THDP17 Decreases Ammonia Production through Glutaminase Inhibition. A New Drug for Hepatic Encephalopathy Therapy

Díaz-Herrero, M. Mar; Campo, J.A. Del; Carbonero-Aguilar, Pilar; Vega‐Pérez, José M.; Iglesias‐Guerra, Fernando; Periñán, Ignacio; Miñano, F.J.; Bautista, Juan; Romero‐Gómez, Manuel

doi:10.1371/journal.pone.0109787

Cited by 14 publications

(9 citation statements)

References 29 publications

(28 reference statements)

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“…Other molecules such as 968, BPTES or THDP17 have also been reported to inhibit glutaminase via different mechanisms with in vitro efficacy. However, despite all efforts, its high in vivo toxicity means it cannot be used for treatment (31,32). Nevertheless, these studies suggest the possibility of many other scaffolds that inhibit glutaminase enzyme activity, enabling further investigations in the field.…”

Section: Fig 3 Changes In Gene Expression In Caco2 a Gene Expressmentioning

confidence: 99%

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

Gil‐Gómez¹,

Gómez-Sotelo²,

Ranchal³

et al. 2018

Rev Esp Enferm Dig

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Section: Fig 3 Changes In Gene Expression In Caco2 a Gene Expressmentioning

confidence: 99%

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

Gil‐Gómez¹,

Gómez-Sotelo²,

Ranchal³

et al. 2018

Rev Esp Enferm Dig

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“…47,48 Inhibitors of intestinal glutaminase have been shown to reduce portal ammonia levels even after treatment with lactulose and antibiotics. 49 However, these have never been studied in humans. Accordingly, direct elimination of ammonia from the gut via purgatory treatments and reduction of proteolytic bacterial flora, as well as reduction of inflammation secondary to gut translocation of bacterial by-products, form the mainstay of HE therapy.…”

Section: Article Highlightsmentioning

confidence: 99%

Refining the Ammonia Hypothesis

Tapper

Jiang

Patwardhan

2015

Mayo Clinic Proceedings

128

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Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the ammonia hypothesis to account for these other factors instructs a solid foundation for the effective treatment and prevention of hepatic encephalopathy.

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“…Glutaminase inhibition is a promising target of drug therapy in HE management. It could be a new era of research that may change HE management principle but nothing solid yet [39].…”

Section: Other Therapiesmentioning

confidence: 99%

Pharmacotherapy of Hepatic Encephalopathy

Al-Muhaideb¹,

Ajlan²

2019

Liver Cirrhosis - Debates and Current Challenges

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Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is a serious neuropsychiatric disorder resulting from liver failure. It is one of the common complications of liver cirrhosis and portosystemic shunting (PSS). Ammonia accumulation is one of the well-established causes. Ammonia is a by-product of the intestinal bacteria as a result of the breakdown of dietary supplements. In the normal state of the liver, the peripheral hepatocyte contains glutaminase that converts glutamine into glutamate and ammonia; ammonia will be detoxified and converted into urea. The variant manifestations were linked to the severity of HE. A wide range of neurological and psychiatric signs have been reported. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) uses asterixis (i.e., flapping tremor) as the first clinical sign of HE. Four factors should be taken into consideration to classify and distinguish HE from other conditions: HE type, severity of manifestations following West-Haven Criteria (WHC), HE time course, and presence of precipitating factors. Nonabsorbable disaccharides (lactulose and lactitol) and rifaximin have been the standard of care as first-and second-line therapies, respectively. Non-pharmacological interventions had a crucial role in HE management. Liver transplantation is the ultimate management of hepatic cirrhosis.

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THDP17 Decreases Ammonia Production through Glutaminase Inhibition. A New Drug for Hepatic Encephalopathy Therapy

Cited by 14 publications

References 29 publications

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

Refining the Ammonia Hypothesis

Pharmacotherapy of Hepatic Encephalopathy

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