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Aims: The efficacy of antiplatelet therapy may vary among different disease subtypes. Prasugrel is generally a more potent, consistent, and fast-acting platelet inhibitor than clopidogrel. This sub-analysis of the phase III comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO-I) trial aimed to assess the differences in efficacy of these treatments for each stroke subtype. Methods: In the PRASTRO-I trial, a total of 3,753 patients with ischemic stroke were recruited from 224 centers throughout Japan and randomized (1:1) to prasugrel (3.75 mg/day) or clopidogrel (75 mg/day) for 96 weeks. For the sub-analysis, strokes were classified as large-artery atherosclerosis, small-artery occlusion (lacunar), stroke of other etiology, and stroke of undetermined etiology. The cumulative incidence of primary events (ischemic stroke, myocardial infarction, and death from other vascular cause) and hazard ratios (HRs) were calculated for each subgroup. Results: For patients with large-artery atherosclerosis, the primary event incidence was 3.8% in the prasugrel group and 4.8% in the clopidogrel group (HR 0.79; 95% confidence interval [CI] 0.45–1.41). For patients with small-artery occlusion, the incidence was 3.3% in the prasugrel group and 3.9% in the clopidogrel group (HR 0.82; 95% CI 0.45–1.50). For patients with stroke of undetermined etiology, the incidence was 4.6% in the prasugrel group and 3.0% in the clopidogrel group (HR 1.56; 95% CI 0.90–2.72). The incidence of bleeding was similar across subtypes. Conclusions: Although statistical significance was not reached, the efficacy of prasugrel was potentially different between stroke subtypes, warranting further studies.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)

Aim: Although high on-treatment platelet reactivity (HTPR) with dual antiplatelet therapy (DAPT) correlates with long-term adverse outcomes in patients undergoing percutaneous coronary intervention, the correlation in Japanese patients remains unclear. Therefore, we examined the relationship between platelet reactivity during DAPT with aspirin and clopidogrel and 1-year clinical outcomes following successful coronary stent implantation. Methods: A prospective, multicenter registry study (j-CHIPS) was conducted in patients undergoing coronary stenting and receiving aspirin and clopidogrel at 16 hospitals in Japan. A VerifyNow point-of-care assay was used to assess platelet reactivity, and a cutoff value to define HTPR was established. Results: Between February 2011 and May 2013, 1047 patients were prospectively enrolled, of which 854 patients with platelet function evaluation at 12–24 h after PCI were included in the final analysis. After 1 year of follow-up, the incidence of the primary endpoint (a composite of all-cause mortality, myocardial infarction, stent thrombosis, and ischemic stroke) was significantly higher in patients with HTPR than in those without (5.9% vs. 1.5%, p = 0.008), and HTPR showed a modest ability to discriminate between patients who did and did not experience major adverse cardiac and cerebrovascular events (area under the curve, 0.60; 95% confidence interval, 0.511–0.688, p = 0.039). HTPR status did not identify patients at risk for major or minor bleeding events. Conclusion: HTPR was significantly associated with adverse ischemic outcomes at 1 year after PCI in Japanese patients receiving maintenance DAPT, indicating its potential as a prognostic indicator of clinical outcomes in this high-risk patient population.

Introduction: The safety of prasugrel in elderly and/or low body weight Japanese patients with ischemic stroke who have a relatively high bleeding risk with antiplatelet therapy remains unknown. Objective: We aimed to investigate the safety and efficacy of long-term prasugrel monotherapy for stroke prevention compared with clopidogrel in elderly and/or low body weight Japanese patients with non-cardioembolic ischemic stroke. Methods: In this randomized, double-blind, comparative, phase III study, elderly (age ≥75 years) and/or low body weight (≤50 kg) Japanese patients with a previous history of non-cardioembolic ischemic stroke were assigned to a prasugrel 3.75 mg (PRA3.75) group, a prasugrel 2.5 mg (PRA2.5) group, or a clopidogrel 50 mg (CLO50) group and followed up for 48 weeks. The primary safety endpoint was the combined incidence of primary safety events, defined as life-threatening, major, and other clinically relevant bleeding. The efficacy endpoint was a composite of ischemic stroke, myocardial infarction, and death from other vascular causes. Results: A total of 654 patients (age 76.4 ± 7.3 years, body weight 55.6 ± 9.3 kg, women 43.9%) from 74 medical institutions within Japan were enrolled. The combined incidence (95% CI) of primary safety events was 4.2% (1.9–7.8%), 1.9% (0.5–4.7%), and 3.6% (1.6–6.9%) in the PRA3.75 group (n = 216), PRA2.5 group (n = 215), and CLO50 group (n = 223), respectively (hazard ratios [HR] PRA3.75/CLO50, 1.13 [0.44–2.93]; PRA2.5/CLO50, 0.51 [0.15–1.69]). The incidences of bleeding leading to treatment discontinuation (95% CI) were 2.3% (0.8–5.3%), 0.9% (0.1–3.3%), and 2.2% (0.7–5.2%) in the PRA3.75, PRA2.5, and CLO50 groups, respectively (HRs PRA3.75/CLO50, 1.01 [0.29–3.48]; PRA2.5/CLO50, 0.41 [0.08–2.12]). There was no significant difference in all bleeding events between groups. The incidence of ischemic stroke, myocardial infarction, and death from other vascular causes was lower, but not significantly so, in patients treated with prasugrel than in patients treated with clopidogrel: PRA3.75, 0.0% (0/216); PRA2.5, 3.3% (7/215); and CLO50, 3.6% (8/223; HRs PRA3.75/CLO50, 0.00 [0.00–0.00]; PRA2.5/CLO50, 0.90 [0.32–2.47]). Conclusions: Elderly and/or low body weight ­Japanese patients with previous non-cardioembolic ischemic stroke who received PRA3.75 showed similar results in terms of primary safety endpoint, and a numerically lower incidence of ischemic stroke, myocardial infarction, and death from other vascular causes, compared with those who received CLO50.

ObjectivesTo examine the incidence of stroke or systemic embolic events (SSEs) and bleeding events in untreated patients with non-valvular atrial fibrillation (NVAF) after widespread use of direct oral anticoagulant agents (DOACs).DesignMulticentre, non-interventional, observational, retrospective cohort study using real-world data in Japan (2016-2018).SettingThe Mie, Musashino University study of NVAF, which used the Mie-Life Innovation Promotion Center Database. This is a regional clinical database involving one university hospital and eight general hospitals in Mie Prefecture in Japan.ParticipantsJapanese patients with NVAF (n=7001).Primary and secondary outcomeThe incidence of SSEs and bleeding events.ResultsA total of 7001 patients with NAVF were registered, and 53.0% were treated with DOACs, 10.6% were treated with warfarin and 36.4% had no treatment. Additionally, 29.5% of patients with a CHADS2 (congestive heart failure, hypertension, age≥75 years, diabetes, previous stroke or transient ischemic attack) score of 3–6 were untreated. In the no treatment group, the SSE rates by the CHADS2 score (0, 1, 2 and 3–6) were 1.4%, 1.4%, 3.2% and 8.0%, respectively. The rates of bleeding events by the CHADS2 score (0, 1, 2 and 3–6) in the no treatment group were 0.7%, 1.0%, 1.2% and 2.9%, respectively. A multivariate analysis of SSEs in components of the CHADS2 showed that the adjusted HRs were 2.32 for heart failure, 1.66 for an age ≥75 years, 1.81 for diabetes mellitus and 5.84 for prior stroke or transient ischaemic attack.ConclusionsApproximately one-third of the patients do not receive any anticoagulation in the modern DOAC era in Japan. The SSE rate increases by the CHADS2 score. The SSE rate is low in patients with a CHADS2 score 1, the use of anticoagulant drug therapy is recommended because of a higher risk of stroke.

Summary Background The effect of prasugrel in terms of the prevention of recurrence of ischaemic stroke is unknown. We investigated the non-inferiority of prasugrel to clopidogrel for prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes in Japanese patients with non-cardioembolic stroke. Methods In this phase 3 randomised, double-blind, non-inferiority trial, patients aged 20–74 years who had had a non-cardioembolic stroke in the previous 1–26 weeks were recruited from 224 hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive prasugrel (3·75 mg/day) or clopidogrel (75 mg/day) orally for 96–104 weeks. Randomisation was stratified according to stroke subtype. The randomisation schedule was generated by an independent statistician who created a computer-generated random number sequence. Patients, investigators, and the funder were masked to treatment allocation. The primary endpoint was combined incidence of ischaemic stroke (fatal and non-fatal), myocardial infarction (fatal and non-fatal), and death from other vascular causes in the intention-to-treat population. The safety endpoint was incidence of bleeding events, comprising life-threatening bleeding, major bleeding, and clinically relevant bleeding. The safety analysis was done in the population excluding trial patients with serious Good Clinical Practice violations, and those who had not taken the trial drug. The predefined non-inferiority margin was an upper 95% CI limit for the risk ratio (RR) of 1·35. The trial was registered with the Japan Pharmaceutical Information Center (JapicCTI-111582). Findings Patients were recruited between Sept 1, 2011, and June 12, 2015. 3747 patients (797 [21%] women) were enrolled, with a mean age of 62·1 (SD 8·5) years. 3753 patients were randomly assigned to treatment and, of these patients, 1885 in the prasugrel group and 1862 in the clopidogrel group were confirmed to have taken the trial drug at least once, and six patients withdrew from the trial before administration of the trial drug. Thus, a total of 3747 patients were included in the full analysis set. 73 (4%) of 1885 patients in the prasugrel group and 69 (4%) of 1862 patients in the clopidogrel group reached the primary endpoint (RR 1·05, 95% CI 0·76–1·44). The incidence of bleeding events was not significantly different between treatment groups; life-threatening bleeding was observed in 18 (1%) patients in the prasugrel group and 23 (1%) patients in the clopidogrel group (RR 0·77, 0·41–1·42). Interpretation The non-inferiority of prasugrel to clopidogrel for the prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes was not confirmed in Japanese patients with non-cardioembolic stroke. No safety concerns were identified. Funding Daiichi Sankyo.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

Background and Purpose: The safety of prasugrel in elderly and/or low body weight Japanese subjects who have a relatively high bleeding risk with antiplatelet therapy remains unknown. We aimed to investigate the safety and efficacy of long-term prasugrel monotherapy for stroke prevention compared with clopidogrel in elderly and/or low body weight Japanese patients with non-cardioembolic stroke. Methods: In this randomized, double-blind, comparative, phase III study, elderly (age ≥75 years) and/or low body weight (≤50 kg) Japanese patients with a previous history of non-cardioembolic stroke were assigned to a prasugrel 3.75 mg group (PRA3.75), a prasugrel 2.5 mg group (PRA2.5), or a clopidogrel 50 mg group (CLO50) and followed up for 48 weeks. The primary safety endpoint was the combined incidence of primary safety events, defined as life-threatening, major, and other clinically relevant bleeding. The efficacy endpoint was a composite of ischemic stroke, myocardial infarction, and death from other vascular causes. Results: A total of 654 subjects (age 76.4±7.3 years; body weight 55.6±9.3 kg; women 43.9%) were enrolled. The combined incidence of primary safety events was 4.2%, 1.9%, and 3.6% in the PRA3.75, PRA2.5, and CLO50 groups, respectively. The incidences of bleeding leading to treatment discontinuation were 2.3%, 0.9%, and 2.2% in the PRA3.75, PRA2.5, and CLO50 groups, respectively, while the incidence of ischemic stroke, myocardial infarction, and death from other vascular causes was numerically lower but non-significant in patients treated with prasugrel than in patients treated with clopidogrel [0.0% (0/216), 3.3% (7/215), and 3.6% (8/223)]. Conclusions: Elderly and/or low body weight Japanese patients with previous non-cardioembolic stroke who received prasugrel 3.75 mg showed similar results in terms of primary safety endpoint and a numerically lower incidence of ischemic stroke, myocardial infarction, and death from other vascular causes compared with those who received clopidogrel 50 mg.

This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for > 4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n = 64) or 2.5 mg/day (group B; n = 65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, patients were classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). The primary endpoint was P2Y12 reaction units (PRU) at the end of each 4 week treatment. A significant reduction in PRU was noted after treatment with prasugrel 3.75 mg/day compared with the pre-dose value (after treatment with clopidogrel) (p

BACKGROUND The aim of this study was to assess the echocardiographic characteristics of chronic hemodialysis (HD) patients with end-stage renal disease (ESRD) in a multicenter prospective cohort study.Methods and Results:Three hundred and fifteen patients with ESRD (67.9±10.6 years, 47.6% male) on chronic HD for ≥1 year were examined on transthoracic echocardiography, including Doppler-derived aortic valve area (AVA) measurement. Only 11.5% and 3.4% of all patients had normal left ventricular (LV) geometry and normal LV filling pattern, respectively. The majority of patients had aortic and mitral valvular calcification, and approximately 50% of all 315 patients had aortic valve narrowing with AVA

IntroductionThere is no proven therapy to reverse or ameliorate fetal growth restriction (FGR). Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has been reported to potentially play a therapeutic role in FGR, but this has not been established. Tadalafil is also a selective PDE5 inhibitor. We have demonstrated the efficacy of tadalafil against FGR along with short-term outcomes and the feasibility of tadalafil treatment. Based on the hypothesis that tadalafil will safely increase the likelihood of increased fetal growth in FGR, we designed this phase II study to prospectively evaluate the efficacy and safety of tadalafil against FGR.Methods and analysisThis study is a multicentre, randomised controlled phase II trial. A total of 140 fetuses with FGR will be enrolled from medical centres in Japan. Fetuses will be randomised to receive either the conventional management for FGR or a once-daily treatment with 20 mg of tadalafil along with the conventional management until delivery. The primary endpoint is fetal growth velocity from the first day of the protocol-defined treatment to birth (g/day). To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery was established in this study. The investigator will evaluate fetal baseline conditions at enrolment and will decide the timing of delivery based on this fetal indication. Infants will be followed up for development until 1.5 years of age.Ethics and disseminationThis study was approved by the Institutional Review Board of Mie University Hospital and each participating institution. Our findings will be widely disseminated through peer-reviewed publications.Trial registration numberUMIN000023778.

Background: This comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO)-I trial investigates the noninferiority of prasugrel to clopidogrel sulfate in the prevention of recurrence of primary events (ischemic stroke, myocardial infarction, and death from other vascular causes), and the long-term safety of prasugrel in Japanese patients with non-cardioembolic stroke. Research design and methods: This was an active-controlled, randomized, double-blind, double-dummy, parallel-group study conducted between July 2011 and March 2016 at multiple centers around Japan. Patients had to meet eligibility criteria before receiving 3.75 mg prasugrel or 75 mg clopidogrel orally once daily for a period of 96–104 weeks. Results: A total of 3747 patients were included in this trial; 1598 in the 3.75 mg prasugrel group and 1551 in the 75 mg clopidogrel group completed the study. During the study period, 287 (15.2%) patients in the prasugrel group and 311 (16.7%) in the clopidogrel group discontinued treatment. Baseline characteristics, safety, and efficacy results are forthcoming and will be published separately. Conclusions: This article presents the study design and rationale for a trial investigating the noninferiority of prasugrel to clopidogrel sulfate with regards to the inhibitory effect on primary events in patients with non-cardioembolic stroke.

IntroductionFew studies have examined the relationship between the pharmacodynamics of antiplatelet drugs and the risk of clinically significant bleeding following percutaneous coronary intervention (PCI) for treating acute coronary syndrome (ACS). We examined the associations between the pharmacodynamics of prasugrel and clopidogrel and the incidence of bleeding events in the acute and chronic phases after PCI.Materials and methodsWe performed a post hoc analysis of the PRASFIT-ACS (PRASugrel compared with clopidogrel For Japanese patIenTs with ACS undergoing PCI) study of patients in whom platelet reactivity was determined as P2Y12 reaction units (PRU; VerifyNow® P2Y12 assay) or vasodilator-stimulated phosphoprotein-phosphorylation reactivity index (VASP-PRI). Japanese patients were randomized to prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg), both in combination with aspirin, for 24–48weeks. The bleeding outcome was a composite of major, minor, and clinically relevant bleeding.ResultsOverall, 66/685 (9.6%) and 65/678 (9.6%) of prasugrel- and clopidogrel-treated patients, respectively, experienced major, minor, or clinically relevant bleeding. PRU and VASP-PRI at 5–12h or in steady state conditions (at 4weeks) were not associated with the risk of bleeding in the acute (to day 3) or chronic (from day 4 to 14days after treatment discontinuation) phases of treatment, respectively. Less than 9% of patients with low on-treatment platelet reactivity (defined as PRU

Ezetimibe has been reported to provide significant incremental reduction in low-density-lipoprotein cholesterol (LDL-C) when added to a statin; however, its effect on coronary atherosclerosis has not yet been evaluated in detail. The aim of this study was to investigate the add-on effect of ezetimibe to a statin on coronary atherosclerosis evaluated by intravascular ultrasound (IVUS).In this prospective randomized open-label study, a total of 51 patients with stable coronary artery disease (CAD) requiring percutaneous coronary intervention (PCI) were enrolled, and assigned to a combination group (n = 26, rosuvastatin 5 mg/day + ezetimibe 10 mg/day) or a monotherapy group (n = 25, rosuvastatin 5 mg/day). Volumetric IVUS analyses were performed at baseline and 6 months after the treatment for a non-PCI site. LDL-C level was significantly reduced in the combination group (-55.8%) versus that in the monotherapy group (-36.8%; P = 0.004). The percent change in plaque volume (PV), the primary endpoint, appeared to decrease more effectively in the combination group compared with the monotherapy group (-13.2% versus -3.1%, respectively, P = 0.050). Moreover, there was a significant group × time interaction in the effects of the two treatments on PV (P = 0.021), indicating the regressive effect of the combination therapy on PV was greater than that of monotherapy for subtly different values of baseline PV in the two treatment groups. Moreover, percent change in PV showed positive correlations with percent change of LDL-C (r = 0.384, P = 0.015).Intensive lipid-lowering therapy with ezetimibe added to usual-dose statin may provide significant incremental reduction in coronary plaques compared with usual-dose statin monotherapy.

Background Few large-scale studies have examined the relationship between bleeding events not related to coronary artery bypass grafting (CABG), and the vascular access route used in acute coronary syndrome (ACS) or in elective treatment of coronary artery disease (CAD). Methods and results We compared the incidence of bleeding events occurring up to 3 days after percutaneous coronary intervention (PCI) or loading dose of prasugrel or clopidogrel in 2 studies of Japanese patients (PRASFIT-ACS, femoral and radial routes, n=683 and 531; PRASFIT-Elective, femoral and radial routes, n=135 and 508). Rates of periprocedural bleeding, bleeding not related to CABG, and puncture site bleeding were consistently lower in the radial access route group than in the femoral access route group in both studies. Risk factors for periprocedural bleeding included sex, body weight, age, and access route in PRASFIT-ACS (femoral access: hazard ratio [HR], 3.739; 95% confidence interval [CI]: 1.727-8.094; radial access: HR, 0.288; 95% CI: 0.128-0.65), and body weight, age, and access route in PRASFIT-Elective (femoral access: HR, 12.32; 95% CI 1.282->100; radial access: HR, 0.125; 95% CI: 0.013-1.205). Conclusions The incidence of periprocedural bleeding is lower with a radial access route than with a femoral access route for PCI in Japanese patients with ACS or those undergoing elective PCI for CAD.

This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio ≥10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria.

Prevention of deep vein thrombosis (DVT) is important in patients undergoing major orthopedic surgery. Although the detection of an elevated D-dimer level is useful for predicting DVT, it is not efficacious in postoperative patients being treated with anti-Xa agents. The soluble platelet glycoprotein VI (sGPVI) level is a marker of activated platelets, but not bleeding. Therefore, sGPVI levels are usually examined as a predictor of DVT in such patients. In the present study, 83 orthopedic patients were treated with 30 mg of edoxaban for prophylaxis of DVT. Fourteen patients developed DVT and 17 patients discontinued the prophylaxis due to decreased hemoglobin levels. Plasma levels of sGPVI in the patients were significantly higher after surgery than before surgery. On day 1, the sGPVI levels increased, while the platelet counts decreased. There were no significant differences in D-dimer, soluble fibrin, or FDP levels in orthopedic patients with and without DVT before surgery and on days 1, 4, and 8. Plasma sGPVI levels were significantly higher in the patients with DVT than in those without DVT on days 1 and 4. Plasma levels of D-dimer were significantly higher in patients with withdrawal than in those without. However, there were no significant differences in sGPVI levels between those with and without withdrawal. As D-dimer levels are known to increase in patients with withdrawal, this parameter is not useful for evaluating the risk of DVT in these patients. In contrast, the sGPVI level is not increased in those with withdrawal and may therefore be useful for evaluating the risk of DVT in postoperative patients treated with an anticoagulant.

Background Thrombotic microangiopathy (TMA) is caused by various conditions, such as decreased a ADAMTS13 level, activated or injured vascular endothelial cells or activated platelets. This study examined the soluble platelet glycoprotein VI (sGPVI) levels in patients with TMA to evaluate the activation of platelets in thrombotic states. Materials and Methods The plasma levels of sGPVI, ADAMTS13 activity, von Willebrand factor (VWF) and VWF propeptide (VWFpp) were measured in patients with TMA. Results The plasma levels of sGPVI were significantly higher in postoperative patients, patients with TMA and those with disseminated intravascular coagulation (DIC) than in those without thrombosis. The plasma levels of sGPVI were the highest in patients with TMA without markedly reduced ADAMTS13 and those were significantly reduced after plasma exchange. Conclusion The measurement of sGPVI level is therefore considered to be important for the diagnosis and evaluation of TMA.

Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.

Background:Prasugrel is being developed in Japan as an antiplatelet therapy for use during percutaneous coronary intervention (PCI). Up to 70% of Japanese patients with coronary artery disease undergo elective PCI. The PRASugrel For Japanese PatIenTs with Coronary Artery Diseases Undergoing Elective PCI (PRASFIT-Elective) study investigated the efficacy and safety of different prasugrel dosing regimens in Japanese patients undergoing elective PCI.Methods and Results:A total of 742 patients scheduled for elective coronary artery stenting were enrolled. Patients were randomized to receive either prasugrel (20/3.75 mg, loading/maintenance dose) or clopidogrel (300/75 mg) in a double-blind manner. Endpoints, including cardiovascular events and bleeding, were assessed at weeks 24–48. The incidence rate of major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke) up to week 24 was 4.1% (15/370) and 6.7% (25/372) in the prasugrel and clopidogrel groups, respectively. Other incidence rates were: non-coronary artery bypass graft-related major bleeding, 0% and 2.2%; major/minor bleeding, 1.6% and 3.0%; and all bleeding events, 38.1% and 34.4% in the prasugrel and clopidogrel groups, respectively. The incidence rate of bleeding-related adverse events was similar in both groups, being 40.8% and 35.8% in the prasugrel and clopidogrel groups, respectively.Conclusions:These results support the risk-benefit profile of an adjusted dosing regimen of prasugrel in Japanese patients undergoing PCI. Larger studies are required to confirm these findings. (Circ J 2014; 78: 2926–2934)

Background: In patients with coronary artery disease (CAD), there is an increasing therapeutic need among interventional cardiologists to conduct dual antiplatelet therapy (DAPT) whose duration is shorter than current guideline-recommended 6–12 months after the implantation of drug-eluting stents. However, no clinical grounds sufficient to rationalize the need are available. Objectives: To define the optimal duration of DAPT and to examine the safety and efficacy of the Endeavor zotarolimus-eluting stent (E-ZES) in real-world Japanese patients with CAD. Study design: The present prospective, nonrandomized, multicenter, controlled study is uniquely designed to examine the analysis set to be formulated after integrating two different databases consisting of the following two study arms: the 3-month DAPT arm, in which 1,210 patients were consecutively enrolled at 106 medical institutions; and the 12-month DAPT arm, in which 1,210 patients will be consecutively extracted from the Endeavor Japan post-marketing surveillance at 60 medical institutions. The primary endpoint is “net adverse cardiac and cerebrovascular events—death, myocardial infarction, cerebrovascular accident, and major bleeding)” at 12 months after implantation. The secondary endpoints are as follows: major adverse cardiac events at 1, 3, 6, 9, and 12 months after implantation; target vessel revascularization and target lesion revascularization at 9 and 12 months after implantation; and stent thrombosis, DAPT compliance, and bleeding events at 12 months after implantation. Noninferiority in the E-ZES's profiles between the study arms will be investigated. Conclusions: The present study will provide insight into the optimal duration of DAPT after the E-ZES implantation in individual, real-world patients with CAD. © 2013 Wiley Periodicals, Inc.

Background CYP2C19 loss-of-function genotype (*2 and/or *3 alleles) is related to low responsiveness to clopidogrel, which is a risk factor for ischemic cardiac events. The contribution of these genotypes to platelet reactivity in Japanese patients in a steady state receiving dual antiplatelet therapy after coronary stenting was evaluated. Methods and results A total of 155 Japanese patients were classified according to their CYP2C19 loss-of-function genotype. Platelet reactivity was assayed by plasma levels of soluble P-selectin and platelet-derived microparticles, light transmittance aggregometry induced by ADP (ADP-LTA), shear stress-induced platelet aggregometry, vasodilator-stimulated phosphoprotein phosphorylation (VASP) index and the VerifyNow-P2Y12 assay. Linear and logistic regression models were used to assess the associations between CYP2C19 loss-of-function genotype and high on-treatment platelet reactivity. In total, 62 patients (40.0%) were extensive metabolizers (EMs), 70 (45.2%) were intermediate metabolizers (IMs) and 23 (14.8%) were poor metabolizers (PMs). ADP-specific assays (ADP-LTA, the VASP index and VerifyNow-P2Y12) differed according to CYP2C19 genotype, with a significant gene-dose effect (PMs>IMs>EMs). CYP2C19 loss-of-function carrier status was associated with more frequent high platelet reactivity. CYP2C19 loss-of-function genotype alone could explain 12.2%, 14.3%, and 14.7% of the variability in the ADP-LTA, VASP and VerifyNow-P2Y12 assays, respectively. Conclusions CYP2C19 loss-of-function genotype is associated with more frequent high platelet reactivity, as assessed by ADP-specific platelet function tests, in Japanese patients.

Prasugrel is a third-generation thienopyridine that achieves potent platelet inhibition with less pharmacological variability than other thienopyridines. However, clinical experience suggests that prasugrel may be associated with a higher risk of de novo and recurrent bleeding events compared with clopidogrel in Japanese patients undergoing percutaneous coronary intervention (PCI). In this review, we evaluate the risk of bleeding in Japanese patients treated with prasugrel at the doses (loading/maintenance doses: 20/3.75 mg) adjusted for Japanese patients, evaluate the risk factors for bleeding in Japanese patients, and examine whether patients with a bleeding event are at increased risk of recurrent bleeding. This review covers published data and new analyses of the PRASFIT (PRASugrel compared with clopidogrel For Japanese patIenTs) trials of patients undergoing PCI for acute coronary syndrome or elective reasons. The bleeding risk with prasugrel was similar to that observed with the standard dose of clopidogrel (300/75 mg), including when bleeding events were re-classified using the Bleeding Academic Research Consortium criteria. The pharmacodynamics of prasugrel was not associated with the risk of bleeding events. The main risk factors for bleeding events were female sex, low body weight, advanced age, and presence of diabetes mellitus. Use of a radial puncture site was associated with a lower risk of bleeding during PCI than a femoral puncture site. Finally, the frequency and severity of recurrent bleeding events during continued treatment were similar between prasugrel and clopidogrel. In summary, this review provides important insights into the risk and types of bleeding events in prasugrel-treated patients. Trial registration numbers: JapicCTI-101339 and JapicCTI-111550.

Anagrelide is a cytoreductive agent for essential thrombocythemia and its common side effects are anemia, headache, palpitation, diarrhea, and fluid retention. However, severe pulmonary adverse effects are rare. A 66-year-old Japanese man with essential thrombocythemia presented with hemoptysis 2 months after starting anagrelide treatment. Interstitial pneumonia was diagnosed based on physical and radiographic findings. Discontinuation of anagrelide and institution of corticosteroids resulted in the improvement of interstitial pneumonia. Severe lung injury associated with anagrelide is a rare but an important adverse event that must be addressed when treating interstitial pneumonia.

Background/objectives Developmental changes of structures in neonatal and infant skin have not been well characterized. The purpose of this study was to clarify changes in skin structures during neonatal and infant growth in vivo. Methods Fifteen healthy, full-term neonates (seven girls, eight boys) were studied. The measurements were performed 4 to 7 days (neonate) and 1, 3, and 6 months after birth on the buttock, upper thigh, and ventral forearm skin using a confocal laser scanning microscope. Developmental changes in dermoepidermal junction structures, stratum corneum thickness, epidermal thickness, and microvascular development were investigated. Results A significant decrease in stratum corneum thickness was observed over the 3 months after birth. Dermal papillae were not observed in neonatal skin but were observed gradually over the next 3 months. Epidermal thickness, determined from the skin surface to the bottom of the epidermal layer, increased significantly from 4 to 7 days to 1 month of age, indicating the formation of dermal papillae and rete ridges. Complicated microvascular structures were observed in neonatal skin but disappeared gradually and were observed only at the dermal papillae at 3 months of age. Conclusions Our results reveal that infant skin is in a developmental stage structurally up to 3 months of age, paralleling skin functional and developmental maturation.

7561Background: CD5+ DLBCL comprises 5-10% of DLBCL and is characterized by various aggressive clinical features and frequent CNS relapse. Our previous retrospective study (Miyazaki et al. Ann Onco...

Immune thrombocytopenic purpura (ITP) is an acquired hemorrhage condition involving accelerated platelet consumption caused by antiplatelet autoantibodies. Although various therapeutic strategies are used to treat patients with ITP, the standard treatment method is steroid therapy. The most important problem with steroid administration may be a prolonged use tendency in many cases, because there are many refractory chronic patients. To elucidate the effects of glucocorticoid on bone mineral density (BMD) in patients with ITP, we retrospectively evaluated the relationship between BMD and the total dose of glucocorticoid or the mean daily dose given. We observed decreased BMD in 66.7% of the patients with ITP to whom glucocorticoid was given, although normal bone BMD was observed in 28.6% of patients with ITP treated without steroids. The mean level of BMD was markedly decreased in steroid-treated patients compared with nonsteroid-treated patients (P < .01). The relationship between BMD and the total dose of glucocorticoid (P = .023) or the mean daily dose revealed a negative correlation (P = .022). Administration of bisphosphonate revealed a significant increase in bone mass in patients at 6 and 12 months after the start of bisphosphonate treatment, despite the aggravation of thrombocytopenia. In conclusion, glucocorticoid-induced osteoporosis was observed in patients with ITP, similar to situation seen in patients with other diseases. Bisphosphonate may be an effective agent for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with ITP scheduled to receive long-term steroid treatment.

Antiplatelet drugs belong to the class of pharmaceuticals that inhibit platelet activation and thereby suppress arterial thrombus formation. They are widely used for primary and secondary prevention of atherothrombotic diseases including coronary heart diseases, ischemic strokes and peripheral arterial diseases. These drugs are broadly classified into two categories: (1) inhibitors of the platelet activation signal-transduction system, and (2) stimulators of production of inhibitory signals such as cAMP and cGMP. The first category comprises ADP receptor (P2Y12) antagonists including ticlopidine, clopidogrel and prasugrel; the serotonin 5-HT2 receptor antagonist sarpogrelate; the cyclooxygenase-1 inhibitor aspirin; and eicosapentaenoic acid. The second category comprises prostacyclin analog, the cyclic nucleotide phosphodiesterase (PDE)-3 inhibitor cilostazol, and the PDE-5 inhibitor dipyridamole. Drugs in the second category stimulate vasodilation, as well as inhibit platelet aggregation. Current clinical trial evidence favors the use of aspirin, clopidogrel and cilostazol as first-line agents in the majority of patients with vascular disease. Clinical trials evaluating novel antiplatelet drugs will impact the direction of future practice.

Platelets are produced by megakaryocytes (MKs) through proplatelet formation (PPF), or cytoplasmic extensions, in vitro. Through the use of video-enhanced light microscopy, as well as localization of cytoskeletal proteins by confocal microscopy, the reaction of fully mature MK proplatelets, derived from murine embryonic stem cells, to various agents was studied. Calyculin A (protein phosphatase 1/2A inhibitor) treatment induced proplatelet retraction. In MKs with PPF, the expression of actin, myosin IIA, monophosphorylated myosin light chain (MLC-P1), and diphosphorylated myosin light chain (MLC-P2) was diffusely located. Following calyculin A treatment, actin was diffusely localized in retracted MKs and was expressed particularly in the periphery. MLC-P1 was also localized primarily in the periphery; however, MLC-P2 was expressed mostly in the inner area of proplatelets. Protein phosphatase inhibitors may result in increased hyperphosphorylation of localized MLC, which could alter the balance of actomyosin force in a cell, and therefore induce proplatelets retraction.

The ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type I domain 13) related markers were measured in the plasma of healthy volunteers and thrombotic microangiopathy (TMA) patients including thrombotic thrombocytopenic purpura (TTP) to examine their efficacy in the diagnosis of TTP. The plasma levels of the ADAMTS13 antigen and ADAMTS13-factor XI complex were significantly lower in TMA patients with a significant decreased ADAMTS13 activity (and these patients were considered to have TTP) than in the healthy volunteers. The plasma levels of ADAMTS13 antigens closely correlated with those of ADAMTS13-factor XI complex. Autoantibody for ADAMTS 13 was also positive in almost all TTP patients. In addition, the ratio of von Willebrand factor (VWF)/ADAMTS13 activity was significantly high in TTP suggesting that this ratio might be more useful for the differential diagnosis of TTP than the ADAMTS13 assay alone. These findings suggest that ADAMTS13 related markers are useful for the diagnosis and analysis of TTP.

SummarySeveral studies have indicated that approximately 25% of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8%). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.Supplementary Material to this article is available at www.thrombosis-online.com.

Primary immune thrombocytopenia (ITP) is an autoimmune disease mediated by the production of autoantibody against platelets. Rituximab, an anti-CD20 antibody, is reported to be useful for treatment of ITP. In Japan, however, robust evidence on this treatment has not been accumulated. Hence, we conducted this open-label phase III clinical trial to confirm the efficacy and safety of rituximab, administered at 375 mg/m² once per week at weekly intervals for 4 consecutive weeks in Japanese patients with chronic ITP, who had relapsed and were refractory to conventional therapy. The primary endpoint was defined as the percentage of patients with a platelet count above 50 × 10⁹/L at week 24 after the first dose of rituximab, which was 30.8% of 26 patients (95% confidence interval 14.3-51.8%). Although the lower confidence limit of primary endpoint failed to meet the pre-specified threshold of 20%, the clinical efficacy of rituximab is substantial in consideration of the 2% response rate in the placebo arm in other clinical studies in patients with chronic ITP. We conclude that rituximab is clinically useful and safe in the treatment of Japanese patients with chronic ITP, achieving the goal of maintaining platelet count and reducing risk of bleeding while minimizing treatment-related toxicity.

Background We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study. Methods Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75 mg) or clopidogrel (300/75 mg) plus aspirin for 24–48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow® P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). Results Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM + PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2–4 and 5–12 h after the loading dose, but was similar in both groups from week 4 onwards. Among IM + PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50–1.96]. Among IM + PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45–1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype. Conclusions Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype.

BACKGROUND Anticoagulation is recommended as standard of care for venous thromboembolism (VTE) (pulmonary embolism [PE]/deep vein thrombosis [DVT]), for which unfractionated heparin (UFH) and warfarin are used in Japan. In the multi-regional AMPLIFY study, a fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for treatment of PE/DVT and was associated with significantly fewer bleeding events. METHODS AND RESULTS Japan phase 3 study (AMPLIFY-J), randomized, active-controlled, open-label study in Japanese subjects with acute PE/DVT, was designed based on AMPLIFY. Key objectives were to investigate safety and efficacy of apixaban in symptomatic PE/DVT subjects during 24-week treatment. UFH/warfarin was used as control treatment. Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. All endpoints and imaging for thrombotic burden were assessed by an event adjudication committee. Eighty subjects were randomized, 33 subjects (41.3%) were aged

Background: In 2011, the Bleeding Academic Research Consortium (BARC) criteria were published to standardize the assessment of bleeding events following PCI. However, the status of bleeding events as assessed using the BARC criteria is not established in Japan. The aim of this post-hoc analysis of the PRASFIT-ACS and PRASFIT-Elective trials was to re-classify the bleeding events from the Thrombolysis in Myocardial Infarction (TIMI) criteria into the BARC criteria. Methods: Bleeding events had previously been assessed in both trials using the TIMI criteria. In the post-hoc analysis, the BARC criteria were applied retrospectively to each category of bleeding. Results: In PRASFIT-ACS, the incidences of severe bleeds (combined type 3 or 5 bleeds according to BARC criteria) were 43/685 [6.3%] with prasugrel and 37/678 [5.5%] with clopidogrel [HR 1.071; 95% CI 0.668–1.667]. Types 3 or 5 events occurred at a higher rate closer to the time of PCI, and then plateaued. In PRASFIT-Elective, Type 3 bleeding occurred in 10/370 (2.7%) patients in the prasugrel group and 12/372 (3.2%) in the clopidogrel group. There was a higher incidence of bleeding events in PRASFIT-ACS than in PRASFIT-Elective, particularly more severe bleeds (combination of type 3 or 5 events). Conclusions: The results obtained with the BARC criteria were similar to those reported using the original TIMI criteria. The incidences of type 3 or 5 events according to the BARC criteria were similar in the prasugrel and clopidogrel groups. Medical interventions might be needed during the acute period of PCI for ACS to reduce the risk of type 2 bleeding events in patients with low platelet aggregation.

Purpose: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4+ T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers.Experimental Design: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 μg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4+ T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein.Results: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8+ and/or CD4+ T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8+ T-cell responses, two patients reacted to previously identified HER263-71 peptide and the other two reacted only to 146HER2 mRNA-transduced cells.Conclusions: CHP-HER2 vaccine was safe and induced HER2-specific CD8+ and/or CD4+ T-cell immune responses.

Plasma levels of granulocyte-derived elastase (GE-XDP), D-dimer, and soluble fibrin (SF) were examined in 177 patients with disseminated intravascular coagulation (DIC) of various etiologies. Plasma levels of GE-XDP and D-dimer, but not SF, were significantly high in patients with sepsis and solid cancer. The ratio of GE-XDP/D-dimer was significantly high in patients with trauma, burn, and sepsis, suggesting that fibrinolysis due to GE-XDP may be dominant in DIC. Plasma levels of GE-XDP and D-dimer, but not SF, were significantly high in patients with overt DIC and correlated with DIC score. Plasma levels of GE-XDP, but not SF, correlated significantly with D-dimer. Plasma levels of D-dimer, but not SF, correlated significantly with plasmin plasmin inhibitor complex (PPIC). Plasma levels of GEXDP and D-dimer, but not SF, were significantly high in nonsurvivors. Plasma levels of GE-XDP, but not SF, correlated significantly with sepsis-related organ failure assessment (SOFA) score. These results suggest that GE-XDP is a potentially useful marker for the diagnosis of overt-DIC and as a predictor of organ failure-related outcome.

Thrombin induced a shape change of UT-7/TPO, a thrombopoietin-dependent human megakaryocytic cell line. Expression of myosin light chain (MLC) kinase was negligible in UT-7/TPO cells, while Rho-kinase and protein kinase C (PKC) were detected. Thrombin stimulated both monophosphorylation at Ser19 and diphosphorylation at Thr18 and Ser19 of 20 kDa MLC, as well as phosphorylation of myosin-binding subunit (MBS) and PKC-potentiated inhibitory phosphoprotein of myosin phosphatase (CPI). The Rho-kinase inhibitor Y-27632 [(+)-(R)-trans-(1-aminoethyl)-N-(4-phynidyl) cyclohexane-carboxamide dihydrochloride, monohydrade] strongly inhibited thrombin-induced shape change, MBS phosphorylation, and mono- and diphosphorylation of MLC. The PKC inhibitor GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) partially inhibited thrombin-induced shape change and MLC diphosphorylation even at the concentration that completely inhibited thrombin-induced CPI phosphorylation. In shape-changed UT-7/TPO cells induced by thrombin, phosphorylated MBS and CPI were colocalized with diphosphorylated MLC at pseudopods, whereas monophosphorylated MLC was mainly located in the cortical region. The accumulation of diphosphorylated MLC was blocked by preincubation with either Y-27632 or GF109203X. These results suggest that Rho-kinase is responsible for the induction of MLC phosphorylation in thrombin-induced shape change of UT-7/TPO cells and that myosin phosphatase inactivation through Rho-kinase-MBS and PKC-CPI pathways could be necessary for enhancement of MLC diphosphorylation which promote the pseudopod formation.

Vascular events caused by arteriosclerosis are the major cause of death in patients under hemodialysis (HD). Arteriosclerosis is associated with lipoprotein abnormalities such as increased serum levels of low-density lipoprotein (LDL), especially of modified LDL (M-LDL) and oxidized LDL (Ox-LDL). We examined the relationship between markers of arteriosclerosis, hemostasis, and lipid metabolism in patients with chronic renal failure, hyperlipidemia, and healthy volunteers. In patients under HD, the serum levels of total cholesterol, LDL, and triglyceride (TG) were decreased, but the serum levels of M-LDL were increased compared to HL and healthy volunteers. In patients with CRF, the serum levels of OxLDL in patients under HD were lower than in those under continuous ambulatory peritoneal dialysis or conservative therapy. The plasma levels of antithrombin and protein C were significantly lower and the plasma levels of thrombomodulin were significantly higher in patients under HD compared to those under conservative therapy. These data show that patients under HD were more in hypercoagulable state than those under conservative therapy. Among patients under HD, only the plasma levels of von Willebrand factor were significantly increased in patients with more than 30 U/L of Ox-LDL compared to those with less than 30 U/L of Ox-LDL. There was no significant difference in the tests of arteriosclerosis among M-LDL values and OxLDL values. These findings suggest that abnormalities of lipid are not the main risk factor for arteriosclerosis disease in patients under HD.

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had

Antiplatelet therapy is widely used with proven benefit for the prevention of further ischemic complications in patients with coronary heart disease and stroke. Treatment guidelines for acute coronary syndrome and percutaneous coronary intervention now recommend the use of oral antiplatelet agents including clopidogrel in combination with aspirin (dual antiplatelet therapy: DAPT) for the prevention of recurrent ischemic events. The limitations of DAPT with clopidogrel include the potential for low response to clopidogrel identified through platelet reactivity or genetic testing, or slower return to normal platelet activity in patients who received clopidogrel prior to emergent or planned surgical procedures. This review will discuss the pharmacologic properties and clinical studies about new antiplatelet drugs including prasugrel, ticagrelor and PAR-1 inhibitors.

The purpose of the present study was to determine if sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling. Forty-one male Sprague–Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day −2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n = 9) for lung tissue were performed. Chronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p

Protein kinase C (PKC)-potentiated inhibitory phosphoprotein of myosin phosphatase (CPI) was detected in human platelets. Like smooth muscle CPI-17, in vitro phosphorylation of platelet CPI by PKC inhibited the activity of myosin phosphatase containing the PP1delta catalytic subunit and the 130-kd myosin-binding subunit (MBS). Treatment of intact platelets with thrombin or the stable thromboxane A(2) analog STA(2) resulted in increased phosphorylation of both CPI and MBS at Thr-696, whereas phorbol myristate acetate (PMA) and the Ca(++) ionophore ionomycin only induced CPI phosphorylation. PMA induced slow adenosine triphosphate (ATP) secretion of fura 2-loaded platelets with no change in cytosolic Ca(++). The PMA-induced increase in CPI phosphorylation preceded phosphorylation of 20-kd myosin light chain (MLC(20)) at Ser-19 and ATP secretion. The PKC inhibitor, GF109203X, inhibited PMA-induced phosphorylation of CPI and MLC(20) with similar IC(50) values. These findings suggest that the activation of PKC by PMA induces MLC(20) phosphorylation by inhibiting myosin phosphatase through phosphorylation of CPI. STA(2)-induced MLC(20) phosphorylation was also diminished but not abolished by GF109203X, even at high concentrations that completely inhibited STA(2)-induced CPI phosphorylation. A combination of the Rho-kinase inhibitor Y-27632 and GF109203X led to a further decrease in STA(2)-induced MLC(20) phosphorylation, mainly because of a significant inhibition of MBS phosphorylation at Thr-696. Inhibition of STA(2)-induced ATP release by Y-27632, GF109203X, or both appeared to correlate with the extent of MLC(20) phosphorylation. Thus, CPI phosphorylation by PKC may participate in inhibiting myosin phosphatase, in addition to the Rho-kinase-mediated regulation of myosin phosphatase, during agonist-induced platelet secretion. (Blood. 2001;97:3798-3805)