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Ogata A.,Osaka University | Tanimura K.,Hokkaido Medical Center for Rheumatic Diseases | Sugimoto T.,National Hospital Organization | Inoue H.,Inoue Hospital | And 9 more authors.
Arthritis Care and Research | Year: 2014

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. The primary end point was to evaluate the noninferiority of TCZ-SC to TCZ-IV regarding the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20) response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic, and immunogenicity parameters were assessed. Results At week 24, ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZ-SC group and in 88.5% (95% CI 83.4, 93.5) of the TCZ-IV group; the weighted difference was -9.4% (95% CI -17.6, -1.2), confirming the noninferiority of TCZ-SC to TCZ-IV. Remission rates of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and the Clinical Disease Activity Index at week 24 were 49.7% and 16.4% in the TCZ-SC group and 62.2% and 23.1% in the TCZ-IV group, respectively. Serum trough TCZ concentrations were similar between the groups over time. Incidences of all adverse events and serious adverse events were 89.0% and 7.5% in the TCZ-SC group and 90.8% and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% of the TCZ-SC group; no serious hypersensitivity was reported in these patients. Conclusion TCZ-SC monotherapy demonstrated comparable efficacy and safety to TCZ-IV monotherapy. TCZ-SC could provide additional treatment options for patients with RA. © 2014 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Ueki Y.,Sasebo Chuo Hospital
Japanese Pharmacology and Therapeutics | Year: 2013

Objective The objective of this study is to assess the usefulness, safety, and user-friendliness of tocilizumab (TCZ) formulation with an autoinjector (AI) (TCZ AI) and to compare with those of TCZ pre-filled syringe formulation (TCZ PFS) in Japanese patients with rheumatoid arthritis (RA). Methods Fifty one patients with RA were subcutaneously administered TCZ at a dose of 162 mg every 2 weeks and examined the efficacy and safety of TCZ. Fifty patients who had been administered TCZ PFS by self-injection switched to self-injecting TCZ AI at Week 12 and 1 patient used TCZ AI without self-injection of PFS. The satisfaction and user-friendliness of the two injection types were surveyed in those patients and related healthcare professionals by using respective questionnaires. Results There were not observed any differences in the efficacy (ACR20, ACR50 and ACR70, DAS28-ESR) and safety (Adverse Event and Injection Site Reaction) between TCZ PFS and TCZ AI formulations. Patients with RA preferred TCZ AI formulation to TCZ PFS formulation in any questions for the satisfaction and user-friendliness in the questionnaires. The healthcare professionals answered that the user-friendliness and satisfaction of TCZ AI were better than or almost equal to those of TCZ PFS. Conclusion Present study demonstrates that TCZ AI formulation rather than TCZ PFS would be preferred by both patients with RA and health-care professionals with high satisfaction in usability, and suggests that TCZ AI formulation would be a useful option in the treatment of RA.

Khan K.N.,Nagasaki University | Kitajima M.,Nagasaki University | Yamaguchi N.,Nagasaki University | Fujishita A.,Saiseikai Nagasaki Hospital | And 3 more authors.
Human Reproduction | Year: 2012

STUDY QUESTIONCan prostaglandin E2 (PGE2) in menstrual and peritoneal fluid (PF) promote bacterial growth in women with endometriosis?SUMMARY ANSWERPGE2 promotes bacterial growth in women with endometriosis. WHAT IS KNOWN ALREADYMenstrual blood of women with endometriosis is highly contaminated with Escherichia coli (E. coli) compared with that of non-endometriotic women: E. coli-derived lipopolysaccharide (LPS) promotes the growth of endometriosis. STUDY DESIGN, SIZE AND DURATIONCase-controlled biological research with a prospective collection of body fluids and endometrial tissues from women with and without endometriosis with retrospective evaluation. PARTICIPANTS/MATERIALS, SETTING AND METHODSPF and sera were collected from 58 women with endometriosis and 28 women without endometriosis in an academic research laboratory. Menstrual blood was collected from a proportion of these women. Macrophages (Mφ) from PF and stromal cells from eutopic endometria were isolated in primary culture. The exogenous effect of PGE2 on the replication of E. coli was examined in a bacterial culture system. Levels of PGE2 in different body fluids and in the culture media of Mφ and stromal cells were measured by ELISA. The effect of PGE2 on the growth of peripheral blood lymphocytes (PBLs) was examined. MAIN RESULTS AND THE ROLE OF CHANCEThe PGE2 level was 2-3 times higher in the menstrual fluid (MF) than in either sera or in PF. A significantly higher level of PGE2 was found in the MF and PF of women with endometriosis than in control women (P < 0. 05 for each). Exogenous treatment with PGE2 dose dependently increased E. coli colony formation when compared with non-treated bacteria. PGE 2-enriched MF was able to stimulate the growth of E. coli in a dilution-dependent manner; this effect was more significantly enhanced in women with endometriosis than in control women (P < 0. 05). PGE2 levels in the culture media of LPS-treated Mφ/stromal cells were significantly higher in women with endometriosis than in non-endometriosis (P < 0. 05 for each). Direct application of PGE2 and culture media derived from endometrial Mφ or stromal cells significantly suppressed phytohemagglutinin-stimulated growth of PBLs. LIMITATIONS AND REASONS FOR CAUTIONFurther studies are needed to examine the association between PGE 2-stimulated growth of E. coli and endotoxin level and to investigate the possible occurrence of sub-clinical infection within vaginal cavity. WIDER IMPLICATIONS OF THE FINDINGSOur findings may provide some new insights to understand the physiopathology or pathogenesis of the mysterious disease endometriosis and may hold new therapeutic potential. STUDY FUNDING/COMPETING INTEREST(S)This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. TRIAL REGISTRATION NUMBERNot applicable. © 2012 The Author.

Shigemasa Y.,Sasebo Chuo Hospital
Gan to kagaku ryoho. Cancer & chemotherapy | Year: 2013

Purpose: The aim of this study was to elucidate the risk factors for recurrence of Stage IIIa colon and rectosigmoid cancer. Patients and methods: The subjects were 93 patients with Stage IIIa colon and rectosigmoid cancer who underwent radical colectomy in this department between 2001 and 2011. Various risk factors for recurrence were examined. Results: The overall recurrence rate was 18% (17/93 cases). Univariate analysis identified a risk factor for recurrence: depth of tumor invasion( ≥serosa exposed[ SE])(hazard ratio[ HR] 10.04, 95% confidence interva[l CI] 3.26-30.89, p<0.0001). The rate of 1, 2, and 3-year relapse-free survival of patients with respect to the depth of tumor invasion( ≥SE) were 76%, 61%, and 56%, respectively. Conclusion: Tumor depth SE or serosa infiltrating( SI) was a risk factor for the recurrence of Stage IIIa colon and rectosigmoid cancer.

Ohyama K.,Nagasaki University | Ueki Y.,Sasebo Chuo Hospital | Kawakami A.,Nagasaki University | Kishikawa N.,Nagasaki University | And 5 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: Analysis of circulating immune complexes (CICs) produced during an immune response may be useful in elucidating some aspects of this process. Identification of antigens incorporated into CICs provides information that may be helpful in developing diagnostic and treatment strategies for autoimmune diseases, infection, cancer, and transplantation therapy, and such information might be more relevant than information on free antigens. Because CICs may contain many antigens, comprehensive identification and profiling of such antigens is more effective than immunoblotting detection. METHODS: We developed a novel proteomic strategy (immune complexome analysis) in which immune complexes (ICs) are separated from serum, digested directly with trypsin, and then subjected to nano-liquid chromatography-tandem mass spectrometry for identifying and profiling antigens in CICs. We applied this strategy to the analysis of CICs in 21 rheumatoid arthritis (RA) patients. Serum samples from 13 healthy donors and 8 osteoarthritis patients were used as controls. RESULTS: CICs containing thrombospondin-1 (TSP-1) and platelet factor 4 (PF4) were found in the serum of 81% and 52% of RA patients, respectively, and in none of the controls. CONCLUSIONS: The ICs in the serum of a majority of the RApatients contained TSP-1 or PF4, and these ICs may have potential as alternative biomarkers. Our technique for immune complexome analysis uses routine clinical samples, simple protocols, and widely available equipment. This method may be generally applicable to the study of the relationship between CICs and certain diseases associated with the immune response in animals and humans.

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