Perception of Adherence to Daily Human Growth Hormone Treatments Among Pediatric and Adolescent Patients in Japan: A Cross-Sectional Survey of Physicians and Caregivers.

Background: Poor adherence to daily human growth hormone (hGH) treatment has been shown to be associated with poor clinical outcomes for growth hormone deficiency (GHD) patients. However, few studies have examined the perception of adherence to hGH treatment among both physicians and caregivers in Japan. Objective: The aim of this study is to examine the perception of adherence for daily hGH treatment among physicians and caregivers of pediatric and adolescent patients treated with GH in Japan. Moreover, we explore reasons for skipping treatment and the potential impact of a once-weekly treatment on adherence. Methods: A cross-sectional survey was conducted in Japan among physicians that prescribe daily hGH treatment and caregivers that have administered daily hGH treatment to children/adolescents for 3 months or longer. The Morisky Medication Adherence Scale (MMAS-8) was used to gauge perceived adherence for both physician and caregiver groups. Caregivers were also questioned regarding reasons for missing injections. Moreover, both groups were asked about the impact of a once-weekly treatment on adherence. Results: Responses were collected from 123 physicians and 112 caregivers. Physicians reported that 18.1% of patients have poor adherence based on the MMAS-8 instrument. In contrast, 32.1% of the caregivers reported poor adherence. "Simply forgetting", "Patient refused/resisted", and being "Busy with school activities, etc" were the most commonly selected reasons by caregivers for missing an injection. Physicians felt that a once-weekly injection could improve adherence for 64.5% of patients with poor adherence. Moreover, 56.9% of the caregivers that reported an experience of missed injections felt that a once-weekly injection would improve their adherence. Conclusion: Approaches to improve adherence to hGH treatment in Japan are continuously needed. While further research is needed to understand factors most likely to improve adherence, availability of a once-weekly treatment is expected to help improve adherence.

Efficacy and Safety of Once-Weekly Somatrogon Compared with Once-Daily Somatropin (Genotropin®) in Japanese Children with Pediatric Growth Hormone Deficiency: Results from a Randomized Phase 3 Study.

INTRODUCTION: Somatrogon is a long-acting recombinant human growth hormone being developed as a once-weekly treatment for children with growth hormone deficiency (GHD). The objective of this phase 3 study (NCT03874013) was to compare the efficacy and safety of once-weekly somatrogon with once-daily Genotropin in Japanese children with GHD. METHODS: In this open-label, randomized, active-controlled study, 44 prepubertal Japanese children with GHD (boys: 3 to <11 years; girls: 3 to <10 years) were randomized 1:1 to receive once-weekly somatrogon or once-daily Genotropin (0.025 mg/kg/day) for 12 months. Dose escalation for somatrogon-treated subjects occurred in the first 6 weeks (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week. The study's primary endpoint was annualized height velocity (HV) at 12 months. RESULTS: Baseline characteristics were similar between treatment groups. Compared with Genotropin-treated subjects, somatrogon-treated subjects had higher least-squares mean HV at 12 months (9.65 cm/year vs. 7.87 cm/year). Once-weekly somatrogon was concluded as being comparable to once-daily Genotropin as the mean treatment difference (somatrogon-Genotropin) in HV was +1.79 cm/year (95% confidence interval, 0.97-2.61), which was greater than the preestablished margin (-1.8 cm/year). For both treatment groups, most adverse events were mild to moderate in severity and a similar proportion of subjects reported injection-site pain, although the somatrogon group reported more painful injections. CONCLUSION: In prepubertal Japanese children with GHD, once-weekly somatrogon was comparable to once-daily Genotropin in terms of annualized (12-month) HV. Both treatments had similar safety and tolerability profiles.

Stimulation of Gs signaling in MC4R cells by DREADD increases energy expenditure, suppresses food intake, and increases locomotor activity in mice.

The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein Gs. Ligand binding to MC4R activates adenylyl cyclase resulting in increased intracellular cAMP levels. cAMP acts as a secondary messenger, regulating various cellular processes. MC4R can also couple with Gq and other signaling pathways. Therefore, the contribution of MC4R/Gs signaling to energy metabolism and appetite remains unclear. To study the effect of Gs signaling activation in MC4R cells on whole body energy metabolism and appetite, we generated a novel mouse strain that expresses a Gs-coupled designer receptors exclusively activated by designer drugs [Gs-DREADD (GsD)] selectively in MC4R-expressing cells (GsD-MC4R mice). Chemogenetic activation of the GsD by a designer drug [deschloroclozapine (DCZ); 0.01∼0.1 mg/kg body wt] in MC4R-expressing cells significantly increased oxygen consumption and locomotor activity. In addition, GsD activation significantly reduced the respiratory exchange ratio, promoting fatty acid oxidation, but did not affect core (rectal) temperature. A low dose of DCZ (0.01 mg/kg body wt) did not suppress food intake, but a high dose of DCZ (0.1 mg/kg body wt) suppressed food intake in MC4R-GsD mice, although either DCZ dose (0.01 or 0.1 mg/kg body wt) did not affect food intake in the control mice. In conclusion, the current study demonstrated that the stimulation of Gs signaling in MC4R-expressing cells increases energy expenditure and locomotor activity and suppresses appetite.NEW & NOTEWORTHY We report that Gs signaling in melanocortin 4 receptor (MC4R)-expressing cells regulates energy expenditure, appetite, and locomotor activity. These findings shed light on the mechanism underlying the regulation of energy metabolism and locomotor activity by MC4R/cAMP signaling.

Contribution of Solid Food to Achieve Individual Nutritional Requirement during a Continuous 438 km Mountain Ultramarathon in Female Athlete.

BACKGROUND: Races and competitions over 100 miles have recently increased. Limited information exists about the effect of multiday continuous endurance exercise on blood glucose control and appropriate intake of food and drink in a female athlete. The present study aimed to examine the variation of blood glucose control and its relationship with nutritional intake and running performance in a professional female athlete during a 155.7 h ultramarathon race with little sleep. METHODS: We divided the mountain course of 438 km into 33 segments by timing gates and continuously monitored the participant's glucose profile throughout the ultramarathon. The running speed in each segment was standardized to the scheduled required time-based on three trial runs. Concurrently, the accompanying runners recorded the participant's food and drink intake. Nutrient, energy, and water intake were then calculated. RESULTS: Throughout the ultramarathon of 155.7 h, including 16.0 h of rest and sleep, diurnal variation had almost disappeared with the overall increase in blood glucose levels (25-30 mg/dL) compared with that during resting (p < 0.0001). Plasma total protein and triglyceride levels were decreased after the ultramarathon. The intake of protein and fat directly or indirectly contributed to maintaining blood glucose levels and running speed as substrates for gluconeogenesis or as alternative sources of energy when the carbohydrate intake was at a lower recommended limit. The higher amounts of nutrient intakes from solid foods correlated with a higher running pace compared with those from liquids and gels to supply carbohydrates, protein, and fat. CONCLUSION: Carbohydrate, protein, and fat intake from solid foods contributed to maintaining a fast pace with a steady, mild rise in blood glucose levels compared with liquids and gels when female runner completed a multiday continuous ultramarathon with little sleep.

Safety and Effectiveness of Apixaban in Japanese Patients With Venous Thromboembolism in Clinical Practice　- A Post-Marketing Surveillance.

BACKGROUND: A post-marketing surveillance study (STANDARD-VTE) evaluated the real-world safety and effectiveness of apixaban in Japanese patients prescribed for either the treatment of venous thromboembolism (VTE) or prevention of recurrent VTE.Methods and Results:Patients newly initiated on apixaban were followed up for 52 weeks or 28 days post-discontinuation. Subgroup analysis was performed on patients with and without active cancer, and on patients with provoked VTE and with unprovoked VTE. A total of 1,119 patients were enrolled. Of these, 43.1% were aged ≥75 years, 46.4% had body weight ≤60 kg, and 21.3% had active cancer; mean serum creatinine was 0.76 mg/dL. The incidence of adverse drug reactions (ADRs) was 8.85%, and that of severe ADRs was 3.22%. Incidence of any bleeding, major bleeding, and recurrent VTE was 6.70%, 3.40%, and 0.80%, respectively. In patients starting apixaban 10 mg twice daily, THE incidence of any bleeding and major bleeding was 7.72% and 3.86%, respectively. In patients with active cancer, THE incidence of any bleeding and major bleeding was 16.81% and 9.24%, respectively. CONCLUSIONS: No new safety signals of apixaban were identified in Japanese patients with VTE. In this study, the safety and effectiveness of apixaban in real-world practice was consistent with the results of the apixaban phase III trial.

Validation of novel identification algorithms for major adverse cardiovascular events in a Japanese claims database.

Predicting clinical outcomes can be difficult, particularly for life-threatening events with a low incidence that require numerous clinical cases. Our aim was to develop and validate novel algorithms to identify major adverse cardiovascular events (MACEs) from claims databases. We developed algorithms based on the data available in the claims database International Classification of Diseases, Tenth Revision (ICD-10), drug prescriptions, and medical procedures. We also employed data from the claims database of Jichi Medical University Hospital, Japan, for the period between October 2012 and September 2014. In total, we randomly extracted 100 potential acute myocardial infarction cases and 200 potential stroke cases (ischemic and hemorrhagic stroke were analyzed separately) based on ICD-10 diagnosis. An independent committee reviewed the corresponding clinical data to provide definitive diagnoses for the extracted cases. We then assessed the algorithms' accuracy using positive predictive values (PPVs) and apparent sensitivities. The PPVs of acute myocardial infarction, ischemic stroke, and hemorrhagic stroke were low only by diagnosis (81.6% [95% CI 72.5-88.7]; 31.0% [95% CI 22.8-40.3]; and 45.5% [95% CI 34.1-57.2], respectively); however, the PPVs were elevated after adding the prescription and procedure data (87.0% [95% CI 78.3-93.1]; 44.4% [95% CI 32.7-56.6]; and 46.1% [95% CI 34.5-57.9], respectively). When we added event-specific prescription and procedure data to the algorithms, the PPVs for each event increased to 70%-98%, with apparent sensitivities exceeding 50%. Algorithms that rely on ICD-10 diagnosis in combination with data on specific drugs and medical procedures appear to be valid for identifying MACEs in Japanese claims databases.

A Retrospective, Cross-Sectional Study on the Prevalence of Hyperuricemia Using a Japanese Healthcare Database.

OBJECTIVES: This study aims to evaluate the prevalence of hyperuricemia (HU) considering both serum uric acid (SUA) levels and medication status of urate-lowering drugs (ULDs), and the association between HU and its comorbidities using a Japanese healthcare database. MATERIALS AND METHODS: The study population consisted of 60,828 subjects who had at least one serum uric acid measurement between the fiscal years (FYs) 2010 and 2014 in a Japanese employment-based health insurance database (MinaCare Co., Ltd., Tokyo, Japan), which includes mutually linked medical/pharmaceutical claims data and health check-up data. Hyperuricemia was defined as a SUA level >7.0 mg/dL of the health check-up data and/or a prescription for a ULD. The association between HU and comorbidities were analyzed by comparing the prevalence of HU of each subgroup defined by presence or absence of comorbidity. RESULTS: The prevalence of HU in FY 2014 was 26.8% [95% confidence interval (CI): 26.2 to 27.3%] in male subjects and 0.9% (95% CI: 0.7 to 1.0%) in female subjects. According to the analyses by sex and age, a trend of increasing prevalence with age was observed in both males and females. The prevalence of HU remained stable both in males and females from FYs 2010 to 2014. The positive association between HU and well-known comorbidities were confirmed with the exception of diabetes mellitus and smoking status in male subjects. CONCLUSION: Our results provided a more accurate prevalence of HU in Japanese population. It is important to increase the awareness on HU in the society to reduce the burden of HU-related diseases.

The effects of topiroxostat on vascular function in patients with hyperuricemia.

Xanthine oxidoreductase (XOR) inhibitors, such as allopurinol and febuxostat, inhibit the catalysis of serum uric acid (SUA) synthesis. In doing so, they are thought to improve vascular endothelial function in patients with hyperuricemia and cardiovascular risk by reducing increases in SUA and reactive oxygen species levels. We performed a retrospective cohort study to evaluate the effects of topiroxostat, a novel XOR inhibitor, on vascular function measured by flow-mediated dilation (FMD) on ultrasonography. In total, 23 patients with hyperuricemia were enrolled. After approximately 8 weeks, topiroxostat was associated with a significant increase in the peak percentage change in diameter (∆FMD) from 4.53% ± 2.09% to 5.54% ± 3.08% (P = .045). It also significantly reduced the SUA levels from 7.31 ± 1.43 to 5.44 ± 1.11 mg/dL (P < .001). Although further studies are needed to validate these results, it appears that topiroxostat improves vascular endothelial function in patients with hyperuricemia.

Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease.

PURPOSE: Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients. METHODS: The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study. RESULTS: The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum. CONCLUSIONS: The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.

High-performance liquid chromatography mass spectrometry of gold and alloy clusters protected by hydrophilic thiolates.

In this work, we found two hydrophilic interaction liquid chromatography (HILIC) columns for high-performance liquid chromatography (HPLC) suitable for the high-resolution separation of hydrophilic metal clusters. The mass distributions of the product mixtures of hydrophilic metal clusters were evaluated via HPLC mass spectrometry (LC/MS) using these HILIC columns. Consequently, we observed multiple clusters that had not been previously reported for glutathionate (SG)-protected gold clusters (Aun(SG)m). Additionally, we demonstrated that Aun-xMx(SG)m alloy clusters (M = Ag, Cu, or Pd) in which part of the Au in the Aun(SG)m cluster is replaced by a heteroelement can be synthesized, similar to the case of hydrophobic alloy clusters. It is easy to evaluate the mass distributions of hydrophilic metal clusters using this method. Thus, remarkable progress in the synthesis techniques of hydrophilic metal clusters through the use of this method is anticipated, as is the situation for hydrophobic metal clusters.

Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38.

PURPOSE: Half-life of SN-38, an active metabolite of irinotecan, remarkably increases in patients with end-stage kidney disease (ESKD), even though SN-38 is excreted in bile. Uremic toxins (UTs), which accumulate in the serum of ESKD patients, were reported to inhibit organic anion-transporting polypeptide (OATP) 1B1-mediated uptake of SN-38; however, the relevance of this finding in a clinical setting is unknown. This study focused on cooperative effects of serum components and UTs on OATP1B1-mediated transport of SN-38. METHODS: Uptake of SN-38 by OATP1B1 was evaluated using cells stably expressing OATP1B1. Serum was obtained from > 400 ESKD patients undergoing hemodialysis. Deproteinized serum was combined with human serum albumin (HSA) to explore the effects of albumin-bound and unbound serum compounds. RESULTS: Uptake clearance of SN-38 in OATP1B1 cells decreased by 40% in the presence of uremic serum residue with albumin compared to that in the presence of normal serum residue. Additional UTs (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, hippuric acid, indole-3-acetic acid, and 3-indoxyl sulfate) combined with normal serum residue in HSA decreased OATP1B1-mediated SN-38 transport by 32.1% compared to that in the presence of normal serum residue. The inhibitory effect of albumin-unbound fraction with UTs and normal serum residue was comparable to that of uremic serum residue, with an uptake decrease of 17.2% compared to that reported in the presence of normal serum residue. CONCLUSIONS: Hepatic uptake of SN-38 via OATP1B1 decreases in ESKD patients through cooperative inhibitory effects of UTs and serum components.

A retrospective, cross-sectional study of real-world values of cardiovascular risk factors using a healthcare database in Japan.

BACKGROUND: Data collected by the Japanese Ministry of Health, Labour and Welfare (MHLW), namely data from the Specific Health Checkups and Specific Health Guidance (MHLW-SH) and the National Health and Nutrition Survey (MHLW-H&N) allow assessment of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) in Japan. Recently, a large database of employment-based health insurance has been developed by MinaCare Co. Ltd. METHODS: A retrospective, cross-sectional study using the Japanese healthcare checkup database developed by MinaCare Co. Ltd. was designed to investigate the distribution of real-world values of BP, LDL-C, and HbA1c in Japan. Data in the MinaCare database were also compared with those in the two national data sources to assess the extent to which the health status in Japan is reflected in each data source. RESULTS: Of the healthcare checkup results of 232515 subjects in the 2011 MinaCare database, 49.9% were male and 50.1% were female. The age of the subjects ranged from < 20 to > 70 years. The proportion of subjects with systolic BP (SBP) ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% generally increased with increasing age. If one focused on the upper-end age group representing the majority of the MinaCare study population (i.e. age range, 55-59 years), the proportions of subjects with SBP ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% were 19.0%/12.2% (males/females), 27.2%/42.7%, and 13.5%/5.4%, respectively. The MinaCare database was mostly comparable with the two national data sources; however, some notable differences in BP and lipid parameters were found between MHLW-H&N and the other two data sources. CONCLUSIONS: Analysis of the MinaCare database indicated that a substantial proportion of subjects did not achieve the target BP, LDL-C, and HbA1c levels to reduce the risk of future cardiovascular and cerebrovascular disease events. The results were generally consistent with those of the national data sources. Considering its characteristics of low selection bias, large sample size, wide age distribution, and high flexibility in analysis of subject-level data, the MinaCare database is highly valuable for studying the health status of the population covered by employment-based health insurance.

Randomized, double-blind trial to evaluate the safety of apixaban with antiplatelet therapy after acute coronary syndrome in Japanese patients (APPRAISE-J).

BACKGROUND: Concomitant anticoagulant therapy may further reduce the risk of thrombotic events in patients with acute coronary syndrome (ACS) when given in addition to current standard antiplatelet therapies. This Phase II, randomized, double-blind, placebo-controlled study in Japanese patients with ACS assessed the bleeding risk of apixaban compared with placebo when given in combination with standard antiplatelet therapy, and followed a similar design to APPRAISE-1, the larger global Phase II study. METHODS AND RESULTS: Patients with recently diagnosed ACS were randomized to receive apixaban 2.5mg twice daily (BID; n=49), apixaban 5mg BID (n=50), or placebo (n=52) in addition to standard antiplatelet therapy for 24 weeks. The composite primary endpoint of major or clinically relevant nonmajor bleeding occurred in 2 patients (4.1%) in each apixaban treatment group and 1 patient (2.0%) in the placebo group, and a dose-dependent increase was seen in all bleeding events. No hemorrhagic strokes occurred in either apixaban treatment group. This study was terminated before completion because the APPRAISE-2 global Phase III trial was stopped based on the recommendation of the Data Monitoring Committee, following an increase in bleeding events without a counterbalancing reduction in ischemic events. CONCLUSIONS: The bleeding profile of apixaban in Japanese patients with ACS was similar to that found in the global APPRAISE-1 study, supporting the safety of apixaban in Japanese patients.

Vesnarinone suppresses TNFα mRNA expression by inhibiting valosin-containing protein.

Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.

Influence of serum in hemodialysis patients on the expression of intestinal and hepatic transporters for the excretion of pravastatin.

It is known that the lipid-lowering agent pravastatin, which is not metabolized by cytochrome P450, is eliminated as an unchanged drug in bile and urine. It is interesting to note that the non-renal clearance of pravastatin in end-stage renal failure patients is decreased compared with that of healthy volunteers. This study investigated the influence of uremic serum and toxins on the transport mechanisms of pravastatin to elucidate the cause of decreased non-renal clearance in end-stage renal failure patients. Caco-2 and Hep3B cells were used as models of intestinal epithelial cells and hepatocytes respectively. Normal and uremic serum were deproteinized by treatment with methanol. 3-Carboxy-4-methyl-5propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, 3-indoxyl sulfate, and p-cresol were chosen as uremic toxins. Uremic serum-treated Caco-2 cells exhibited significantly increased accumulation of pravastatin and significantly decreased expression of MRP2 mRNA compared with normal serum-treated Caco-2 cells. In addition, the expression of MRP2 mRNA tended to decrease in cells treated with CMPF, indole-3-acetic acid, or 3-indoxyl sulfate. Uremic serum-treated Hep3B cells showed a significantly decreased initial uptake rate of pravastatin; furthermore, the expressions of OATP1B1 and OATP2B1 mRNA were decreased compared to normal serum-treated Hep3B cells. These results suggest that the decrease in the non-renal clearance of pravastatin in end-stage renal failure patients is partly induced by the downregulation of intestinal MRP2 and hepatic OATP1B1 and/or OATP2B1 by various uremic toxins in end-stage renal failure patients.