658:Inactivation, Metabolic
chemical_list: D000641:Ammonia
keywords: Acetyl-l-carnitine (PubChem CID: 7045767); Ammonia; Carglumic acid (PubChem CID: 121396); Cirrhosis; Glycerol phenylbutyrate (PubChem CID: 10482134); Hepatic encephalopathy; Lactitol (PubChem CID: 157355); Lactulose (PubChem CID: 11333); Liver failure; Metabolic disorders; Rifaximin (PubChem CID: 6436173); Sodium benzoate (PubChem CID: 517055); Sodium phenylacetate (PubChem CID: 23690424); Sodium phenylbutyrate (PubChem CID: 5258); Urea cycle; l-ornithine (PubChem CID: 6262)