Analysis of the disposition of a novel p38 MAPK inhibitor, AKP-001, and its metabolites in rats with a simple physiologically based pharmacokinetic model.

5-[(2-Chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001) is a potent p38 mitogen-activated protein kinase inhibitor that is being developed to specifically target the intestines for the treatment of inflammatory bowel disease. According to the ante-drug concept, AKP-001 was designed to be metabolized to inactive forms via the first-pass metabolism to avoid undesirable systemic exposure. The purpose of this study is to investigate the pharmacokinetic characteristics of AKP-001 and its metabolites (M1 and M2) in rats, utilizing a simple physiologically based pharmacokinetic (PBPK) model.

Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: a prospective, multicentre, observational study in Japan.

Objective: The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept.

Methods: Japanese RA patients in 28-joint DAS with CRP (DAS28-CRP) remission (<2.3) after >2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week, multicentre, non-blinded, prospective, observational study.

Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept.

Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after.

Phase III, multicenter, open-label, long-term study of the safety of abatacept in Japanese patients with rheumatoid arthritis and an inadequate response to conventional or biologic disease-modifying antirheumatic drugs.

Objectives: To examine the long-term safety of intravenous (IV) abatacept treatment in Japanese patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or other conventional or biologic disease-modifying antirheumatic drugs.

Methods: This Phase III, open-label, long-term study (NCT00484289) comprised Japanese patients with RA who had completed abatacept Phase I or Phase II studies, and new patients intolerant to MTX. Patients from Phase I and Phase II studies received a weight-tiered dosing equivalent of 10 mg/kg abatacept, with MTX at doses up to 8 mg/week; newly enrolled patients received weight-tiered 10 mg/kg abatacept monotherapy.

Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study.

Objectives: To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy.

Methods: Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks.

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study.

Objectives: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration.

Methods: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves.

Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study).

A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points.

Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis.

Objective: To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ-SC) monotherapy to intravenous TCZ infusion (TCZ-IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease-modifying antirheumatic drugs (DMARDs).

Methods: This study had a double-blind, parallel-group, double-dummy, comparative phase III design. Patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study.

Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors.

Objectives The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. Methods We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy.

Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors.

Objectives: The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy.

Methods: We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy.

Encapsulation of anion/cation in the central cavity of tetrameric polyoxometalate, composed of four trititanium(IV)-substituted α-Dawson subunits, initiated by protonation/deprotonation of the bridging oxygen atoms on the intramolecular surface.

Preparation and structural characterization of a novel polyoxometalate (POM), [(P(2)W(15)Ti(3)O(60.5))(4)(NH(4))](35-) 1, i.e.

Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with Sjögren's syndrome: a double-blind placebo-controlled multicenter trial.

The effects of rebamipide on dry mouth and salivary secretion in Sjögren's syndrome patients were investigated in a double-blind placebo-controlled study. Rebamipide (100 mg TID) or placebo was administered for eight weeks and patient-assessed improvement of dry mouth and increase in salivary secretion measured by the Saxon test were evaluated. At two, four, and eight weeks, dry mouth improvement rates were, respectively, 26.

Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese.

Mutations in WFS1 are reported to be responsible for two conditions with distinct phenotypes; DFNA6/14/38 and autosomal recessive Wolfram syndrome. They differ in their associated symptoms and inheritance mode, and although their most common clinical symptom is hearing loss, it is of different types. While DNFA6/14/38 is characterized by low frequency sensorineural hearing loss (LFSNHL), in contrast, Wolfram syndrome is associated with various hearing severities ranging from normal to profound hearing loss that is dissimilar to LFSNHL (Pennings et al.

Femtosecond pulse amplification by a two-photon arranged photorefractive amplifier.

Femtosecond pulse amplification by a two-photon arranged photorefractive amplifier (TAPA) has been demonstrated. A gain bandwidth of 32 THz has been achieved with an extraction efficiency of 27 %.

Evaluation of Pneumocystis pneumonia infection risk factors in patients with connective tissue disease.

We conducted a retrospective, clinical evaluation of connective tissue disease (CTD) patients who were tested for either sputum or bronchoalveolar lavage fluid Pneumocystis polymerase chain reaction (PC-PCR) and analyzed the risk factors that cause Pneumocystis pneumonia (PCP) susceptibility and fatality. PC-PCR was performed on 66 CTD patients who presented with symptoms, data, or radiological findings strongly suggesting respiratory infection. Patients with higher oral corticosteroid doses, use of oral methotrexate (MTX), bilateral lung findings, positive beta-D-glucan, and no prophylaxis use were more susceptible to PCP.

Leptospirosis in squirrels imported from United States to Japan.

We diagnosed leptospirosis in 2 patients exposed to southern flying squirrels imported from the United States to Japan. Patients worked with exotic animals in their company. Leptospira isolates from 1 patient and 5 of 10 squirrels at the company were genetically and serologically identical and were identified as Leptospira kirschneri.

Inflammatory pseudotumour (plasma cell granuloma) arising in the maxillary sinus.

Conclusions: Inflammatory pseudotumours in the maxillary sinus may present as malignant tumours and manifest locally aggressive features characteristic of such tumours. Despite their locally destructive features, they pursue a benign course after local excision.

Objective: Inflammatory pseudotumour (plasma cell granuloma) is an uncommon non-neoplastic lesion comprising a proliferation of spindle myofibroblasts and chronic inflammatory cells.

A rare case of systemic sclerosis complicated with multiple autoimmune diseases (Sjögren's syndrome, Graves' disease, and primary biliary cirrhosis).

Abstract We report the case of a 54-year-old woman with systemic sclerosis and Sjögren's syndrome, followed by a simultaneous onset of Graves' disease and primary biliary cirrhosis. Eight years after the patient was diagnosed with systemic sclerosis and secondary Sjögren's syndrome, she complained of thirst and lower extremity muscle weakness. Initially, these symptoms were thought to be due to her original diseases, but laboratory data revealed thyroid dysfunction as well as liver dysfunction, and further tests confirmed the diagnoses of Graves' disease and primary biliary cirrhosis.

Ulcerative colitis followed by the development of Behçet's disease.

A 34-year-old man who had a history of ulcerative colitis (UC) was admitted to our hospital with complaints of arthralgia, erythema nodosum, recurrent oral aphthous ulcers and bloody stools. A colonoscopy revealed multiple aphthous ulcers on his cecum and colon and also revealed a transmural ulcer on his rectum consistent with a diagnosis of UC. The patient was HLA-B51 positive.

Increased IL-15 production of muscle cells in polymyositis and dermatomyositis.

In polymyositis (PM)/dermatomyositis (DM), various cytokines, especially macrophage-derived cytokines such as IL-1alpha, IL-1beta and tumor necrosis factor (TNF)-alpha, are expressed in the inflammatory foci. We previously reported that IL-15, a novel cytokine with a biological activity similar to that of IL-2, is expressed in muscle cells in PM/DM. In the present study, we set out to investigate the regulation of IL-15 in cultured myoblasts.