BACKGROUND The most widely used treatment of portal-systemic encephalopathy (PSE) is the administration of oral, non-absorbable disaccharides. Theoretically, the inhibition of intestinal disaccharidases should induce malabsorption of disaccharides and increase delivery of undigested carbohydrates to the colon, thus stimulating the effects of lactulose and other non-absorbable disaccharides (that is, lactitol and lactose). AO-128 is an N-substituted derivative of valeolamine, an aminocyclitol that selectively inhibits intestinal disaccharidases. This study was performed to investigate whether AO-128 could be used as adjuvant therapy for the treatment of mild PSE in cirrhotic patients. METHODS A double-blind, randomized, controlled trial was performed in 35 cirrhotic patients with PSE. Patients were given a 2-week treatment consisting of AO-128 (2 mg three times daily) or an identical placebo. The following features of PSE syndrome were assessed in a semiquantitative fashion before and after I and 2 weeks of therapy: mental state, asterixis, number connection test (NCT), venous blood ammonia concentration, electroencephalogram (EEG), and overall PSE index (PSEI). More patients receiving AO-128 than patients receiving placebo showed >40% improvement in the PSEI (83% versus 35%; P < 0.05). The mean stool pH decreased from 5.8+/-0.3 to 5.5+/-0.3 (P < 0.004) after AO-128 treatment, whereas no changes were observed in the placebo group. The EEG and nitrogen balance did not show significant changes in any of the two groups. A significant improvement was seen in the NCT performance after AO-128 (from grade 2.0+/-1.04 to grade 1.25+/-0.87; P < 0.05). Seven patients treated with AO-128 developed diarrhea, as compared with none in the placebo group (P < 0.05). CONCLUSIONS These results suggest that AO-128 may be useful in the treatment of PSE, although further studies are required to establish the benefit of AO-128 and determine adequate individual doses.