Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy.

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

3D printing of a controlled urea delivery device for the prevention of tooth decay.

Dental caries is one of the most widespread chronic infectious diseases in the world. It is mainly caused by the production of acid in the biofilm from the bacterial metabolism of carbohydrates. Nowadays, the prevention of caries is mainly based on the use of topical formulations containing fluoride. However, effective fluoride supplementation may not be sufficient in high-risk individuals, leading to the exploration of alternative strategies such as the neutralization of acid in the oral cavity. Urea is hydrolyzed into ammonia by oral bacteria, leading to a local alkalization that may counteract tooth decay. Herein, we report the fabrication of 3D printed personalized dental trays with a local and prolonged release of urea. Composite filaments with tunable urea release kinetics were produced by hot melt extrusion of poly(ε-caprolactone) and poly(vinyl alcohol) or poly(ethylene glycol) blends mixed with urea. The filaments were further used to 3D print by fused deposition modeling objects capable of releasing urea in a sustained and spatially controlled manner. In vitro studies performed in the presence of Streptococcus salivarius demonstrated the ability of urea released from a 3D printed model toothguards to reduce the pH drop induced by carbohydrates. This study showed the potential of urea-loaded devices to reduce cariogenic acidification of the environment surrounding the enamel by delivering urea directly to the tooth surface.