Flisiak Robert, Horban Andrzej, Gallay Philippe, Bobardt Michael, Selvarajah Suganya, Wiercinska-Drapalo Alicja, Siwak Ewa, Cielniak Iwona, Higersberger Jozef, Kierkus Jarek, Aeschlimann Christian, Grosgurin Pierre, Nicolas-Métral Valérie, Dumont Jean-Maurice, Porchet Hervé, Crabbé Raf, Scalfaro Pietro
Department of Infectious Diseases, Medical University of Bialystok, Bialystok, Poland.
Hepatology. 2008 Mar;47(3):817-26. doi: 10.1002/hep.22131.
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).
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.
Debio-025是一种口服亲环素（Cyp）抑制剂，在体外具有强大的抗丙型肝炎病毒活性。在一项随机、双盲、安慰剂对照研究中，研究了其对病毒载量的影响以及对细胞内Cyp水平的影响。每日两次口服1200毫克，经过14天治疗后，丙型肝炎病毒平均载量显著下降3.6 log(10)（P < 0.0001），对研究中所代表的3种基因型（1、3和4）均有作用。此外，治疗期间无病毒反弹表明Debio-025对耐药性的选择具有高屏障。在接受Debio-025治疗的患者中，外周血单核细胞中环孢菌素B（CypB）水平从67±6（标准误）纳克/毫克蛋白质（基线）在第15天降至5±1纳克/毫克蛋白质（P < 0.01）。
Debio-025导致CypB水平大幅下降，这与丙型肝炎病毒载量的降低相一致。这些是支持CypB可能在丙型肝炎病毒复制中起重要作用以及Cyp抑制是抗丙型肝炎药物开发的有效靶点这一假说的首批初步人体数据。
