Evaluation of the efficacy and tolerability of fixed-dose combination therapy of azilsartan and amlodipine besylate in Japanese patients with grade I to II essential hypertension.

BACKGROUND: Guidelines for the management of hypertension recommend using drugs with different mechanisms of action in antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products. OBJECTIVE: The objective of this study was to compare the efficacy and tolerability of the FDC of azilsartan (AZI) and amlodipine besylate (AML) with those of AZI monotherapy and AML monotherapy in Japanese patients with grade 1 to 2 essential hypertension. METHODS: This was a multicenter, randomized, double-blind, parallel-group study. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive 1 of the following 5 treatments for 8 weeks: FDC containing AZI 20 mg and AML 5 mg (AZI/AML 20/5 mg), FDC containing AZI 20 mg and AML 2.5 mg (AZI/AML 20/2.5 mg), AZI 20 mg, AML 5 mg, or AML 2.5 mg once daily in a fasting or fed state. The primary end point was the change from baseline (week 0) in the seated trough diastolic blood pressure at week 8 (last observation carried forward [LOCF]), and the secondary end point was the change from baseline in the seated trough systolic blood pressure at week 8 (LOCF). Tolerability was assessed based on adverse events, vital signs, and physical examination findings. RESULTS: Of the 800 patients who provided informed consent, 603 were randomized to receive AZI/AML 20/5 mg (150 patients), AZI/AML 20/2.5 mg (151 patients), AZI 20 mg (151 patients), AML 5 mg (75 patients), or AML 2.5 mg (76 patients). The mean baseline systolic/diastolic blood pressure was 160.7/100.3 mm Hg. The mean change from baseline in seated blood pressure at week 8 (LOCF) was -35.3/-22.3 mm Hg in the AZI/AML 20/5 mg group and -31.4/-19.2 mm Hg in the AZI/AML 20/2.5 mg group, indicating a reduction significantly greater than that in corresponding monotherapy groups (-21.5/-13.9 mm Hg in the AZI 20 mg group, -26.4/-15.5 mm Hg in the AML 5 mg group, and -19.3/-11.6 mm Hg in the AML 2.5 mg group; p < 0.0001 for all contrast tests). No remarkable difference was found in the incidences of adverse events, vital signs, and physical examination findings among the treatment groups. CONCLUSION: This study found that the FDC of AZI/AML 20/5 mg and 20/2.5 mg exhibited greater antihypertensive effects compared with each monotherapy. The FDC of AZI/AML had a similar safety profile to that of each monotherapy and was tolerable to Japanese patients with grade 1 to 2 essential hypertension. JAPAN PHARMACEUTICAL INFORMATION CENTER REGISTRATION: Japic CTI-111606.

Efficacy and safety of a 60-week treatment with candesartan in Japanese patients with mild to moderate chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is an increasingly common cardiovascular disease despite recent advances in its diagnosis and management. METHODS AND RESULTS: A multicenter, open-label study was designed to assess the efficacy and safety of 60-week treatment with candesartan in Japanese patients with mild to moderate CHF. Primary efficacy endpoints were changes from baseline in plasma brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), end-diastolic dimension, and New York Heart Association (NYHA) functional class. Two hundred and eighty-nine eligible patients were divided into 2 groups based on the daily dose at the end of treatment: high-dose (HD, 8mg, N=170) and low-dose (LD, 2 or 4mg, N=119). Neither plasma BNP levels nor LVEF changed from the baseline to the end of treatment in the LD group, whereas BNP significantly improved from 61.6 to 50.1pg/mL (p=0.0005) and LVEF from 57.2 to 60.1% (p=0.0005) in the HD group. The changes in NYHA functional class were comparable between groups: 21.2% improved and 76.3% unchanged in the LD group and 20.6% improved and 79.4% unchanged in the HD group. No safety concerns were observed in either group. CONCLUSIONS: HD candesartan was more effective in improving plasma BNP levels and cardiac function than LD in Japanese CHF patients. Both LD and HD candesartan were well tolerated in CHF patients.

Suppression of RUNX1 by siRNA in megakaryocytic UT-7/GM cells.

RUNX1 is a transcription factor that plays critical roles in hematopoietic proliferation and differentiation. Megakaryocyte is a precursor cell of platelets. Several reports have implied that RUNX1 is important in megakaryocytic differentiation and proliferation. However, the mechanism is not well understood. In this study, we employed a megakaryocytic cell line UT-7/GM and suppressed the RUNX1 gene expression by siRNA. Knocking down of RUNX1 induced the increase of megakaryocyte-specific gene expression and down-regulation of polyploidization. RUNX1 overexpression decreased the PF4 and GPIIb promoter activities. These results suggest that RUNX1 promotes proliferation of megakaryocytic cell line but not megakaryocytic gene expression in UT-7/GM cells.

RUNX1 suppression induces megakaryocytic differentiation of UT-7/GM cells.

The transcription factor RUNX1 plays a crucial role in hematopoiesis. RUNX1 regulates both differentiation and proliferation of hematopoietic cells. Several reports have shown that RUNX1 participates in megakaryopoiesis, which is a process that leads to formation of platelets. However, to date, the mechanisms by which this occurs have not been fully elucidated. In the present study, we investigated whether siRNA-mediated depletion of RUNX1 affected megakaryopoiesis of UT-7/GM cells. The depletion of RUNX1 in UT-7/GM cells resulted in up-regulation of the expression of megakaryocytic markers and polyploidization, while cell proliferation was down-regulated. Furthermore, the overexpression of RUNX1 decreased the activity of megakaryocytic gene promoters. These results suggest that RUNX1 down-regulates terminal differentiation of megakaryocytes and promotes proliferation of megakaryocytic progenitors.