Effect of COVID-19 Infection on Presenteeism: A Cohort Study Using Large Health Insurance-Based Data in Japan.

OBJECTIVE: Presenteeism occurs when employees attend work despite experiencing problems and ill-health that require sick leave. This study examined whether presenteeism worsened following COVID-19 infection. METHODS: We used the DeSC, a large health insurance claims database. Participants were 9241 individuals who responded to questionnaires at baseline (June 2020) and 6 months later, had been continuously insured for at least 6 months prior to baseline, and reported being employed. Propensity score matching was performed. Adjusted multiple logistic regression was used to estimate odds ratios and 95% confidence intervals of worsening presenteeism from baseline according to COVID-19 infection compared with noninfection. RESULTS: Conditional logistic regression analysis showed that the adjusted OR for presenteeism in the COVID-19-infected group was 1.555 (95% confidence interval, 1.086-2.225). CONCLUSIONS: The findings suggest that COVID-19 infection affected worsening of presenteeism.

Impact of COVID-19 Infection on Health-Related Quality of Life in the Japanese Population: A Large Health-Insurance-Based Database Study.

Evidence for acute or long-term coronavirus disease 2019 (COVID-19) infection is relatively limited. We aimed to evaluate the impact of COVID-19 infection on health-related quality of life (HRQoL) in the Japanese population. Eligible study participants were 13,365 employees and their dependents who answered questionnaires at baseline and 18 months later and who had at least 6 months of continuous enrolment before and after baseline. Of the 711 study participants who developed COVID-19 infection, 29.0% reported a decline in HRQoL, whereas 25.2% of uninfected participants reported a decline. The adjusted odds ratios (95% confidence intervals) for the association between COVID-19 infection and declines in HRQoL in the age categories of less than 30 years, 30s, 40s, 50s, and 60 years or higher were 0.54 (0.15-1.92), 1.70 (1.03-2.81), 1.14 (0.82-1.57), 1.05 (0.77-1.42), and 0.87 (0.46-1.64), respectively. This study demonstrates a differential association between COVID-19 infection and declines in HRQoL by age group. A 1.7-fold increase in the odds of negative changes in HRQoL was observed in only those in their 30s. Further studies are needed to elucidate differences in the impact of COVID-19 infection on HRQoL between younger people such as those in their 30s and the older population.

Investigation of time profile of FEV1 across the onset of potential COPD: a retrospective cohort study using medical checkup data in Japan.

This study compared the time profile of FEV1 after COPD diagnosis among rapid decliners, slow decliners, and sustainers in the year of COPD diagnosis. COPD subjects were identified from the annual medical checkup records of Hitachi, Ltd., employees in Japan (April 1998-March 2019). Subjects were categorized into 3 groups (rapid decliner [decrease of FEV1 ≥ 63 mL/year], slow decliner [< 63 and ≥ 31 mL/year], and sustainer [< 31 mL/year]) for 5 years. The time profile of FEV1 was compared using mixed-effects model for 5 years after diagnosis; risk factors of rapid decliner were detected using logistic model/gradient boosting decision tree. Of 1294 eligible subjects, 18.6%, 25.7%, and 55.7% were classified as rapid decliners, slow decliners, and sustainers, respectively. The annual rates of FEV1 decline were similar 3 years before and until COPD diagnosis. The mean FEV1 in rapid decliners was 2.82 ± 0.04 L in year 0 and 2.41 ± 0.05 L in year 5, and in sustainers, it was 2.67 ± 0.02 L and 2.72 ± 0.02 L (year 0, p = 0.0004). In conclusion, FEV1 declined yearly before diagnosis and the time profiles of FEV1 were different in the 3 groups after COPD diagnosis. Therefore, appropriate treatment of the 3 groups with regular lung function tests is necessary to follow FEV1 decline after COPD onset.

The Japanese aggrenox (extended-release dipyridamole plus aspirin) stroke prevention versus aspirin programme (JASAP) study: a randomized, double-blind, controlled trial.

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).

Machine Learning Methods for the Diagnosis of Chronic Obstructive Pulmonary Disease in Healthy Subjects: Retrospective Observational Cohort Study.

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 <0.7 during two consecutive examinations. 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.

Association Between Olfactory Impairment and Disease Severity and Duration in Parkinson's Disease.

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 123iodine-labeled N-(3-fluoropropyl)-2ß-carbomethoxy-3ß-(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 < 0.0001). Olfaction in the combined patient group was significantly impaired compared with age-matched controls in each category (P < 0.0001). CONCLUSIONS: These findings imply a close association between olfactory dysfunction and disease severity and duration in PD.

Design, statistical analysis and sample size calculation of dose response study of telmisartan and hydrochlorothiazide.

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).

Renoprotective effects of telmisartan in the 5/6 nephrectomised rats.

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-beta1) 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-beta1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. 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.

Comparable pharmacodynamics, efficacy, and safety of linagliptin 5 mg among Japanese, Asian and white patients with type 2 diabetes.

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.

The Effects of an Uninterrupted Switch from Donepezil to Galantamine without Dose Titration on Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease.

AIMS: To elucidate the efficacy of galantamine on cognition and behavioral and psychological symptoms of dementia (BPSD) in outpatients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) who have switched from donepezil to galantamine. MATERIALS AND METHODS: We performed an uninterrupted switch from donepezil to galantamine without a washout period or dose titration in 44 ambulatory outpatients with amnestic MCI (n = 12) or mild-to-moderate AD (n = 32). Three months after the switch, the efficacy of galantamine was evaluated with the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory (NPI) and NPI Brief Questionnaire Form (NPI-Q), respectively, using the Wilcoxon signed-rank test. RESULTS: NPI scores improved significantly on BPSD, especially on delusions, agitation and aberrant motor activity in AD patients (p = 0.027); improvement was remarkable in patients with moderate AD (MMSE score 10-19; p = 0.007), while insignificant in those with MCI (MMSE score ≥24; p = 0.648). The NPI-Q score also improved significantly regarding both the severity of the disease (p = 0.009) and caregiver distress (p = 0.012) in AD patients. MMSE scores hardly improved in either MCI (p = 0.394) or AD patients (p = 0.265). CONCLUSIONS: An uninterrupted switch from donepezil to galantamine could be a useful alternative treatment option for AD patients whose BPSD are unresponsive to donepezil, or whose caregivers are not satisfied with donepezil treatment. © 2014 S. Karger AG, Basel.

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: a 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients.

BACKGROUND: The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug. OBJECTIVES: In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. METHODS: In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. RESULTS: Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%]). CONCLUSIONS: Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted.

Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. OBJECTIVE: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. METHODS: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. RESULTS: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C(max)) increased in a manner that was less than dose proportional. T(max) ranged from 1.50 to 6.00 hours, and elimination t((1/2)) ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V(d) (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t((1/2)) ranged from approximately 10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (approximately 1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was >or=80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. CONCLUSIONS: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.

Design, statistical analysis and sample size calculation of a phase IIb/III study of linagliptin versus voglibose and placebo.

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.

Mitochondrial alterations in dorsal root ganglion cells in sporadic amyotrophic lateral sclerosis.

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 < 0.0001). Regularly spaced transverse processes similar to the rungs of a ladder were occasionally observed in the intermembrane space, along with infrequent but markedly increased cristae and stubby mitochondria. We concluded that mitochondrial abnormalities may be involved in the degenerative processes in the dorsal root ganglion cells in sporadic ALS. These findings therefore suggest that ALS is a widespread, more generalized disorder than previously thought, and that the degeneration is not confined to the motor neuron system.