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Background: Identification of the factors associated with a rapid decline in forced expiratory volume in 1 second (FEV1) at an early stage of chronic obstructive pulmonary disease (COPD) is of particular clinical importance because it may allow timely medical intervention to slow down progression of lung function decline in patients. This study aimed to compare the time profile of FEV1 after COPD diagnosis among rapid decliners, slow decliners, and sustainers and the patient characteristics in the year of COPD diagnosis.Methods: COPD patients were identified from data collected from the annual medical checkup records of Hitachi, Ltd. employees in Japan from April 1998 to March 2019. Patients were categorized by FEV1 for 5 years (years 1-5) in 3 groups (rapid decliner, slow decliner, and sustainer). Patients with a decrease of FEV1 ≥63 mL/year were considered rapid decliners; those with 1 across the onset of COPD (from year ‑3 to 5) were investigated in those groups.Results: Of 1294 eligible participants, 241 (18.6%) were classified as rapid decliners. The annual rates of FEV1 decline were similar 3 years before and until COPD diagnosis (year -3 to 0) and were 0.05 mL in rapid decliners, 0.05 mL in slow decliners, and 0.07 mL in sustainers. After COPD diagnosis, these 3 categories started diverging in their lung function trajectory. The mean FEV1 in rapid decliners was 2.82 L in year 0 and 2.41 L in year 5. Rapid decliners had decreased body mass index, waist circumference, and body fat percentage at the time of COPD diagnosis compared with sustainers.Conclusions: FEV1 declined yearly before diagnosis in rapid decliners, slow decliners, and sustainers. The time profiles of FEV1 were different in the 3 groups after COPD diagnosis. Therefore, regular lung function tests are necessary to follow FEV1 decline after COPD onset in a timely manner.

BACKGROUND: The association between olfactory dysfunction and disease duration and severity in Parkinson's disease (PD) remains controversial. OBJECTIVE: The objective of this study was to examine the relationship between olfactory dysfunction and disease severity and duration in patients with recently diagnosed parkinsonism and patients with PD with a previous diagnosis. METHODS: Olfactory function was evaluated in 79 patients with recently diagnosed parkinsonism, 71 patients with PD with a previous diagnosis—with patients in both groups free of cognitive impairment—and 128 age‐matched controls. The Odor‐Stick Identification Test for Japanese score was counted as the numbers of correct answers, responses of indistinguishable, and responses of odorless. Parkinsonism was evaluated using the Movement Disorder Society Criteria, the Unified Parkinson Disease Rating Scale (UPDRS) Part III, and (123)iodine‐labeled N‐(3‐fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl) nortropane single photon emission computed tomography (DaTscan). RESULTS: In the patients with recently diagnosed parkinsonism having the UPDRS Part III score ≥5 (mean [standard deviation: SD] score: 6.3 [1.9]) and with a positive DaTscan, the mean (SD) numbers of correct answers, responses of indistinguishable and responses of odorless were 4.3 (2.2), 1.6 (2.0), and 1.2 (2.2), respectively. In patients with PD with a previous diagnosis (mean [SD] UPDRS Part III score: 10.9 [3.2]), these numbers were 2.5 (2.2), 2.2 (2.5), and 3.8 (4.6), respectively. The patients with PD with a previous diagnosis showed more significant deterioration than the patients with recently diagnosed parkinsonism in the numbers of correct answers and responses of odorless (P

BACKGROUND Airflow limitation is a critical physiological feature in chronic obstructive pulmonary disease (COPD), for which long-term exposure to noxious substances, including tobacco smoke, is an established risk. However, not all long-term smokers develop COPD, meaning that other risk factors exist. OBJECTIVE This study aimed to predict the risk factors for COPD diagnosis using machine learning in an annual medical check-up database. METHODS In this retrospective observational cohort study (ARTDECO [Analysis of Risk Factors to Detect COPD]), annual medical check-up records for all Hitachi Ltd employees in Japan collected from April 1998 to March 2019 were analyzed. Employees who provided informed consent via an opt-out model were screened and those aged 30 to 75 years without a prior diagnosis of COPD/asthma or a history of cancer were included. The database included clinical measurements (eg, pulmonary function tests) and questionnaire responses. To predict the risk factors for COPD diagnosis within a 3-year period, the Gradient Boosting Decision Tree machine learning (XGBoost) method was applied as a primary approach, with logistic regression as a secondary method. A diagnosis of COPD was made when the ratio of the prebronchodilator forced expiratory volume in 1 second (FEV1) to prebronchodilator forced vital capacity (FVC) was RESULTS Of the 26,101 individuals screened, 1213 met the exclusion criteria, and thus, 24,815 individuals were included in the analysis. The top 10 predictors for COPD diagnosis were FEV1/FVC, smoking status, allergic symptoms, cough, pack years, hemoglobin A1c, serum albumin, mean corpuscular volume, percent predicted vital capacity, and percent predicted value of FEV1. The areas under the receiver operating characteristic curves of the XGBoost model and the logistic regression model were 0.956 and 0.943, respectively. CONCLUSIONS Using a machine learning model in this longitudinal database, we identified a number of parameters as risk factors other than smoking exposure or lung function to support general practitioners and occupational health physicians to predict the development of COPD. Further research to confirm our results is warranted, as our analysis involved a database used only in Japan.

Aims: To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naIve. After a 2 to 4-week washout and placebo run-in, 561 patients were randomized (2 : 2 : 2 : 1) to double-blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks. Results: Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were −0.87% (−1.04, −0.70; p < 0.0001) and −0.88% (−1.05, −0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were −0.32% (−0.49, −0.15; p = 0.0003) and −0.39% (−0.56, −0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug-related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia. Conclusions: Linagliptin showed superior glucose-lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM.

Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).

The purpose of the present study was to investigate the renoprotective effect of telmisartan, an angiotensin II receptor antagonist, on the early stages of diabetic nephropathy in obese Zucker rats, which is a type 2-related diabetes mellitus model. Telmisartan 1, 3 or 10 mg/kg/day was orally administered to 7-week-old rats that demonstrated glucose tolerance without albuminuria or proteinuria, for 24 consecutive weeks (Experiment A). In another experiment (Experiment B), oral administration of telmisartan 10 mg/kg/day was initiated at the age of 16 weeks after the rats demonstrated marked proteinuria, and continued for 24 weeks. Telmisartan inhibited the increase in proteinuria and albuminuria in a dose-dependent manner, and the inhibition for all telmisartan groups was statistically significant by the completion of administration (Experiment A). Telmisartan also displayed similar inhibitory effects on proteinuria and albuminuria in Experiment B. Histologically, telmisartan [3 and 10 mg/kg/day] was associated with a significant decrease in the progression of glomerulosclerosis, and significantly improved interstitial cell infiltration, interstitial fibrosis and dilation and atrophy of renal tubules. Furthermore, telmisartan treatment was associated with a tendency towards normalized plasma lipids (total cholesterol and triglyceride). Our results suggest that telmisartan has a definite renoprotective effect against renal injury in type II diabetic nephropathy.

Little information is available regarding the morphological changes in the mitochondria in amyotrophic lateral sclerosis (ALS). In particular, mitochondrial changes in dorsal root ganglion cells have not yet been examined. We therefore conducted an electron microscopic examination of the mitochondria in dorsal root ganglion cells in 11 sporadic ALS patients, and 12 age-matched, non-neurological control individuals in order to determine whether or not they are affected in ALS. In both the controls and ALS patients, unusual inclusion bodies were frequently observed in the mitochondria in the somata of the ganglion cells. The inclusions consisted of an aggregate of tubules measuring approximately 40 nm in diameter varying in size and number. Such inclusions were frequently present in the cristae and/or intermembrane space, often expanding to form large bundles in the dilated intermembrane space. These structures quite frequently protruded outward unilaterally or bilaterally and were partially surrounded by the outer membrane of the mitochondria. The number of inclusions was significantly higher in the ALS patients than in the controls (P

Many patients with hypertension take some antihypertensive drugs with complementary mechanisms of action to lower their blood pressure and achieve the therapeutic goals reducing the risk of cardiovascular events. Telmisartan, angiotensin II receptor blocker, and hydrochlorothiazide, diuretic are two antihypertensive drugs that have a well-recognized clinical efficacy. Their combination is expected to be one of the most appropriate therapies for hypertensive patients. However there is no information to show the effective dose combination of two drugs for the Japanese patients with mild to moderate hypertension. Therefore, the prospective, randomized, double-blinded study was planed for showing the dose response surface of two components. The 3 by 3 factorial design was applied for this purpose and the approach for calculating sample size was proposed. This study was registered with ClinicalTrial.gov (NCT00153049).

Aims/Introduction The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials. Materials and Methods Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90). Results Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group. Conclusions Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups.

Aims In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52 weeks. Methods Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10 mg, while the linagliptin groups maintained dosage. Results In all, 540 patients received at least one dose of linagliptin 5 or 10 mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10 mg. Conclusions These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10 mg for up to 52 weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain.

Background: The Japanese Aggrenox Stroke Prevention vs. Aspirin Programme (JASAP) study was a double-blind, randomized clinical trial to compare the efficacy and safety of extended-release dipyridamole plus aspirin versus aspirin alone over 1 year in 1294 patients with non-cardioembolic ischemic stroke. We analyzed the effect of mean and maximum as well as variation of blood pressure on recurrence of ischemic stroke and intracranial hemorrhage (ICH) in patients enrolled in the JASAP study. Methods: We analyzed individual blood pressure at all visits including baseline, weeks 0, 1 and then every 4 weeks to a maximum of 124 weeks to compare mean and maximum systolic and diastolic blood pressure (BP) as well as standard deviation (SD) of variations of individual BP measurements. Results: Mean Systolic BP (SBP) for the last 3 months was significantly higher (140.6 mmHg vs. 135.4 mmHg, p = 0.002) in patients with than without ischemic stroke, while SD of variation of individual SBP measurements was significantly larger in patients with than without ICH (12.0 mmHg vs. 9.2 mmHg, p = 0.025). Mean diastolic BP (DBP) at the last visit was significantly higher in patients with than without ICH (84.0 mmHg vs. 78.1 mmHg, p = 0.012). Although ICH was tended to be more frequent in the highest tertile than in the lowest tertile of SD of variation of SBP (HR 1.513, 95% CI 0.298-2.286, p = 0.090) and of maximum SBP (HR 1.637, 95% CI 0.982-2.728, p = 0.059), such trend was not seen in ischemic stroke of SD of variation of SBP (HR 1.034, 95% CI 0.792-1.351, p = 0.804) and of maximum SBP (HR 0.925, 95% CI 0.699-1.225, p = 0.588) Conclusion: Despite of small sample size and different treatment arms, these results indicate that mean, maximum, and variation of SBP and DBP may affect differently on the occurrence of ischemic and hemorrhagic strokes in patients on antiplatelet agents.

Background Many patients with diabetes mellitus (DM) require a combination of antidiabetic drugs with complementary mechanisms of action to lower their hemoglobin A1c levels to achieve therapeutic targets and reduce the risk of cardiovascular complications. Linagliptin is a novel member of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of antidiabetic drugs. DPP-4 inhibitors increase incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) levels, inhibit glucagon release and, more importantly, increase insulin secretion and inhibit gastric emptying. Currently, phase III clinical studies with linagliptin are underway to evaluate its clinical efficacy and safety. Linagliptin is expected to be one of the most appropriate therapies for Japanese patients with DM, as deficient insulin secretion is a greater concern than insulin resistance in this population. The number of patients with DM in Japan is increasing and this trend is predicted to continue. Several antidiabetic drugs are currently marketed in Japan; however there is no information describing the effective dose of linagliptin for Japanese patients with DM. Methods This prospective, randomized, double-blind study will compare linagliptin with placebo over a 12-week period. The study has also been designed to evaluate the safety and efficacy of linagliptin by comparing it with another antidiabetic, voglibose, over a 26-week treatment period. Four treatment groups have been established for these comparisons. A phase IIb/III combined study design has been utilized for this purpose and the approach for calculating sample size is described. Discussion This is the first phase IIb/III study to examine the long-term safety and efficacy of linagliptin in diabetes patients in the Japanese population. Trial registration Clinicaltrials.gov (NCT00654381).

The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx).Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium.An immunohistochemical staining for transforming growth factor—beta (TGF-β1) was also performed. The suppression of urinary protein was statistically significant in surviving animals dosed with telmisartan.The enalapril group's urinary protein was also significantly suppressed for these same parameters in surviving animals. Histopathologically, telmisartan significantly decreased the progression of glomerulosclerosis and the interstitial cell infiltration at all doses tested. As assessed by immunohistochemical staining the TGF-β1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. Thus, the progressive Thus, telmisartan ameliorates the progressive nephropathy in the remaining kidney after 5/6 Nx by non-haemodynamic as well as antihypertensive actions of the drug. pharmacological properties of telmisartan, clinical studies have been conducted to evaluate the clinical effectiveness and safety of telmisartan on diabetic nephropathy in patients with type 2 diabetes. It has been reported that telmisartan arrested progressive renal dysfunction in hypertensive patients with early-stage diabetic nephropathy. Makino et al.8reported the effectiveness of this drug therapy in suppressing the progression of nephropathy in type 2 diabetic patients with or without hypertension, without serious safety concerns. Remuzzi and Remuzzi9reviewed the potential protective effects of telmisartan on renal function deterioration and suggested that telmisartan may effectively ameliorate renal dysfunction in patients affected by the metabolic syndrome. In addition, telmisartan also showed renoprotective effects in some animal models: spontaneously hypertensive rats (SHR),10as well as the hypertensive diabetic model that combines SHR with streptozotocininduced diabetes.11Ohmura et al.12investigated the mechanism of the renoprotective effect of telmisartan using obese Zucker diabetic rats. Ciclosporin A-induced nephropathy in pigs was attenuated by telmisartan without any reduction of blood pressure (BP).13This animal data suggested that the suppressive effect on the progression of nephropathy might be due to both haemodynamic and non-haemodynamic action(s) of the drug.

Diethyl 1-fluoro-1-phenylsulfonylmethanephosphonate was prepared and was transformed into 1-fluoroalkanephosphonate and phenyl 1-fluorovinyl sulfones, which are useful monofluorinated building blocks.

Diethyl 1-fluoro-1-phenylsulfonylmethanephosphonate was prepared and was transformed into 1-fluoroalkanephosphonate and phenyl 1-fluorovinyl sulfones, which are useful monofluorinated building blocks.