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Drug Design, Development and Therapy 2015Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease.... (Comparative Study)
Comparative Study
INTRODUCTION
Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition.
MATERIALS AND METHODS
Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE(-/-)) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition - such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification - were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB) in aortic tissue.
RESULTS
Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE(-/-) mice (olmesartan medoxomil/amlodipine besylate: 122,277±6,795 μm(2), number [n]=14; versus control: 177,502±10,814 μm(2), n=9; P<0.001). Treatment with amlodipine besylate (n=5) alone did not reach significance. However, a trend toward a decrease in lesion size in the amlodipine besylate-treated animals could be observed. In the histological analysis of atherosclerotic lesion composition, significantly thicker fibrous caps were found in treatment with amlodipine besylate (amlodipine: 5.12±0.26 μm, n=6; versus control: 3.98±0.18 μm, n=10; P<0.01). Furthermore, all sections revealed morphological signs of calcification, but no difference could be detected. Treatment with the combination of olmesartan medoxomil and amlodipine besylate showed no effect on lesion composition. Electrophoretic mobility shift assays of nuclear extracts demonstrated reduced activity of the transcription factor NF-κB when treated with olmesartan medoxomil, amlodipine besylate, or their combination, as compared to controls.
CONCLUSION
Combined treatment with olmesartan medoxomil and amlodipine besylate attenuated atherosclerotic lesion progression, possibly due to anti-inflammatory mechanisms. Our data support the hypothesis that even in advanced atherosclerosis anti-inflammatory treatment, using angiotensin II type 1 receptor blockers and calcium channel antagonists of the dihydropyridine type can attenuate atherosclerotic lesion progression.
Topics: Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Angiotensin II Type 1 Receptor Blockers; Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Disease Progression; Electrophoretic Mobility Shift Assay; Female; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B
PubMed: 26251572
DOI: 10.2147/DDDT.S85203 -
Journal of the... Dec 2015The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase...
The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling.
HYPOTHESIS/INTRODUCTION
The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity.
MATERIALS AND METHODS
The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment.
RESULTS
Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001.
CONCLUSIONS
These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.
Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Cardiovascular System; Densitometry; Diastole; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Myosin-Light-Chain Phosphatase; Olmesartan Medoxomil; Phosphorylation; Receptor, Angiotensin, Type 1; Rho Guanine Nucleotide Exchange Factors; Systole; rho-Associated Kinases; rhoA GTP-Binding Protein
PubMed: 26240115
DOI: 10.1177/1470320315594324 -
Journal of Clinical Pharmacology Apr 2016Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with... (Randomized Controlled Trial)
Randomized Controlled Trial
Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (ΔΔQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of ΔΔQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1-sided 95%CI <10 milliseconds for ΔΔQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for ΔΔQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated.
Topics: Adolescent; Adult; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Electrocardiography; Female; Healthy Volunteers; Heart; Humans; Long QT Syndrome; Male; Middle Aged; Olmesartan Medoxomil; Young Adult
PubMed: 26239632
DOI: 10.1002/jcph.610 -
Journal of Clinical Hypertension... Jan 2016This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding... (Randomized Controlled Trial)
Randomized Controlled Trial
This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.
Topics: Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Diuretics; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Olmesartan Medoxomil
PubMed: 26176708
DOI: 10.1111/jch.12621 -
PloS One 2015Blockade of the renin-angiotensin-aldosterone system exhibits a renoprotective effect; however, blockade of this system may also decrease hemoglobin (Hb) and... (Randomized Controlled Trial)
Randomized Controlled Trial
The Decrement of Hemoglobin Concentration with Angiotensin II Receptor Blocker Treatment Is Correlated with the Reduction of Albuminuria in Non-Diabetic Hypertensive Patients: Post-Hoc Analysis of ESPECIAL Trial.
Blockade of the renin-angiotensin-aldosterone system exhibits a renoprotective effect; however, blockade of this system may also decrease hemoglobin (Hb) and erythropoietin (EPO) levels. We evaluated the correlation between reduced albuminuria and decreased hemoglobin concentrations after treatment with an angiotensin II receptor blocker (ARB). Two hundred forty-five non-diabetic hypertensive participants with established albuminuria and relatively preserved renal function were treated with an ARB (40 mg/day olmesartan) for eight weeks. Subsequent changes in various clinical parameters, including Hb, EPO, and albuminuria, were analyzed following treatment. After the 8-week treatment with an ARB, Hb and EPO levels significantly decreased. Patients with a greater decrease in Hb exhibited a greater reduction in 24-hour urinary albumin excretion compared with patients with less of a decrease or no decrease in Hb, whereas no associations with a decline in renal function and EPO levels were noted. Multivariate logistic regression analysis demonstrated a correlation between the reduction of urine albumin excretion and the decrease in Hb levels (after natural logarithm transformation, adjusted odds ratio 1.76, 95% confidence interval 1.21-2.56, P = 0.003). Linear regression analysis also supported this positive correlation (Pearson correlation analysis; R = 0.24, P < 0.001). Decreased Hb concentrations following ARB treatment were positively correlated with reduced albuminuria in non-diabetic hypertensive patients, regardless of decreased blood pressure and EPO levels or renal function decline.
Topics: Albuminuria; Angiotensin Receptor Antagonists; Case-Control Studies; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Receptors, Angiotensin; Renin-Angiotensin System; Treatment Outcome
PubMed: 26098847
DOI: 10.1371/journal.pone.0128632 -
Journal of Clinical Pharmacology Jan 2016
Randomized Controlled Trial
Topics: Adult; Antihypertensive Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Heart Rate; Humans; Linear Models; Long QT Syndrome; Male; Middle Aged; Models, Biological; Olmesartan Medoxomil; Young Adult
PubMed: 26096571
DOI: 10.1002/jcph.572 -
Drug Design, Development and Therapy 2015A fixed-dose combination of amlodipine and olmesartan is used to treat high blood pressure in patients whose hypertension is not sufficiently controlled with either drug... (Comparative Study)
Comparative Study Randomized Controlled Trial
A fixed-dose combination of amlodipine and olmesartan is used to treat high blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The objective of this study was to evaluate the bioequivalence of two fixed-dose combinations, ie, amlodipine orotate/olmesartan medoxomil 10/40 mg and amlodipine besylate/olmesartan medoxomil 10/40 mg, in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted in 30 healthy adult volunteers. Blood samples were collected for up to 72 hours post-dose in each period. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. For both amlodipine and olmesartan, the 90% confidence intervals for the geometric mean ratios of AUClast and time to peak plasma concentration fell within the bioequivalence acceptance criteria. The two fixed-dose combinations showed similar safety profiles. Amlodipine orotate/olmesartan medoxomil 10/40 mg was bioequivalent to amlodipine besylate/olmesartan medoxomil 10/40 mg.
Topics: Adult; Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Antihypertensive Agents; Area Under Curve; Cross-Over Studies; Female; Humans; Male; Middle Aged; Salts; Therapeutic Equivalency; Young Adult
PubMed: 26082611
DOI: 10.2147/DDDT.S82820 -
Biological & Pharmaceutical Bulletin 2015The aim of this study was to evaluate the effect of olmesartan (OLME), an angiotensin II receptor antagonist, on an intestinal mucositis model. Briefly, daily...
In a methotrexate-induced model of intestinal mucositis, olmesartan reduced inflammation and induced enteropathy characterized by severe diarrhea, weight loss, and reduced sucrose activity.
The aim of this study was to evaluate the effect of olmesartan (OLME), an angiotensin II receptor antagonist, on an intestinal mucositis model. Briefly, daily intraperitoneal (i.p.) injections of methotrexate (MTX) 7 mg/kg were administered to rats on 3 consecutive days. A subset of these rats was also pretreated with oral administration of OLME (0.5, 1.0, or 5.0 mg/kg) or vehicle as a control 30 min prior to MTX injection. Body weight, feces scoring, and death were recorded daily. On day 4, the rats were killed, and intestinal tissues were assayed for levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, myeloperoxidase and sucrose activity, and histopathological findings. A significant reduction in body weight was observed in the MTX+1.0 mg/kg OLME group (p<0.01). The feces scores for the MTX+0.5 mg/kg OLME and MTX+5.0 mg/kg OLME groups were also significantly higher (p<0.001). Sucrose activity was reduced in all groups treated with OLME (p<0.05). Treatment with MTX+OLM at all doses resulted in reduced inflammatory infiltration, ulcerations, vasodilation, and hemorrhagic areas (p<0.05), as well as reduced concentrations of myeloperoxidase (p<0.001). The IL-1β and TNF-α levels were decreased in the MTX+OLME 5.0 mg/kg (p<0.01 and p<0.05, respectively) compared with the MTX-alone group. Overall, antiinflammatory activity was observed in rats with MTX-induced intestinal mucositis that were administered OLME. However, further studies are needed to elucidate the adverse effects of OLME.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Diarrhea; Disease Models, Animal; Imidazoles; Inflammation; Interleukin-1beta; Intestinal Mucosa; Intestine, Small; Male; Methotrexate; Mucositis; Neoplasms; Olmesartan Medoxomil; Rats, Wistar; Sucrose; Tetrazoles; Tumor Necrosis Factor-alpha; Weight Loss
PubMed: 25947920
DOI: 10.1248/bpb.b14-00847 -
Journal of Stroke and Cerebrovascular... Jul 2015Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan... (Clinical Trial)
Clinical Trial
BACKGROUND
Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan.
METHODS
We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/β-2-glycoprotein I (β2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment.
RESULTS
After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/β2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (<140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred.
CONCLUSIONS
Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.
Topics: Aged; Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biomarkers; Blood Pressure; Drug Substitution; Female; Humans; Hypertension; Japan; Lipoproteins, LDL; Male; Middle Aged; Olmesartan Medoxomil; Peptide Fragments; Peroxiredoxins; Prospective Studies; Stroke; Time Factors; Treatment Outcome; beta 2-Glycoprotein I
PubMed: 25891757
DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.015 -
Health and Quality of Life Outcomes Feb 2015A post-hoc analysis was performed on the data from a 54 weeks phase III study (ClinicalTrials.gov identifier: NCT00923091) to measure changes in the health-related... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A post-hoc analysis was performed on the data from a 54 weeks phase III study (ClinicalTrials.gov identifier: NCT00923091) to measure changes in the health-related quality of life (HRQoL) of 2,690 patients aged ≥18 with moderate-to-severe hypertension who received one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ), using the MINICHAL and EQ-5D instruments.
METHODS
Descriptive statistics were used to assess blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors that could possibly have influenced HRQoL. Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores.
RESULTS
Patients' baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients' baseline EQ-5D index and VAS scores were 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients' QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. The ANCOVA showed that changes in patients' HRQoL was likely to have been influenced by patients' achievement of blood pressure control, the amount of concomitant medication and patients' last used dosage strength of antihypertensive. Linear regression showed that blood pressure improvement may have been associated with improved HRQoL.
CONCLUSIONS
This study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients' HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive impacted on patients' HRQoL.
Topics: Adult; Aged; Amlodipine; Analysis of Variance; Antihypertensive Agents; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Middle Aged; Olmesartan Medoxomil; Quality of Life; Tetrazoles; Treatment Outcome
PubMed: 25879524
DOI: 10.1186/s12955-015-0216-6