RESUMEN

Because environmental stress can reduce crop growth and yield, the identification of genes that enhance agronomic traits is increasingly important. Previous screening of full-length cDNA overexpressing (FOX) rice lines revealed that OsTIFY11b, one of 20 TIFY proteins in rice, affects plant size, grain weight, and grain size. Therefore, we analyzed the effect of OsTIFY11b and nine other TIFY genes on the growth and yield of corresponding TIFY-FOX lines. Regardless of temperature, grain weight and culm length were enhanced in lines overexpressing TIFY11 subfamily genes, except OsTIFY11e. The TIFY-FOX plants exhibited increased floret number and reduced days to flowering, as well as reduced spikelet fertility, and OsTIFY10b, in particular, enhanced grain yield by minimizing decreases in fertility. We suggest that the enhanced growth of TIFY-transgenic rice is related to regulation of the jasmonate signaling pathway, as in Arabidopsis. Moreover, we discuss the potential application of TIFY overexpression for improving crop yield.

Asunto(s)

Ciclopentanos/metabolismo , Oryza/crecimiento & desarrollo , Oryza/genética , Oxilipinas/metabolismo , Proteínas de Plantas/genética , Transducción de Señal , Ciclopentanos/farmacología , Flores/efectos de los fármacos , Flores/crecimiento & desarrollo , Expresión Génica , Calor , Oryza/citología , Oryza/efectos de los fármacos , Oxilipinas/farmacología , Transducción de Señal/efectos de los fármacos

RESUMEN

[This corrects the article DOI: 10.1186/s12959-015-0035-3.].

Asunto(s)

Relación Normalizada Internacional/normas , Sistemas de Atención de Punto/normas , Warfarina/uso terapéutico , Monitoreo de Drogas , Humanos , Rivaroxabán/uso terapéutico

RESUMEN

BACKGROUND: Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. METHODS: The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. RESULTS: The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. CONCLUSIONS: Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.

Asunto(s)

Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Hemorragia/inducido químicamente , Rivaroxabán/efectos adversos , Warfarina/efectos adversos , Anciano , Anemia/complicaciones , Anticoagulantes/administración & dosificación , Femenino , Humanos , Japón , Masculino , Análisis Multivariante , Inhibidores de Agregación Plaquetaria/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Rivaroxabán/administración & dosificación , Accidente Cerebrovascular/prevención & control , Warfarina/administración & dosificación

RESUMEN

BACKGROUND: In Japan, the standard of care for the treatment of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) consists of intravenous unfractionated heparin (UFH) followed by warfarin, which was recently compared with rivaroxaban, an oral factor Xa inhibitor, in randomized trials. AIM: To examine the length of hospital stay in patients with PE and/or DVT receiving rivaroxaban compared to Japanese standard therapy in the Japanese (J)-EINSTEIN PE and DVT program. METHODS: Open-label, randomized clinical trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients with acute, confirmed symptomatic proximal PE and/or DVT. Decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Analyses were conducted in the intention-to-treat (ITT) population. RESULTS: In the ITT population (N = 97), overall patient characteristics were similar in both treatment arms. The median length of stay in rivaroxaban patients was 10.0 days (interquartile range [IQR] 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0) for patients on standard therapy (p = 0.016). All of the four DVT patients who were not hospitalized for the index event were in the rivaroxaban arm. CONCLUSIONS: Our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. The limitations of our study include small sample size and the generalizability of the findings to the real-world setting. Further research is warranted to identify PE and/or DVT patients in Japanese clinical practice who may potentially be managed as outpatients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01516814 and NCT01516840.

Asunto(s)

Anticoagulantes/uso terapéutico , Embolia Pulmonar/tratamiento farmacológico , Rivaroxabán/uso terapéutico , Trombosis de la Vena/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Femenino , Heparina/uso terapéutico , Humanos , Japón , Tiempo de Internación , Masculino , Persona de Mediana Edad , Tromboembolia Venosa/tratamiento farmacológico , Warfarina/uso terapéutico

RESUMEN

High-dose calcium channel blocker (CCB) shows strong blood pressure (BP) lowering effect. Currently available of controlled-release (CR) nifedipine 80 mg per day clinical data are limited to monotherapy and short-term or long-term retrospective studies. We report the safety and efficacy results of a 52-week, prospective open-label study, in which Japanese patients with essential hypertension were treated with CR nifedipine [80 mg per day; 40 mg bis in die (BID; twice daily)] in combination with other antihypertensive drugs. The patients with inadequate BP control despite treatment with CR nifedipine (40 mg once daily) in combination with other antihypertensive drugs were enrolled. The primary objective of this study was to assess the long-term safety of CR nifedipine (80 mg per day). Efficacy variables included changes in the mean sitting BP, the target BP achievement rate and the BP response rate. CR nifedipine (80 mg per day) was generally well tolerated, with the most common drug-related treatment-emergent adverse event being tachycardia (6.9% of patients). Serious treatment-emergent adverse events were reported in three (4.2%) patients. By week 52, the mean reductions in sitting systolic and diastolic BP were 19.4 and 13.6 mm Hg, respectively. The target BP achievement and BP response rates after 52 weeks of treatment were 32.4 and 63.4%, respectively. Based on these findings, long-term treatment with CR nifedipine at 40 mg BID in combination with antihypertensive drugs was well tolerated and effective in Japanese patients with essential hypertension.

Asunto(s)

Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Nifedipino/efectos adversos , Nifedipino/uso terapéutico , Anciano , Pueblo Asiatico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Preparaciones de Acción Retardada , Método Doble Ciego , Quimioterapia Combinada , Hipertensión Esencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nifedipino/administración & dosificación , Estudios Prospectivos , Estudios Retrospectivos , Taquicardia/inducido químicamente , Taquicardia/fisiopatología , Resultado del Tratamiento

RESUMEN

BACKGROUND: The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban. METHODS: We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5-2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding. RESULTS: Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4-23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group. CONCLUSIONS: The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01516840 and NCT01516814.

RESUMEN

BACKGROUND: The J-ROCKET AF study found that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcome in patients with atrial fibrillation (AF). The aim of this subgroup analysis was to assess the safety and efficacy of rivaroxaban and warfarin in relation to patient age. METHODS AND RESULTS: A total of 39.0% were elderly (aged ≥75 years). In elderly patients, the principal safety outcome occurred at 25.05%/year with rivaroxaban vs. 16.95%/year on warfarin (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.02-2.16), whereas the primary efficacy endpoint occurred at 2.18%/year vs. 4.25%/year (HR, 0.51; 95% CI: 0.20-1.27), respectively. There were significant interactions in the principal safety outcomes of rivaroxaban compared with warfarin between the elderly and non-elderly groups, but not in the primary efficacy endpoints (P=0.04 and 0.82 for both interactions, respectively). Furthermore, in elderly patients, in the rivaroxaban group there was a trend to increase the principal safety outcome regardless of renal function. In elderly patients with preserved renal function, however, patients on rivaroxaban had a marginally favorable trend in the primary efficacy endpoint incidence rate compared with patients on warfarin. CONCLUSIONS: There is a need to carefully consider the risks and benefits of therapy with rivaroxaban in elderly patients with non-valvular AF.

Asunto(s)

Envejecimiento , Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa , Morfolinas , Tiofenos , Warfarina , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Morfolinas/efectos adversos , Estudios Prospectivos , Factores de Riesgo , Rivaroxabán , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Warfarina/administración & dosificación , Warfarina/efectos adversos

RESUMEN

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84-1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66-1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03-2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25-1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.

Asunto(s)

Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa/uso terapéutico , Fibrinolíticos/uso terapéutico , Hipertensión/tratamiento farmacológico , Morfolinas/uso terapéutico , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , Anciano , Pueblo Asiatico , Fibrilación Atrial/complicaciones , Método Doble Ciego , Inhibidores del Factor Xa/efectos adversos , Femenino , Fibrinolíticos/efectos adversos , Humanos , Hipertensión/complicaciones , Japón , Masculino , Morfolinas/efectos adversos , Rivaroxabán , Tiofenos/efectos adversos , Resultado del Tratamiento , Warfarina/efectos adversos

RESUMEN

BACKGROUND: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was noninferior to warfarin with respect to the principal safety outcome. In this subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin in relation to patients' CHADS2 scores. RESULTS: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and 4. No statistically significant interactions were observed between principal safety outcome event rates and CHADS2 scores with respect to treatment groups (P value for interaction = .700). Irrespective of stratification into moderate- and high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no differences in principal safety outcome event rates were observed between rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio [HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11; 95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end point rate in the rivaroxaban-treated group was numerically lower than in the warfarin-treated group, regardless of risk group stratification (moderate-risk group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P value for interaction = .935). CONCLUSION: This subanalysis indicated that the safety and efficacy of rivaroxaban compared with warfarin were similar, regardless of CHADS2 score.

Asunto(s)

Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Morfolinas/uso terapéutico , Accidente Cerebrovascular/prevención & control , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , Anciano , Anticoagulantes/efectos adversos , Pueblo Asiatico , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etnología , Fibrilación Atrial/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Morfolinas/efectos adversos , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Rivaroxabán , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etnología , Accidente Cerebrovascular/mortalidad , Tiofenos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Warfarina/efectos adversos

RESUMEN

BACKGROUND: The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. METHODS: Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. RESULTS: The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate -2.13; 95% confidence interval [CI]: -.26 to -3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: -1.14; 95% CI: -3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. CONCLUSION: Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF.

Asunto(s)

Anticoagulantes/uso terapéutico , Pueblo Asiatico , Fibrilación Atrial/tratamiento farmacológico , Isquemia Encefálica/prevención & control , Inhibidores del Factor Xa/uso terapéutico , Morfolinas/uso terapéutico , Accidente Cerebrovascular/prevención & control , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , Anticoagulantes/efectos adversos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etnología , Fibrilación Atrial/mortalidad , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnología , Isquemia Encefálica/mortalidad , Método Doble Ciego , Inhibidores del Factor Xa/efectos adversos , Humanos , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/etnología , Japón , Morfolinas/efectos adversos , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Rivaroxabán , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etnología , Accidente Cerebrovascular/mortalidad , Tiofenos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Warfarina/efectos adversos

Asunto(s)

Anticoagulantes/administración & dosificación , Fibrilación Atrial/complicaciones , Embolia/prevención & control , Morfolinas/administración & dosificación , Accidente Cerebrovascular/prevención & control , Tiofenos/administración & dosificación , Warfarina/administración & dosificación , Femenino , Humanos , Masculino

RESUMEN

This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective.

Asunto(s)

Fibrilación Atrial/tratamiento farmacológico , Morfolinas/farmacología , Morfolinas/farmacocinética , Tiofenos/farmacología , Tiofenos/farmacocinética , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Humanos , Modelos Biológicos , Rivaroxabán

RESUMEN

BACKGROUND: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. METHODS: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). RESULTS: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). CONCLUSIONS: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group.

Asunto(s)

Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/prevención & control , Inhibidores del Factor Xa/uso terapéutico , Morfolinas/uso terapéutico , Accidente Cerebrovascular/prevención & control , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Pueblo Asiatico , Método Doble Ciego , Inhibidores del Factor Xa/efectos adversos , Femenino , Humanos , Ataque Isquémico Transitorio/complicaciones , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Estudios Prospectivos , Rivaroxabán , Prevención Secundaria , Tiofenos/efectos adversos , Resultado del Tratamiento , Warfarina/efectos adversos

RESUMEN

The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.

Asunto(s)

Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Morfolinas/administración & dosificación , Tiofenos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Fibrilación Atrial/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Morfolinas/farmacocinética , Tiempo de Tromboplastina Parcial , Simulación de Paciente , Tiempo de Protrombina , Rivaroxabán , Tiofenos/farmacocinética

RESUMEN

BACKGROUND: In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15 mg once daily was given to patients with creatinine clearance (CrCl) ≥ 50 ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30-49 ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment. METHODS AND RESULTS: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78-1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25-2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively). CONCLUSIONS: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function.

Asunto(s)

Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Pueblo Asiatico , Fibrilación Atrial/tratamiento farmacológico , Morfolinas/efectos adversos , Morfolinas/uso terapéutico , Insuficiencia Renal/inducido químicamente , Accidente Cerebrovascular/prevención & control , Tiofenos/efectos adversos , Tiofenos/uso terapéutico , Administración Oral , Anciano , Anciano de 80 o más Años , Anticoagulantes/farmacología , Fibrilación Atrial/fisiopatología , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Japón , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Morfolinas/farmacología , Insuficiencia Renal/metabolismo , Insuficiencia Renal/fisiopatología , Reproducibilidad de los Resultados , Factores de Riesgo , Rivaroxabán , Tiofenos/farmacología , Resultado del Tratamiento , Warfarina/efectos adversos , Warfarina/uso terapéutico

RESUMEN

Plasma proteins mediate thrombogenesis, inflammation, endocardial injury and structural remodelling in atrial fibrillation (AF). We hypothesised that anti-coagulation with rivaroxaban, a direct factor Xa inhibitor, would differentially modulate biologically-relevant plasma proteins, compared with warfarin, a multi-coagulation protein antagonist. We performed unbiased liquid chromatography/tandem mass spectroscopy and candidate multiplexed protein immunoassays among Japanese subjects with non-valvular chronic AF who were randomly assigned to treatment with 24 weeks of rivaroxaban (n=93) or warfarin (n=94). Nine metaproteins, including fibulin-1 (p=0.0033), vitronectin (p=0.0010), haemoglobin α (p=0.0012), apolipoproteins C-II (p=0.0017) and H (p=0.0023), complement C5 precursor (p=0.0026), coagulation factor XIIIA (p=0.0026) and XIIIB (p=0.0032) subunits, and 10 candidate proteins, including thrombomodulin (p=0.0004), intercellular adhesion molecule-3 (p=0.0064), interleukin-8 (p=0.0007) and matrix metalloproteinase-3 (p=0.0003), were differentially expressed among patients with and without known clinical risk factors for stroke and bleeding in AF. Compared with warfarin, rivaroxaban treatment was associated with a greater increase in thrombomodulin (Δ 0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase-9 (Δ 2.2 vs. -4.9 pg/ml, p=0.0757) over 24 weeks. Only modest correlations were observed between protein levels and prothrombin time, factor Xa activity and prothrombinase-induced clotting time. Plasma proteomics can identify distinct functional patterns of protein expression that report on known stroke and bleeding risk phenotypes in an ethnically-homogeneous AF population. The greater upregulation of thrombomodulin among patients randomised to rivaroxaban represents a proof-of-principle that pharmacoproteomics can be employed to discern novel effects of factor Xa inhibition beyond standard pharmacodynamic measures.

Asunto(s)

Anticoagulantes/uso terapéutico , Fibrilación Atrial/sangre , Fibrilación Atrial/tratamiento farmacológico , Proteínas Sanguíneas/metabolismo , Inhibidores del Factor Xa , Morfolinas/uso terapéutico , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , Anciano , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Biomarcadores/sangre , Femenino , Hemorragia/sangre , Hemorragia/etiología , Humanos , Masculino , Morfolinas/efectos adversos , Proteómica , Factores de Riesgo , Rivaroxabán , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Tiofenos/efectos adversos , Trombosis/sangre , Trombosis/etiología , Warfarina/efectos adversos

RESUMEN

BACKGROUND: The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation (AF). A separate trial, J-ROCKET AF, compared the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF. METHODS AND RESULTS: J-ROCKET AF was a prospective, randomized, double-blind, phase III trial. Patients (n=1,280) with non-valvular AF at increased risk for stroke were randomized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines. The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinically relevant bleeding, in the on-treatment safety population. The primary efficacy endpoint was the composite of stroke and systemic embolism. Non-inferiority of rivaroxaban to warfarin was confirmed; the rate of the principal safety outcome was 18.04% per year in rivaroxaban-treated patients and 16.42% per year in warfarin-treated patients (hazard ratio [HR] 1.11; 95% confidence interval 0.87-1.42; P<0.001 [non-inferiority]). Intracranial hemorrhage rates were 0.8% with rivaroxaban and 1.6% with warfarin. There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin (HR, 0.49; P=0.050). CONCLUSIONS: J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice.

Asunto(s)

Anticoagulantes/administración & dosificación , Fibrilación Atrial/complicaciones , Embolia/prevención & control , Morfolinas/administración & dosificación , Accidente Cerebrovascular/prevención & control , Tiofenos/administración & dosificación , Warfarina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Método Doble Ciego , Embolia/etiología , Femenino , Humanos , Hemorragias Intracraneales/inducido químicamente , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Estudios Prospectivos , Rivaroxabán , Accidente Cerebrovascular/etiología , Tiofenos/efectos adversos , Warfarina/efectos adversos

RESUMEN

The latest report has estimated the number of rice genes to be approximately 32,000. To elucidate the functions of a large population of rice genes and to search efficiently for agriculturally useful genes, we have been taking advantage of the Full-length cDNA Over-eXpresser (FOX) gene-hunting system. This system is very useful for analyzing various gain-of-function phenotypes from large populations of transgenic plants overexpressing cDNAs of interest and others with unknown or important functions. We collected the plasmid DNAs of 13,980 independent full-length cDNA (FL-cDNA) clones to produce a FOX library by placing individual cDNAs under the control of the maize Ubiquitin-1 promoter. The FOX library was transformed into rice by Agrobacterium-mediated high-speed transformation. So far, we have generated approximately 12,000 FOX-rice lines. Genomic PCR analysis indicated that the average number of FL-cDNAs introduced into individual lines was 1.04. Sequencing analysis of the PCR fragments carrying FL-cDNAs from 8615 FOX-rice lines identified FL-cDNAs in 8225 lines, and a database search classified the cDNAs into 5462 independent ones. Approximately 16.6% of FOX-rice lines examined showed altered growth or morphological characteristics. Three super-dwarf mutants overexpressed a novel gibberellin 2-oxidase gene,confirming the importance of this system. We also show here the other morphological alterations caused by individual FL-cDNA expression. These dominant phenotypes should be valuable indicators for gene discovery and functional analysis.

Asunto(s)

Perfilación de la Expresión Génica/métodos , Genoma de Planta , Oryza/genética , Secuencia de Bases , Cartilla de ADN , ADN Complementario , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rhizobium/genética

RESUMEN

Glucose-induced insulin secretion from beta-cells is often impaired in diabetic condition and by exposure to diabetogenic pharmacological agents. In pancreatic beta-cells, intracellular glucose metabolism regulates exocytosis of insulin granules, according to metabolism-secretion coupling in which glucose-induced mitochondrial ATP production plays an essential role. Impaired glucose-induced insulin secretion often results from impaired glucose-induced ATP elevation in beta-cells. Mitochondrial ATP production is driven by the proton-motive force including mitochondrial membrane potential (DeltaPsi(m)) generated by the electron transport chain. These electrons are derived from reducing equivalents, generated in the Krebs cycle and transferred from cytosol by the shuttles. Here, roles of the determinants of mitochondrial ATP production in impaired glucose-induced insulin secretion are discussed. Cytosolic alkalization, H(+) leak in the inner membrane by uncoupler (e.g. free fatty acid exposure), decrease in the supply of electron donors including NADH and FADH(2) to the respiratory chain, and endogenous mitochondrial ROS (e.g. Na(+)/K(+)-ATPase inhibition) all reduce hyperpolarlization of DeltaPsi(m) and ATP production, causing decresed glucose-induced insulin release. The decrease in the supply of NADH and FADH(2) to the respiratory chain derives from impairments in glucose metabolism including glycolysis (e.g. MODY2 and exposure to NO) and the shuttles (e.g. diabetic state and exposure to ketone body).

Asunto(s)

Adenosina Trifosfato/metabolismo , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocondrias/metabolismo , Humanos , Modelos Biológicos , Especies Reactivas de Oxígeno