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Hiromi Rakugi - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Azilsartan Improves Salt Sensitivity by Modulating the Proximal Tubular Na+-H+ Exchanger-3 in Mice
2016Co-Authors: Masaki Hatanaka, Jun-ya Kaimori, Satoko Yamamoto, Isao Matsui, Takayuki Hamano, Yoshitsugu Takabatake, Carolyn M. Ecelbarger, Shiro Takahara, Yoshitaka Isaka, Hiromi RakugiAbstract:A potent angiotensin II type-1 receptor blocker, Azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, Azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that Azilsartan could also improve salt sensitivity; thus, we examined the effect of Azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received Azilsartan (1.0 mg/kg/day), can-desartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the Azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (Azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; Azilsartan or candesartan vs. vehicle). The Azilsartan group also showed higher urinary fractional excre-tion of sodium during the dark period than the candesartan and vehicle groups (Azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 Azilsartan vs. candesartan or vehicle). A pressure—natriuresis curve demonstrated that Azilsartan treat-ment restored salt sensitivity. Immunofluorescence and western blotting showed lower lev
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New mechanism leading to alleviation of salt-sensitive hypertension by a powerful angiotensin receptor blocker, Azilsartan
Receptors & Clinical Investigation, 2016Co-Authors: Jun-ya Kaimori, Masaki Hatanaka, Satoko Yamamoto, Shiro Takahara, Yoshitaka Isaka, Naotsugu Ichimaru, Hiromi RakugiAbstract:Hypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, Azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which Azilsartan brought about this reaction. We speculated that Azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with Azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by Azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with Azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by Azilsartan treatment may lead to totally new drug discoveries.
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Azilsartan Improves Salt Sensitivity by Modulating the Proximal Tubular Na+-H+ Exchanger-3 in Mice
PLOS ONE, 2016Co-Authors: Masaki Hatanaka, Jun-ya Kaimori, Satoko Yamamoto, Isao Matsui, Takayuki Hamano, Yoshitsugu Takabatake, Carolyn M. Ecelbarger, Shiro Takahara, Yoshitaka Isaka, Hiromi RakugiAbstract:A potent angiotensin II type-1 receptor blocker, Azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, Azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that Azilsartan could also improve salt sensitivity; thus, we examined the effect of Azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received Azilsartan (1.0 mg/kg/day), candesartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the Azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (Azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; Azilsartan or candesartan vs. vehicle). The Azilsartan group also showed higher urinary fractional excretion of sodium during the dark period than the candesartan and vehicle groups (Azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 Azilsartan vs. candesartan or vehicle). A pressure—natriuresis curve demonstrated that Azilsartan treatment restored salt sensitivity. Immunofluorescence and western blotting showed lower levels of Na+-H+ exchanger-3 (NHE3) protein (the major sodium transporter in renal proximal tubules) in the Azilsartan group, but not in the candesartan or vehicle groups. However, Azilsartan did not affect NHE3 transcription levels. Interestingly, we did not observe increased expression of downstream sodium transporters, which would have compensated for the increased flow of sodium and water due to non-absorption by NHE3. We also confirmed the mechanism stated above using cultured opossum kidney proximal tubular cells. Results revealed that a proteasomal inhibitor (but not a lysosomal inhibitor) blocked the Azilsartan-induced decrease in NHE3 protein expression, suggesting that Azilsartan increases NHE3 ubiquitination. In conclusion, Azilsartan (but not candesartan) improved salt sensitivity possibly by decreasing NHE3 expression via ubiquitin—proteasomal degradation.
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Azilsartan improves salt sensitivity by modulating the proximal tubular na h exchanger 3 in mice
PLOS ONE, 2016Co-Authors: Masaki Hatanaka, Jun-ya Kaimori, Satoko Yamamoto, Isao Matsui, Takayuki Hamano, Yoshitsugu Takabatake, Carolyn M. Ecelbarger, Shiro Takahara, Yoshitaka Isaka, Hiromi RakugiAbstract:A potent angiotensin II type-1 receptor blocker, Azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, Azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that Azilsartan could also improve salt sensitivity; thus, we examined the effect of Azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received Azilsartan (1.0 mg/kg/day), candesartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the Azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (Azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; Azilsartan or candesartan vs. vehicle). The Azilsartan group also showed higher urinary fractional excretion of sodium during the dark period than the candesartan and vehicle groups (Azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 Azilsartan vs. candesartan or vehicle). A pressure—natriuresis curve demonstrated that Azilsartan treatment restored salt sensitivity. Immunofluorescence and western blotting showed lower levels of Na+-H+ exchanger-3 (NHE3) protein (the major sodium transporter in renal proximal tubules) in the Azilsartan group, but not in the candesartan or vehicle groups. However, Azilsartan did not affect NHE3 transcription levels. Interestingly, we did not observe increased expression of downstream sodium transporters, which would have compensated for the increased flow of sodium and water due to non-absorption by NHE3. We also confirmed the mechanism stated above using cultured opossum kidney proximal tubular cells. Results revealed that a proteasomal inhibitor (but not a lysosomal inhibitor) blocked the Azilsartan-induced decrease in NHE3 protein expression, suggesting that Azilsartan increases NHE3 ubiquitination. In conclusion, Azilsartan (but not candesartan) improved salt sensitivity possibly by decreasing NHE3 expression via ubiquitin—proteasomal degradation.
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Mechanism of reduction of expression of NHE3 protein with Azilsartan.
2016Co-Authors: Masaki Hatanaka, Jun-ya Kaimori, Satoko Yamamoto, Isao Matsui, Takayuki Hamano, Yoshitsugu Takabatake, Carolyn M. Ecelbarger, Shiro Takahara, Yoshitaka Isaka, Hiromi RakugiAbstract:Azilsartan, candesartan, or vehicle was applied to confluent opossum kidney (OK) cells for 24 h. Representative immunoblot (A) with a summary of all data (B) showed that Azilsartan significantly reduced NHE3 protein expression compared with candesartan and vehicle, whereas the NHE3 transcription level remained unchanged in the three groups (C). Azilsartan or vehicle was applied to confluent OK cells for 24 h alone or in combination with the angiotensin II receptor type-2 antagonist PD123319. Immunoblot results (D) and a summary of all data (E) showed that Azilsartan reduced NHE3 protein expression compared with vehicle treatment, and that PD123319 did not affect these results. Next, Azilsartan or vehicle was applied to confluent OK cells for 24 h alone or in combination with lactacystin (proteasomal inhibitor) or leupeptin (lysosomal inhibitor). Representative immunoblot (F) with a summary of all data (G) showed that Azilsartan significantly reduced NHE3 protein expression compared with vehicle. Leupeptin did not change this result, but lactacystin cancelled out the effect of Azilsartan. Furthermore, OK cells were transiently transfected with HA-Ub; Azilsartan, candesartan, or vehicle was subsequently added to the OK cells. Then, HA-Ub was immunoprecipitated with an anti-HA antibody and immunoblotted with anti-NHE3 antibody to detect NHE3 ubiquitination. Representative data indicated that Azilsartan induced more ubiquitination than candesartan and vehicle (H). However, similar band patterns were not observed with other sample lanes when control vector-transfected OK cell lysates were immunoprecipitated with an anti-HA antibody, or when HA-Ub expression vector-transfected OK cell lysates were immunoprecipitated with IgG from control mice. (I) Pulse-chase experiments with 35S-methionine revealed that Azilsartan enhanced NHE3 protein degradation. (J) Immunofluorescent images identified a greater number of NHE3-positive puncta that merged with Ub in OK cells induced by Azilsartan. We took 20 images per sample in a blinded fashion and quantified the puncta that co-localized with NHE3 and ubiquitin. Bar = 50 μm. NHE3, Na+-H+ exchanger-3; AT2R, angiotensin II type-2 receptor; Ub, ubiquitin; NS, not significant. Data represent mean ± standard deviation. n = 3–6 for each group.
Stuart Kupfer - One of the best experts on this subject based on the ideXlab platform.
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Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with Azilsartan medoxomil.
The American Journal of Medicine, 2012Co-Authors: George L Bakris, William B. White, Domenic A Sica, William C. Cushman, Michael A. Weber, Alison Handley, Eric Song, Stuart KupferAbstract:Abstract Background Chlorthalidone has proven efficacy to reduce cardiovascular morbidity and mortality, yet it is infrequently used in practice. This study provides a direct comparison of chlorthalidone with hydrochlorothiazide, each combined with the angiotensin receptor blocker Azilsartan medoxomil, on blood pressure reduction and control rates. Methods This is a randomized, double-blind, titrate-to-target blood pressure trial comparing the single-pill combination of Azilsartan medoxomil and chlorthalidone versus co-administration of Azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension. After 2 weeks of treatment with Azilsartan medoxomil 40 mg alone, all participants also received 12.5 mg of diuretic for 4 weeks (up to week 6) and were titrated to 25 mg for another 4 weeks (up to week 10) if they failed to achieve target blood pressure. The primary end point was change in clinic systolic blood pressure. Target blood pressure was defined as clinic blood pressure Results The mean age of the 609 participants was 56.4 years, and the mean baseline clinic blood pressure was 164.6/95.4 mm Hg. The primary end point analysis at week 6 demonstrated a greater reduction of clinic systolic blood pressure for the chlorthalidone (−35.1 mm Hg) versus hydrochlorothiazide combination (−29.5 mm Hg) (mean difference, −5.6 mm Hg; 95% confidence interval, −8.3 to −2.9; P P P P = .38), and hypokalemia was uncommon in both groups. Conclusions Chlorthalidone combined with Azilsartan medoxomil provides better blood pressure reduction and a higher likelihood of achieving blood pressure control than hydrochlorothiazide combined with Azilsartan medoxomil. This benefit occurred without a difference in safety measurements.
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effects of the angiotensin receptor blocker Azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension
Hypertension, 2011Co-Authors: William B. White, Michael Weber, Domenic A Sica, George L Bakris, Alfonso Perez, Stuart KupferAbstract:Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of Azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of Azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (−14.3 mm Hg) more than 320 mg of valsartan (−10.0 mm Hg; P P =0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: −1.4 mm Hg [95% CI: −3.3 to 0.5]). For clinic systolic BP, both doses of Azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that Azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.
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effects of the angiotensin receptor blocker Azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension
Hypertension, 2011Co-Authors: William B. White, Michael Weber, Domenic A Sica, George L Bakris, Alfonso Perez, Charlie Cao, Stuart KupferAbstract:Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of Azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of Azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P<0.001) and 40 mg of olmesartan (-11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: -1.4 mm Hg [95% CI: -3.3 to 0.5]). For clinic systolic BP, both doses of Azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that Azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.
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Effects of the Angiotensin Receptor Blocker Azilsartan Medoxomil Versus Olmesartan and Valsartan on Ambulatory and Clinic Blood Pressure in Patients With Stages 1 and 2 Hypertension
Hypertension, 2011Co-Authors: William B. White, Michael Weber, Domenic A Sica, George L Bakris, Alfonso Perez, Charlie Cao, Stuart KupferAbstract:Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of Azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of Azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P
William B. White - One of the best experts on this subject based on the ideXlab platform.
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Azilsartan Medoxomil for Treating Hypertension—Clinical Implications of Recent Trials
Spring, 2012Co-Authors: William L. Baker, William B. WhiteAbstract:Objective: To evaluate the efficacy, safety, and clinical role of Azilsartan medoxomil, an angiotensin-II receptor blocker (ARB) that recently gained US Food and Drug Administration approval for lowering of blood pressure (BP) in patients with hypertension. Methods: A systematic review of the literature was performed through October 2011 using the keywords and medical subject headings Azilsartan, Azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Citations eligible for inclusion were in vitro or in vivo evaluations of Azilsartan medoxomil with no restrictions on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted from each citation. Results: Three trials are available in full publication form, with others available only as abstracts. Azilsartan medoxomil 40 mg and 80 mg daily significantly improves both systolic and diastolic BP from baseline compared with placebo, and the 80 mg dose has greater efficacy than other ARBs, including olmesartan 40 mg daily and valsartan 320 mg daily. Improvements in both 24-hour BP using ambulatory monitoring and clinic BPs, as well as a higher proportion of patients reaching goal, have been seen with Azilsartan medoxomil. Additional information shows added BP lowering when Azilsartan medoxomil is combined with chlorthalidone. Adverse events are similar with Azilsartan medoxomil compared to other ARBs and include headache, dizziness, urinary tract infections, and fatigue. Conclusions: Azilsartan medoxomil is a safe and effective ARB with a unique pharmacologic profile compared with other agents, including slowed angiotensin-II type 1 (AT1) receptor dissociation rates and improved receptor specificity. Studies have shown Azilsartan medoxomil 80 mg once daily to reduce BP to a greater extent than valsartan and olmesartan, with similar safety and tolerability.
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Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with Azilsartan medoxomil.
The American Journal of Medicine, 2012Co-Authors: George L Bakris, William B. White, Domenic A Sica, William C. Cushman, Michael A. Weber, Alison Handley, Eric Song, Stuart KupferAbstract:Abstract Background Chlorthalidone has proven efficacy to reduce cardiovascular morbidity and mortality, yet it is infrequently used in practice. This study provides a direct comparison of chlorthalidone with hydrochlorothiazide, each combined with the angiotensin receptor blocker Azilsartan medoxomil, on blood pressure reduction and control rates. Methods This is a randomized, double-blind, titrate-to-target blood pressure trial comparing the single-pill combination of Azilsartan medoxomil and chlorthalidone versus co-administration of Azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension. After 2 weeks of treatment with Azilsartan medoxomil 40 mg alone, all participants also received 12.5 mg of diuretic for 4 weeks (up to week 6) and were titrated to 25 mg for another 4 weeks (up to week 10) if they failed to achieve target blood pressure. The primary end point was change in clinic systolic blood pressure. Target blood pressure was defined as clinic blood pressure Results The mean age of the 609 participants was 56.4 years, and the mean baseline clinic blood pressure was 164.6/95.4 mm Hg. The primary end point analysis at week 6 demonstrated a greater reduction of clinic systolic blood pressure for the chlorthalidone (−35.1 mm Hg) versus hydrochlorothiazide combination (−29.5 mm Hg) (mean difference, −5.6 mm Hg; 95% confidence interval, −8.3 to −2.9; P P P P = .38), and hypokalemia was uncommon in both groups. Conclusions Chlorthalidone combined with Azilsartan medoxomil provides better blood pressure reduction and a higher likelihood of achieving blood pressure control than hydrochlorothiazide combined with Azilsartan medoxomil. This benefit occurred without a difference in safety measurements.
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Azilsartan Medoxomil: A New Angiotensin II Receptor Antagonist for Treatment of Hypertension
Annals of Pharmacotherapy, 2011Co-Authors: William L. Baker, William B. WhiteAbstract:Objective:To evaluate the efficacy, safety, and clinical role of Azilsartan medoxomil, an angiotensin II receptor blocker (ARB) that recently gained Food and Drug Administration approval for towering of Wood pressure (BP) in patients with hypertension.Data Sources:A systematic review of the literature was performed through August 2011 using MEDLINE, Web of Science, and International Pharmaceutical Abstracts and the key words and MeSH terms Azilsartan, Azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Abstracts presented in the last 2 years from the annual meetings of appropriate medical societies were reviewed in addition to a search of clintcaltrials.gov.Study Selection and Data Extraction:Studies eligible for inclusion were in vitro or in vivo evaluations of Azilsartan medoxomil, with no restrictions on patient population or Indication. Data related to the patient populations and outcomes of interest were extracted from each publication.Data Synthesis:Three trials are available in full publication for...
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effects of the angiotensin receptor blocker Azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension
Hypertension, 2011Co-Authors: William B. White, Michael Weber, Domenic A Sica, George L Bakris, Alfonso Perez, Stuart KupferAbstract:Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of Azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of Azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (−14.3 mm Hg) more than 320 mg of valsartan (−10.0 mm Hg; P P =0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: −1.4 mm Hg [95% CI: −3.3 to 0.5]). For clinic systolic BP, both doses of Azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that Azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.
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effects of the angiotensin receptor blocker Azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension
Hypertension, 2011Co-Authors: William B. White, Michael Weber, Domenic A Sica, George L Bakris, Alfonso Perez, Charlie Cao, Stuart KupferAbstract:Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of Azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of Azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P<0.001) and 40 mg of olmesartan (-11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: -1.4 mm Hg [95% CI: -3.3 to 0.5]). For clinic systolic BP, both doses of Azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that Azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.
Kazuaki Enya - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label, Multicenter Study
Advances in Therapy, 2018Co-Authors: Kazuaki Enya, Ben T. Saji, Takuya Kato, Hiroyuki Okamoto, Emiko KoumuraAbstract:Introduction Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of Azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients. Methods In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of Azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of Azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg. Results Mean maximum plasma concentration ( C _max) of Azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration ( T _max) of unchanged Azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to Azilsartan occurred during the study. Conclusion Our data suggest that pediatric patients weighing less than 50 kg may have approximately 2-fold greater exposure to Azilsartan than those weighing at least 50 kg at the same dose. Exposure to Azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose. Trial Registration ClinicalTrials.gov identifier, NCT02451150. Funding Takeda Pharmaceutical Co. Ltd.
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Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label, Multicenter Study
Advances in Therapy, 2018Co-Authors: Kazuaki Enya, Ben T. Saji, Takuya Kato, Hiroyuki Okamoto, Emiko KoumuraAbstract:Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of Azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients. In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of Azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of Azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg. Mean maximum plasma concentration (Cmax) of Azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (Tmax) of unchanged Azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC0–24) and 0 h to infinity (AUC0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to Azilsartan occurred during the study. Our data suggest that pediatric patients weighing less than 50 kg may have approximately 2-fold greater exposure to Azilsartan than those weighing at least 50 kg at the same dose. Exposure to Azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose. ClinicalTrials.gov identifier, NCT02451150. Takeda Pharmaceutical Co. Ltd.
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Effect of Azilsartan versus candesartan on morning blood pressure surges in Japanese patients with essential hypertension
Blood Pressure Monitoring, 2014Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Kenkichi Sugiura, Yoshinori IkedaAbstract:Morning blood pressure (BP) surge is reported as a risk factor for cardiovascular events and end-organ damage independent of the 24-h BP level. Controlling morning BP surge is therefore important to help prevent onset of cardiovascular disease. We compared the efficacy of Azilsartan and candesartan in controlling morning systolic BP (SBP) surges by analyzing relevant ambulatory BP monitoring data in patients with/without baseline BP surges. As part of a 16-week randomized, double-blind study of Azilsartan (20–40 mg once daily) and candesartan (8–12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was carried out using ambulatory BP monitoring at baseline and week 14. The effects of study drugs on morning BP surges, including sleep trough surge (early morning SBP minus the lowest night-time SBP) and prewaking surge (early morning SBP minus SBP before awakening), were evaluated. Patients with sleep trough surge of at least 35 mmHg were defined by the presence of a morning BP surge (the ‘surge group’). Sleep trough surge and prewaking surge data were available at both baseline and week 14 in 548 patients, 147 of whom (Azilsartan 76; candesartan 71) had a baseline morning BP surge. In surge group patients, Azilsartan significantly reduced both the sleep trough surge and the prewaking surge at week 14 compared with candesartan (least squares means of the between-group differences −5.8 mmHg, P=0.0395; and −5.7 mmHg, P=0.0228, respectively). Once-daily Azilsartan improved sleep trough surge and prewaking surge to a greater extent than candesartan in Japanese patients with grade I–II essential hypertension.
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Effect of Azilsartan versus candesartan on nocturnal blood pressure variation in Japanese patients with essential hypertension.
Blood pressure, 2013Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Masataka Igeta, Yoshinori IkedaAbstract:Abnormal variations in night-time hypertension such as "non-dipping" type (< 10% decrease in nocturnal systolic blood pressure [SBP] from daytime SBP) are a risk factor for cardiovascular events independent of 24-h BP. As part of a randomized, double-blind study of Azilsartan (20-40 mg once daily) and candesartan (8-12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was performed using ambulatory BP monitoring (ABPM) at baseline and Week 14. Effects of study drugs on nocturnal BP variations according to patients' nocturnal SBP dipping status were evaluated. ABPM data were available for 273 patients treated with Azilsartan and 275 with candesartan. In the dipping group (≥ 10% decrease from daytime SBP), Azilsartan produced a greater reduction from baseline in daytime than in night-time SBP (- 14.1 and - 10.9 mmHg, respectively), and the change in daytime SBP was significantly greater with Azilsartan than with candesartan (p = 0.0077). In the non-dipping group, Azilsartan produced a greater reduction from baseline in night-time than in daytime SBP (- 20.2 and - 9.9 mmHg, respectively), and reductions in both night-time SBP (p = 0.02) and daytime SBP (p = 0.0042) were significantly greater with Azilsartan than with candesartan. Once-daily Azilsartan improved non-dipping night-time SBP to a greater extent than candesartan in Japanese patients with grade I-II essential hypertension.
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Effect of Azilsartan versus candesartan on nocturnal blood pressure variation in Japanese patients with essential hypertension.
Blood Pressure, 2013Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Masataka Igeta, Yoshinori IkedaAbstract:AbstractBackground. Abnormal variations in night-time hypertension such as “non-dipping” type (< 10% decrease in nocturnal systolic blood pressure [SBP] from daytime SBP) are a risk factor for cardiovascular events independent of 24-h BP. Methods. As part of a randomized, double-blind study of Azilsartan (20–40 mg once daily) and candesartan (8–12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was performed using ambulatory BP monitoring (ABPM) at baseline and Week 14. Effects of study drugs on nocturnal BP variations according to patients’ nocturnal SBP dipping status were evaluated. Results. ABPM data were available for 273 patients treated with Azilsartan and 275 with candesartan. In the dipping group (≥ 10% decrease from daytime SBP), Azilsartan produced a greater reduction from baseline in daytime than in night-time SBP (− 14.1 and − 10.9 mmHg, respectively), and the change in daytime SBP was significantly greater with Azilsartan than with candesartan (p = 0....
Yoshinori Ikeda - One of the best experts on this subject based on the ideXlab platform.
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Effect of Azilsartan versus candesartan on morning blood pressure surges in Japanese patients with essential hypertension
Blood Pressure Monitoring, 2014Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Kenkichi Sugiura, Yoshinori IkedaAbstract:Morning blood pressure (BP) surge is reported as a risk factor for cardiovascular events and end-organ damage independent of the 24-h BP level. Controlling morning BP surge is therefore important to help prevent onset of cardiovascular disease. We compared the efficacy of Azilsartan and candesartan in controlling morning systolic BP (SBP) surges by analyzing relevant ambulatory BP monitoring data in patients with/without baseline BP surges. As part of a 16-week randomized, double-blind study of Azilsartan (20–40 mg once daily) and candesartan (8–12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was carried out using ambulatory BP monitoring at baseline and week 14. The effects of study drugs on morning BP surges, including sleep trough surge (early morning SBP minus the lowest night-time SBP) and prewaking surge (early morning SBP minus SBP before awakening), were evaluated. Patients with sleep trough surge of at least 35 mmHg were defined by the presence of a morning BP surge (the ‘surge group’). Sleep trough surge and prewaking surge data were available at both baseline and week 14 in 548 patients, 147 of whom (Azilsartan 76; candesartan 71) had a baseline morning BP surge. In surge group patients, Azilsartan significantly reduced both the sleep trough surge and the prewaking surge at week 14 compared with candesartan (least squares means of the between-group differences −5.8 mmHg, P=0.0395; and −5.7 mmHg, P=0.0228, respectively). Once-daily Azilsartan improved sleep trough surge and prewaking surge to a greater extent than candesartan in Japanese patients with grade I–II essential hypertension.
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Effect of Azilsartan versus candesartan on nocturnal blood pressure variation in Japanese patients with essential hypertension.
Blood pressure, 2013Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Masataka Igeta, Yoshinori IkedaAbstract:Abnormal variations in night-time hypertension such as "non-dipping" type (< 10% decrease in nocturnal systolic blood pressure [SBP] from daytime SBP) are a risk factor for cardiovascular events independent of 24-h BP. As part of a randomized, double-blind study of Azilsartan (20-40 mg once daily) and candesartan (8-12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was performed using ambulatory BP monitoring (ABPM) at baseline and Week 14. Effects of study drugs on nocturnal BP variations according to patients' nocturnal SBP dipping status were evaluated. ABPM data were available for 273 patients treated with Azilsartan and 275 with candesartan. In the dipping group (≥ 10% decrease from daytime SBP), Azilsartan produced a greater reduction from baseline in daytime than in night-time SBP (- 14.1 and - 10.9 mmHg, respectively), and the change in daytime SBP was significantly greater with Azilsartan than with candesartan (p = 0.0077). In the non-dipping group, Azilsartan produced a greater reduction from baseline in night-time than in daytime SBP (- 20.2 and - 9.9 mmHg, respectively), and reductions in both night-time SBP (p = 0.02) and daytime SBP (p = 0.0042) were significantly greater with Azilsartan than with candesartan. Once-daily Azilsartan improved non-dipping night-time SBP to a greater extent than candesartan in Japanese patients with grade I-II essential hypertension.
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Effect of Azilsartan versus candesartan on nocturnal blood pressure variation in Japanese patients with essential hypertension.
Blood Pressure, 2013Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kazuomi Kario, Masataka Igeta, Yoshinori IkedaAbstract:AbstractBackground. Abnormal variations in night-time hypertension such as “non-dipping” type (< 10% decrease in nocturnal systolic blood pressure [SBP] from daytime SBP) are a risk factor for cardiovascular events independent of 24-h BP. Methods. As part of a randomized, double-blind study of Azilsartan (20–40 mg once daily) and candesartan (8–12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was performed using ambulatory BP monitoring (ABPM) at baseline and Week 14. Effects of study drugs on nocturnal BP variations according to patients’ nocturnal SBP dipping status were evaluated. Results. ABPM data were available for 273 patients treated with Azilsartan and 275 with candesartan. In the dipping group (≥ 10% decrease from daytime SBP), Azilsartan produced a greater reduction from baseline in daytime than in night-time SBP (− 14.1 and − 10.9 mmHg, respectively), and the change in daytime SBP was significantly greater with Azilsartan than with candesartan (p = 0....
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comparison of the efficacy and safety of Azilsartan with that of candesartan cilexetil in japanese patients with grade i ii essential hypertension a randomized double blind clinical study
Hypertension Research, 2012Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kenkichi Sugiura, Yoshinori IkedaAbstract:Azilsartan is a novel angiotensin receptor blocker being developed for hypertension treatment. This 16-week, multicenter, randomized, double-blind study compared the efficacy and safety of Azilsartan (20–40 mg once daily by forced titration) and its ability to provide 24-h blood pressure (BP) control, with that of candesartan cilexetil (candesartan; 8–12 mg once daily by forced titration) in 622 Japanese patients with grade I–II essential hypertension. Efficacy was evaluated by clinic-measured sitting BP, and by ambulatory BP monitoring (ABPM) at week 14. Participants (mean age: 57 years, 61% males) had a mean baseline sitting BP of 159.8/100.4 mm Hg. The mean change from baseline in sitting diastolic BP at week 16 (primary endpoint) was −12.4 mm Hg in the Azilsartan group and −9.8 mm Hg in the candesartan group, demonstrating a statistically significant greater reduction with Azilsartan vs. candesartan (difference: −2.6 mm Hg, 95% confidence interval (CI): −4.08 to −1.22 mm Hg, P=0.0003). The week 16 (secondary endpoint) mean change from baseline in sitting systolic BP was −21.8 mm Hg and −17.5 mm Hg, respectively, a significant decrease with Azilsartan vs. candesartan (difference: −4.4 mm Hg, 95% CI: −6.53 to −2.20 mm Hg, P<0.0001). On ABPM, the week 14 mean changes from baseline in diastolic and systolic BP were also significantly greater with Azilsartan over a 24-h period, and during the daytime, night-time and early morning. Safety and tolerability were similar among the two groups. These data demonstrate that once-daily Azilsartan provides a more potent 24-h sustained antihypertensive effect than that of candesartan but with equivalent safety.
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Comparison of the efficacy and safety of Azilsartan with that of candesartan cilexetil in Japanese patients with grade I–II essential hypertension: a randomized, double-blind clinical study
Hypertension Research, 2012Co-Authors: Hiromi Rakugi, Kazuaki Enya, Kenkichi Sugiura, Yoshinori IkedaAbstract:Azilsartan is a novel angiotensin receptor blocker being developed for hypertension treatment. This 16-week, multicenter, randomized, double-blind study compared the efficacy and safety of Azilsartan (20–40 mg once daily by forced titration) and its ability to provide 24-h blood pressure (BP) control, with that of candesartan cilexetil (candesartan; 8–12 mg once daily by forced titration) in 622 Japanese patients with grade I–II essential hypertension. Efficacy was evaluated by clinic-measured sitting BP, and by ambulatory BP monitoring (ABPM) at week 14. Participants (mean age: 57 years, 61% males) had a mean baseline sitting BP of 159.8/100.4 mm Hg. The mean change from baseline in sitting diastolic BP at week 16 (primary endpoint) was −12.4 mm Hg in the Azilsartan group and −9.8 mm Hg in the candesartan group, demonstrating a statistically significant greater reduction with Azilsartan vs. candesartan (difference: −2.6 mm Hg, 95% confidence interval (CI): −4.08 to −1.22 mm Hg, P=0.0003). The week 16 (secondary endpoint) mean change from baseline in sitting systolic BP was −21.8 mm Hg and −17.5 mm Hg, respectively, a significant decrease with Azilsartan vs. candesartan (difference: −4.4 mm Hg, 95% CI: −6.53 to −2.20 mm Hg, P
