Efficacy of MK615 for the treatment of patients with liver disorders

AIM:To investigate the hepatoprotective effect of MK615,a Japanese apricot extract,in an animal model,and its clinical therapeutic effect.METHODS:Wistar rats were administered physiological saline(4 mL/kg) or MK615 solution(4 mL/kg) for 7 d.On the sixth d,acute hepatic injury was induced by administering a single intraperitoneal injection(ip) of D-galactosamine hydrochloride(D-GalN)(600 mg/kg).Plasma levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were determined,and liver tissues were used for histopathological analysis.Fifty-eight patients with liver disorders [hepatitis C(n = 40),non-alcoholic fatty liver disease(n = 15),and autoimmune liver disease(n = 3)] were orally administered commercially available Misatol ME-containing MK615(13 g/d) daily for 12 wk.Blood and urine were sampled immediately before and 6 wk,12 wk,and 16 wk after the start of intake to measure various biochemical parameters.The percentage change in ALT and AST levels after 12 wk from the pre-intake baseline served as a primary endpoint.RESULTS:D-GalN effectively induced acute hepatic injury in the rats.At 48 h after the ip injection of D-GalN,the plasma levels of ALT(475.6 ± 191.5 IU/L vs 225.3 ± 194.2 IU/L,P < 0.05) and AST(1253.9 ± 223.4 IU/L vs 621.9 ± 478.2 IU/L,P < 0.05) in the MK615 group were significantly lower than the control group.Scattered single cell necrosis,loss of hepatocytes,and extensive inflammatory cell infiltration were observed in hepatic tissue samples collected from the control group.However,these findings were less pronounced in the group receiving MK615.At the end of the clinical study,serum ALT and AST levels were significantly decreased compared with pre-intake baseline levels from 103.5 ± 58.8 IU/L to 71.8 ± 39.3 IU/L(P < 0.05) and from 93.5 ± 55.6 IU/L to 65.5 ± 34.8 IU/L(P < 0.05),respectively.A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 26(45%) of the 58 patients,while 25(43%) patients exhibited similar AST level reductions.The chronic hepatitis C group exhibited significant ALT and AST level reductions from 93.4 ± 51.1 IU/L to 64.6 ± 35.1 IU/L(P < 0.05) and from 94.2 ± 55.5 IU/L to 67.2 ± 35.6 IU/L(P < 0.05),respectively.A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 20(50%) of the 40 patients.ALT levels in both the combined ursodeoxycholic acid(UDCA) treatment and the UDCA uncombined groups were significantly lower after Misatol ME administration.MK615 protected hepatocytes from D-GalN-induced cytotoxicity in rats.Misatol ME decreased elevated ALT and AST levels in patients with liver disorders.CONCLUSION:These results suggest that MK615 and Misatol ME are promising hepatoprotective agents for patients with liver disorders.

Clinical usefulness of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis

AIM To evaluate the therapeutic effects of ursodeoxycholic acid(UDCA) on autoimmune hepatitis(AIH).METHODS A total 136 patients who were diagnosed with AIH were included in our study. All of the patients underwent a liver biopsy, and had at least a probable diagnosis on the basis of either the revised scoring system or the simplified scores. Initial treatment included UDCA monotherapy(Group U, n = 48) and prednisolone(PSL) monotherapy(Group P, n = 88). Group U was further classified into two subgroups according to the effect of UDCA: Patients who had achieved remission induction with UDCA monotherapy and showed no sign of relapse(Subgroup U1, n = 34) and patients who additionally received PSL during follow-up(Subgroup U2, n = 14). We compared the clinical and histological findings between each groups, and investigated factorscontributing to the response to UDCA monotherapy.RESULTS In Group U, 34 patients(71%) achieved and maintained remission over 49(range: 8-90) mo(Subgroup U1) and 14 patients(29%) additionally received PSL(Subgroup U2) during follow-up. Two patients in Subgroup U2 achieved remission induction once but additionally required PSL administration because of relapse(15 and 35 mo after the start of treatment). The remaining 12 patients in Subgroup U2 failed to achieve remission induction during follow-up, and PSL was added during 7(range: 2-18) mo. Compared with Subgroup U2, Subgroup U1 had significantly lower alanine aminotransferase(ALT) levels at onset(124 IU/L vs 262 IU/L, P = 0.023) and a significantly higher proportion of patients with mild inflammation(A1) on histological examination(70.6% vs 35.7%, P = 0.025). When multivariate analysis was performed to identify factors contributing to the response to UDCA monotherapy, only a serum ALT level of 200 IU/L or lower was found to be associated with a significant difference(P = 0.013).CONCLUSION To prevent adverse events related to corticosteroids, UDCA monotherapy for AIH needs to be considered in patients with a serum ALT level of 200 IU/L or lower.

Impact of interferon-free antivirus therapy on lipid profiles in patients with chronic hepatitis C genotype 1b

AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b(HCV1b) infection.METHODS Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1 b infection, and changes in serum lipids of those who achieved sustained virologic response(SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir(DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir(SOF + LDV). SVR was achieved in 121(85.8%) of 141 patients treated with DCV + ASV and 132(97.8%) of 135 patients treated with SOF + LDV. In the two patient groups(DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were analyzed.RESULTS Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDVSVR group than in the DCV + ASV-SVR group(P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol(DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of therapy.CONCLUSION Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol.