BackgroundElbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.MethodsThe study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.ResultsIn part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.ConclusionTreatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection.ClinicalTrials.gov identifierNCT02203149.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-016-1285-y) contains supplementary material, which is available to authorized users.
The microstructure and magnetic property relationship in L10 ordered FePt–Al–O and FePt–Ag granular thin films have been studied. As-sputtered FePt–Al–O films, composed of isolated fine spherical FePt particles of ∼2 nm diameter with a disordered face-centered-cubic (fcc) structure, exhibit superparamagnetism. Annealing above 650 °C induces a transformation from a disordered fcc structure to ordered L10 phase and the films become magnetically hard. The microstructures of these films change greatly depending on the film compositions and annealing conditions, which are correlated with the magnetic properties. It was found that FePt particles smaller than 5 nm do not order at 500 °C, while the continuous FePt film orders perfectly at the same temperature, suggesting that the ordering temperature, Tc, decreases significantly when the particle size becomes less than 5 nm. In the FePt–Ag granular thin film, when the Ag composition is around 50 at. %, high coercivity (∼10 kOe) and fine uniform microstructure are obtained by annealing the films at 550 °C for 1 h. The changes in the magnetic properties of these granular films are discussed based on microstructural observation results.
Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in nonJapanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Doselimiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached. (Cancer Sci 2009; 100: 1728-1734) H istone acetylation and deacetylation play important roles in post-translational modification of core nucleosomal histones that affect chromatin structure and gene expression.(1-3) The acetylation status of histones and non-histone proteins is determined by the opposing activities of HAT and HDAC. In general, acetylation of histones promotes a more relaxed chromatin structure, allowing increased transcriptional activity. HDAC can act as transcriptional repressors, due to histone deacetylation, and consequently promote chromatin condensation. HDAC inhibitors selectively alter gene transcription, in part, by chromatin remodeling and by changes in the structure of proteins in transcription factor complexes.(4) Further, HDAC have many non-histone protein substrates such as hormone receptors, chaperone proteins, and cytoskeletal proteins that regulate many biological processes, including proliferation, differentiation, apoptosis, and other forms of cell death.(5) Defects in both HAT and HDAC activities that result in aberrant gene expression, signal transduction, and cell-cell signaling have been described in a variety of cancers.(6-9) Genes that encode HAT enzymes are translocated, amplified, overexpressed, and/or mutated in cancers, including both hematological and epithelial malignancies. HDAC have been shown to be involved in oncogenic transformation by mediating the function of transcription factors.Vorinostat (suberoylanilide hydroxamic acid, Zolinza; Merck & Co., Whitehouse Station, NJ, USA) is a small-molecule inhibitor of class I and class II HDAC.(10) Inhibition of HDAC activity by vorinostat has been shown to promote cell cycle arrest, differentiation, and apoptosis of cancer cells through regulation of gene expression.(11-16) Clinically, vorinostat ...
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