ABSTRACT
BACKGROUND/AIMS: Chronic hepatocellular damage is closely associated with hepatic fibrosis and fatal complication in most liver diseases. The aim of this study is to compare the efficacy and safety of biphenyl dimethyl dicarboxylate (DDB) and ursodeoxycholic acid (UDCA) in patients with abnormal ALT. METHODS: One-hundred thirty-five patients with elevated ALT were randomized to receive either 750 mg/day of DDB or 300 mg/day of UDCA for 24 weeks in 4 referral hospitals. Ninety-three (69%) patients had non-alcoholic steatohepatitits, 27 (20%) had alcoholic hepatitis, and 15 (11%) had chronic hepatitis. The primary end point was the rate of ALT normalization at week 24. The secondary endpoints were changes in AST, liver stiffness, and the incidence of adverse events. RESULTS: A total of 101 patients completed 24 weeks of therapy. ALT normalization at week 24 was observed in 44 (80.0%) patients in DDB group and 16 (34.8%) in UDCA group (p<0.001). Higher mean reduction of ALT levels from baseline to 24 weeks was seen in DDB group compared with UDCA group (-70.0% vs. -35.9%, p<0.001). Normalization of AST level (p=0.53) and change in the liver stiffness (p=0.703) were not significantly different between the two groups. Severe adverse drug reaction occurred in 1 patient in DDB group but the subject continued therapy during the study period. CONCLUSIONS: DDB was not inferior to UDCA for normalizing ALT level. Furthermore it was safe and well tolerated by patients with abnormal ALT.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Alanine Transaminase/blood , Cholagogues and Choleretics/therapeutic use , Dioxoles/therapeutic use , Double-Blind Method , Drug Administration Schedule , Follow-Up Studies , Hepatitis, Alcoholic/drug therapy , Hepatitis, Chronic/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Tertiary Care Centers , Treatment Outcome , Ursodeoxycholic Acid/therapeutic useABSTRACT
Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-â (TGF-â). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-â T. cruzi, or SB-431542, an inhibitor of TGF-â receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-â signalling had been shown previously to be highly activated. We demonstrated that TGF-â treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-â secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-â levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.