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The EXCITE-HT study aimed to evaluate the efficacy and safety of esaxerenone versus thiazide diuretics (trichlormethiazide) as second-line treatment for Japanese patients with uncontrolled essential hypertension. This was a 12-week, multicenter, randomized, open-label, parallel-group study. The non-inferiority of esaxerenone to trichlormethiazide was confirmed if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic blood pressure (SBP)/diastolic blood pressure (DBP) change between groups was below 3.9/2.1 mmHg. A total of 295 and 290 patients were included in the esaxerenone and trichlormethiazide groups, respectively. The non-inferiority of esaxerenone to trichlormethiazide was demonstrated: least squares mean change differences in morning home SBP/DBP at end of treatment (EOT) were −2.2 (95% CI, −3.6, −0.8) mmHg for SBP/−0.6 (−1.4, 0.2) mmHg for DBP. Morning home, bedtime home, and office BP significantly decreased (all p  < 0.001) from baseline to EOT in both groups. The urinary albumin-to-creatinine ratio and N-terminal pro-brain natriuretic peptide level decreased from baseline to Week 12 in both groups, with no notable intergroup difference. Serum potassium elevations occurred more frequently with esaxerenone, while serum potassium reductions occurred more with trichlormethiazide. Uric acid elevations were observed in both groups, but more frequently with trichlormethiazide than esaxerenone. No cases of gout occurred in this study. Reductions in estimated glomerular filtration rate were similarly observed in both groups. EXCITE-HT is the first randomized controlled study to demonstrate evidence that esaxerenone is non-inferior to trichlormethiazide as second-line treatment for Japanese patients with uncontrolled essential hypertension, with no new safety concerns.

Abstract Context Although adding spironolactone to renin-angiotensin system blockers reduces albuminuria in adults with chronic kidney disease and type 2 diabetes, it increases the risk of hyperkalemia. Objective To assess whether a lower dose of spironolactone (12.5 mg/d) reduces the risk of hyperkalemia while maintaining its effect on reducing albuminemia. Design Multicenter, open-label, randomized controlled trial. Setting This study was conducted from July 2016 to November 2020 in ambulatory care at 3 diabetes medical institutions in Japan. Patients We enrolled 130 Japanese adults with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration rate ≥30 mL/min/1.73 m2, and serum potassium level <5.0 mEq/L. Interventions The participants were randomly assigned to the spironolactone-administered and control groups. Main outcome measures Changes in urine albumin-to-creatinine ratio (UACR) from baseline over the 24-week interventional period. Results The spironolactone group showed a significant reduction in UACR from baseline (mean decrease, 103.47 ± 340.80 mg/gCre) compared with the control group, which showed an increased UACR (mean increase, 63.93 ± 310.14 mg/gCre; P = .0007, Wilcoxon rank-sum test and t test). Although the spironolactone group had a statistically significant increase in serum potassium levels, none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, participants with a higher initial serum potassium level tended to have a smaller increase (estimate, −0.37, analysis of covariance). Conclusions Low-dose spironolactone administration reduced albuminuria without causing hyperkalemia. Spironolactone administration, the oldest known and most cost-effective mineralocorticoid receptor antagonist, at lower doses should be reconsidered.

In clinical settings, untreatable biliary sludge in the gallbladder can be observed in older adults with advanced dementia. The underlying cause of biliary sludge existence in patients with dementia is currently unknown. Therefore, we aimed to investigate the prevalence, risk factors, and related outcomes of biliary sludge formation in the gallbladder of older adults with dementia. Cross-sectional study. Geriatric ward of University Hospital in Japan. Inpatients aged 80 and older living with dementia. We evaluated the presence of biliary sludge by diagnostic ultrasonography and collected data regarding patient demographic information, cognition (mini-mental state examination [MMSE]), physical activity (Barthel Index), oral food intake (food intake level scale [FILS]), clinical stage of dementia (functional assessment staging [FAST] of dementia), and patient performance status (Zubrod/ Karnofsky score). Male sex, larger gallbladder volume and calories from oral intake were significantly associated with the presence of biliary sludge (P = .02, .02, .002, respectively). There was a significant negative correlation between the FAST stage and the FILS level in all patients (P < .001). More advanced dementia and dysphagia was more likely to be found in patients with Alzheimer disease (AD) with biliary sludge, compared to patients with AD without biliary sludge (FAST 7a, FILS II and FAST 6c, FILS V, respectively, P = .06, 04). A logistic regression analysis revealed that the eating status of FILS I and II, generally called \"fasting or anorexia\", was a significant risk factor for forming biliary sludge in older adults with dementia (P = .031, odds ratio: 5.25, 95% confidence interval: 1.16-23.72). Fasting status may be associated with the existence of biliary sludge in older adults with dementia. Therefore, supportive care for eating might be an important solution to comfortable end-of-life care for older adults with advanced dementia.

Background/Objectives: The predominant etiology of healthcare-associated pneumonia (HCAP) that frequently manifests in elderly with advanced dementia is aspiration pneumonia in which the deteriorated upper respiratory protective reflexes are significant responsible triggers. However, the association of HCAP with cerebral degeneration has not been investigated. Therefore, a cross-sectional and retrospective cohort study was conducted to elucidate the association of aspiration pneumonia-related factors with HCAP in elderly with dementia. Methods: Of the 154 participants (87.9 years), 30 of Alzheimer’s type dementia (AD) or 124 of vascular dementia (VaD) were assigned to the pneumonia group or the control group. Participant’s characteristics, including cognition, clinical pattern and stage of dementia, physical and eating abilities, latency of the swallowing reflex (LTSR), threshold of CRS, and tongue moisture (TOM), were evaluated. Result: The progression of dementia and the decline in LTSR, CRS, and TOM were synchronized (p < 0.05). Participants in the pneumonia group who were male, with eating difficulties, prolonged LTSR, lacunar infarction, or a smoking history, were significantly observed. The multiple logistic analysis indicated that the LTSR was a significant independent factor for developing HCAP (p = 0.01). Furthermore, as the possessed number of aspiration pneumonia-related factors increased, the odds ratio for HCAP became significantly higher (p < 0.001). Blunted CRS, male gender, and lacunar infarctions were evident in VaD participants but not in AD participants. Finally, the incidence of HCAP in VaD was 2.11 times higher than that in AD (p = 0.005). Conclusions: The higher incidence of HCAP in VaD than AD may be due to different underlying pathophysiological mechanisms between them.

This prespecified subanalysis of the multicenter, randomized, open-label, parallel-group EXCITE-HT study aimed to examine the non-inferiority of esaxerenone to trichlormethiazide as a second-line antihypertensive agent according to the basal antihypertensive agent used (angiotensin receptor blocker [ARB] or calcium channel blocker [CCB]). The primary endpoint, change in morning home systolic/diastolic blood pressure (SBP/DBP) from baseline to end of treatment was similar between the two groups (intergroup difference in least squares mean change [95% confidence interval]: −1.3 [−3.8, 1.3]/−0.2 [−1.6, 1.3] mmHg for ARB; −2.7 [−4.2, −1.2]/−0.8 [−1.7, 0.1] mmHg for CCB). The respective incidences of serum potassium levels <3.5 mEq/L and ≥5.5 mEq/L in the ARB subgroup were 3.4% and 4.2% for esaxerenone and 7.9% and 0% for trichlormethiazide; in the CCB subgroup, they were 2.8% and 0.6% for esaxerenone and 13.9% and 1.2% for trichlormethiazide, respectively. The incidence of uric acid level ≥7.0 mg/dL was numerically higher in the trichlormethiazide group than the esaxerenone group in both the ARB and CCB subgroups. The non-inferiority of esaxerenone to trichlormethiazide in lowering morning home BP was demonstrated regardless of whether the basal antihypertensive agent was an ARB or CCB. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering SBP, without any new safety concerns. Serum potassium levels tended to be higher when esaxerenone was combined with an ARB than with a CCB, but this can be mitigated if administered according to the package insert. A subgroup analysis of the EXCITE-HT study according to basal antihypertensive agent demonstrated the non-inferiority of esaxerenone to trichlormethiazide in lowering morning home BP regardless irrespective of the basal antihypertensive agent. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering SBP, without any new safety concerns. A subgroup analysis of the EXCITE-HT study according to basal antihypertensive agent demonstrated the non-inferiority of esaxerenone to trichlormethiazide in lowering morning home BP regardless irrespective of the basal antihypertensive agent. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering SBP, without any new safety concerns.

The mechanism whereby 17β-estradiol (E2) mediates insulin gene transcription has not been fully elucidated. In this study, exposure of hamster insulinoma (HIT-T15) cells to 5 × 10⁻⁹ to 1 × 10⁻⁷ M E2 led to a concentration-dependent decrease of insulin mRNA levels. Transient expression of the estrogen receptor (ER) in HIT-T15 cells revealed that estrogen receptor α (ERα) repressed transcription of the rat insulin Il promoter in both ligand-dependent and ligand-independent manners. The N-terminal A/B domain of ERα was not required for either activity. However, the repression was absent with mutated ER lacking the DNA-binding domain. Moreover, introducing mutations in the D-box and P-box of the zinc finger of ER (C227S, C202L) also abolished the repression. Deletion of the insulin promoter region revealed that nucleotide positions - 238 to - 144 (relative to the transcriptional start site) were needed for ER repression of the rat insulin Il gene. PDX1- and BETA2-binding sites were required for the repression, but an estrogen response element-like sequence or an AP1 site in the promoter was not involved. In conclusion, we found that estrogen repressed insulin mRNA expression in a beta cell line. In addition, the ER suppressed insulin gene transcription in a ligand-independent matter. These observations suggest ER may regulate insulin transcription by indirect genomic signaling.

We previously reported the efficacy and safety of low-dose (12.5 mg/day) spironolactone for chronic kidney disease (CKD) with diabetes. Few studies have examined the characteristics of patients who may have reduced urinary albumin-creatinine ratio (UACR) on mineralocorticoid receptor antagonists. In this study, we aimed to identify the clinical characteristics of patients prone to benefit from UACR reduction with low-dose spironolactone.INTRODUCTIONWe previously reported the efficacy and safety of low-dose (12.5 mg/day) spironolactone for chronic kidney disease (CKD) with diabetes. Few studies have examined the characteristics of patients who may have reduced urinary albumin-creatinine ratio (UACR) on mineralocorticoid receptor antagonists. In this study, we aimed to identify the clinical characteristics of patients prone to benefit from UACR reduction with low-dose spironolactone.This was a post-hoc analysis of a previous trial and included 55 patients assigned to the spironolactone group. Univariate regression analysis was performed to determine the association between the change in UACR after 24 weeks of low-dose spironolactone administration and baseline exploratory parameters. Multiple regression analysis was conducted on the associated parameters, and regression models were created for analysis. A similar analysis was performed for changes in serum potassium levels and estimated glomerular filtration rate (eGFR) after 24 weeks of spironolactone administration.METHODSThis was a post-hoc analysis of a previous trial and included 55 patients assigned to the spironolactone group. Univariate regression analysis was performed to determine the association between the change in UACR after 24 weeks of low-dose spironolactone administration and baseline exploratory parameters. Multiple regression analysis was conducted on the associated parameters, and regression models were created for analysis. A similar analysis was performed for changes in serum potassium levels and estimated glomerular filtration rate (eGFR) after 24 weeks of spironolactone administration.In the univariate analysis, baseline UACR, triglyceride levels, and eGFR were associated with changes in UACR. The regression coefficient estimates were significant for baseline UACR, triglyceride levels, and eGFR (p = 0.002, 0.017, and 0.003, respectively). The reduction in UACR was greater with higher baseline UACR and triglyceride levels, and lower baseline eGFRs. The increase in serum potassium levels due to low-dose spironolactone administration showed a negative correlation with baseline serum potassium levels and no correlation with baseline eGFR, suggesting its safety.RESULTSIn the univariate analysis, baseline UACR, triglyceride levels, and eGFR were associated with changes in UACR. The regression coefficient estimates were significant for baseline UACR, triglyceride levels, and eGFR (p = 0.002, 0.017, and 0.003, respectively). The reduction in UACR was greater with higher baseline UACR and triglyceride levels, and lower baseline eGFRs. The increase in serum potassium levels due to low-dose spironolactone administration showed a negative correlation with baseline serum potassium levels and no correlation with baseline eGFR, suggesting its safety.It may not be too late to start treatment with low-dose spironolactone, even in patients with relatively advanced CKD with diabetes.CONCLUSIONSIt may not be too late to start treatment with low-dose spironolactone, even in patients with relatively advanced CKD with diabetes.

We previously reported the efficacy and safety of low-dose (12.5 mg/day) spironolactone for chronic kidney disease (CKD) with diabetes. Few studies have examined the characteristics of patients who may have reduced urinary albumin-creatinine ratio (UACR) on mineralocorticoid receptor antagonists. In this study, we aimed to identify the clinical characteristics of patients prone to benefit from UACR reduction with low-dose spironolactone. This was a post hoc analysis of a previous trial and included 55 patients assigned to the spironolactone group. Univariate regression analysis was performed to determine the association between the change in UACR after 24 weeks of low-dose spironolactone administration and baseline exploratory parameters. Multiple regression analysis was conducted on the associated parameters, and regression models were created for analysis. A similar analysis was performed for changes in serum potassium levels and estimated glomerular filtration rate (eGFR) after 24 weeks of spironolactone administration. In the univariate analysis, baseline UACR, triglyceride levels, and eGFR were associated with changes in UACR. The regression coefficient estimates were significant for baseline UACR, triglyceride levels, and eGFR (p = 0.002, 0.017, and 0.003, respectively). The reduction in UACR was greater with higher baseline UACR and triglyceride levels, and lower baseline eGFRs. The increase in serum potassium levels due to low-dose spironolactone administration showed a negative correlation with baseline serum potassium levels and no correlation with baseline eGFR, suggesting its safety. It may not be too late to start treatment with low-dose spironolactone, even in patients with relatively advanced CKD with diabetes.

Disclosure: A. Oiwa: None. D. Hiwatashi: None. T. Takeda: None. T. Miyamoto: None. I. Kawata: None. M. Koinuma: None. S. Kubota: None. S. Takayama: None. M. Yamazaki: None. M. Komatsu: None. Objective: To evaluate the albuminuria-lowering effect and safety regarding hyperkalemia of adding low-dose spironolactone (12.5 mg/day) to the renin-angiotensin system (RAS) blockers in adults with chronic kidney disease and type 2 diabetes. Research Design and Methods: This was a multicenter, open-label, randomized controlled trial. We enrolled 130 Japanese individuals aged ≥20 years with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration ≥30 mL/min/1.73 m2, and serum potassium level <5.0 mEq/L. They were randomly assigned to the spironolactone-administered and control groups. The main outcomes were changes in urine albumin-to-creatinine ratio (UACR), serum potassium levels and renal function from baseline to the 24-week interventional period. Results: The spironolactone-administered group showed a significant reduction in UACR by a mean of 103.47 ± 340.80 mg/gCre from baseline compared with the control group that showed increased UACR by a mean of 63.93 ± 310.14 mg/gCre (p = 0.0007, Wilcoxon rank-sum test and T-test). As for serum potassium levels, although there was a statistically significant increase (p = 0.0026), none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, there was a tendency that the higher the initial potassium level, the smaller the increase in serum potassium level (estimate −0.37, analysis of covariance). Conclusions: This study first demonstrated that low-dose spironolactone administration reliably reduced albuminuria and was safe against hyperkalemia. The administration of spironolactone, which is the oldest known and most cost-effective of all the other mineralocorticoid receptor antagonists, should be re-evaluated with consideration of lower doses. Presentation: Thursday, June 15, 2023

Recombinant adenoviruses, carrying herpes simplex virus thymidine kinase ( HSVtk ) genes, were developed to evaluate the possibility of tissue-specific gene therapy for thyroid carcinomas. The HSVtk gene was driven by a minimal thyroglobulin (TG) promoter (AdTGtk) and a tandemly repeated minimal TG promoter (Ad2×TGtk) to obtain thyroid-specific cell killing ability. The transduction of HSVtk genes by infection with Ad2×TGtk followed by ganciclovir (GCV) treatment showed more powerful cytotoxicity for TG-producing FRTL5 cells, a rat normal thyroid cell line, and FTC-133 cells, a human follicular thyroid carcinoma cell line, than when infected with AdTGtk in vitro . The cell killing ability of Ad2×TGtk was 10- to 30-fold higher than that of AdTGtk and similar to that of AdCMVtk, which carries HSVtk under the control of CMV promoter. Whereas after treatment with adenovirus/GCV to non–TG-producing cell lines (undifferentiated thyroid carcinoma cell lines and carcinoma cell lines from other tissues), Ad2×TGtk and AdTGtk needed more than 100-fold concentrated GCV to reach IC 50 compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2×TGtk for tissue-specific cytotoxicity in vivo . After adenovirus/GCV treatment for FTC-133 tumor-bearing nude mice, Ad2×TGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2×TGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2×TGtk and intraperitoneal administrations with GCV in vivo , whereas severe liver damages were observed after treatment with AdCMVtk/GCV. These data indicate a beneficial effect of Ad2×TGtk for tissue-specific gene therapy for TG-producing thyroid carcinomas without toxicity for normal tissues.