Denosumab-induced hypocalcemia in patients with solid tumors and renal dysfunction: a multicenter, retrospective, observational study.

BACKGROUND: Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr < 30 mL/min), but it is not completely known whether denosumab can be used in them. We aimed to determine the association between renal function and hypocalcemia development during denosumab treatment. METHODS: We included patients with solid cancer and bone metastases who started denosumab treatment between April 2017 and March 2019. They were classified into four groups based on creatinine clearance (Ccr; mL/min): normal (Ccr ≥ 80), mild (50 ≤ Ccr ˂80), moderate (30 ≤ Ccr ˂50), and severe (Ccr ˂30). Hypocalcemia was evaluated using the Common Terminology Criteria for Adverse Events (v5.0) based on the albumin-adjusted serum calcium levels; its incidence (stratified by renal function) and risk factors were investigated using a Chi-square test and logistic regression analysis. RESULTS: Of 524 patients (age: 69 ± 11 years; 303 men), 153 had a normal renal function and 222, 117, and 32 had mild, moderate, and severe renal dysfunction. The albumin-adjusted serum calcium level was higher than the measured (total) calcium level in most patients. The incidence of grade ≥ 1 hypocalcemia was 32.0% in the normal group and 37.4%, 29.9%, and 62.5% in the mild, moderate, and severe renal dysfunction groups, respectively. It was, therefore, higher in the severe renal dysfunction groups than in the normal group (P = 0.002). The incidence of grade ≥ 3 hypocalcemia did not differ significantly among the groups. Pre-treatment low serum calcium levels and severe renal dysfunction were risk factors for hypocalcemia. CONCLUSIONS: Evaluating denosumab-induced hypocalcemia required albumin adjustment, and its incidence was high among patients with severe renal dysfunction. Reduced serum calcium levels and severely impaired renal function were associated with an elevated hypocalcemia risk.

Delivery catheter system carries more physiological right ventricular septal pacing than stylet system.

INTRODUCTION: The Mt. FUJI multicenter trial demonstrated that a delivery catheter system had a higher rate of successful right ventricular (RV) lead deployment on the RV septum (RVS) than a conventional stylet system. In this subanalysis of the Mt. FUJI trial, we assessed the differences in electrocardiogram (ECG) parameters during RV pacing between a delivery catheter system and a stylet system and their associations with the lead tip positions. METHODS: Among 70 patients enrolled in the Mt FUJI trial, ECG parameters, RV lead tip positions, and lead depth inside the septum assessed by computed tomography were compared between the catheter group (n = 36) and stylet group (n = 34). RESULTS: The paced QRS duration (QRS-d), corrected paced QT (QTc), and JT interval (JTc) were significantly shorter in the catheter group than in the stylet group (QRS-d: 130 ± 19 vs. 142 ± 15 ms, p = .004; QTc: 476 ± 25 vs. 514 ± 20 ms, p < .001; JTc: 347 ± 24 vs. 372 ± 17 ms, p < .001). This superiority of the catheter group was maintained in a subgroup analysis of patients with an RV lead tip position at the septum. The lead depth inside the septum was greater in the catheter group than in the stylet group, and there was a significant negative correlation between the paced QRS-d and the lead depth. CONCLUSION: Using a delivery catheter system carries more physiological depolarization and repolarization during RVS pacing and deeper screw penetration in the septum in comparison to conventional stylet system. The lead depth could have a more impact on the ECG parameters rather than the type of pacing lead.

Association of Malnutrition and High Bleeding Risk with Long-Term Prognosis in Patients with Acute Coronary Syndrome following Percutaneous Coronary Intervention.

BACKGROUND: Malnutrition in cardiovascular disease is associated with poor prognosis, especially in patients with heart failure and acute coronary syndrome (ACS). High bleeding risk is also linked to coronary artery disease prognosis, including ACS. However, whether the extent of malnutrition and high bleeding risk have a cumulative impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention remains unclear. METHODS: We analyzed 275 patients with ACS treated with percutaneous coronary intervention. The Controlling Nutritional Status score and Japanese version of the Academic Research Consortium for High Bleeding Risk criteria (J-HBR) were retrospectively evaluated. The primary and secondary outcomes were adjusted using the inverse probability treatment weighting method. RESULTS: The prevalence of moderate or severe malnutrition in this cohort was 16%. Kaplan-Meier analysis showed a significantly higher incidence of major adverse cardiovascular and cerebrovascular events in patients who were moderately or severely malnourished than in those who were not. Notably, the incidence of these major events was similar between severely malnourished patients with J-HBR and those without. CONCLUSION: Moderate or severe malnutrition has a significant impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention.

Palatability of Aripiprazole Gummies Prepared from Commercially Available Products: Pharmaceutical Formulation for Improving Patient Adherence.

Good adherence to medication is critical for successfully treating psychiatric disorders. Tailor-made pharmaceutical formulations can provide a suitable dosage form to meet the specific needs of individual patients who exhibit poor adherence to industrially manufactured products. Herein, we prepared aripiprazole (ARP) gummies (ARP-Gs) using a commercially available ARP formulation. We aimed to clarify the palatability of ARP-Gs by performing a gustatory sensation test in healthy volunteers. We performed two types of organoleptic masking of ARP-Gs, cocoa- and fruit-flavoured gummies (6.0 mg of ARP/3.5 g of gummy), and conducted two different gustatory sensation tests for each ARP-G. Ten young, healthy volunteers (mean ± standard deviation, 23.7 ± 1.2 years) were enrolled in each trial. The overall palatability of ARP-Gs was evaluated using the 100-mm visual analogue scale (VAS). Receiver operating characteristic (ROC) curve analysis was performed between VAS scores of total ARP-G palatability and acceptability assessed using a 5-point rating scale. Among cocoa-flavoured ARP-Gs, those combining aspartame, cocoa powder, and banana flavour (ABC-ARP-G) exhibited the highest VAS scores for total palatability. Similarly, the VAS scores of grapefruit-flavoured ARP-Gs (GF-ARP-G) showed the highest values considering all fruit-flavoured ARP-Gs. The VAS scores for ABC-ARP-G and GF-ARP-G greatly exceeded the cut-off values of acceptability calculated using the ROC curve. We developed two types of ARP-Gs with organoleptic masking as tailor-made pharmaceutical formulations. ABC-ARP-Gs and GF-ARP-Gs could be acceptable in patients. ARP-Gs could be an alternative to currently available pharmaceutical formulations to enhance their adherence and meet the specific needs of individual patients.

Usefulness of delivery catheter on accurate right ventricular septal pacing: Mt FUJI trial.

AIMS: Although the delivery catheter system for pacemaker-lead implantation is a new alternative to the stylet system, no randomized controlled trial has addressed the difference in right ventricular (RV) lead placement accuracy to the septum between the stylet and the delivery catheter systems. This multicentre prospective randomized controlled trial aimed to prove the efficacy of the delivery catheter system for accurate delivery of RV lead to the septum. METHODS AND RESULTS: In this trial, 70 patients (mean age 78 ± 11 years; 30 men) with pacemaker indications of atrioventricular block were randomized to the delivery catheter or the stylet groups. Right ventricular lead tip positions were assessed using cardiac computed tomography within 4 weeks of pacemaker implantation. Lead tip positions were classified into RV septum, anterior/posterior edge of the RV septal wall, and RV free wall. The primary endpoint was the success rate of RV lead tip placement to the RV septum. RESULTS: Right ventricular leads were implanted as per allocation in all patients. The delivery catheter group had higher success rate of RV lead deployment to the septum (78 vs. 50%; P = 0.024) and narrower paced QRS width (130 ± 19 vs. 142 ± 15 ms P = 0.004) than those in the stylet group. However, there was no significant difference in procedure time [91 (IQR 68-119) vs. 85 (59-118) min; P = 0.488] or the incidence of RV lead dislodgment (0 vs. 3%; P = 0.486). CONCLUSION: The delivery catheter system can achieve a higher success rate of RV lead placement to the RV septum and narrower paced QRS width than the stylet system. TRIAL REGISTRATION NUMBER: jRCTs042200014 (https://jrct.niph.go.jp/en-latest-detail/jRCTs042200014).

Pulmonary Hypertension Associated with Diffuse Panbronchiolitis That Improved with Erythromycin and Home Oxygen Therapy.

Pulmonary hypertension (PH) often complicates chronic lung disease. However, there are few reports of PH associated with diffuse panbronchiolitis, and there is no effective treatment. We herein report a 64-year-old woman diagnosed with PH due to diffuse panbronchiolitis. She received erythromycin, carbocysteine, and home oxygen therapy (1 L O2/min). After 4 months of therapy, the respiratory function (diffusing capacity of the lungs for carbon monoxide: 23.3% to 76.1%) and PH (mean pulmonary arterial pressure: 50 to 28 mmHg; pulmonary vascular resistance: 680 to 518 dynes・sec・cm-5; pre- vs post-therapy, respectively) had improved markedly.

Feasibility study of a LED light irradiation device for the treatment of chronic neck with shoulder muscle pain/stiffness.

Neck with shoulder muscle stiffness/pain is a common disorder. Commonly used physical therapy, pharmacotherapy, acupuncture, and moxibustion only temporarily alleviate the disorder in most cases, thus the disorder often recurs. Low power laser therapy is often used for neck and shoulder stiffness/pain and has been effective in clinical trials. In this study, we evaluated the safety and effectiveness of a newly developed self-care device for disorders including neck with shoulder muscle stiffness/pain. The device incorporates light-emitting diodes (LEDs), which are safer than lasers, as its light source. Ten adults with neck with shoulder muscle stiffness/pain were subject to LED irradiation (wavelength 780 nm ± 15 nm, output 750 mW, power density 3.8 W/cm2, energy density 5.7×102 J/cm2) for 3 minutes on the affected shoulder at a standard acupuncture point (GB21, Jianjing). Immediately after irradiation, the subjective symptoms of the neck with shoulder muscle stiffness and pain evaluated by a visual analog scale were improved from 58.3 mm ± 18.7 mm to 45.5 mm ± 21.5 mm and from 45.8 mm ± 23.3 mm to 39.4 mm ± 21.8 mm, respectively. The symptoms further improved after 15 minutes of irradiation. The skin temperature at the irradiated point increased from 34.3°C ± 1.1°C to 41.0°C ± 0.7°C. The increase in skin temperature was observed within approximately 5 cm of the irradiated area. There was no effect on the heart rate variability, a measure of the autonomic nervous system; however, the baroreflex sensitivity was slightly increased. No irradiation-related adverse skin events were observed. Our LED irradiation device was found to be safe, and it improved the subjective symptoms of muscle stiff neck with shoulders.

Efficacy and safety of propranolol cream in infantile hemangioma: A prospective pilot study.

Infantile hemangioma (IH) is a common tumor in infants that gradually resolves and is often untreated. However, for cosmetic reasons, parents often opt for treatment. Oral propranolol, the first-line therapy for IH, is sometimes associated with several side effects, including hypotension, bradycardia, and hypoglycemia. No clinical studies on topical propranolol have been conducted using standardized procedures. We evaluated the efficacy and safety of topical propranolol in patients with IH. This multicenter, prospective pilot study was conducted from June 2019 to October 2020 and involved eight Japanese infants aged 35-150 days with proliferating IH. Patients were treated with 5% propranolol cream twice daily. We examined the efficacy rate based on central evaluation (complete or near-complete healing of the target hemangioma) at weeks 24 and 12, respectively, compared to baseline values. The efficacy rate at week 24 was 68.8% (95% confidence interval: 44.1-85.9%). The surface area, maximum diameter, and color intensity of the target IH decreased over time. Adverse event and drug-related adverse event rates were 87.5% and 0%, respectively. Propranolol cream may be effective and safe in Japanese patients with IH and may be considered a first-choice treatment for small and superficial IHs in cosmetically problematic areas.

Retrospective multicentre study on the effectiveness of first-line direct-acting antivirals against hepatitis C virus genotype-1.

WHAT IS KNOWN AND OBJECTIVE: In Japan, ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir are recommended as first-line treatments for patients with untreated hepatitis C virus genotype 1. Although they have demonstrated a high efficacy in clinical trials, there are no direct comparative studies. Clarification of their effectiveness and safety in real-world clinical practice is required. Therefore, we conducted a retrospective multicentre study on the effectiveness of these direct-acting antivirals in real-world clinical practice. METHODS: We retrospectively evaluated the clinical data of untreated patients with persistent HCV genotype 1 infection who started first-line treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir or glecaprevir/pibrentasvir between September 2015 and January 2019 at 11 medical institutions in Japan. The primary efficacy endpoint was a sustained virologic response after 12 weeks of treatment. The secondary endpoints included sustained virologic response after 24 weeks of treatment and end of treatment response. The safety endpoint was treatment completion rate. RESULTS AND DISCUSSION: During the study, 420 patients (median age, 70 years; 181 males) received ledipasvir/sofosbuvir, 48 (median age 72, years; 29 males) received elbasvir/grazoprevir and 63 (median age 66, years; 35 males) received glecaprevir/pibrentasvir. For ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir, the sustained virologic response after 12 weeks of treatment was 98.6%, 97.9% and 100%; the sustained virologic response after 24 weeks of treatment was 99.0%, 97.7% and 100%; the end of treatment response was 99.8%, 97.9% and 98.4%; and the treatment completion rate was 98.3%, 91.7% and 100% respectively. WHAT IS NEW AND CONCLUSION: In real-world clinical practice, hepatitis C virus treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir was effective with safety.

Omeprazole suppresses endothelial calcium response and eNOS Ser1177 phosphorylation in porcine aortic endothelial cells.

BACKGROUND: Although high doses of proton pump inhibitors can elicit an anticancer effect, this strategy may impair vascular biology. In particular, their effects on endothelial Ca2+ signaling and production of endothelium-derived relaxing factor (EDRF) are unknown. To this end, we investigated the effects of high dosages of omeprazole on endothelial Ca2+ responses and EDRF production in primary cultured porcine aortic endothelial cells. METHODS AND RESULTS: Omeprazole (10-1000 µM) suppressed both bradykinin (BK)- and thapsigargin-induced endothelial Ca2+ response in a dose-dependent manner. Furthermore, omeprazole slightly attenuated Ca2+ mobilization from the endoplasmic reticulum, whereas no inhibitory effects on endoplasmic reticulum Ca2+-ATPase were observed. Omeprazole decreased BK-induced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and tended to decrease BK-induced nitric oxide production. Production of prostaglandin I2 metabolites, especially 6-keto-prostaglandin 1α, also tended to be reduced by omeprazole. CONCLUSION: Our results are the first to indicate that high doses of omeprazole may suppress both store-operated Ca2+ channels and partially the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, and decreased BK-induced, Ca2+-dependent phosphorylation of eNOS(Ser1177). Thus, high dosages of omeprazole impaired EDRF production by attenuating intracellular Ca2+ signaling.

Diagnostic and prognostic significance of serum angiopoietin-1 and -2 concentrations in patients with pulmonary hypertension.

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH.

Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.

Comparison of delivery catheter-based and stylet-based right ventricular lead placement at the right ventricular septum under fluoroscopic guidance judged by cardiac CT (Mt. FUJI): a study protocol for the Mt. FUJI randomised controlled trial.

INTRODUCTION: Pacing-induced cardiomyopathy occasionally occurs in patients undergoing pacemaker implantation. Although compared with right ventricular (RV) apical pacing, RV septal pacing can attenuate left ventricular dyssynchrony; the success rate of lead placement on the RV septum using the stylet system is low. Additionally, no randomised controlled trial has addressed the issue regarding the accuracy of RV lead placement on the RV septum using the stylet and delivery catheter systems. This study hypothesises that a newly available delivery catheter system can improve the accuracy of RV lead placement on the RV septum. METHODS AND ANALYSIS: In a multicentre, prospective, randomised, single-blind, controlled trial, 70 patients with pacemaker indication owing to atrioventricular block will be randomised to either the delivery catheter or stylet group before the pacemaker implantation procedure. The position of the RV lead tip will be assessed using ECG-gated cardiac CT in all patients within 4 weeks after pacemaker implantation. Lead tip positions are classified into three groups: (1) RV septum, (2) anterior/posterior edge of the RV septal wall and (3) RV free wall. The primary endpoint will be the success rate of RV lead tip placement on the RV septum, which will be evaluated using cardiac CT. ETHICS AND DISSEMINATION: This study will be conducted according to the stipulations of the Helsinki Declaration and the institutional review board of Hamamatsu University School of Medicine. The results of the study will be disseminated at several research conferences and will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: jRCTs042200014; Pre-results.

Real-time breath recognition by movies from a small drone landing on victim's bodies.

In local and global disaster scenes, rapid recognition of victims' breathing is vital. It is unclear whether the footage transmitted from small drones can enable medical providers to detect breathing. This study investigated the ability of small drones to evaluate breathing correctly after landing on victims' bodies and hovering over them. We enrolled 46 medical workers in this prospective, randomized, crossover study. The participants were provided with envelopes, from which they were asked to pull four notes sequentially and follow the written instructions ("breathing" and "no breathing"). After they lied on the ground in the supine position, a drone was landed on their abdomen, subsequently hovering over them. Two evaluators were asked to determine whether the participant had followed the "breathing" or "no breathing" instruction based on the real-time footage transmitted from the drone camera. The same experiment was performed while the participant was in the prone position. If both evaluators were able to determine the participant's breathing status correctly, the results were tagged as "correct." All experiments were successfully performed. Breathing was correctly determined in all 46 participants (100%) when the drone was landed on the abdomen and in 19 participants when the drone hovered over them while they were in the supine position (p < 0.01). In the prone position, breathing was correctly determined in 44 participants when the drone was landed on the abdomen and in 10 participants when it was kept hovering over them (p < 0.01). Notably, breathing status was misinterpreted as "no breathing" in 8 out of 27 (29.6%) participants lying in the supine position and 13 out of 36 (36.1%) participants lying in the prone position when the drone was kept hovering over them. The landing points seemed wider laterally when the participants were in the supine position than when they were in the prone position. Breathing status was more reliably determined when a small drone was landed on an individual's body than when it hovered over them.

Verification of a cocktail approach for quantitative drug-drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug.

A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82-1.09, and 2 combinations ranged between 0.74-1.32.The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.

Clinical evaluation of drug-drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers.

AIMS: The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. METHODS: We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. RESULTS: The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC0-∞ of selexipag, whereas it significantly increased AUC0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69-2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93-2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. CONCLUSION: Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.

Transient Laterality of Cerebral Oxygenation Changes in Response to Head-of-Bed Manipulation in Acute Ischemic Stroke.

BACKGROUND: Cerebral oxygenation monitoring provides important information for optimizing individualized management in patients with acute ischemic stroke (AIS). Although changes in cerebral oxygenation are known to occur in response to head-of-bed (HOB) elevation within 72 h after onset, changes in cerebral oxygenation during stroke recovery are unclear. We compared changes in total- (tHb), oxygenated- (HbO2), and deoxygenated-hemoglobin (deoxyHb) concentrations in response to HOB manipulation between the timeframes within 72 h and 7-10 days after AIS onset. METHODS: We measured forehead ΔtHb, ΔHbO2, and ΔdeoxyHb in response to HOB elevation (30°) within 72 h (first measurement) and 7-10 days (second measurement) after AIS onset using time-resolved near-infrared spectroscopy. RESULTS: We enrolled 30 participants (mean age 72.8 ± 11.3 years; 13 women) with a first AIS. There were no significant differences in ΔtHb, ΔHbO2, or ΔdeoxyHb measurements on the infarct or contra-infarct side. At the first measurement, ΔtHb, ΔHbO2, and ΔdeoxyHb measured on the contra-infarct side did not correlate with those measured on the infarct side: ΔtHb (r = 0.114, p = 0.539); ΔHbO2 (r = 0.143, p = 0.440); ΔdeoxyHb (r = 0.227, p = 0.221). Notably, at the second measurement, correlation coefficients of ΔtHb and ΔHbO2 between the contra-infarct and infarct sides were statistically significant: ΔtHb (r = 0.491, p = 0.008); ΔHbO2 (r = 0.479, p = 0.010); ΔdeoxyHb (r = 0.358, p = 0.054). CONCLUSION: Although changes in cerebral oxygenation in response to HOB elevation had a laterality difference between hemispheres within 72 h of AIS onset, the difference had decreased, at least partially, 7-10 days after AIS onset.

Ease of Taking and Palatability of Fixed-Dose Orally Disintegrating Mitiglinide/Voglibose Tablets.

Fixed-dose combination (FDC) medicines containing two or more active pharmaceutical ingredients (APIs) in a single dosage form have been reported to improve patient adherence to a greater extent than single dosages of individual components (ICs). Orally disintegrating tablets (ODTs) are easier to swallow than conventional tablets. The aim of this study was to elucidate the clinical pharmaceutical characteristics of taking a FDC-ODT and two IC-ODTs. We prepared three ODTs containing mitiglinide, voglibose, and mitiglinide/voglibose and three corresponding placebo ODTs and performed 2 independent clinical trials with 13 healthy subjects (mean age, 23.4 ± 1.6 years). One trial evaluated the ease of taking tablets and the amount of water required for taking the tablets; placebo ODTs were used in order to avoid administering APIs. The other trial evaluated the bitterness, sweetness and overall palatability of ODTs containing APIs during disintegration and after spitting out. Ease and taste were evaluated using both a visual analog scale (VAS) and a verbal rating scale (VRS). The results of the VAS and VRS evaluation indicated that FDC-ODT could ease tablet intake unlike IC-ODTs. In addition, FDC-ODT reduced the amount of water required for tablet intake in contrast to IC-ODTs. Taste evaluation results did not reveal any difference between FDC-ODT and IC-ODTs, except for the sweetness score after spitting out. In conclusion, FDC-ODT is easy to take and can help improve patient adherence.

Calcium Release from Endoplasmic Reticulum Involves Calmodulin-Mediated NADPH Oxidase-Derived Reactive Oxygen Species Production in Endothelial Cells.

BACKGROUND: Previous studies demonstrated that calcium/calmodulin (Ca2+/CaM) activates nicotinamide adenine dinucleotide phosphate oxidases (NOX). In endothelial cells, the elevation of intracellular Ca2+ level consists of two components: Ca2+ mobilization from the endoplasmic reticulum (ER) and the subsequent store-operated Ca2+ entry. However, little is known about which component of Ca2+ increase is required to activate NOX in endothelial cells. Here, we investigated the mechanism that regulates NOX-derived reactive oxygen species (ROS) production via a Ca2+/CaM-dependent pathway. METHODS: We measured ROS production using a fluorescent indicator in endothelial cells and performed phosphorylation assays. RESULTS: Bradykinin (BK) increased NOX-derived cytosolic ROS. When cells were exposed to BK with either a nominal Ca2+-free or 1 mM of extracellular Ca2+ concentration modified Tyrode's solution, no difference in BK-induced ROS production was observed; however, chelating of cytosolic Ca2+ by BAPTA/AM or the depletion of ER Ca2+ contents by thapsigargin eliminated BK-induced ROS production. BK-induced ROS production was inhibited by a CaM inhibitor; however, a Ca2+/CaM-dependent protein kinase II (CaMKII) inhibitor did not affect BK-induced ROS production. Furthermore, BK stimulation did not increase phosphorylation of NOX2, NOX4, and NOX5. CONCLUSIONS: BK-induced NOX-derived ROS production was mediated via a Ca2+/CaM-dependent pathway; however, it was independent from NOX phosphorylation. This was strictly regulated by ER Ca2+ contents.