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Nishida W.,Ehime University | Nagata M.,Kokogawa W City Hospital | Imagawa A.,Osaka University | Hanafusa T.,Osaka Medical College | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Insulin administration causes various types of immune responses to insulin.Wepreviously reported three cases of type 1 diabetes mellitus (T1DM) triggered by insulin administration in Japanese type 2 diabetes mellitus patients. CopyrightObjective: The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically.Methods: Data for six patients (four men and two women) with insulin-triggered T1DM aged 59.5 ± 12.8 years were collected. Serum or urinary C-peptides, islet-related autoantibodies, insulin antibody, humanleukocyte antigen, ortheinsulingenevariablenumberoftandemrepeatgenotypewereanalyzed. Th1- or Th2-associated responses were evaluated using an Enzyme-Linked ImmunoSpot assay.Results: None of the subjects had received insulin therapy or had an autoantibody to the 65-kDa isoform of glutamic acid decarboxylase before insulin administration. After insulin administration blood glucose control deteriorated acutely without any apparent cause, whereas C-peptide levels rapidly decreased to insulin-deficient levels. The mean duration of insulin administration to the development of T1DMwas7.7±6.1months.Islet-related autoantibodiesbecamepositive,whereasinsulin allergy orahigh titerofinsulinantibodywasobservedinseveralcases.AllhadT1DMhigh-riskhumanleukocyteantigenclass II (IDDM1) and the insulin gene variable number of tandem repeats genotype (IDDM2). GAD-reactive and insulin peptide-reactive Th1 cells, but not Th2 cells, were identified in two of four cases.Conclusions: The findings suggest that insulin administration may have triggered TIDM in patients with type 2 diabetes mellitus. IDDM1 and IDDM 2 as well as autoreactive T cells may contribute to the development of T1DM. Developing insulin-triggered T1DM if a patient's blood glucose control acutely deteriorates after insulin administration should be carefully considered. © 2014 by the Endocrine Society. Source


Yuzawa Y.,Nagoya University | Yuzawa Y.,Fujita Health University Hospital | Hotta O.,Sendai Shakai Hoken Hospital | Suzuki H.,Saitama University | And 36 more authors.
Japanese Pharmacology and Therapeutics | Year: 2011

Background: C. E. R. A. (Continuous Erythropoietin Receptor Activator) is an innovative erythropoiesis stimulating agent (ESA) with unique activity against erythropoietin receptor, and shows a significantly prolonged half-life after the administration. In the present study we evaluated the efficacy and safety profiles of subcutaneous (SC) or intravenous (IV) C. E. R. A. dosing once every 4 weeks (Q4W) in Japanese patients chronic kidney disease (CKD) not on dialysis previously treated with recombinant human erythropoietin (rHuEPO). Methods: CKD patients (n = 101) not on dialysis were assigned to 100 μg (n = 78) or 150 μg (n = 23) of C. E. R. A. by depending on previous rHuEPO doses of under 4500 IU/wk or over 4500 IU/wk, respectively. C. E. R. A. was administered Q4W via either SC (n = 70) or IV (n = 31) routes based on doctor's decision. After 8 weeks in switching period, the doses of C. E. R. A. Q4W were adjusted from 25 to 400 μg to maintain Hb levels of 11-13 g/dL (10-12 g/dL, in the patients with any histories or complications of cardiovascular diseases) as a maintenance period for the following 40 weeks. Primary endpoint was the percentage of patients whose mean Hb levels were within the 11-13 g/dL during 18-24 weeks. Results: The percentages of patients whose mean Hb levels maintain within each target Hb of 11-13 g/dL and 10-12 g/dL during 18-24 weeks were 79.2% and 100%, respectively. No significant differences in the maintenance rate were found between SC and IV route for 48 weeks. The mean (SD) slope of regression line of Hb levels were 0.116 (0.148) g/dL/week after switching from rHuEPO to C. E. R. A. administration. This parameter was also similar between both routes. Adverse event profiles were similar to those reported in rHuEPO and no antibodies against C. E. R. A. were detected in any patients examined. Conclusions: C. E. R. A. could safely switch from rHuEPO by dosing Q4W, successfully maintain target Hb levels of 11-13 g/dL by dose adjustment and is generally well tolerated in Japanese patients with CKD not on dialysis. Source


Tsuruta Y.,Meiyo Clinic | Itami N.,Nikko Memorial Hospital | Hashimoto N.,H N Medic | Masakane I.,Yabuki Hospital | And 20 more authors.
Japanese Pharmacology and Therapeutics | Year: 2011

Background: C. E. R. A., continuous erythropoietin receptor activator, is an innovative erythropoiesis stimulating agent (ESA) with unique activity to erythropoietin receptor, and shows a significantly prolonged half-life. This study was undertaken to confirm validity of switching dose from recombinant human erythropoietin (rHuEPO) and evaluate maintenance ratio by intravenous C. E. R. A. dose once every 4 weeks (Q4W) and the safety for 48 weeks in hemodialysis patients. Methods: Patients (n = 156) on hemodialysis were assigned either 100 μg (n = 99) or 150 μg (n = 57) C. E. R. A. group by the previous weekly rHuEPO dose of < 4500 IU/week or ≧ 4500 IU/week, respectively. C. E. R. A. was administered Q4W with doses adjusted ranging from 25 to 400 μg to maintain target Hb levels of 10-12 g/dL. Primary endpoint was the percentage of patients whose mean hemoglobin (Hb) maintained within the target Hb levels during 17-24 weeks. Results: The percentage of patients whose mean Hb levels maintain within 10-12 g/dL during 17-24 weeks and 42-48 weeks were 69.2% and 66.0%, respectively. In the group assigned 100 μg and 150 μg of C. E. R. A., the percentage of patients who keep the change within 1.0 g/dL from baseline Hb level at both 4 weeks and 8 weeks were 61.6% and 59.6% and mean (SD) slope of regression line were 0.058 (0.109) and 0.078 (0.185), respectively, after switching from rHuEPO to C. E. R. A. These parameters were similar between two groups. Adverse event profiles were similar to those of rHuEPO, and no antibodies against C. E. R. A. were detected in any patients examined. Conclusions: C. E. R. A. administration Q4W could safely switch from rHuEPO and successfully maintain target Hb levels of 10-12 g/dL and is generally well tolerated for 48 weeks in hemodialysis patients. Source


Watanabe Y.,Kasugai Municipal Hospital | Itami N.,Nikko Memorial Hospital | Hashimoto N.,H N Medic | Kurosawa A.,Sumiyoshi Clinic Hospital | And 31 more authors.
Japanese Pharmacology and Therapeutics | Year: 2011

Background: This study was designed to examine the clinical effects of C. E. R. A., a continuous erythropoietin receptor activator, administered intravenously (i. v.) at a dose level of 50 μg once every 2 weeks to EPO naïve renal anemia patients on hemodialysis. Methods: EPO naïve renal anemia patients were treated with C. E. R. A. i. v. at 50 μg once every 2 weeks during the correction period of anemia in order to attain the Hb levels of above 11 g/dL. The observation period established was 24 weeks, and the primary endpoint investigated was the percentage of patients who achieved the Hb levels of above 10 g/dL and the delta (Δ) Hb levels of 1 g/dL from baseline. Results: The Hb levels of renal anemia patients treated with C. E. R. A. were successfully corrected above 11 g/dL. The percentage of patients who attained Hb levels of above 10 g/ dL and the Δ Hb levels of above 1 g/dL from baseline was found to be 91.7%. It was shown from the present study, moreover, that the safety profiles of C. E. R. A. were similar to those of existing ESAs, erythropoiesis stimulating agents, and that the antibodies against C. E. R. A. were not detected in all the patients examined. Conclusions: This study has firstly disclosed that the administrations of C. E. R. A. i. v. at a dose level of 50 μg once every 2 weeks provided smooth as well as gradual increases of the Hb levels in patients with renal anemia on hemodialysis. Source


Kikuchi K.,Tokyo Womens Medical University | Akiba T.,Tokyo Womens Medical University | Nitta K.,Tokyo Womens Medical University | Masakane I.,Yabuki Shima Clinic | And 24 more authors.
Therapeutic Apheresis and Dialysis | Year: 2014

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90μg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135μg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG-IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness. © 2014 International Society for Apheresis. Source

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