Yoshimura Y.,Kawasaki Medical School
Journal of Clinical Psychopharmacology | Year: 2017
OBJECTIVES: This study aims to determine the optimal tolerability dose ranges of risperidone (RIS) and olanzapine (OLZ) administered during schizophrenia maintenance phase. METHODS: Two-year continuation rates of prescription at discharge were examined using a retrospective cohort study method. Adult patients with schizophrenia and related psychotic disorders, receiving antipsychotic monotherapy with RIS or OLZ at discharge, were included. The primary outcome measures were the time to treatment discontinuation and 2-year continuation rates at 4 modal dose ranges of each drug. We estimated the optimal tolerability dose ranges by comparing the continuation rates at various modal doses. RESULTS: Of 648 patients, 344 received RIS and 304 received OLZ. The RIS 2-year continuation rates at 4 daily modal dose ranges were significantly different (0.5–2.5 mg: 46.0%, 3.0–5.0 mg: 40.0%, 5.5–7.5 mg: 30.0%, and 8.0–10.0 mg: 28.0%), with the difference favoring RIS at lower doses (0.5–5.0 mg) more than higher doses (5.5–10.0 mg). In contrast, there were no significant differences among OLZ 4 modal dose ranges (2.5–7.5 mg: 49.1%, 10.0–15.0 mg: 42.6%, 17.5–22.5 mg: 40.9%, and 25.0–30.0 mg: 39.0%). The time to treatment discontinuation significantly favored OLZ over RIS. However, it did not significantly differ between RIS and OLZ at lower doses. CONCLUSIONS: It is suggested that the optimal tolerability dose range during maintenance treatment is 0.5 to 5.0 mg/d for RIS and 2.5 to 30 mg/d for OLZ, and that RIS at lower doses is comparable with OLZ at lower doses. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Kaku K.,Kawasaki Medical School |
Araki T.,Takeda Pharmaceutical |
Yoshinaka R.,Takeda Pharmaceutical
Diabetes Care | Year: 2013
OBJECTIVE-Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. RESEARCH DESIGN AND METHODS-This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25-200mg oncedaily)withthe primary end point of changein A1C at week12. A nonblinded group received 1 mg glimepiride once daily as an active control. RESULTS-A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; -0.54, -0.67, -0.88, -1.27, -1.29, and -1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and -1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group. CONCLUSIONS-TAK-875 producedclinically and statistically significantimprovementsin glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.© 2013 by the American Diabetes Association.
Kosodo Y.,Kawasaki Medical School
Cellular and Molecular Life Sciences | Year: 2012
Interkinetic nuclear migration (INM) is an oscillatory nuclear movement that is synchronized with the progression of the cell cycle. The efforts of several researchers, following the first report of INM in 1935, have revealed many of the molecular mechanisms of this fascinating phenomenon linking the timing of the cell cycle and nuclear positioning in tissue. Researchers are now faced with a more fundamental question: is INM important for tissue, particularly brain, development? In this review, I summarize the current understanding of the regulatory mechanisms governing INM, investigations involving several different tissues and species, and possible explanations for how nuclear movement affects cell-fate determination and tissue formation. © 2012 Springer Basel AG.
Otsuki T.,Kawasaki Medical School
International journal of immunopathology and pharmacology | Year: 2011
Silicosis patients suffer from pulmonary fibrosis caused by silica inhalation, as well as autoimmune diseases known as the adjuvant effects of silica. Caplan syndrome complicated with rheumatoid arthritis (RA) is well known epidemiologically, and the incidence of complicated systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and antineutrophilic cytoplasmic antibody (ANCA)-related nephritis have been reported frequently in silicosis patients. To explore the detailed mechanisms of silica-induced dysregulation of autoimmunity, we had focused on Fas/CD95 and Fas-mediated apoptosis because Fas is one of the most important molecules regarding apoptosis of lymphocytes and its alteration makes some T cells survive longer. Additionally, if the long-survived T cells include the self-recognizing T-cell clones, it is easily thought that autoimmune diseases will appear in this situation. Furthermore, regulatory T cells (Treg) showing CD4+25+ and forkhead box P3 (FoxP3)-positive have been a central player in regulating activation of self- and foreign-antigen recognizing T cells, and it has been reported that activation of Treg causes its higher expression of Fas/CD95. Thus, in this review, we introduce the alteration of Fas and related molecules as found in silicosis and also present the Treg function of the CD4+25+ fraction in peripheral blood mononuclear cells derived from silicosis patients.
Kaku K.,Kawasaki Medical School
Expert Opinion on Pharmacotherapy | Year: 2014
Introduction: Type 2 diabetes mellitus (T2DM) is currently at epidemic proportions and the forecast is for a continued sharp increase in global prevalence. An even larger proportion of the population has prediabetes (impaired glucose tolerance [IGT]) underscoring the urgent need for preventive strategies. Even in the presence of adequate glycosylated hemoglobin (HbA1c) levels, postprandial hyperglycemia can occur and is known to have a stronger association with cardiovascular morbidity than fasting glucose. The α-glucosidase inhibitor voglibose is widely used in Japan to improve postprandial hyperglycemia. Areas covered: This review examines the literature for the pharmacology, pharmacokinetics, clinical efficacy and safety of voglibose in patients with T2DM. Particular focus is on its efficacy in preventing T2DM in individuals with IGT and its efficacy as add-on therapy or in combination with other oral antidiabetic agents in patients with T2DM. Expert opinion: As the relationship between glucose levels and cardiovascular risk extends below the diabetic threshold, postprandial hyperglycemia is recognized as a key therapeutic target in the treatment of T2DM. Strategies to prevent the progression of IGT to overt T2DM have enormous potential to reduce the individual and societal burden of disease. Voglibose is the first oral antidiabetic agent to gain approval in Japan for this indication. © 2014 Informa UK, Ltd.
Satoh M.,Kawasaki Medical School
Clinical and Experimental Nephrology | Year: 2012
Renal dysfunction and cardiovascular disorders affect each other adversely and worsen existing pathophysiological conditions. These disorders are extremely diverse in terms of pathology. Vascular disorders, in particular vascular endothelial dysfunction, are common risk factors for each other. Early endothelial dysfunction reduces vascular relaxation and causes inflammatory cell infiltration and slight inflammation in blood vessels. Endothelial dysfunction in the kidneys manifests as albuminuria. Proactive treatment is required in the early phase of endothelial dysfunction to prevent cardiovascular disease in chronic kidney disease patients. © 2012 Japanese Society of Nephrology.
Kaku K.,Kawasaki Medical School
Expert Opinion on Pharmacotherapy | Year: 2013
Introduction: Fasiglifam, a novel G protein-coupled receptor 40 (GPR40) agonist, has demonstrated glucose-lowering effects in type 2 diabetes mellitus (T2DM) through stimulation of glucose-dependent insulin secretion. Areas covered: This review is based on a PubMed search for all articles on fasiglifam and TAK-875. The pharmacology of fasiglifam is reviewed, focusing on studies in human volunteers and patients with T2DM. All published clinical trials with fasiglifam in T2DM are summarized, including two 12-week dose-ranging studies (one from Japan and the other from Central and North America), both of which employed glimepiride as an active comparator. Expert opinion: Fasiglifam, a novel glucose-dependent insulin secretagogue, is the first GPR40 agonist to enter Phase III clinical evaluation. It has been shown to produce statistically significant and clinically relevant improvements in glycemic control in patients with early-stage T2DM. Furthermore, its tolerability and safety profile was comparable to placebo and no dose-related adverse effects were observed. Importantly, fasiglifam was comparable to placebo with regards to the incidence of hypoglycemia and it produced significantly fewer episodes compared with glimepiride. Fasiglifam is an interesting and novel oral anti-diabetic agent which may offer new avenues for treating T2DM, but clearly more thorough clinical evaluation is still needed. © 2013 Informa UK, Ltd.
Kaku K.,Kawasaki Medical School
Expert Opinion on Pharmacotherapy | Year: 2015
Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence.Areas covered: A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin.Expert opinion: Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients satisfaction, and medication adherence. © 2015 Taylor & Francis.
Nakamura M.,Kawasaki Medical School
Journal of hepato-biliary-pancreatic sciences | Year: 2013
This study was performed to evaluate the outcomes of laparoscopic distal pancreatectomy (LDP) and laparoscopic pancreatoduodenectomy (LPD) compared with the open method using meta-analysis. A literature search was performed to identify comparative studies of laparoscopic versus open pancreatectomy. Perioperative outcomes were evaluated by meta-analysis using a fixed effect model and random effects model. Twenty-four studies of LDP and three studies of LPD matched the selection criteria, including 2,904 patients of DP and 109 patients of PD. Compared with ODP, LDP showed statistically significant differences with respect to less blood loss, lower transfusion rates, lower wound infection rates, lower morbidity rates, and shorter hospital stays. LPD showed significantly longer operative times compared with OPD. There was no significant difference in oncological outcomes between laparoscopic pancreatectomy and the open technique. This meta-analysis included the largest number of patients and number of articles comparing LDP and ODP, and LDP showed significantly better perioperative outcomes. This meta-analysis suggests that LDP is a reasonable operative method for benign tumors and some ductal carcinomas in the pancreas.
Shiotani A.,Kawasaki Medical School |
Cen P.,University of Texas Health Science Center at Houston |
Graham D.Y.,Baylor College of Medicine
Seminars in Cancer Biology | Year: 2013
In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding atrophic gastritis and its effects on acid secretion, gastric microflora, and its tight association with gastric cancer has been rediscovered, confirmed, and expanded. Methods to stratify cancer risk based on endoscopic and histologic findings or serologic testing of pepsinogen levels and H. pylori testing have been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis will essentially prevent subsequent development of gastric cancer. For all, the age-related progression in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inflammation and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and secondary cancer prevention starts with H. pylori eradication and cancer risk stratification to identify those at higher risk who should also be considered for secondary cancer prevention programs. Japan has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with significant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their lead. We provide specific recommendations on instituting practical primary and secondary gastric cancer prevention programs as well identifying research needed to make elimination of gastric cancer both efficient and cost effective. © 2013.