Abstract accepted to CASL 2010

Accepted abstract

An abstract was accepted to 2010 CASL meeting.

Abstract AST-120 (spherical carbon adsorbent) treatment prevents hyperammonemia and brain edema in cirrhotic rats was accepted to the Canadian Association for the Study of Liver ( CASL), held on February 27th - March 2nd, at Toronto, Canada. This oral talk will be given by Cristina.

Related Publication

Oral

AST-120 (spherical carbon adsorbent) treatment prevents hyperammonemia and brain edema in cirrhotic rats.

Cristina R. Bosoi, Christian Parent-Robitaille, Mélanie Tremblay, Christopher F. Rose.

AIMS: The pathogenesis of hepatic encephalopathy (HE) is multifactorial involving gut-derived toxins such as ammonia. Liver disease leads to hyperammonemia and neurotoxic levels of ammonia which have been demonstrated to induce oxidative stress. Therefore a primary treatment target for HE is to decrease ammonia production in the gastrointestinal tract. AST-120 (spherical carbon adsorbent), an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600m2/g acts as a sink for neuro- and hepato-toxins present in the gut. In this study, we evaluated the protective effect of AST-120 in lowering arterial ammonia and oxidative stress and in attenuating brain edema in rats with cirrhosis. METHODS: Secondary biliary cirrhosis was induced in rats by bile-duct ligation (BDL) for 6 weeks. BDL and SHAM-operated rats received AST120 (dispersed in methylcellulose (MC)) by gavage at a dose of 0.1, 1 or 4g/kg/day for 6 weeks. Control BDL and SHAM-operated groups received MC only. AST and ALT were measured to assess liver function. Ammonia and reactive oxygen species (ROS) were measured in arterial plasma using a commercially available kit and DCFDA-fluorescent technique respectively. Brain water content was measured in the frontal cortex using the specific gravimetric technique. RESULTS: AST-120 was well-tolerated with no deaths in either of the treatment groups. Brain water content increased in BDL vs SHAM-operated rats (79.2±0.2% vs 78.7±0.1%, p<0.05). All AST-120 treatments, 0.1, 1 and 4g/kg/day, normalised brain water content in BDL rats. Arterial ammonia levels increased in the BDL control group vs SHAM-operated controls (169.9±21.1uM vs 70.5±14.4uM, p<0.05) and decreased significantly to SHAM levels in 0.1g/kg/day (117.2±12.6uM, p<0.05), 1g/kg/day (78.9±22.3uM, p<0.05) and 4g/kg/day (48.7±19.5uM, p<0.05) AST-120 treated BDL rats. Circulating levels of ROS were significantly increased in BDL vs SHAM-operated rats (11 fold, p<0.001). AST-120 treatments did not attenuate arterial levels of ROS compared to respective SHAM-operated controls. Liver functions enzymes, AST and ALT, were increased in all BDL rats compared to their respective SHAM-operated controls (p<0.001) but were not attenuated following AST120 treatments. CONCLUSIONS: AST-120 treatment normalized brain water content and decreased arterial ammonia levels but did not demonstrate an effect on systemic ROS. Long-term treatment with AST-120 is a safe, non-antibiotic alternative with significant ammonia-lowering effect as well as a protective effect on the development of brain edema in rats with chronic liver failure. Additional studies are warranted to evaluate the effects of AST-120 on HE in patients with advanced liver disease.