Angiotensin Receptor Blocker Olmesartan Research Articles

Are the Newest Angiotensin Receptor Blockers Preferred than the Old Members in COVID-19 Patients with Cardiovascular Comorbidity?

Background and Objective: The cardiovascular diseases are the most frequent comorbidities of Covid-19 infection. The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) employs the angiotensin converting enzyme 2 (ACE2) receptor to invade cells. Angiotensin receptor blockers (ARBs) do not directly interact with ACE2 receptor, but they could affect course of Covid-19 infection because they increase expression of ACE2 and this could offer more binding sites for the virus. However, this could support cardiopulmonary protective effects of the ACE2/Ang-(1-7)/Mas axis. Also, sensitivity of an individual to COVID-19 infection might be affected by ACE2 polymorphism. To my knowledge, there are no clinical data to explain whether use of ARBs in COVID-19 patients with cardiovascular diseases is the same for all members or that some ARB members are preferred than others? This review tries to shed light on this issue. Materials and Methods: Wide literature search using many key words related to ARBs and COVID-19. Results: The newest ARBs (Olmesartan medoxomil and Azilsartan medoxomil) block the angiotensin II receptor 1 (AT1R) with inverse agonist activities, have no antagonistic effects on AT2R, upregulate ACE2 and stimulate ACE2/Ang-(1-7)/Mass receptor pathway. They are poor activators of peroxisome proliferator-activated receptor-γ (PPARγ) whose activation is not needed for their metabolic benefits. In addition, Olmesartan medoxomil inhibits ACE and decreases the plasma level of angiotensin II. Conclusion: In spite of their favorable pharmacological profiles, there is no enough evidence to support choice of the newest ARBs rather than the old ones for treatment of cardiovascular morbidities in COVID-19 patients.

Severe cases of sprue‐like enteropathy associated with angiotensin receptor blockers other than olmesartan

Background Sprue-like enteropathy (SLE) has been reported in patients with arterial hypertension who are treated with the angiotensin receptor blocker (ARB) olmesartan. It is currently controversial whether this is a class effect or specific to olmesartan. Methods A systematic literature search was conducted in Medline/PubMed, Embase, Web of Science and Scopus without language, publication year or publication status restrictions up to October 2019 to retrieve publications on SLE related to all ARBs excluding olmesartan. Results Overall, 17 reports including a total of 21 patients describing SLE cases were identified with the following ARBs: candesartan (n = 1), eprosartan (n = 1), irbesartan (n = 4), losartan (n = 7), telmisartan (n = 4) and valsartan (n = 4). The treatment duration among these ARB-treated patients varied from 2 months to up to 13 years, while the onset of enteropathy-related symptoms ranged from 2 months to 10 years from treatment initiation. The most frequently reported SLE symptoms were as follows: chronic diarrhoea, abdominal symptoms, loss of appetite and weight loss (3-27 kg). Symptomatic treatment with antibiotics, corticosteroids and dietary modifications did not significantly improve the SLE symptoms in patients while on treatment with ARBs. However, diarrhoea resolved in all 21 patients after the withdrawal of ARBs and other gastrointestinal symptoms had resolved on follow-up in all but two patients. Conclusions SLE is observed in patients treated with ARBs other than olmesartan. This suggests a class effect in the rare event of patients treated with ARBs developing SLE.

Abstract 15: Hypertension drug Olmesartan medoxomil promotes colonic tumorigenesis in AOM-induced CRC rat model

Abstract Some retrospective studies suggest an inverse risk-association between the use of angiotensin signaling inhibitors and colorectal cancer (CRC). The angiotensin receptor blocker olmesartan medoxomil (OLM) is commonly prescribed for hypertension treatment. Here we sought to determine the chemopreventive efficacy of OLM using the azoxymethane (AOM)-induced CRC rat model. Male and female F344 rats (n=6/gender/group) were randomized and subcutaneously injected with 20 mg/kg of AOM once weekly for two weeks. One week later, AIN76-A diets containing OLM (0 ppm to 480 ppm) were fed to rats. Six weeks after treatment, rats were euthanized and evaluated for toxicity and aberrant crypt foci (ACF) inhibition. OLM-fed rats, particularly at ≥160 ppm, showed signs of toxicity. There was a modest decrease in the total ACFs without any change in multicrypt ACFs in male rats; however in females there was an increase in multicrypt ACFs as compared to the control diet group. For tumor efficacy evaluation, 5-week-old F344 rats were randomized (n=30/gender/group) and CRC was induced as described above. At the adenoma stage (12-weeks after AOM-treatment), rats were administered OLM (0, 20 and 40 ppm) in the diet for 33 weeks, and colonic tumors were evaluated. In the control group, there was a huge disparity in colonic tumor incidence and multiplicity between genders with ~3-fold less tumors in female rats. Surprisingly, colon tumor incidence was significantly increased (3-fold; p<0.0002) in the OLM-treated female rats (77% OLM vs 24% control). Colon tumor multiplicity analysis also showed tumor promoting effects. In the 20 ppm OLM-treated male and female rats, colonic adenocarcinoma multiplicities were increased by ~91% (p<0.01) and ~362% (p<0.0001), respectively, when compared with their respective controls. Although there was no dose response, similar tumor promoting effects were found in 40 ppm OLM-treated rats. To understand male vs female colon tumor disparities and OLM tumor promoting effects, we carried out RNA-Seq analysis of colonic tumors. Reflecting tumor data, gene expression analysis also showed significant differences between male and female rats with respect to type II-interferon, PI3K-AKT, cholesterol, lipid droplet, mucin, IL-3, cell-cycle and nucleotide GPCR signaling pathways. OLM treatment significantly upregulated 586 and 740 genes, and downregulated 648 and 564 genes in male and female rat tumors, respectively. Of the 293 common genes identified, Irx5, Lrrn1, Ly6g6e, Sccpdh, Hoxd12, Igfbp1, Krt81 and DSC3 were upregulated up to 245-fold; and Rfxapl1, Serpinb3a, REg3b, Bnc1 and Ak4 were down-regulated 10 - 200-fold with OLM treatment. In conclusion, chronic administration of OLM did not provide any chemopreventive benefit against colonic tumors in the AOM-induced F344 rat CRC model. Further studies are warranted to assess the risk of colon cancer associated with long-term OLM use, particularly in females. (Supported by NCI HHSN 261201500038I and VA Merit Award) Citation Format: Venkateshwar Madka, Yuting Zhang, Gopal Pathuri, Janani Panneerselvam, Nicole Stratton, Anil Singh, Shizuko Sei, Jennifer Fox, Chinthalapally V. Rao. Hypertension drug Olmesartan medoxomil promotes colonic tumorigenesis in AOM-induced CRC rat model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 15.

Effect of Gonadectomy and Angiotensin II Receptor Blockade in a Mouse Model of Isoproterenol-induced Cardiac Diastolic Dysfunction.

Although heart failure (HF) with preserved ejection fraction (HFpEF) is more common in postmenopausal women than in men, the effect of sex hormones on cardiac diastolic function remains unclear. We examined the effect of gonadectomy with or without the angiotensin receptor blocker olmesartan (Olm) in an isoproterenol (ISO) -induced mouse model of left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction. ISO or ISO with Olm were administered for 28 days in sham-operated male and female, castrated (CAS), and ovariectomized (OVX) mice. LV ejection fraction (EF) and E/A ratio were analyzed by echocardiography, and the LV and lung weight corrected by tibial length were used as indices of LVH and lung congestion, respectively. On echocardiography, systolic function did not differ between the four groups. LV/tibial length (TL) and Lung/TL significantly increased in all groups. The LV/TL ratio was lower in castrated-ISO vs. Male-Sham-ISO but did not differ between Female-Sham-ISO and OVX-ISO. However, the Lung/TL ratio of OVX-ISO was greater than that of Female-Sham-ISO. Olm prevented LV hypertrophy in all groups. The decrease in E/A and increase in lung weight were improved by Olm in Male-Sham and OVX-ISO but not in the other groups. These sex differences suggest that sex hormones play a pivotal role in modulating cardiac hypertrophy and diastolic dysfunction induced by chronic β-adrenoceptor stimulation, and thus affect the therapeutic potential of angiotensin receptor blockade.

Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension.

Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serumuric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.

Spectroscopic and molecular docking studies of the binding of the angiotensin II receptor blockers (ARBs) azilsartan, eprosartan and olmesartan to bovine serum albumin

Angiotensin receptor blockers (ARBs) represent a group of widely used therapeutic agents for the effective control of hypertension and other cardiovascular problems. Herein, the interactions of three important members of the ARBs (azilsartan, eprosartan and olmesartan) with bovine serum albumin (BSA) have been explored employing a set of simple spectroscopic approaches complemented with molecular docking studies. Steady state fluorescence emission results demonstrated the ARBs-induced quenching of the intrinsic fluorescence of BSA, which turned out to be a result of the formation of non-fluorescent complexes. The determined Stern-Volmer and binding constants were in the 104 magnitude, which were declined with the increase in temperature that primarily indicated static type of quenching. Subsequent analysis of the fluorescence data to explore the thermodynamic characteristics of these interactions showed spontaneous reactions with negative ΔH◦ values and positive ΔS◦ values, which suggest the involvement of electrostatic binding forces along with hydrogen bonding. Competitive binding studies were conducted with the aid of known BSA site markers to find the binding region of BSA for the investigated ligands. This was further supported by molecular docking simulations that ascertained the efficient binding of the three ligands to Sudlow site I (subdomain IIA) in the BSA structure.

Personalised Single-Pill Combination Therapy in Hypertensive Patients: An Update of a Practical Treatment Platform.

Despite the improvements in the management of hypertension during the last three decades, it continues to be one of the leading causes of cardiovascular morbidity and mortality worldwide. Effective and sustained reductions in blood pressure (BP) reduce the incidence of myocardial infarction, stroke, congestive heart failure and cardiovascular death. However, the proportion of patients who achieve the recommended BP goal (< 140/90 mmHg) is persistently low, worldwide. Poor adherence to therapy, complex therapeutic regimens, clinical inertia, drug-related adverse events and multiple risk factors or comorbidities contribute to the disparity between the potential and actual BP control rate. Previously we published a practical therapeutic platform for the treatment of hypertension based on clinical evidence, guidelines, best practice and clinical experience. This platform provides a personalised treatment approach and can be used to improve BP control and simplify treatment. It uses long-acting, effective and well-tolerated angiotensin receptor blocker (ARB) olmesartan, in combination with a calcium channel blocker amlodipine, and/or a thiazide diuretic hydrochlorothiazide. These drugs were selected based on the availability in most European Countries of single-pill, fixed formulations in a wide range of doses for both dual- and triple-drug combinations. The platform approach could be applied to other ARBs or angiotensin-converting enzyme inhibitors available in single-pill, fixed-dose combinations. Here, we present an update, which takes into account the results of the recently published studies and extends the applicability of the platform to common conditions that are often neglected or poorly considered in clinical practice guidelines.Electronic supplementary materialThe online version of this article (doi:10.1007/s40292-017-0239-7) contains supplementary material, which is available to authorized users.

Effect of Olmesartan on the Level of Oral Cancer Risk Factor PAI1.

To study if the angiotensin receptor blocker olmesartan reduces levels of plasminogen activator inhibitor 1 (PAI1), a risk factor for oral cancer, in a mouse model and therefore whether it could be used in the treatment of this malignancy. Twelve transgenic PAI1 mice aged 16-20 weeks were divided in two groups each containing six animals. One group was given olmesartan every day for 30 days in drinking water in an amount corresponding to their weight, 0.005 mg/g, while the second group did not receive any medication (control group). Blood samples were obtained from animals of both groups, before and after one month of olmesartan administration and plasma PAI1 levels were measured using enzyme-linked immunosorbent assay. In the olmesartan-treated group, a significant decrease of PAI1 level was found after 1 month of treatment (11.9±8.6 vs. 21.7±7.2 ng/ml, respectively; p=0.028). However, no statistically significant difference was observed in PAI1 levels between the olmesartan-treated and control groups after one month, (p=0.177). Olmesartan did not significantly affect PAI1 levels in this mouse model.

PS 01-26] THE ROLE OF ACTIVATED RENIN-ANGIOTENSIN SYSTEM FOR THE MRP8/TLR4 SIGNALING IN DIABETIC NEPHROPATHY

Objective: We previously reported that myeloid-related protein 8 (MRP8: S100A8) / toll-like receptor 4 (TLR4) signaling activated by macrophage (Mϕ)-mediated glucolipotoxicity might play an important role in the progression of diabetic nephropathy. Although local activation of the renin-angiotensin system (RAS) in the kidney has been observed in concurrence with the MRP8/TLR4 activation in the diabetic-hyperlipidemic model mice, the relationship between these signals is unknown. Design and Method: In vivo, diabetic-hyperlipidemic mice by STZ plus high-fat diet (STZ-HFD mice) or db/db mice were treated with an angiotensin-receptor blocker olmesartan (Olm, 0.5 microg/kg/min, 4wk) or angiotensin II (AngII, 0.3 microg/kg/min, 2wk), respectively. In vitro, Mϕ was stimulated with mesangial cell-conditioned medium (Mes-sup) with or without a TLR4 antagonist. Expression of MRP8 mRNA and inflammatory pathway in detail were evaluated with TaqMan real-time PCR and THP1-dual reporter cell line, respectively. Results: Angiotensinogen (Agt) mRNA was locally upregulated in the glomeruli of STZ-HFD mice, whose changes also occurred in TLR4 knockout mice. Olm effectively suppressed upregulation of glomerular MRP8/TLR4 and Agt in STZ-HFD mice, which were associated with reduction of albuminuria, Mϕ infiltration and proinflammatory/profibrotic gene expressions in the kidney. Besides, a subpressor dose of AngII markedly worsened albuminuria and increased glomerular infiltrated MRP8-positive cells in db/db mice. Since glomerular infiltrated Mϕ showed obviously high MRP8 positivity compared to tubulointerstitial Mϕ, we speculated the intraglomerular crosstalk between Mϕ and glomerular intrinsic cells. Mes-sup stimulation, rather than proximal tubular cell-conditioned medium, potently induced MRP8 expression and also interferon regulatory factor (IRF)-pathway, which could cause the ER stress, in Mϕ. This induction was partially abrogated by the TLR4 antagonist. Conclusions: RAS activation in diabetic kidney could contribute to progression of nephropathy through promoting intraglomerular crosstalk, which may trigger MRP8 production in glomerular infiltrated Mϕ.

Olmesartan Prevents Microalbuminuria in db/db Diabetic Mice Through Inhibition of Angiotensin II/p38/SIRT1-Induced Podocyte Apoptosis

Background/Aims: Blockage of the renin-angiotensin II system (RAS) prevents or delays albuminuria in diabetic patients. The aim of this study was to investigate the inhibitory mechanism of the angiotensin receptor blocker olmesartan on albuminuria in a murine model of diabetic nephropathy. Methods: Male db/db diabetic mice were fed with placebo or 20 mg/kg olmesartan by daily gavage for 12 weeks. Conditionally immortalized mouse podocytes were treated with glucose, angiotensin II, olmesartan or p38 inhibitor s8307 in different experimental conditions after differentiation. Results: Olmesartan reduced albuminuria in db/db mice without change in body weight and glycemia. The increase of apoptotic cells and decrease of podocytes in the diabetic glomerulus were prevented by olmesartan. Moreover, olmesartan restored silent mating type information regulation 1 (SIRT1) expression in diabetic glomeruli. Furthermore, olmesartan treatment suppressed p38 phosphorylation but did not restore adenosine 5‘-monophosphate-activated protein kinase (AMPK) phosphorylation in the diabetic glomerulus. In vitro study revealed that olmesartan prevented angiotensin II/p38/SIRT1 induced podocyte apoptosis, but it only slightly prevented high glucose/AMPK/SIRT1 induced podocyte apoptosis. In addition, the p38 inhibitor s8307 reversed SIRT1 expression and angiotensin II induced podocyte apoptosis. Conclusions: Olmesartan reduced albuminuria in diabetic nephropathy through inhibiting angiotensin II/p38/SIRT1 triggered podocyte apoptosis.

PP.23.12

Objective: The aim of this study was to assess influence of different variants of combined treatment of hypertension, including with type 2 diabetes (T2D), with application of angiotensin receptor blocker (ARB) olmesartan or angiotensin-converting enzyme (ACE) inhibitor ramipril on apelin blood levels. Design and method: We examined 62 patients with hypertension grades 2–3 (24 men and 38 women), aged 43 to 70 years, of which 36 patients had concomitant T2D, before and after 12 weeks of combined treatment. Antihypertensive therapy included ARB olmesartan 20–40 mg/day (14 hypertension patients and 18 hypertension patients with T2D) or ACE inhibitor ramipril 10–20 mg/day (12 hypertension patients and 14 hypertension patients with T2D) with calcium antagonist lercanidipine 10–20 mg/day. All patients treated with lipid-lowering therapy with atorvastatin 20 mg/day. Patients with T2D received antidiabetic therapy with metformin 1000 mg/day. Control group consisted of 14 volunteers. The apelin blood levels determined by ELISA. Results: Basal apelin blood levels in hypertension patients (0,886(0,846;0,937) ng/ml) and in hypertensive patients with T2D (0,882(0,788;0,924) ng/ml) were significantly lower (p < 0,01 and p < 0,001, respectively) than in control group – 1,097(0,944;1,171) ng/ml. In the dynamics of combined treatment with using of olmesartan we found significant increase of apelin blood levels in hypertension patients from 0,896(0,839;0,919) ng/ml to 0,922(0,851;1,019) ng/ml (p < 0,05) and in hypertension patients with T2D from 0,899(0,841;0,964) ng/ml to 0,989(0,904;1,085) ng/ml, (p < 0,01). Among patients treated with ramipril, apelin levels didn’t change significantly after treatment in either group of patients. In patients treated with olmesartan in contrast to those who have used ramipril, we observed the significant negative correlation of apelin blood levels with diastolic blood pressure (DBP) both in hypertension patients (R = -0,65, p < 0,05) and in hypertension patients with T2D (R = -0,73, p < 0,001). Conclusions: We found increased apelin blood levels in patients with hypertension, including with T2D, influenced by treatment with ARB olmesartan, which correlated with the degree of reduction of DBP. In view of the data obtained using in combined therapy of ARB may be particularly appropriate in patients with hypertension, both without T2D and with T2D, which had initial low levels of this cardioprotective and antidiabetic factor.

Heart failure: New data do not SUPPORT triple RAAS blockade.

The SUPPORT trial evaluated the effect of adding the angiotensin-receptor blocker olmesartan to a combination of angiotensin-converting-enzyme inhibitors and β-blockers in hypertensive patients with chronic stable heart failure. Unfortunately, this triple renin-angiotensin-aldosterone system blockade was associated with worsening of renal function and increases in cardiac events and mortality.

Assessment of In vitro pharmacological activity of Olmesartan by analytical techniques

Background: Free radical oxidative stress has been implicated in the pathology of a wide variety of clinical disorders. Antioxidants are agents which scavenge the free radicals and prevent the damage caused by them. Angiotensin II receptor blockers used in the treatment of hypertension has also been reported to protect organs such as kidney and heart. Although the mechanisms of these protective effects are not fully understood, it is generally thought that their antioxidant effects likely play a role. Hence, this in vitro study was done to demonstrate the antioxidant pharmacological activity of a commonly used Angiotensin receptor blocker Olmesartan. Methods: In this study, we demonstrated the antioxidant pharmacological activity of Olmesartan in vitro by 1,1 Diphenyl 2-picryl hydrazide (DPPH) and nitric oxide (NO) free radical scavenging assays. Results: Olmesartan showed significant free radical scavenging activity by DPPH and NO radical scavenging assays. Conclusion: Hence, Olmesartan, which is an antihypertensive drug, may be effective also as an antioxidant in a wide variety of disease conditions caused by oxidative stress.

Acute Kidney Injury

Acute kidney injury (AKI) is a frequent and serious clinical condition which is associated with poor outcomes, including high mortality rate. Classically, it was considered as an acute condition, potentially reversible with full restitution if patient survives the acute phase of the disease. However, recent epidemiologic and observational studies underscore the association of an episode of AKI with long-term adverse outcomes such as chronic kidney disease, end-stage renal disease, cardiovascular events, and premature death. The increasing incidence of AKI, the association with severe in-hospital complications and long-term outcomes and death, the rise in costs, and the potentially preventable nature of AKI make it as a major public health issue, raising the interest of investigators in the field. Focusing on avoidance of the syndrome or its complications, the burden of the disease that is estimated in more than 13 million people/year all around the world could be effectively reduced. In this special issue devoted to AKI, the potential protective effects of diverse interventions were explored in five basic research studies. Y.-Y. Chen et al. explored the effect of 2-methoxyestradiol against ischemia/reperfusion injury. The protective effect of the angiotensin-receptor blocker olmesartan in rats exposed to tacrolimus is addressed by N. O. Al-Harbi et al. The influence of acute superoxide radical scavenging on systemic hemodynamic and kidney function was investigated by Z. Miloradovic et al. in a model of induced postischemic AKI. Z. O. Ibraheem et al. evaluated the impact of high fructose feeding in rat model of gentamicin induced nephrotoxicity. Finally, W. Zhang et al. addressed the feasibility and efficacy of hypoxia preconditioning to enhance MSC-based therapy of AKI. Contrast induced nephropathy (CIN) was addressed in three clinical studies. The beneficial effect of atorvastatin and rosuvastatin administered at high doses and before iodinated contrast administration was addressed by M. Peruzzi et al. concluding that they have a consistent and beneficial preventive effect on CIN and may actually halve its incidence. The incidence of CI-AKI and ERD in patients who received iodixanol (isoosmolar) versus iohexol (low-osmolar) during angiography for cardiac indication was examined by H.-R. Chua et al. who found advanced age, emergent cardiac conditions, and critical illness as stronger predictors of CI-AKI. J. Malyszko et al. sought cytokine midkine as a potential early marker of renal injury after contrast administration. In a series of critically ill patients with AKI, C.-M. Zheng et al. found that anion gap value predicts short-term mortality in patients with metabolic acidosis and AKI, whereas the strong ion gap value predicts both short-term and long-term mortality among such patients. Dr. H. E. Liu et al. explored genetic polymorphisms of ERCC1 and TP53 as risk factors for cisplatin- and carboplatin-induced nephrotoxicity. Dr. B. B. Albino et al. wondered whether the duration of extended dialysis was associated with complications in AKI patients. The frequency of TGF-β and IFN-γ genotype as risk factors for AKI and death in ICU patients is explored by C. C. Grabulosa et al. who found no association with these outcomes. S. N. Fernandez et al. compared the efficacy of heparin and citrate for anticoagulation in critically ill children on CRRT and found that citrate is a safe and effective anticoagulation method. In a large cohort of AKI patients V.-C. Wu et al. found a decreasing risk of long-term ESRD and mortality in patients surviving an episode of AKI-requiring dialysis, AKI nonrequiring dialysis, and no AKI, respectively. Finally, pathophysiology of cisplatin-induced AKI and nephrotoxicity of contrast media were reviewed by A. Ozkok and C. L. Edelstein and M. Andreucci et al., respectively. We hope this special issue on AKI collaborates in raising the awareness on this clinical condition that challenges not only nephrologists and intensivists who mostly deal with patients with AKI but also primary care physicians, clinicians, surgeons, radiologists, and those who are “in the right place at the right time” to prevent the onset of AKI or, even more, the disease leading to AKI. Raul Lombardi Emmanuel A. Burdmann Alejandro Ferreiro Fernando Liano

Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes.

To assess the ability of olmesartan (OLM) to prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes. This prespecified ECG substudy of Randomised OlmesArtan and Diabetes MicroAlbuminuria Prevention (ROADMAP), which compared OLM with placebo, assessed the signs of left ventricular remodeling in patients with a 12-lead ECG at baseline and after at least 2 years. Cornell voltage QRS duration product (primary objective), Cornell voltage index and Sokolow-Lyon index were assessed. In total, 9418 ECG recordings and 1513 patients from ROADMAP were analyzed (placebo, n = 736; OLM, n = 777). Quartiles defined by baseline Cornell voltage QRS duration product were assessed and the proportion of patients in the highest quartile (≥200 mVms) increased from 24.0 to 26.5% in the placebo group and decreased from 25.5 to 22.3% in the OLM group [odds ratio (OR) 0.598 (95% confidence interval [CI] 0.440-0.813); P = 0.0011]. The OR did not change after adjustment for baseline parameters. By the end of study, 38.7% of patients in the placebo group and 34.7% in the OLM group shifted from a lower to a higher quartile or remained in the highest quartile of Cornell voltage QRS duration product [OR 0.797 (95% CI 0.637-0.996); P = 0.0465]. This translated into a 20.3% risk reduction with OLM and suggested OLM attenuated the progression of left ventricular remodeling versus placebo. OLM substantially delayed the development of left ventricular remodeling in type 2 diabetes. This effect was not explained by the differences in blood pressure control. Thus, OLM delayed the onset of microalbuminuria, as well as the ECG signs of cardiac structural adaptation in type 2 diabetes.

Sprue-like histology in patients with abdominal pain taking olmesartan compared with other angiotensin receptor blockers

AimsA severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has been described in patients taking the angiotensin receptor blocker (ARB) olmesartan. It is unknown whether there are any...

Central aortic pressure indices and their correlation with brachial pressure in hypertensive subjects on newer angiotensin receptor blockers olmesartan and telmisartan

Background: Efficacy of Fixed-dose combination of olmesartan and amlodipine on central aortic pressure and Aortic pulse wave velocity (PWV), which are independent predictors of adverse cardiovascular events in hypertension is lacking. Aim of this study was to correlate the effects of fixed-dose combination therapy with olmesartan 20mg and amlodipine 5mg on central aortic blood pressure (CBP) indices in mild to moderate hypertensive subjects with controlled office BP. Methods: Twenty seven patients with brachial systolic BP 140 mmHg and/or diastolic BP 90 mmHg on three office readings who received fixed-dose combination therapy with olmesartan 20mg and amlodipine 5mg for atleast 12 weeks were included. CBP was measured with Periscope using standard cuff BP measurements and proprietary software utilizing a validated transfer function to convert the brachial waveform. Statistical analysis was done with SPSS version 10. Results: Average age of the study group was 47 years. Carotid femoral pulse wave velocity was 1210.2 454.5 cm/sec. Average brachial SBP, DBP and pulse pressure (PP) at the end of the study was 138.8 11.5, 75.9 9.6 and 62.1 12.8 mm of Hg. Average aortic SBP, DBP and pulse pressure (PP) at the end of the study was 121.5 13.8, 75.6 6.0 and 45.4 12.3 mm of Hg. Aortic augmentation pressure and aortic augmentation index noted were 13.7 9.1 mm of Hg and 28.1 10.7 respectively. A significant positive correlation was noted between brachial SBP and aortic SBP (r1⁄40.603, p < 0.001), brachial DBP and aortic DBP (r1⁄40.775, p < 0.001), brachial PP and aortic PP (r1⁄40.622, p<0.001). Conclusions: Combination therapy with fixed-dose olmesartan 20mg and amlodipine 5mg were shown to substantially benefit pulsatile hemodynamics (i.e. CBP and indices, AIx and PWV) and have beneficial effects on central aortic BP beyond brachial BP lowering with excellent correlation between the two BP parameters.

Cardiorenal protection in experimental hypertension with renal failure: comparison between vasopeptidase inhibition and angiotensin receptor blockade

Objective: The aim of the present study was to compare the preventive impact of treatment with a vasopeptidase inhibitor (VPI) with an angiotensin-receptor blocker (ARB) on left ventricular (LV) function and renal damage in rats with renal failure after 5/6 renal ablation (Nx).Methods: Rats (n = 15–20, each group) underwent either sham-operation (Sham) or 5/6 renal ablation (Nx). Two additional groups of Nx-animals (groups Nx-VPI and Nx-ARB) were treated with the VPI ilepatril (AVE7688, 30 mg kg−1 d−1) or with the ARB olmesartan (10 mg kg−1 d−1). Animals were followed for 4 weeks.Results: Systolic blood pressure (SBP), LV hypertrophy (LVH) and LV end-diastolic pressure (LVEDP) were increased 4 weeks after Nx (p < 0.05). LV pressure rise (+dP/dt/LVPmax), LV pressure fall (−dP/dt/LVPmax), and creatinine clearance decreased, while albuminuria and renal glomerulosclerosis index (GSI) increased with Nx (p < 0.05, respectively). In comparison to Nx, treatment with both VPI and ARB normalized SBP, LVH, LVEDP, +dP/dt/LVPmax, and −dP/dt/LVPmax to Sham control levels. GSI, but not creatinine clearance, was also normalized in response to both treatments. The significant increase in albuminuria observed in Nx (+230-fold versus Sham, p < 0.0001) was partially reduced in Nx-VPI (+47-fold versus Sham, p < 0.0001) and fully abolished in Nx-ARB.Conclusions: Both ilepatril and olmesartan conferred strong cardiorenal protective effects in rats with renal failure. While cardioprotection was clearly comparable with both treatment regimens, the ARB provided a better protection against the increase in albuminuria, although renal function and structural kidney changes were similarly affected by the VIP and ARB.

ARB-Based Single-Pill Platform to Guide a Practical Therapeutic Approach to Hypertensive Patients

Hypertension is a major modifiable risk for the development of cardiovascular, cerebrovascular and renal diseases. Thus, effective treatment of high blood pressure is an important strategy for reducing disease burden; however, in spite of the availability of numerous effective therapies only 30-40 % of patients with hypertension achieve the recommended blood pressure goals of <140/90 mmHg. Lack of adherence to therapy and reluctance to intensify therapy are cited frequently to explain the discrepancy between potential and attained outcomes. Adherence is closely related to the tolerability, effectiveness and complexity of therapy. Therapeutic inertia may be influenced by concerns over tolerability, as well as the lack of clear preferences for therapies when managing patients with risk factors and comorbidities. Effective and well-tolerated single pill combination therapies are now available that improve adherence and simplify treatment. The combination of a renin-angiotensin system blocker with a calcium channel blocker and a diuretic improves adherence to therapy. We have devised a practical tool for orienting the application of well-tolerated single pill 2/3 drug fixed dose combination therapies in clinical situations commonly encountered when treating hypertensive patients. This approach employs the angiotensin receptor blocker olmesartan alone or in combinations with amlodipine and/or hydrochlorothiazide. This platform is based on clinical evidence, guidelines, best practice, and clinical experience where none of these is available. We believe it will increase the percentage of hypertensive patients who achieve blood pressure control when applied as part of an integrative approach that includes regular follow-up and instruction on lifestyle changes.

Olmesartan vs. Ramipril in Elderly Hypertensive Patients: Review of Data from Two Published Randomized, Double-Blind Studies

Hypertension is a frequent condition among individuals over 65years of age worldwide and is one of the most important risk factors for cardiovascular (CV) disease. Effective drug treatment of elderly hypertensives is usually associated with a marked reduction in CV morbidity and mortality. Among the different classes of antihypertensive agents, angiotensin receptor blockers (ARBs) and ACE-inhibitors are supposed to provide the best efficacy in lowering blood pressure (BP) and protecting target organ damage while featuring a good tolerability profile. However, up to date, few randomized clinical studies have directly compared the activity and safety of ARBs and ACE-inhibitors in elderly hypertensive patients. Aim of this review of published and unpublished pooled data from two recent randomized, double-blind, controlled trials, is to offer a comprehensive head-to-head comparison of the antihypertensive efficacy of the ARB olmesartan medoxomil vs. the ACE-inhibitor ramipril in a large study population including more than 1,400 hypertensive subjects aged 65-89years with mild-to-moderate essential hypertension. The efficacy of the two drugs was separately evaluated in subgroups of patients classified according to the presence of metabolic syndrome, reduced renal function, CV risk level, gender, class of age, type of arterial hypertension and previous antihypertensive treatments. Olmesartan showed a greater efficacy than ramipril both in terms of clinic BP reduction and rate normalization. Olmesartan appeared significantly superior to ramipril in providing a more homogeneous and long-lasting 24-h BP control and maintaining an effective antihypertensive action in the last 6-h period from drug intake. In subgroups of patients with additional clinical conditions, olmesartan gave comparable, and in some cases greater, BP responses than those achieved with the ACE-inhibitor. The incidence of adverse events was similar for both drugs. Olmesartan may thus represent an effective alternative to ACE-inhibitors among first-line drug treatments for hypertension in older people.