OBJECTIVE: Secondary, prespecified analysis of a single-arm, open-label study evaluating the efficacy of olmesartan medoxomil (OM) plus hydrochlorothiazide (HCTZ) in patients with hypertension and type 2 diabetes. METHODS: After placebo run-in, 192 patients received OM 20 mg/day for 3 weeks. If blood pressure (BP) remained >/=120/70 mmHg, patients were uptitrated every 3 weeks to OM 40 mg/day, OM/HCTZ 40/12.5 mg/day, and OM/HCTZ 40/25 mg/day. Efficacy was evaluated by 24-hour ambulatory BP monitoring. Secondary endpoints included changes in ambulatory systolic BP (SBP) and diastolic BP (DBP) during daytime (08:00 to 16:00) and nighttime (22:00 to 06:00), as well as achievement of prespecified ambulatory BP targets in the total cohort and subgroups based on gender, race, hypertension severity, and age (>/=65 or <65 years). Dipper status (nocturnal decrease in BP >/=10% of mean daytime BP) was assessed. RESULTS: At baseline, mean ambulatory BP was 151.2 +/- 12.7/87.6 +/- 9.0 mmHg during the daytime and 140.3 +/- 13.1/78.1 +/- 8.6 mmHg during the nighttime. Mean daytime and nighttime ambulatory BP was reduced from baseline by 22.3 +/- 13.7/12.0 +/- 8.9 mmHg and 18.8 +/- 12.4/10.2 +/- 7.2 mmHg, respectively. The reduction in daytime ambulatory SBP was 24.4 +/- 11.8 mmHg in Blacks, 21.7 +/- 14.2 mmHg in non-Blacks, 23.6 +/- 12.3 mmHg in females, 21.2 +/- 14.8 mmHg in males, 23.4 +/- 11.6 mmHg in patients aged >/=65 years, and 21.9 +/- 14.4 mmHg in those aged <65 years. Ambulatory BP targets of <130/80, <125/75, and <120/80 mmHg were reached by 51.7%, 36.0%, and 32.6% of patients during the daytime and 69.8%, 60.5%, and 50.6% of patients during the nighttime. After 12 weeks of treatment, 36.4% of baseline nondippers converted to dippers. CONCLUSIONS: OM +/- HCTZ effectively lowered ambulatory BP in patients with type 2 diabetes and hypertension, enabling them to achieve ambulatory BP targets during both the daytime and nighttime.

Angiotensin (Ang)II, the effector arm of the locally active renin-angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-alpha-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-alpha stimulation (0.1 ng/ml x 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (real-time polymerase chain reaction) in cell lysates. TNF-alpha stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-alpha-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, down-regulates TNF-alpha-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine.

ATRAP (angiotensin II type 1 receptor-associated protein) is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous angiotensin II (ANG II) infusion on the intrarenal expression and distribution of ATRAP, and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1000, or 2500 ng/kg/min for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney, but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2500 ng/kg/min) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and alpha-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng/kg/min), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic-model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

The remnant kidney model in C57BL/6 mice does not develop progressive chronic kidney disease (CKD). In this study we modified the model to mimic features of human CKD and to define accelerants of disease progression using three strains of mice. Following the procedure, there was a progressive increase in albuminuria, progressive loss in renal function, severe glomerulosclerosis and interstitial fibrosis, hypertension, cardiac fibrosis, and anemia by 4 weeks in CD-1 mice and by 12 weeks in 129S3 mice. In contrast, even after 16 weeks, the C57BL/6 mice with a remnant kidney had modestly increased albuminuria without increased blood pressure and without developing CKD or cardiac fibrosis. The baseline blood pressure, determined by radiotelemetry in conscious animals, correlated with CKD progression rates in each strain. Administering angiotensin II overcame the resistance of C57BL/6 mice to CKD following renal mass reduction, displaying high blood pressure and albuminuria, severe glomerulosclerosis, and loss of renal function by 4 weeks. Decreasing blood pressure with olmesartan, but not hydralazine, in CD-1 mice with a remnant kidney reduced CKD progression and cardiac fibrosis. C57BL/6 mice with a remnant kidney and DOCA-salt hypertension developed modest CKD. Each strain had similar degrees of interstitial fibrosis in three different normotensive models of renal fibrosis. Thus, reducing renal mass in CD-1 or 129S3 mice mimics many features of human CKD. Angiotensin II can convert the C57BL/6 strain from CKD resistant to susceptible in this disease model.Kidney International advance online publication, 25 August 2010; doi:10.1038/ki.2010.287.

Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.

Background: Hypertension often occurs concomitantly with diabetes mellitus, such that >50% of adults with type 2 diabetes have hypertension. These individuals are at a greater risk of developing renal and cardiovascular disease. The currently recommended BP goal of <130/80 mmHg for patients with type 2 diabetes is achieved in only 37.5% of treated patients with diabetes and hypertension. Methods: The antihypertensive efficacy of olmesartan medoxomil (OM) +/- hydrochlorothiazide (HCTZ) was investigated in prespecified subgroups (age <65/>/=65 years, Blacks/non-Blacks, males/females, or stage 1/stage 2 hypertension) of patients with hypertension and type 2 diabetes enrolled in an open-label, single-arm study (n = 192). Patients started treatment with OM 20 mg/day and were uptitrated at 3-week intervals to OM 40, OM/HCTZ 40/12.5, and OM/HCTZ 40/25 mg/day if BP was >/=120/70 mmHg. The primary endpoint was the change in mean 24-hour ambulatory SBP from baseline to week 12, assessed by mean 24-hour ambulatory BP monitoring. Secondary endpoints included changes in mean 24-hour ambulatory DBP, mean daytime ambulatory BP, mean nighttime ambulatory BP, and mean office seated BP, and the proportions of patients achieving prespecified ambulatory BP targets. Setting: This was a multicenter study (24 sites) that took place between November 2006 and November 2007 in the US. Results: BP reductions were significant (p < 0.0001) and similar among subgroups of patients with type 2 diabetes. Following dose titration to OM/HCTZ 40/25 mg/day, similar proportions of patients in the age, race, and sex subgroups (approximately 60-64% across these subgroups) achieved an ambulatory BP target of <130/80 mmHg. A larger proportion of patients with type 2 diabetes and stage 1 hypertension achieved this same goal compared with patients with stage 2 hypertension (75% vs 46.3%). The combination of OM/HCTZ was well tolerated in all patient subgroups irrespective of age, race, sex, or hypertension severity. Conclusions: In this open-label study, OM/HCTZ combination therapy was efficacious and well tolerated in subgroups of patients with diabetes and hypertension. [Clinical Trials Registry Number: NCT00403481].

Importance of the field: Cardiovascular disease is a major cause of premature death and disability worldwide, and effective blood pressure (BP) control is crucial for the reduction of cardiovascular risk in patients with hypertension. Despite this, many will fail to attain recommended BP goals. A reappraisal of European guidelines led to revised recommendations for BP reduction to values within the SBP/DBP range of 130 - 139/80 - 85 mmHg in all patients with hypertension, including higher-risk groups such as those with diabetes. Areas covered in this review: The majority of hypertensive patients will require the enhanced blood-pressure-lowering effects of at least two antihypertensive drugs with complementary mechanisms of action to achieve these goals. What the reader will gain: The angiotensin II receptor blocker (ARB) olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide (HCTZ) provide greater antihypertensive efficacy when used in combination than as monotherapy with either component, with a similar tolerability profile. In addition, there is evidence that higher doses of olmesartan may prolong the antihypertensive effect of this ARB, and a number of US 'treat-to-target' and European add-on clinical trials have been conducted to assess the efficacy and safety of high-dose olmesartan plus HCTZ in a wide range of patients with mild-to-severe hypertension. Take home message: Combination therapy with olmesartan, including the high 40-mg dose, plus HCTZ is an effective and safe treatment option for controlling BP in patients with mild-to-severe hypertension, particularly those who fail to achieve recommended BP goals with monotherapy.

OBJECTIVE: Clinical studies indicate that the remission, regression or both of nephrotic-range albuminuria are exerted by angiotensin II receptor blockers (ARBs) in diabetes. The current study was performed to test the hypothesis that these effects of ARBs are associated with regression of glomerular podocyte injury. METHODS: We examined the effects of an ARB, olmesartan, on glomerular podocyte injury in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with overt albuminuria. RESULTS: At baseline (55-week-old), diabetic Otsuka-Long-Evans-Tokushima-Fatty rats showed severe albuminuria with desmin-positive areas (an index of podocyte injury) in both superficial and juxtamedullary glomeruli, and podocyte injury was much greater in juxtamedullary than in superficial glomeruli. At 75-week-old, Otsuka-Long-Evans-Tokushima-Fatty rats had developed more severe albuminuria and superficial glomerular podocyte injury, whereas juxtamedullary glomerular podocyte injury did not advance further. Olmesartan (10 mg/kg per day) decreased albuminuria and superficial glomerular desmin staining to levels that were lower than those at baseline, whereas advanced juxtamedullary glomerular podocyte injury was not changed. CONCLUSION: The current study demonstrates for the first time that juxtamedullary glomerular podocyte injury reaches a severe condition at an earlier time than superficial glomerular podocyte injury during the progression of overt albuminuria in type 2 diabetic rats. Our data also support the hypothesis that the antialbuminuric effects of ARBs are associated with regression of superficial glomerular podocyte injury in type 2 diabetes with nephrotic-range albuminuria.

The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0+/-1.8 g g(-1) to 0.8+/-0.8 g g(-1) (P=0.0242) in Olm-G and from 1.4+/-1.3 g g(-1) to 0.9+/-1.0 g g(-1) (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients.Hypertension Research advance online publication, 12 August 2010; doi:10.1038/hr.2010.145.

To clarify the role of endogenous angiotensin (Ang)-converting enzyme 2 (ACE2) and its cleavage product, Ang 1-7, in the atherogenic stimulation of vascular cells, we investigated the effect of pharmacological inhibition of ACE2 and Mas, an Ang 1-7 receptor, on cellular responses against Ang II stimulation. We measured extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by western blot, smooth muscle cell (SMC) proliferation by WST assay and the adhesion of monocytes labeled with PKH67 to endothelial cells (ECs) by fluorescence microplate reader. Cells were pretreated with Ang 1-7, olmesartan (Ang II type 1 receptor (AT1) blocker), DX600 (ACE2 inhibitor), -Ala7-Ang1-7 (D-Ala; Mas antagonist), or combinations of treatments before the application of Ang II. Treatment with Ang II increased phosphorylated ERK 1/2 of SMC and EC, proliferation of SMC and adhesion of monocyte to EC, which were blocked by olmesartan. Pretreatment with DX600 either did not accelerate or only slightly accelerated these cellular responses. However, when Ang II signaling through AT1 was reduced by olmesartan, the additional treatment with DX600 significantly blunted some of the effect of olmesartan. Similarly, pretreatment with D-Ala reduced the inhibitory effect of olmesartan in response to Ang II stimulation. Endogenous ACE2 in vascular cells may contribute to counteracting the Ang II-mediated cellular response partly by upregulating the Ang 1-7 signaling through Mas.Hypertension Research advance online publication, 12 August 2010; doi:10.1038/hr.2010.147.

Effective antihypertensive therapy is crucial for preventing cardiovascular events; however, blood pressure (BP) control rates remain poor. The objective of this analysis was to determine the efficacy of olmesartan/amlodipine in age, severity and gender-based subgroups of patients with moderate-to-severe hypertension uncontrolled by amlodipine monotherapy. Patients with uncontrolled BP after 8 weeks' amlodipine 5 mg monotherapy (n=755) were randomized to continue amlodipine 5 mg or receive olmesartan (10-40 mg) plus amlodipine 5 mg for 8 weeks. Patients whose BP remained suboptimal were uptitrated to olmesartan/amlodipine 20/5, 40/5 or 40/10 mg. Changes in BP and numbers of controlled patients were calculated separately to assess efficacy in patients aged <65 or >/=65 years, in those with moderate or severe hypertension, and in males and females. The antihypertensive effects of olmesartan/amlodipine were similar in patients aged <65 and >/=65 years of age. Compared with patients with moderate hypertension at baseline, those with severe hypertension tended to show higher decreases in BP, but achieved lower goal rates despite this. Females showed larger mean reductions in diastolic (1.61 mm Hg; P=0.003) and systolic BP (1.72 mm Hg; P=0.053) than males, independent of age and dose. This gender difference appeared to be higher and more consistent across dose groups for patients <50 years of age, but the difference in the pattern between both age groups was not statistically significant (P=0.1526). These results suggest that olmesartan/amlodipine is effective and safe in a wide range of patients, regardless of age or hypertension severity. Small differences in responsiveness between females and males may exist, which require further investigation.Journal of Human Hypertension advance online publication, 5 August 2010; doi:10.1038/jhh.2010.74.

Background: In a previously reported randomized, double-blind, parallel-group study of the efficacy and tolerability of olmesartan medoxomil (OLM) and azelnidipine (AZL) combination therapy compared with monotherapy with each agent in Japanese patients with essential hypertension (the REZALT study), the use of a combination of OLM, an angiotensin II receptor blocker, plus AZL, a dihydropyridine calcium channel blocker, was associated with significantly greater reductions in office sitting blood pressure (BP) and 24-hour ambulatory BP compared with monotherapy with either agent, and was well tolerated. Objective: This article reports the results from an a priori planned analysis and post hoc analyses of the diurnal BP and pulse rate (PR) profiles of OLM/AZL versus monotherapy with either agent from the REZALT study. Methods: Male and female Japanese outpatients with essential hypertension were eligible if they met the following inclusion criteria: age >/=20 years; systolic BP (SBP) >/=140 to <180 mm Hg and diastolic BP (DBP) >/=90 to <110 mm Hg; and 24-hour ambulatory SBP/ DBP >/=135/>/=80 mm Hg. Patients were randomly assigned to receive OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM 20 mg, or AZL 16 mg, once daily for 12 weeks. The effectiveness of the treatments was assessed using 24-hour ambulatory BP monitoring (ABPM) and PR, analyzed by time period (BP and PR, 24 hours, daytime [7 AM-<10 PM], nighttime [10 PM-<7 AM], and early morning [6 AM-<9 AM]; PR, morning [6 AM -<11 AM]) and dipping status at baseline (dippers [(Daytime BP - Nighttime BP)/Daytime BP >/=10%] or nondippers [(Daytime BP - Nighttime BP)/Daytime BP <10%]). Results: A total of 867 patients were enrolled, and 862 randomized patients were included in the full analysis set (590 men, 272 women; mean age, 56.6 years). A total of 839 patients had assessable ABPM data (213, 211, 206, and 209 patients in the OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM, and AZL groups, respectively). No clinically significant between-group differences were observed in baseline demographic and clinical characteristics. Combination therapy was associated with significantly greater antihypertensive effects on 24-hour ABPM compared with either monotherapy in all of the time periods, as follows: SBP/DBP reductions with OLM/AZL 20/16 mg in the daytime, nighttime, and early morning were -22.6/-14.1, -21.2/-12.5, and -20.6/-11.9 mm Hg, respectively (all, P < 0.05 vs the other 3 treatment groups). The SBP/DBP reductions with OLM/AZL 10/8 mg (daytime, -18.2/-11.0 mm Hg; nighttime, -18.1/-10.0 mm Hg; and early morning, -15.6/-9.3 mm Hg) were also significantly greater than with OLM 20 mg (-11.8/-6.7, -12.8/-7.2, and -11.0/ -6.9 mm Hg, respectively; all, P < 0.01) and AZL 16 mg (-13.1/-7.8, -10.2/-5.5, and -9.9/-6.1 mm Hg; all, P < 0.001) in all of the time periods. The antihypertensive effects associated with OLM/AZL 10/8 mg or 20/16 mg were significantly greater than those with monotherapies regardless of dipping pattern at baseline (all, P < 0.05) in all of the time periods, with the exception of nighttime reduction with OLM/AZL 10/8 mg versus OLM in dippers. The numbers of patients who had any increase in BP were 12/213 (5.6%) with OLM/AZL 10/8 mg, 13/211 (6.2%) with OLM/AZL 20/16 mg, 35/206 (17.0%) with OLM, and 36/209 (17.2%) with AZL. The AZL-containing regimens were associated with reduced morning PR (mean [95% CI] changes from baseline to week 12: -1.5 beats/min [-2.5 to -0.4] with OLM/AZL 10/8 mg, -2.1 beats/min [-3.0 to -1.1] with OLM/AZL 20/16 mg, 0.4 beat/min [-0.5 to 1.3] with OLM, and -1.9 beats/min [-2.8 to -1.0] with AZL). Conclusion: In this study in Japanese patients with essential hypertension, the reductions in daytime, nighttime, and early-morning BP assessed using 24-hour ABPM were significantly greater with combination OLM/AZL than with either monotherapy, regardless of dipping pattern at baseline. Japan Pharmaceutical Information Center registration number: JapicCTl-060286.

Background: Patients with hypertension may require a combination of >/=2 antihypertensive agents to achieve blood pressure (BP) control. Objective: The aim of this study was to determine whether a triple combination of olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) had a clinically significant benefit compared with dual combinations of the individual components in patients with moderate to severe hypertension. Methods: This was a multicenter, randomized, doubleblind, parallel-group study in which triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was compared with dual combinations of the individual components-OM 40 mg/AML 10 mg in fixed-dose combination, OM 40 mg/HCTZ 25 mg in fixed-dose combination, and AML 10 mg + HCTZ 25 mg-in patients aged >/=18 years who had a mean seated BP >/=140/100 mm Hg or >/=160/90 mm Hg. The study consisted of a 3-week washout period with no study medication and a 12-week double-blind treatment period. In the first 2 weeks of the double-blind treatment period, all patients were randomized to receive dual combination treatment or placebo. All patients assigned to a dual combination treatment group continued the assigned treatment until week 4, and all patients assigned to placebo were switched at week 2 to receive 1 of the dual combination treatments until week 4. At week 4, patients either continued dual combination treatment or switched to triple combination treatment until week 12. The primary end point was the change in seated diastolic BP (SeDBP) from baseline to week 12; SeDBP reduction of >/=2 mm Hg was considered a clinically significant benefit. Secondary efficacy end points included the change in seated systolic BP (SeSBP) at week 12 and the percentages of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm Hg, and SeDBP <90 mm Hg at week 12. The tolerability of the treatments was also evaluated based on adverse events (AEs), clinical laboratory evaluations (chemistry, hematology, and urinalysis), physical examinations, and 12-lead ECGs. Results: The 2492 randomized patients (52.9% male, 66.8% white, 30.4% black) had a mean (SD) age of 55.1 (10.9) years and a mean weight of 96.0 (22.9) kg. Diabetes was present in 15.5% of the population, chronic cardiovascular disease in 9.1%, and chronic kidney disease in 4.1%. At baseline, the mean SeBP was 168.5/100.9 mm Hg. At week 12, triple combination treatment was associated with significantly greater least squares mean reductions in SeBP compared with the dual combinations (SeDBP: -21.8 vs -15.1 to -18.0 mm Hg, respectively [P < 0.001]; SeSBP: -37.1 vs -27.5 to -30.0 mm Hg [P < 0.001]). A significantly higher proportion of patients receiving triple combination treatment reached BP targets compared with the dual combinations at week 12 (P < 0.001). The proportions of patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the triple combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment groups receiving OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, and AML 10 mg + HCTZ 25 mg, respectively (P < 0.001, triple combination vs each dual combination). The incidence of treatment-emergent AEs (TEAEs) was 58.4% for triple combination treatment and 51.7% to 58.9% for the dual combinations; most TEAEs were mild or moderate in severity. The most common TEAEs in the triple combination treatment group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). In total, 52 patients (2.3%) discontinued the study due to TEAEs-6 (1.0%) in the OM 40 mg/AML 10 mg group, 12 (2.1%) in the OM 40 mg/HCTZ 25 mg group, 11 (2.0%) in the AML 10 mg + HCTZ 25 mg group, and 23 (4.0%) in the OM 40 mg + AML 10 mg + HCTZ 25 mg group. Thirty-two patients (1.4%)-4 (0.7%), 5 (0.9%), 5 (0.9%), and 18 (3.1%) in the respective treatment groups-discontinued the study due to drug-related TEAEs. Conclusions: In these adult patients with moderate to severe hypertension, triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was associated with significant BP reductions compared with dual combinations of the individual components. All treatments were generally well tolerated. ClinicalTrials. gov identifier: NCT00649389.

Abstract Objective: To compare blood pressure (BP) goal achievement associated with the use of valsartan-based single pill combinations (SPCs) vs. angiotensin II receptor blocker (ARB)-based free combinations (FCs) among adult hypertension patients. Research design and methods: Data were collected from physician-administered chart review of adult hypertension patients in the South Central region. All patients had uncontrolled BP before initiating one of the index therapies (SPCs: valsartan/amlodipine or valsartan/hydrochlorothiazide [HCTZ], FCs: ARB + calcium channel blocker [CCB] or ARB + HCTZ) between 07/2008 and 06/2009. Up to three BP measures were collected starting from 45 days after the therapy initiation. BP goal was <130/80 mmHg for patients with diabetes, chronic renal disease or coronary heart disease; or <140/90 mmHg for patients without these comorbidities. The Kaplan-Meier method with log-rank test was used to compare rates of BP goal achievement associated with valsartan-based SPCs vs. ARB-based FCs over time. Cox proportional hazard models were used to estimate the likelihood of BP goal achievement associated with SPCs vs. FCs, controlling for demographics, baseline BP, hypertension history, comorbidities, prior and concurrent use of anti-hypertensive medications, and physician specialty. Results: The study included 812 patients: 414 on valsartan-based SPCs (209 on valsartan/amlodipine and 205 on valsartan/HCTZ) and 398 on ARB-based FCs (200 on ARB + CCB and 198 on ARB + HCTZ). The ARBs in the FC group included valsartan, losartan, olmesartan, telmisartan, irbesartan and candesartan. In the ARB FC group, the most commonly used ARB and CCB were valsartan (29.1%) and amlodipine (81.5%), respectively. During the observation period (81 days for valsartan SPC patients and 90 days for ARB FC patients), 65.9% of valsartan SPC patients and 55.8% of the ARB FC patients achieved BP goal. Over time, the rates of BP goal achievement were consistently higher among valsartan SPC vs. ARB FC patients (p = 0.01): 31.1% vs. 28.9% and 69.1% vs. 59.2% at month 3 and 6 after therapy initiation, respectively. Cox regression confirmed that valsartan SPC patients were more likely to achieve BP goal (HR = 1.22; p = 0.05). A similar trend was observed in the subgroup analyses comparing SPC of valsartan/amlodipine vs. FCs of ARB + CCB and SPC of valsartan/HCTZ vs. FCs of ARB + HCTZ. Limitations: Non-randomization of treatments, limited generalizability, and no records of BP measures within 45 days. Conclusions: Patients using valsartan-based SPCs were significantly more likely to achieve BP goal than those treated with ARB-based FCs in the real-world clinical practice in the South Central region. The significance was achieved at two-sided alpha = 0.05.

Metabolic regulation plays an important role in modifying coronary vascular tone. We hypothesized that hydrogen peroxide, purinergic components, and angiotensin, produced by cardiac myocytes control coronary vascular tone in proportion to metabolism. We measured changes in the diameter of isolated, pressurized coronary arterioles in response to supernatant from isolated cardiac myocytes in rats (stimulated for 20-, 60-, and 120-min at 400bpm). Changes in the diameter of arterioles were determined under control conditions following treatment of arterioles with an adenosine receptor antagonist, 8-PSPT, a P2Y1 receptor antagonist, MRS-2179, or an angiotensin II receptor antagonist, olmesartan. A supernatant (500mul to a 2ml bath) from myocytes stimulated for 20-, 60- and 120-min caused graded vasodilation (14.1+/-0.4, 20.2+/-1.6, 53.8+/-6.2%, P<0.01 vs. non-stimulated, respectively). In 20-min stimulation, catalase with myocyte supernatants eliminated vasodilation. Following 60-min stimulation, catalase converted myocyte supernatant-induced vasodilation to a vasoconstriction (-15.1+/-1.0%), and this vasoconstriction was eliminated by olmesartan. Upon 120-min stimulation, catalase partially reduced the vasodilation by myocyte supernatants (37.2+/-3.8%). The remaining vasodilation was converted to a vasoconstriction with 8-PSPT and MRS2179, and this vasoconstriction was completely eliminated with olmesartan. Cardiac myocytes modulate vascular tone through the net effects of hydrogen peroxide, purinergic components (adenosine and ADP), and angiotensin in proportion to ischemia.

[(11)C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[18F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate.

Hideki Terashima, Mikio Kato, Hiroaki Yasumo, Hiroshi Tsuchida, Makoto Mizuno and Toshio Sada. Fibrosis is the final common pathway for various tissue lesions that lead to chronic progressive organ failure and consequently effective antifibrotic drugs are strongly desired. However, there are few animal models in which it is possible to evaluate fibrosis sensitively in a short period of time. We therefore generated two transgenic rats harboring a firefly luciferase reporter gene under the control of the 5'-flanking region of rat alpha1(I) collagen (Col1a1-Luc Tg rats) and alpha2(I) collagen (Col1a2-Luc Tg rats). The luciferase activities of these transgenic rats were highly correlated with the hydroxyproline content in various organs. In unilateral ureteral obstruction (UUO), a well-characterized model of renal fibrosis, the luciferase activity in obstructed kidneys showed a significant increase after even 3 days of UUO, while the hydroxyproline content showed little increase. In addition, the renal hydroxyproline content had a higher correlation with the luciferase activity than alpha1(I) collagen mRNA level for over two weeks after UUO. Although both an angiotensin II (ANG II) type 1 receptor blocker (ARB) olmesartan and a transforming growth factor-beta (TGF-beta) type I receptor kinase (ALK5) inhibitor SB-431542 inhibited renal luciferase activities in UUO, only SB-431542 inhibited luciferase activity induced by TGF-beta1 in isolated glomeruli. Double immunostaining for luciferase and alpha-smooth muscle actin (alpha-SMA) revealed that some alpha-SMA positive tubular epithelial cells and tubular interstitial cells produced type I collagen, which would lead to renal fibrosis. Thus, collagen reporter transgenic rats would be very useful for the evaluation of antifibrotic effects and analysis of their mechanisms.

Summary 1. Metabolic syndrome is an independent risk factor for cardiovascular disease. SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP fatty) rat, established as a new rat model of metabolic syndrome, develops spontaneously obesity, severe hypertension and exhibits hypertriglyceridemia, hypercholesterolemia, and abnormal glucose tolerance. Using SHRSP fatty rats, we examined whether oxidative stress was correlated with vascular dysfunction in small and large caliber coronary arteries in ex vivo beating hearts, isolated mesenteric arteries and aortas by comparison with normal rats, Wistar-Kyoto rats (WKY). Vasodilation of coronary arteries was determined by microangiography of the Langendorf heart. 2. Compared to WKY, acetylcholine (ACh) and sodium nitroprusside (SNP)-induced relaxations were impaired in the coronary arteries of SHRSP fatty rats. The mesenteric arteries and aorta of SHRSP fatty rats exhibited impaired relaxation responses to ACh and SNP, decreased cGMP production, and reduced soluble guanylyl cyclase protein expression. Superoxide release, angiotensin II and 3-nitrotyrosine contents were increased. 3. SHRSP fatty rats were orally administered olmesartan, an angiotensin II receptor type 1 (AT(1)) antagonist, and amlodipine, a calcium channel blocker, at doses of 5 and 8 mg/kg/day, respectively, for 8 weeks. Both olmesartan and amlodipine reduced blood pressure, but only olmesartan prevented the development of abnormal vascular and biochemical parameters in the SHRSP fatty rats. 4. The results indicated that in the SHRSP fatty rats, the impaired nitric oxide- and cGMP-mediated relaxation of vascular smooth muscle cells were linked to AT(1) receptor-induced oxidative-nitrative stress, which occurred concurrently with severe hypertension and metabolic abnormalities in vivo.

Background and Objective: Elevated systolic BP (SBP) is a major contributor to cardiovascular disease. SBP control reduces the occurrence of stroke, heart failure, and cardiovascular and total mortality. The aim of this study was to analyze the magnitude of SBP reductions and the achievement of individual SBP targets in the original BENIFORCE study. Methods: An olmesartan medoxomil-based treatment algorithm was evaluated in a double-blind, placebo-controlled titration study in 276 patients with stage 1 (47.1%) or 2 (52.9%) hypertension. After placebo run-in, patients were randomized to placebo (12 weeks) or olmesartan medoxomil 20 mg/day (weeks 1-3). Olmesartan medoxomil was uptitrated to 40 mg/day (weeks 4-6), then olmesartan medoxomil/hydrochlorothiazide (HCTZ) 40/12.5 mg per day (weeks 7-9), and olmesartan medoxomil/HCTZ 40/25 mg per day (weeks 10-12) if BP remained >/=120/80 mmHg at any time interval. Setting: The BENIFORCE study was a multicenter (29 sites) study conducted between January and October 2007 in the US. Results: In patients receiving olmesartan medoxomil-based therapy, 81.0%, 67.2%, and 46.6% of patients with stage 1 hypertension and 70.4%, 49.4%, and 23.5% of patients with stage 2 hypertension achieved SBP targets of <140, <130, and <120 mmHg, respectively (all p < 0.01 vs placebo). The proportions of patients achieving SBP targets increased with escalating doses of olmesartan medoxomil and HCTZ, administered alone or in combination, and was highest for combination therapy. Similarly, escalating doses of olmesartan medoxomil or olmesartan medoxomil/HCTZ increased the proportion of patients achieving SBP reductions of >15 but </=30, >30 but </=45, and >45 mmHg compared with placebo. Conclusion: An olmesartan medoxomil-based treatment algorithm effectively reduced SBP and achieved SBP targets in patients with stage 1 or 2 hypertension. This regimen resulted in >80% of patients achieving SBP reductions of >/=15 mmHg while 44% achieved SBP reductions of >30 mmHg.

OBJECTIVE(S): To assess the efficacy and safety of once daily olmesartan medoxomil 20 mg in Indian patients with stage 1 essential hypertension. METHOD(S): This was an open label, multicentre, real world observational postmarketing surveillance conducted in male and female patients (N=825), in age group of 18 to 65 yrs who had clinically diagnosed stage 1 hypertension (JNC-7 guidelines) and were prescribed olmesartan medoxomil 20 mg once daily as treatment. There were total of seven study visits, Visit-1 (day 1) and end of study visit-7 (end of week 8). Except for those patients who did not achieve the target BP levels, all the patients continued to receive olmesartan medoxomil 20 mg for 8 weeks, given once a day at 24 hourly intervals. At end of surveillance (EOS; week 8) visit-7 clinical response to treatment was determined by "responder rate" and changes in level of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Responder rate criteria was defined as, SBP and DBP levels of <140 mmHg and <90 mmHg respectively, and for hypertensive patients with diabetes mellitus SBP and DBP levels of < 130 mmHg and < 80 mmHg respectively. RESULT(S): There were significant changes in mean sitting systolic and diastolic blood pressure, the primary end point of the study. From baseline visit to the end of the surveillance visit-7 (week 8), a mean change of -18.7 (147.86 to 129.16; p < .0001; 95% CI) in sitting SBP and a mean change of -14.47 (95.99 to 81.56; p < .0001; 95% CI) in sitting DBP respectively was observed with olmesartan 20 mg once daily. The response rate at the end of study was 81.82% and 70.18% for SBP and DBP respectively, in stage 1 hypertensive patients without diabetes mellitus. It was 73.38% and 65.47% respectively for SBP and DBP in patients with diabetes. Overall efficacy of Olmesartan medoxomil 20 mg was excellent to very good in 92.5% patients, only 05 (0.6%) of patients, reported of poor efficacy. Tolerability as assessed globally was reported to be excellent to very good by 92.1% of patient, with only one patient (0.1%) reported it to be poor. The most common adverse events reported were dizziness (82.52%), headache (63%), respiratory tract infection (50.40%) and nausea (40.24%); all the AE's were mild-moderate in nature which did not require stoppage of treatment. CONCLUSION(S): Our findings reiterated that Olmesartan medoxomil 20 mg once daily is not only effective in achieving the desired BP in a significant number of patients, it also shows excellent tolerability and hence compliance. Olmesartan is a valuable option for treatment of essential hypertension in adult Indian patients.