Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log 10 after a 14-day oral treatment with 1200 mg twice daily (P < 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025-treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 ؎ 6 (standard error) ng/mg protein (baseline) to 5 ؎ 1 ng/mg protein at day 15 (P < 0.01). Conclusion: Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs. (HEPATOLOGY 2008; 47:817-826.)

The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-␣2a (PEG IFN␣2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-␣2a 180 g/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 g/week PEG IFN-␣2a. In patients with genotypes 1 and 4, the 600-and 1,000-mg combination treatments induced a continuous decay in viral load that reached ؊4.61 ؎ 1.88 and ؊4.75 ؎ 2.19 log 10 IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by ؊5.91 ؎ 1.11 and ؊5.89 ؎ 0.43 log 10 IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-␣2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-␣2a.

Summary Background Constipation is a prevalent gastrointestinal disorder. Patient dissatisfaction with prescribed medications is common, and there is need for alternative management strategies. Evidence shows that Bifidobacterium species may be beneficial in constipation. Aim To investigate changes in physiological and clinical measures of gut function in patients with chronic constipation following the consumption of Bifidobacterium lactis NCC2818, compared to placebo. Methods Participants were randomised to a 4‐week supplementation with B. lactis NCC2818 (1.5 x 1010 CFU/d) or placebo. Gut transit time was measured using a radio‐opaque marker, while symptoms and quality of life were assessed using validated questionnaires. Gut microbiota composition was assessed using quantitative polymerase chain reaction. Analysis of covariance was used for normally distributed variables, and Mann‐Whitney test for non‐normally distributed variables. Results Seventy‐five participants were randomised. There was no significant difference between the probiotic and placebo groups in gut transit time change from baseline to week 2 (−11.7 hours, SD 33.0 hours vs −12.9 hours, SD 33.6 hours; P = 0.863) or to week 4 (−20.4 hours, SD 32.5 h vs −8.7 hours, SD 33.8 hours; P = 0.103). There were also no improvements in stool output, symptoms, or quality of life. No differences were found in Bifidobacterium concentrations between the probiotic and placebo groups at week 4 (9.5 log10/g dry faeces, SD 0.3 vs 9.4 log10/g, SD 1.0; P = 0.509). Conclusions Bifidobacterium lactis NCC2818 was not effective in the management of mild chronic constipation. This study highlights the importance of further studies and their publication to better understand the strain‐specific effects of probiotics.