The Burden of Attention-Deficit/Hyperactivity Disorder Traits in Adult Patients with Major Depressive Disorder in Japan.

Purpose: Symptoms of attention-deficit/hyperactivity disorder (ADHD) often overlap with and are hidden by those of mood disorders, including major depressive disorder (MDD), resulting in adult ADHD patients being misdiagnosed as MDD. This study aims to examine if diagnosed MDD patients are more likely to exhibit ADHD traits and if the presence of ADHD traits increases the humanistic burden, including the impairment of health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and health-care resource utilization (HRU), on MDD patients in Japan. Methods: This study utilized existing National Health and Wellness Survey (NHWS) data. The 2016 Japan NHWS is an internet-based survey comprising a total of 39,000 respondents, including those with MDD and/or ADHD. A randomly selected subset of the respondents responded to the Japanese-version Adult ADHD self-report scale (ASRS-v1.1; ASRS-J) symptom checklist. Respondents were considered ASRS-J-positive if the total score was ≥36. The HRQoL, WPAI, and HRU were assessed. Results: Among MDD patients (n = 267), 19.9% were screened ASRS-J-positive, while 4.0% of non-MDD respondents (n = 8885) were ASRS-J-positive. There was a significant association between MDD status and ASRS-J status (crude odds-ratio [OR]: 5.9) as well as between MDD status and ADHD-diagnosis status (crude OR: 22.6). MDD patients who were ASRS-J positive experienced significantly lower HRQoL and higher WPAI than those who were ASRS-J negative. Limitations of this study include potential recall bias owing to the self-report nature of the survey and lack of objective confirmation of MDD diagnosis through review of medical records. Conclusion: This study demonstrated a significant association between MDD status and exhibiting ADHD traits. Adult MDD patients screened ASRS-J-positive experienced significantly higher humanistic burden than patients screened ASRS-J-negative. Our results emphasize the importance of ensuring appropriate screening of ADHD and looking out for potentially hidden ADHD symptoms when diagnosing and treating MDD in adulthood.

The Burden of Undiagnosed Adults With Attention-Deficit/Hyperactivity Disorder Symptoms in Japan: A Cross-Sectional Study.

Background Symptoms experienced by adult patients with attention-deficit/hyperactivity disorder (ADHD) frequently result in functional impairment across academic/occupational functioning, daily life, and social functioning. A substantial proportion of undiagnosed and untreated ADHD has been suggested in Japan. This study aims to better understand the potential undiagnosed ADHD population in Japan by quantifying the burden associated with ADHD symptoms through a comparison of the prevalence of comorbidities, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and healthcare resource utilization (HRU) between undiagnosed potential ADHD respondents who were screened positive and negative using Adult ADHD Self-Report Scale (ASRS)-v1.1. Methodology Respondents from Japan National Health and Wellness Survey 2016 who answered ASRS-v1.1 without an ADHD diagnosis were included. Respondents checking ≥4 items from ASRS-A and ≥9 from ASRS-A+B were classified as ASRS A+ (n = 309) and ASRS AB+ (n = 227), respectively. ASRS negative (n = 9,280) were respondents who were neither ASRS A+ nor ASRS AB+. Data on the presence of comorbidities, HRQoL, WPAI, and HRU were compared. Results ASRS A+ and ASRS AB+ respondents reported higher coexistence of mental comorbidities (depression, generalized anxiety disorder, bipolar disorder, obsessive-compulsive disorder, etc.), sleep problems (insomnia, narcolepsy, sleep apnea, etc.), and physical comorbidities (non-alcoholic steatohepatitis, allergy, and asthma). They also reported greater WPAI and HRU and lower HRQoL than matched ASRS-negative respondents. Conclusions A significantly higher burden was identified among undiagnosed adults with potential ADHD symptoms. Appropriate diagnosis may help those at risk or those who present with symptoms overlapping with ADHD.

Factors Associated With Treatment Adherence and Satisfaction in Type 2 Diabetes Management in Japan: Results From a Web-Based Questionnaire Survey.

INTRODUCTION: To identify factors associated with treatment adherence and satisfaction in patients with type 2 diabetes (T2DM) in Japan. METHODS: A web-based questionnaire survey was conducted from 6 to 17 March 2019 in patients with T2DM aged ≥ 20 years receiving diabetes treatment. Treatment adherence and satisfaction were self-assessed/reported by the patients. A multiple logistic regression model and the chi-square test were used to assess associated factors. RESULTS: Responders (N = 1000) were aged 63.8 (standard deviation 11.9) years, and 739 (73.9%) were male. Adherence to treatment was reported in 941 (94.1%) patients and was significantly associated with higher household income (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.11-3.86), age (OR 1.04, 95% CI 1.02-1.07), employment (OR 0.30, 95% CI 0.15-0.60) and having ≥ 1 impaired basic activity of daily living (BADL) (OR 0.33, 95% CI 0.13-0.82). Satisfaction with treatment was reported by 575 (57.5%) and was significantly associated with receiving/understanding guidance on how pharmacologic therapies are tailored (OR 1.73, 95% CI 1.19-2.51), male sex (OR 1.55, 95% CI 1.10-2.19), higher household income (OR 1.45, 95% CI 1.09-1.94) and age (OR 1.02, 95% CI 1.00-1.03). Treatment adherence was negatively associated with lower household income and having ≥ 1 impaired BADL in patients aged < 65 years, but not in those aged ≥ 65 years. Treatment satisfaction was positively associated with higher household income and receiving/understanding guidance on exercise therapy and the importance of achieving target haemoglobin A1c levels in patients aged ≥ 65 years, but with receiving/understanding guidance on the tailoring of pharmacologic therapies in patients aged < 65 years. CONCLUSION: Lower age, lower household income, employment and impaired BADL may negatively impact treatment adherence in patients with T2DM. Appropriate physician guidance may promote treatment satisfaction. Differences in perspectives between patients aged < 65 and those aged ≥ 65 years should be considered. TRIAL REGISTRATION: Japan Pharmaceutical Information Center, JapicCTI-194636.

A Claims-Based Cohort Study on the Treatment Patterns of Japanese Patients with Type 2 Diabetes Mellitus and the Association of Early First Physician Visit with Time to Prescription of Oral Hypoglycemic Agents.

INTRODUCTION: This study aimed to investigate the relationships between timing of the first physician visit after detection of an abnormal glycated hemoglobin (HbA1c) value at routine annual check and the time to antidiabetic treatment prescription; and understand treatment patterns in patients newly diagnosed with type 2 diabetes mellitus (T2DM). METHODS: This retrospective, longitudinal, observational cohort study examined data from JMDC Inc., an administrative claims database. Patients with HbA1c value of at least 6.5% at routine annual check, aged 20 years or older, and prescribed at least one antidiabetic drug were included. This cohort was classified into early physician visit and delayed physician visit groups based on the timing of the first physician visit relative to the median. Patients were monitored from the date of first HbA1c checkup of at least 6.5% to the date of first physician visit with an HbA1c test, and from the date of the first physician visit to the date of prescription of first-line and second-line T2DM treatments. The time to first prescription of antidiabetic treatment for the two groups was then compared. RESULTS: Of 4798 eligible patients, 54.8% were prescribed first-line T2DM therapy less than 2 months from the first physician visit for T2DM diagnosis. A lower percentage of the early group compared with the delayed group required T2DM pharmacological therapy in less than 2 months (46.1% vs. 63.4%). The early group had a longer median time to prescription of first-line therapy [92 days vs. 15 days, p < 0.0001; hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.24, 1.39] and second-line therapy (1599 days vs. 1315 days, p < 0.0001; HR 1.22, 95% CI 1.11, 1.34) compared with the delayed group. CONCLUSION: In Japanese patients with T2DM, early physician visit after abnormal HbA1c detection at routine annual check is associated with a longer period before T2DM medication requirement, and may improve disease course.

Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis.

BACKGROUND & AIMS: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required. METHODS: We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-based metabolic tracing of the fate of isotopically labelled fructose upon administration to the human liver. RESULTS: Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression, which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. CONCLUSIONS: We have provided preclinical evidence using human livers to support the use of KHK inhibition to improve steatosis, fibrosis, and inflammation in the context of NAFLD. LAY SUMMARY: We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future.

Perspectives of patients and physicians regarding hypertensive management from an online survey for excellence: a subanalysis of the PARADOX study by physician categories.

An existing clinical problem in Japan is the high prevalence of uncontrolled hypertension despite the availability of various effective therapies. Here, we analyzed survey data to gain insight into this paradox from physicians' perspectives, with results categorized according to specialty (i.e., with or without certification by the Japanese Society of Hypertension [JSH]), institution type, gender, and age. A web-based survey of typical educational activities for patients regarding hypertension management was conducted in Japan between October 19 and 31, 2017. Differences between physician groups were investigated per category. Survey results from 541 physicians were analyzed: 59 JSH certified (i.e., 'specialist') vs 482 non-JSH certified (i.e., 'nonspecialist') physicians; 192 general practitioners vs 349 hospital physicians; 500 males vs 41 females; and 178 younger (mean age: 40.7 years), 174 middle-aged (52.0 years) or 189 older (61.3 years) physicians. The most statistically significant differences between groups were observed in the category of physician specialty. Compared with nonspecialists, specialist physicians were more conscious of providing education on patient lifestyle modifications, more aware of patient- and physician-derived issues, and understood and followed the treatment guidelines. General practitioners cared more about the patient's burden than did hospital physicians. Younger physicians identified the need to incorporate the patient's perspective into their treatment. This analysis shows that the provision and perceptions of education differ between physician categories. Compared with specialist physicians, nonspecialists were less likely to provide adequate guidance on lifestyle modifications, possibly due to their uncertainty in understanding treatment guideline recommendations. Further education of nonspecialists on hypertension management may be warranted.

Physician and patient perspectives on hypertension management and factors associated with lifestyle modifications in Japan: results from an online survey.

We conducted a survey to examine the gaps between Japanese physician and patient perspectives on hypertension management and to investigate important factors that may help solve the "hypertension paradox" in Japan. Web-based surveys of patients and physicians were conducted in Japan between October 19 and 31, 2017. The data collected included physician and patient perspectives on hypertension education, adherence to lifestyle modifications and antihypertensive medication, and reasons for treatment adherence/nonadherence. Factors relating to specific patient behaviors (e.g., monitoring their home blood pressure [BP] daily) were analyzed by multivariate logistic regression analysis. Of the 541 physicians and 881 patients included in the analyses, both groups recognized that the extent of lifestyle changes was insufficient. Approximately 80% of physicians reported that they fully or sufficiently provided education to patients about reasons for hypertension treatment and its associated risks, target BP levels, and lifestyle modifications. Only 40-50% of patients considered those topics having been fully or sufficiently discussed. Logistic regression analyses revealed that positive lifestyle modifications (daily home BP monitoring, salt intake <6 g/day, and daily aerobic exercise for ≥30 min) were positively associated with receiving feedback from physicians about specific lifestyle modifications and patient motivation for maintaining their target BP. In conclusion, perception of the amount of education provided by physicians on hypertension management was lower in patients than in physicians. In addition to effective regular follow-up regarding lifestyle modifications, patient motivation by physicians is an important factor for improving lifestyle modifications and achieving effective hypertension management in Japan.

Comparative Effectiveness of Angiotensin II Receptor Blockers in Patients With Hypertension in Japan　- Systematic Review and Network Meta-Analysis.

Background: Angiotensin II receptor blockers (ARBs) are widely used for the management of hypertension in Japan; however, comparative efficacy data within the ARB drug class remain limited. Methods and Results: This systematic literature review identified randomized controlled trials (RCT) indexed in PubMed and Ichushi in Japanese patients with hypertension receiving ARB monotherapy (azilsartan, candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan) in at least 1 arm. Of 763 RCTs identified, 77 met the eligibility criteria; of which, 37 reported mean change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline in the office setting and were used to construct the network. A fixed-effects model (FEM) showed the effect of each drug vs. the reference, azilsartan. Using the FEM, the mean (95% credible interval) change from baseline in SBP/DBP for candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, and valsartan was 3.8 (2.9-4.8)/2.6 (2.0-3.1), 4.8 (2.0-7.5)/3.7 (1.8-5.6), 3.0 (0.8-5.1)/1.9 (0.5-3.3), 3.2 (1.2-5.1)/2.7 (1.3-4.1), 3.2 (0.8-5.6)/2.0 (0.3-3.6), and 3.1 (1.1-5.1)/2.4 (1.1-3.8) mmHg, respectively. Conclusions: The results of this meta-analysis provide evidence that azilsartan has a more favorable efficacy profile than the other ARBs in reducing SBP and DBP.

Antihypertensive treatment for hypertensive patients with heart failure using real-world Japanese data: subanalysis of the Retrospective study of antihypertensives for lowering blood pressure (REAL) study.

The number of patients with heart failure (HF) is rapidly increasing. Although hypertension is related to onset of HF, antihypertensive treatment status for these patients has not been fully examined. We conducted a claims-based study to discern the treatment status of Japanese hypertensive patients with HF. Two Japanese databases (2008-2016) from acute care hospitals and health insurance societies were used to analyze prescription rates for antihypertensive drug class or category of diuretics in all hypertensive patients and the subset of patients with HF. Totals of hypertensive patients and those with HF in each database in 2015 were 4,191,666 and 1,404,008 patient-months, and 1,382,732 and 148,194 patient-months, respectively. In the acute care hospitals database, calcium channel blockers (CCBs) (55.0-56.5%) and angiotensin II receptor blockers (49.4-54.7%) were prescribed most. ß-blockers (38.7-48.0%) and diuretics (42.3-45.6%) were prescribed more for hypertensive patients with HF than for all hypertensive patients (21.5-24.8% and 25.5-26.7%, respectively). Loop diuretics were also prescribed more often for hypertensive patients with HF (68.3-76.0% from acute care hospitals and 47.8-55.8% from health insurance societies) than for all hypertensive patients (56.7-61.7% and 16.4-18.3%). The size of medical institution had a greater effect on drug selection than patient age in both patient groups. Given recommendations in guidelines for hypertensive patients with HF, the differences in drug choice in comparison with all hypertensive patients appear reasonable. However, some deviations, such as the high rate of CCBs in frontline and preference for angiotensin II receptor blockers over angiotensin-converting enzyme inhibitors, did not appear to follow guidelines.

Comparison of persistence and adherence between DPP-4 inhibitor administration frequencies in patients with type 2 diabetes mellitus in Japan: a claims-based cohort study.

Objective: To explore persistence and adherence with once-daily, twice-daily, or once-weekly DPP-4 inhibitors (DPP-4i) in Japanese patients with type 2 diabetes.Methods: This retrospective, longitudinal, observational cohort study used data from the Japanese nationwide hospital-based Medical Data Vision (MDV) administrative claims database. Data were collected for patients given a new DPP-4i prescription between May 2015 and June 2017 with 1-year follow-up until May 2018. Treatment persistence was defined as the total duration of continuous prescription. Adherence to treatment was measured as the proportion of days covered (PDC).Results: A total of 598,419 patients with a prescription for DPP-4i treatment were identified in the MDV database. Of the 39,826 patients who met the inclusion criteria, 82.4% were receiving once-daily DPP-4i, 15.6% twice-daily DPP-4i, and 2.0% once-weekly DPP-4i. Twelve-month persistence rates with once-daily regimens were 66.3% versus 64.7% with twice-daily (p = .1187), and versus 38.8% with once-weekly, regimens (p < .0001) in the overall population (including untreated [UT] and previously treated [PT] patients); 62.8% with once-daily versus 58.3% with twice-daily (p = .0309), and versus 12.3% with once-weekly regimens (p < .0001) in the UT cohort; and 68.6% with once-daily versus 67.9% with twice-daily (p = .5471), and versus 49.1% with once-weekly regimens (p < .0001) in the PT cohort. In the overall population, 97.8% of patients had a mean PDC of 0.97 with once- and twice-daily, and 65.8% of patients had a mean PDC of 0.74 with once-weekly, DPP-4i regimens.Conclusions: Overall, persistence at 12 months was highest in patients receiving once-daily DPP-4i regimens.

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve.

GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic ß cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.

Treatment patterns of antihypertensive fixed-dose combinations according to age and number of agents prescribed: Retrospective analysis using a Japanese claims database.

AIM: To determine the real-world use of fixed-dose combinations (FDC) of antihypertensive agents using data collected from a nationwide medical database of acute hospitals in Japan. METHODS: We carried out a retrospective analysis of data from the Medical Data Vision database for patients with hypertension who received an antihypertensive drug prescription between April 2014 and March 2015. The prescription rate of antihypertensive FDC were assessed by class, age and according to combinations. RESULTS: In total, data from 59 867 patients aged 70.0 ± 11.9 years (mean ± SD) were analyzed. Patients were prescribed 1.9 ± 1.0 oral antihypertensive agents (mean ± SD). Overall, 58.6% of patients were prescribed two or more antihypertensive agents, and the most frequently prescribed classes were calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB). As the number of concomitant antihypertensive agents prescribed increased, the prescription rate of a CCB + an ARB FDC decreased, whereas the prescription rate of an ARB + a diuretic FDC increased. This trend was the same regardless of age. Of the 12 222 patients who were prescribed a CCB + an ARB, 26.0% received a FDC. In contrast, of the 922 patients prescribed an ARB + a thiazide diuretic, 80.6% received a FDC. Medium doses of both CCB and ARB agents, and low doses of diuretics were the most frequently prescribed for each class. CONCLUSIONS: Our analyses show that the real-world use of FDC varies depending on the combination of agent class and the number of prescriptions; the latter was similar regardless of age. Geriatr Gerontol Int 2019; 19: 1077-1083.

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity.

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

Endoscopic Ultrasonography-guided Fine-needle Aspiration Revealed Metastasis-induced Acute Pancreatitis in a Patient with Adrenocortical Carcinoma.

A 26-year-old woman complained of upper abdominal pain. Computed tomography (CT) showed acute pancreatitis, a left adrenal tumor and solitary right pulmonary metastasis. She underwent left adrenalectomy; the adrenal tumor was diagnosed as adrenocortical carcinoma (ACC). When preparing to resect the pulmonary metastasis, she suffered a second acute pancreatic attack. Magnetic resonance cholangiopancreatography (MRCP) showed that the proximal main pancreatic duct (MPD) was dilated, and the distal MPD was diminished; however, no pancreatic tumor was observed on CT or MRCP. Endoscopic ultrasonography revealed a solitary pancreatic mass, which was diagnosed as pancreatic metastasis from ACC by endoscopic ultrasonography-guided fine-needle aspiration.

Treatment patterns and adherence to antihypertensive combination therapies in Japan using a claims database.

Fixed-dose combinations (FDCs) for blood pressure control can simplify prescribing, improve medication adherence, and be cost-effective. In Japan, real-world data about the class effects of antihypertensive drugs on medication adherence are limited. Using the nationwide database of medical health claims from Diagnosis Procedure Combination hospitals, treatment patterns and adherence were analyzed for 47,891 patients prescribed antihypertensive medication between April 2014 and March 2015. Adherence was assessed by the proportion of days covered (expressed as % PDC). Patients were prescribed a mean of 2.0 ± 1.0 antihypertensive drugs and 2.4 ± 1.7 pills for their index prescription. Mean adherence overall was 91.5% PDC and was inversely correlated with the number of antihypertensive drugs or pills prescribed on the index date. Mean % PDC was significantly higher (all P < 0.0001) for CCB + ARB versus ARB + thiazide diuretic combinations and for CCB + ARB + ß-blocker versus CCB + ARB + thiazide diuretic combinations. Adherence was significantly higher (P < 0.0001) for FDC (CCB + ARB) versus corresponding single-drug combinations, but not for other comparisons of FDCs versus single-drug combinations. On the other hand, FDCs were not always used effectively; specifically, FDCs were frequently used concomitantly with a single agent(s) from the same drug class(es) as the FDC. From the results of our study, no clear differences were observed in medication adherence according to the presence or absence of FDC formulations, and there were cases in which FDCs were not being utilized effectively to simplify prescribing.

Humoral Hypercalcemia of Malignancy with a Parathyroid Hormone-Related Peptide-Secreting Intrahepatic Cholangiocarcinoma Accompanied by a Gastric Cancer.

Humoral hypercalcemia of malignancy (HHM) is caused by the oversecretion of parathyroid hormone-related peptide (PTHrP) from malignant tumors. Although any tumor may cause HHM, that induced by intrahepatic cholangiocarcinoma (ICC) or gastric cancer (GC) is rare. We report here a 74-year-old male who displayed HHM with both ICC and GC and showed an elevated serum PTHrP level. Treatment of the hypercalcemia with saline, furosemide, elcatonin, and zoledronic acid corrected his serum calcium level and improved symptoms. Because treatment of ICC should precede that of GC, we chose chemotherapy with cisplatin (CDDP) and gemcitabine (GEM). Chemotherapy reduced the size of the ICC and decreased the serum PTHrP level. One year after diagnosis, the patient was alive in the face of a poor prognosis for an ICC that produced PTHrP. Immunohistochemical staining for PTHrP was positive for the ICC and negative for the GC, leading us to believe that the cause of the HHM was a PTHrP-secreting ICC. In conclusion, immunohistochemical staining for PTHrP may be useful in discovering the cause of HHM in the case of two cancers accompanied by an elevated serum PHTrP level. Chemotherapy with CDDP and GEM may be the most appropriate treatment for a PTHrP-secreting ICC.

Persistent reflux symptoms cause anxiety, depression, and mental health and sleep disorders in gastroesophageal reflux disease patients.

Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients.

Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.

Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists.

Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.