Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy.

AIM: Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography. METHODS: This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (≥9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12. RESULTS: Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4-67.6; P<0.001). CONCLUSION: In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients.

Mechanistic insight into the initiation step of the coupling reaction of oxetane or epoxides and CO2 catalyzed by (salen)CrX complexes.

The most active and robust current catalysts for the copolymerization of carbon dioxide and epoxides or oxetanes, (salen)CrX in conjunction with PPNX (PPN(+) = (Ph3P)2N(+)) or n-Bu4NX (X = Cl, N3, CN, NCO), are characterized both in solution by infrared spectroscopy and in the solid-state by X-ray crystallography. All anions (X) afford six-coordinate chromium(III) PPN(+) or n-Bu4N(+) salts composed of trans-(salen)CrX2(-) species. Of the X groups investigated in (salen)CrX, chloride is easily displaced by the others, that is, the reaction of (salen)CrCl with 2 equiv of N3(-), CN(-), or NCO(-) quantitatively provide (salen)Cr(N3)2(-), (salen)Cr(CN)2(-), and (salen)Cr(NCO)2(-), respectively. On the other hand, addition of less than 2 equiv of azide to (salen)CrCl leads to a Schlenk (ligand redistribution) equilibrium of the three possible anions both in solution and in the solid-state as shown by X-ray crystallography and electrospray ionization mass spectrometry. It was further demonstrated that all trans-(salen)CrX2(-) anions react with the epoxide or oxetane monomers in TCE (tetrachloroethane) solution to afford an equilibrium mixture containing (salen)CrX x monomer, with the oxetane adduct being thermodynamically more favored. The ring-opening steps of the bound cyclic ether monomers by X(-) were examined, revealing the rate of ring-opening of the epoxides (cyclohexene oxide and propylene oxide) to be much faster than of oxetane, with propylene oxide faster than cyclohexene oxide. Furthermore, both X anions in (salen)CrX2(-) were shown to be directly involved in monomer ring-opening.

Mechanistic studies of the copolymerization reaction of oxetane and carbon dioxide to provide aliphatic polycarbonates catalyzed by (Salen)CrX complexes.

Chromium salen derivatives in the presence of anionic initiators have been shown to be very effective catalytic systems for the selective coupling of oxetane and carbon dioxide to provide the corresponding polycarbonate with a minimal amount of ether linkages. Optimization of the chromium(III) system was achieved utilizing a salen ligand with tert-butyl groups in the 3,5-positions of the phenolate rings and a cyclohexylene backbone for the diimine along with an azide ion initiator. The mechanism for the coupling reaction of oxetane and carbon dioxide has been studied. Based on binding studies done by infrared spectroscopy, X-ray crystallography, kinetic data, end group analysis done by (1)H NMR, and infrared spectroscopy, a mechanism of the copolymerization reaction is proposed. The formation of the copolymer is shown to proceed in part by way of the intermediacy of trimethylene carbonate, which was observed as a minor product of the coupling reaction, and by the direct enchainment of oxetane and CO 2. The parity of the determined free energies of activation for these two processes, namely 101.9 kJ x mol (-1) for ring-opening polymerization of trimethylene carbonate and 107.6 kJ x mol (-1) for copolymerization of oxetane and carbon dioxide supports this conclusion.