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Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.
Yamamoto, E, Usuku, H, Sueta, D, Suzuki, S, Nakamura, T, Matsui, K, Matsushita, K, Iwasaki, T, Sakaino, N, Sakanashi, T, et al
Advances in therapy. 2024;(3):1284-1303
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INTRODUCTION In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION Japan Registry of Clinical Trials (jRCTs071190043).
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Experimental periprosthetic fractures with collarless polished tapered cemented stems.
Yagura, T, Oe, K, Kobayasi, F, Sogawa, S, Nakamura, T, Iida, H, Saito, T
International orthopaedics. 2024
Abstract
PURPOSE After cemented total hip arthroplasty, the risk of periprosthetic fracture (PPF) of taper-slip stems is higher than that of composite-beam stems. We aimed to assess the conditions resulting in PPFs of taper-slip stems using a falling weight. METHODS Taper-slip stems were fixed to five types of simulated bone models using bone cement, and the fractures were evaluated by dropping stainless-steel weights from a predetermined height onto the heads. The periprosthetic fracture height in 50% of the bone models (PPFH50) was calculated using the staircase method. RESULTS For the fixation with 0° of flexion, the values for PPFH50 were 61 ± 11, 60 ± 13, above 110, 108 ± 49, and 78 ± 12 cm for the cobalt-chromium-molybdenum alloy, stainless steel alloy (SUS), titanium alloy (Ti), smooth surface, and thick cement mantle models, respectively; for the fixation with 10° of flexion (considering flexure), the PPFH50 values were 77 ± 5, 85 ± 9, 90 ± 2, 89 ± 5, and 81 ± 11 cm, respectively. The fracture rates of the polished-surface stems were 78.6 and 35.7% at the proximal and distal sites, respectively (p < 0.05); the fracture rates of the smooth-surface stems were 14.2 and 100%, respectively (p < 0.05). CONCLUSION The impact tests demonstrated that the conditions that were less likely to cause PPFs were use of Ti, a smooth surface, a thick cement mantle, and probably, use of SUS.
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Utility of biphasic calcium phosphate cement as a seal for root-end filling.
Nakamura, T, Hayashi, M, Tamura, M, Kaketani, M, Ito, T, Takamizawa, T, Suzuki, Y, Yasukawa, T, Sugawara, A, Takeichi, O
Dental materials journal. 2023;(3):412-417
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The recently developed biphasic calcium phosphate cement (BCPC) consists of α-tricalcium phosphate-tetracalcium phosphate as the solid phase and calcium phosphate solution as the liquid phase. BCPC powder is composed of a single solid solution with a monomodal size distribution. Here, we used a bacterial leakage model to examine the utility of BCPC as a seal for root-end filling. We prepared large (median particle size=9.96 µm; BCPC-L) and small (median particle size=4.84 µm; BCPC-S) BCPC powders. In total, 45 single-rooted teeth were instrumented, resected at the root-end, and retrofilled with experimental materials. Mineral trioxide aggregate (MTA) was used as the control. After visual confirmation of BCPC powder size and retrofilling quality by microscopy, bacterial leakage tests were conducted using Enterococcus faecalis. The bacterial leakage tests did not reveal any significant differences between BCPC-S and MTA. Our findings suggest that BCPC-S is useful for root-end filling.
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Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial.
Katakami, N, Mita, T, Yoshii, H, Shiraiwa, T, Yasuda, T, Okada, Y, Kurozumi, A, Hatazaki, M, Kaneto, H, Osonoi, T, et al
Cardiovascular diabetology. 2023;(1):143
Abstract
BACKGROUND This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.
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Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.
Ohta, H, Uemura, Y, Sone, T, Tanaka, S, Soen, S, Mori, S, Hagino, H, Fukunaga, M, Nakamura, T, Orimo, H, et al
Calcified tissue international. 2023;(4):430-439
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The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.
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High Cathode Loading and Low-Temperature Operating Garnet-Based All-Solid-State Lithium Batteries - Material/Process/Architecture Optimization and Understanding of Cell Failure.
Yamada, H, Ito, T, Nakamura, T, Bekarevich, R, Mitsuishi, K, Kammampata, SP, Thangadurai, V
Small (Weinheim an der Bergstrasse, Germany). 2023;(36):e2301904
Abstract
All-solid-state lithium batteries (ASSLBs) are prepared using garnet-type solid electrolytes by quick liquid phase sintering (Q-LPS) without applying high pressure during the sintering. The cathode layers are quickly sintered with a heating rate of 50-100 K min-1 and a dwell time of 10 min. The battery performance is dramatically improved by simultaneously optimizing materials, processes, and architectures, and the initial discharge capacity of the cell with a LiCoO2 -loading of 8.1 mg reaches 1 mAh cm-2 and 130 mAh g-1 at 25 °C. The all-solid-state cell exhibits capacity at a reduced temperature (10 °C) or a relatively high rate (0.1 C) compared to the previous reports. The Q-LPS would be suitable for large-scale manufacturing of ASSLBs. The multiphysics analyses indicate that the internal stress reaches 1 GPa during charge/discharge, which would induce several mechanical failures of the cells: broken electron networks, broken ion networks, separation of interfaces, and delamination of layers. The experimental results also support these failures.
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Effects of sodium bicarbonate bath on the quality of sleep: An assessor-blinded, randomized, controlled, pilot clinical trial.
Tamaoki, S, Matsumoto, S, Sasa, N, Hoei, T, Tojo, R, Nakamura, T, Aoyagi, Y
Complementary therapies in clinical practice. 2023;:101714
Abstract
BACKGROUND Sleep is fundamental to a healthy life, and sleep disorders are an important health issue in healthcare. Whole-body warm water bathing is a non-pharmacological, safe (non-invasive), and widely used method for comforting. Here, we explored the feasibility and preliminary effectiveness of sodium bicarbonate bath (SBB) on sleep quality. METHODS Healthy adults without sleep disturbances were randomly assigned to shower baths (SHB), tap-water baths (TWB, placebo tablets), or SBB. All participants took a bath (shower, tap-water, or SBB) once a day for 10 min, after dinner, for 7 days. Sleepscan-derived sleep parameters, including total sleep time (TST), symptom questionnaires, and salivary α-amylase concentration were evaluated as outcome measures. RESULTS Forty participants were enrolled (14, 13, and 13 in SHB, TWB, and SBB groups, respectively) and 38 participants completed the trial (13, 12, and 13, respectively). The recruitment, adherence, and completion rates were 90.9% (40/44), 95.0% (38/40), and 95.0% (38/40), respectively. The SBB group showed a significant increase (12.35 [mean]±10.07 [standard deviation] min) in the mean TST at 1-week post-intervention (p = 0.0041) than the SHB (-1.81 ± 14.58 min; p = 0.0231) and TWB (4.54 ± 10.97 min; p = 0.0377) groups. The TST scores at 1-week post-intervention, sleep onset latency, wake after sleep onset, and sleep efficiency were significantly different between the groups. Sleep satisfaction by questionnaire was significantly improved with intervention in the SBB group than that in the SHB and TWB groups. Salivary α-amylase levels significantly improved in the SBB and TWB groups than in the SHB group, with the change being greater in the SBB group. CONCLUSIONS SBB for 7 days had positive effects that improved sleep quality of adults. Further studies are needed to examine the efficacy and safety of SBB for prolonged usage in people diagnosed with insomnia, using objective sleep measurements, and to investigate potential sleep-enhancing mechanisms of action.
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Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.
Ishijima, M, Nakamura, T, Shimizu, K, Hayashi, K, Kikuchi, H, Soen, S, Omori, G, Yamashita, T, Uchio, Y, Chiba, J, et al
Osteoarthritis and cartilage. 2022;(6):852-861
Abstract
OBJECTIVES We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/μmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/μmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.
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Search for nutritional and inflammatory marker ratios to predict neutropenia in FEC therapy for breast cancer: A retrospective observational study.
Nakamura, T, Matsubara, H
International journal of clinical pharmacology and therapeutics. 2022;(10):422-429
Abstract
OBJECTIVE Nutritional and inflammatory marker ratios are known to predict response to chemotherapy in breast cancer, but whether they predict adverse effects caused by chemotherapy remains unclear. We investigated whether nutritional and inflammatory marker ratios before starting FEC therapy (5-fluorouracil, epirubicin, and cyclophosphamide) predict grade 4 neutropenia as a serious adverse effect. MATERIALS AND METHODS 61 patients with breast cancer who started FEC therapy for the first time as preoperative or postoperative chemotherapy were studied. Relevant nutritional and inflammatory marker ratios were compared between patients who developed grade 4 neutropenia (n = 44) and those who did not (n = 17). RESULTS In univariate analysis, occurrence of neutropenia was related significantly (p < 0.05) to pre-FEC-therapy white blood cell count, platelet count, neutrophil count, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and modified Glasgow prognostic score. Analysis using cutoff values obtained from receiver operating characteristic curves showed that LMR, NLR, and PLR predicted grade 4 neutropenia. However, multivariate logistic regression analysis identified no independent factor associated with grade 4 neutropenia. A post-hoc power analysis revealed an inadequate sample size. CONCLUSION Inflammatory marker ratios, especially PLR, may predict grade 4 neutropenia caused by FEC therapy for breast cancer. Although multivariate analysis identified no independent predictive markers in this study due to inadequate sample size, further prospective large-scale research is needed to examine the usefulness of nutritional and inflammatory marker ratios for predicting adverse effects.
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Safety and effectiveness of eribulin in Japanese patients with soft tissue sarcoma including rare subtypes: a post-marketing observational study.
Kawai, A, Narahara, H, Takahashi, S, Nakamura, T, Kobayashi, H, Megumi, Y, Matsuoka, T, Kobayashi, E
BMC cancer. 2022;(1):528
Abstract
BACKGROUND Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with over 100 described subtypes. While these cancers are infrequent, the prognosis is quite poor, particularly for those with stage IV metastatic disease. Patients for whom curative resection is difficult or those with recurrent metastatic disease are treated with chemotherapy, although the options are very limited. Eribulin is an approved treatment of all STS subtypes in Japan. Efficacy and safety data for the treatment of rare STS subtypes other than liposarcoma and leiomyosarcoma (L-type sarcomas) are limited. This nationwide, multicenter, prospective, post-marketing observational study was conducted to assess the real-world effectiveness and safety of eribulin in Japanese patients with STS. METHODS Patients with all types of STS and who consented to eribulin treatment were eligible to participate. The observation period was 1 year, starting at treatment initiation, and clinical outcomes were followed up for 2 years after initiating treatment. The primary endpoint was overall survival (OS). Additional outcomes included time-to-treatment failure (TTF), objective response rate (ORR), disease control rate (DCR), and safety. ORR and DCR were evaluated using imaging findings. Effectiveness results were analyzed both for all patients and by STS subtype. RESULTS A total of 256 patients were enrolled; 252 and 254 were included in the effectiveness and safety analysis set, respectively. Most patients (83.1%) received an initial eribulin dose of 1.4 mg/m2 (standard dose). Respective median OS (95% confidence interval [CI]) was 10.8 (8.5-13.1), 13.8 (10.1-22.3) and 6.5 (5.7-11.1) months for all, L-type, and non-L-type subtypes. The respective median TTF (95% CI) was 2.5 (2.1-2.8), 2.8 (2.3-3.7), and 2.2 (1.6-2.6) months. The ORR and DCR were 8.1 and 42.6%, respectively. Adverse drug reactions (ADRs) and serious ADRs were reported for 83.5 and 18.9% of patients, respectively. The main ADRs were associated with myelosuppression. No significant difference was observed in the incidence of ADRs for patients ≥65 versus <65 years old. CONCLUSIONS Eribulin demonstrated effectiveness and a manageable safety profile for patients with STS, although the effectiveness of eribulin was not demonstrated for some non-L-type subtypes. TRIAL REGISTRATION NCT03058406 ( ClinicalTrials.gov ).