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Angiotensin II receptor antagonists are tetrazole derivatives used in the treatment of high blood pressure, and are also indicated for the treatment of heart failure (NYHA class II-IV). They are used alone or in combination with other classes of antihypertensives or diuretics for the effective management of high blood pressure. In this study, we aim to evaluate the thermal stability and degradation kinetics for the principal compounds used in therapy from this class, namely telmisartan, valsartan, olmesartan medoxomil, and losartan potassium. To obtain the thermoanalytical data for the kinetic investigations, the TG and DTG curves were registered at five different heating rates (β = 2, 4, 6, 8, and 10 °C min−1). The kinetic methods used were a preliminary ASTM E698 method and two isoconversional methods: Flynn–Wall–Ozawa and Friedman. For each molecule, the results showed complex decomposition processes consisting of complex reaction sequences. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine “BOS” compounds are well known drugs that are used as inhibitors of human furin by an induced-fit mechanism, in which tryptophan W254 in the furin catalytic cleft acts as a molecular transition energy gate. The binding of “BOS” drug into the active center of furin has been computationally studied using the density functional theory (DFT) and ONIOM multiscaling methodologies. The binding enthalpies of the W254 with the furin-BOS is −32.8 kcal/mol (“open”) and −18.8 kcal/mol (“closed”), while the calculated torsion barrier was found at 30 kcal/mol. It is significantly smaller than the value of previous MD calculations due to the relaxation of the environment, i.e., nearby groups of the W254, leading to the reduction of the energy demands. The significant lower barrier explains the experimental finding that the dihedral barrier of W254 is overcome. Furthermore, sartans were studied to evaluate their potential as furin inhibitors. Sartans are AT1 antagonists, and they effectively inhibit the hypertensive effects induced by the peptide hormone Angiotensin II. Here, they have been docked into the cavity to evaluate their effect on the BOS ligand via docking and molecular dynamics simulations. A consistent binding of sartans within the cavity during the simulation was found, suggesting that they could act as furin inhibitors. Finally, sartans interact with the same amino acids as W254, leading to a competitive binding that may influence the pharmacological efficacy and potential drug interactions of sartans.

Abstract Background Telmisartan (TLT) is a prototypic angiotensin receptor blocker largely used to treat hypertension worldwide. In addition to its cardioprotective effects, TLT presents pleiotropic activities and notably displays noticeable anti-inflammatory and antitumor effects. The repression of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint may be implicated antitumor action of TLT, as it is the case with many other compounds equipped with a biphenyl moiety. We have used molecular modeling to compare the interaction of TLT and derivatives with the PD-L1 dimer protein. Results Two molecules, TLT-dimer and TLT-acylglucuronide, were found to form more stable complexes with PD-L1 than TLT itself. In parallel, the docking analysis performed with a series of 12 sartans led to the identification of Olmesartan as a potential PD-L1 binder. The stacked biphenyl unit of Olmesartan positions the molecule along the groove delimited by the two protein monomers. The flanking tetrazole and imidazole moieties, on each side of the biphenyl unit of Olmesartan, contribute favorably to the protein interaction via specific hydrogen bonding interactions. Conclusions The computational analysis suggests a possible binding of Olmesartan to PD-L1 dimer and thus offers novel perspectives for the design of small molecules capable of interrupting the PD-1/PD-L1 immune checkpoint. Experimental studies are warranted to validate the hypothesis. Graphical abstract

Background: Telmisartan (TLT) is a prototypic angiotensin receptor blocker largely used to treat hypertension worldwide. In addition to its cardioprotective effects, TLT presents pleiotropic activities and notably displays noticeable anti-inflammatory and antitumor effects. The repression of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint may be implicated antitumor action of TLT, as it is the case with many other compounds equipped with a biphenyl moiety. We have used molecular modeling to compare the interaction of TLT and derivatives with the PD-L1 dimer protein. Results: Two molecules, TLT-dimer and TLT-acylglucuronide, were found to form more stable complexes with PD-L1 than TLT itself. In parallel, the docking analysis performed with a series of 12 sartans led to the identification of Olmesartan as a potential PD-L1 binder. The stacked biphenyl unit of Olmesartan positions the molecule along the groove delimited by the two protein monomers. The flanking tetrazole and imidazole moieties, on each side of the biphenyl unit of Olmesartan, contribute favorably to the protein interaction via specific hydrogen bonding interactions. Conclusions: The computational analysis suggests a possible binding of Olmesartan to PD-L1 dimer and thus offers novel perspectives for the design of small molecules capable of interrupting the PD-1/PD-L1 immune checkpoint. Experimental studies are warranted to validate the hypothesis. [ABSTRACT FROM AUTHOR]

IntroductionTransforming growth factor β (TGFβ) metabolism plays an important role in the pathogenesis of Marfan syndrome (MFS). Accordingly, drug therapy uses TGFβ receptor blockade to slow down the cardiovascular manifestations, above all aortic root dilatation. Angiotensin II type 1 receptor blockers (ARBs) have been shown to reduce TGFβ levels in adults. Data on childhood are lacking and are now being investigated in the TiGer For Kids study presented here.MethodsWe examined 125 children without chronic disease and 31 pediatric Marfan patients with a proven FBN1 variant with regard to TGFβ levels. In addition, we measured TGFβ levels during the initiation of ARB therapy in pediatric Marfan patients.ResultsIn children without chronic disease, TGFβ levels were found to decrease from childhood to adolescence (p

Aims: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. Methods: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. Results: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. Conclusion: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

With the increasing number of patients diagnosed with hypertension, the annual consumption of sartan drugs has surged, resulting in their ubiquitous detection in aquatic environments. This increases concerns about their environmental persistence and unexpected toxicity. This study explores the applications of ferrate(VI) (Fe(VI)) in removing sartan blood pressure regulators (losartan (LOS), valsartan (VAL), and telmisartan (TEL)). Results demonstrate that sartans could be effectively removed by Fe(VI). Oxidation of LOS by Fe(VI) was pH-dependent at pH 7.0–9.0, with HFeO 4 – dominating the reaction. The second-order rate constants (k app) of LOS with Fe(VI) decreased with increasing solution pH, and k app was calculated to be 148.37 M−1 s−1 at pH 8.0. Furthermore, the Fe(VI)-Fe(III), Fe(VI)-S(IV), and Fe(VI)-S 2 O 3 2– systems demonstrated the enhancement for the elimination of LOS, while the Fe(VI)–HCO 3 – system inhibited the reaction. Oxidizing product (OP) analysis suggested that the major transformation patterns of LOS, VAL, and TEL treated by Fe(VI) and its activation systems included oxidation, imidazole ring cleavage, cyclization, N-dealkylation, and bond cleavage. Multiple OPs were estimated to be more persistent and mobile than parent sartans, while their toxicity toward aquatic organisms might be several times lower than those of their parents. Overall, this study elucidates the oxidizing feasibility of Fe(VI) and related activation systems to eliminate sartans in water treatment. [ABSTRACT FROM AUTHOR]

A genotoxic carcinogen, N‐nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N‐nitrosamines, such as N‐nitrosodiethylamine (NDEA), were later detected in other sartan products. N‐nitrosamines are pro‐mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6‐alkyl‐guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA‐methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error‐free fashion and this can result in nonlinear dose responses and a point of departure or "practical threshold" for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench‐mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans. [ABSTRACT FROM AUTHOR]

Aims: Polypharmacy is one of the most typical features of geriatrics. Unreliable drug usage belongs to its risks, among others. One way of reducing this risk is to integrate more drugs into one tablet (polypill). Nowadays this could be done especially in cardiovascular medicine. Real world data from the health care provided in Slovakia, which would reflect the potential for switching from more tabs with one drug towards the polypill in seniors, are almost unknown. Methods: We used the "Slovak Audit of atrial FIbrillation Study" (SAFIS) data (3 706 patients, average age 80.5 years) and evaluated how frequently patients had the combination of an angiotensin converting enzyme inhibitor (ACEI) or an AT1-receptor for angiotensin II inhibitor (ARB) and a diuretic, an ACEI/ARB and a betablocker (BB), an ACEI/ARB and a statin or at least 3 out of these 4 drug groups at discharge. Results: The average number of recommended drugs was 9.1 at discharge. A diuretic, BB, statin or ACEI/ARB was recommended in 68.9, 64.1, 31.9 and 52.4% of patients respectively. Simultaneous treatment with a diuretic and an ACEI/ARB, BB and an ACEI/ARB, statin and an ACEI/ARB was recommended in 37.9, 36.2, and 19.7% patients respectively. The frequency of these co-treatments was typically higher than 40% in 65-79 yrs. old, declining with age moderately, but staying above 20% even in the oldest (90 yrs. and older) for combinations of an ACEI/ARB with a diuretic or a BB. At least 3 drugs from the groups ACEI/ARB, BB, diuretics, statins were recommended in 38.6% of patients. Conclusion: The potential for the reduction of the number of daily used tablets with their integration in a polypill is really high in seniors. [ABSTRACT FROM AUTHOR]

Introduction: Based on the observation of beneficial effects on cancer metabolism, microenvironment, or VEGF-signaling, several non-anticancer drugs have been discussed as useful in renal cell carcinoma (RCC). In the present study, we investigated the prognostic impact of concomitant medication in RCC and correlated comedication with cell-cycle and proliferation activity in corresponding surgical specimen. Methods: A total of 388 patients who underwent surgery for localized RCC were included. The individual medication was evaluated according to substance classes. Tissue microarrays from corresponding tumor specimen were immunohistochemically (IHC) stained for Cyclin D1 and Ki67 and semi-quantitatively evaluated. Uni- and multivariate analyses were used to compare survival outcomes. For the comparison of IHC expression according to medication subgroups, Kruskal–Wallis analysis was performed. Results: Median follow-up was 57.93 months (95% CI 53.27–69.43) and median OS accounted for 181.12 months (129.72–237.17). Univariate analysis identified pathological standard variables (T-stage > T2, Grading > G2, L1, N1, M1, sarcomatoid subtype, necrosis) as significant determinants of OS. Moreover, statin use (p = 0.009) and sartan use (p = 0.032) were significantly associated with improved OS. Multivariate analysis identified M1-stage (p < 0.001), statin and sartan use (p = 0.003 and p = 0.033, respectively) as independent prognosticators of survival. Expression of Ki67 was significantly reduced in patients with statin use (p = 0.013), while Cyclin D1 expression showed no correlation with comedication. Conclusions: Concomitant intake of statins and sartans identifies as an independent predictor of OS in RCC, and reduced Ki67 expression was significantly associated with statin use. Further evaluation of drug repurposing approaches with these substances in RCC appear warranted. [ABSTRACT FROM AUTHOR]

Muslim scholars made tremendous contribution in various fields of science and their benefaction of work exhibits in all branches of medicine. Cancer is discussed by then Muslim scholars like Ibn Sina, Razi, Ismail Jurjani ,Hunain b. Ishaque, Rabban Tabri, Ahmad b. Mohammad Tabri, , Ibn ul Quff, Ibn Zuhr etc. In their descriptions cancer means Sartan (crab) as it reflects the true character of disease, since it sticks to the part stubbornly like a Sartan. Galen states that Sartan is the result of an excess of black bile. It may be due to an excessive hotness and dryness of liver by which consumed foods transform into irritant morbid matter. Concurrently, the spleen becomes weak and is unable to absorb the Sawda (black bile). Muslim scholars classified and distinguished clearly among the varieties of cancer in relation to specific organs such as eye, stomach, bladder, penis, uterus, mouth, and nerve tumours. The need of the hour is to evaluate and analyse the disease along with its pathophysiology, predisposing factors, differential diagnosis, and varieties of therapeutic paradigms that include nutrition, drugs, Ishal (bowel cleansing), Tanqia (evacuation of morbid matter from the body), surgical and non surgical interventions i.e. leaching , Amal kai (cauterization). Since the cancer is spreading at an incredible rate in both developed and developing countries but no way of relief is ensured yet in any system of medicine. Greco-Arabic literature has rich potential to intervene in palliative way in such dreadful disease. Likewise, Ray born Razi asserted that when cancer is at the beginning, it can be kept stationary and can be prevented from ulceration. This systematic review highlights relevant Greco-Arabic literature on cancer. [ABSTRACT FROM AUTHOR]

Résumé L’insuffisance cardiaque congestive représente généralement une insuffisance cardiaque droite et gauche combinée, qui provoque une congestion pulmonaire et un œdème périphérique. Le cœur subit d’importants remaniements : la fibrose gêne le fonctionnement électrique et mécanique de l’organe et la fonction ventriculaire s’altère progressivement jusqu’à entraîner le décès. Les différents traitements disponibles permettent de ralentir l’évolution de cette pathologie, prolongeant de ce fait la survie des malades. Summary Congestive heart failure generally represents combined right- and left-sided heart failure, which provokes pulmonary congestion and peripheral oedema. The heart is subject to significant changes: fibrosis affects the electrical and mechanical functioning of the organ and the ventricular function gradually deteriorates eventually leading to death. The different available treatments help to slow down the progress of this disease, thereby extending patients’ survival. [ABSTRACT FROM AUTHOR]

Cancer has been defined as, malignant growth characterized by the uninhibited proliferation of cells, often affecting healthy tissues locally or throughout the body. Cancer is not a new disease some of the cancers that most often affect women are breast, colon, endometrial, lung, cervical, skin, and ovarian cancers. The most significant risk factor for cancer is age; two-thirds of all cases were in those older than age 65 years, Owing to its high incidence in nature, it is the second leading cause of death after cardiovascular aetiology. Unani or Greek-o-Arab medicine originated in Greece about 2500 years back and is based upon the four humours theory, Unani scholars believed that the body contained four humours (Akhlaat) any imbalance of these fluids will result in disease and excess of black bile (Sauda) in a particular organ site was thought to cause cancer (Sartan). The world's oldest recorded case of breast cancer hails from ancient Egypt in 1500 BC and it was recorded that there was no treatment for the cancer, only palliative treatment. According to inscriptions, surface tumours were surgically removed in a similar manner as they are removed today. So it is an effort through this paper to highlight the preventive measures mention in the classical Unani literature for cancer prevalent amongst females and some of the cancers can be prevented by avoiding the accumulation of abnormal humours inside the body. [ABSTRACT FROM AUTHOR]

Aims To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). Methods and results A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e.=0.07) (-0.043 z/year, s.e.=0.04) in patients receiving Losartan and 0.51 mm/year (s.e.=0.06) (-0.01 z/year, s.e.= 0.03) in those receiving placebo (P=0.36 for the comparison on slopes in millimeter per year and P=0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. Conclusion Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients. [ABSTRACT FROM AUTHOR]

New preventive strategies for atherosclerosis are needed. In this study, we tested whether a new therapeutic approach consisting of low-dose treatment with a statin and sartan combination could prevent atherogenic diet-induced impairment of the arterial wall in guinea pigs. Twenty-five Dunkin-Hartley guinea pigs were randomly assigned to five experimental groups: 1) normal diet; 2) atherogenic diet (AD); 3) AD + a low-dose atorvastatin and valsartan combination (5 mg/kg/day and 2.4 mg/kg/day, respectively); 4) AD + low-dose atorvastatin (5 mg/kg/day); 5) AD + low-dose valsartan (2.4 mg/kg/day). After 8 weeks of treatment, the animals were killed, blood samples collected and thoracic and abdominal aortas isolated. The atherogenic diet significantly impaired maximal thoracic aorta endothelium-dependent relaxation by 40.1% relative to the normal diet. The low-dose combination, compared to the separate drugs, completely preserved thoracic aorta endothelium-dependent relaxation at the level of the group receiving normal diet. This substantial effect was associated with a significant change in the expression of NOS3 ( R =0.93; P =0.0002) and IL1b ( R =−0.79; P =0.003) genes. In addition, treatment with the low-dose combination or the separate drugs also prevented atherosclerotic plaque formation. We found that treatment with the low-dose atorvastatin and valsartan combination has the capability to completely protect the arterial wall from atherogenic diet-induced damage in the guinea pig model. Further studies evaluating this new therapeutic approach are desirable. [ABSTRACT FROM AUTHOR]

Abstract: In this study we have investigated the in vitro angiotensin II receptor antagonist and antioxidant activity of a series of compounds in which the antioxidant pharmacophores (selenium, phenol, benzothiophene, ebselen or nitroxide) have been incorporated into the AT1 receptor antagonist (sartan) milfasartan. Activity of these compounds was assessed in tissue-based assays. The novel molecules (30nM), nitrasartan or phenol-milfasartan, retained AT1 receptor antagonist potency in rat isolated right atria. Antioxidant capacity of the substituted sartans was examined in an AAPH (2,2′-azobis (2-amidinopropane) hydrochloride)-induced haemolysis assay (mouse C57/BL6 isolated erythrocytes). Each of the antioxidant pharmacophores (10μM), except benzothiophene, protected against radical-mediated lysis. Of the novel sartans, only analogues incorporating selenium, phenol or nitroxide (nitrasartan) protected against radical-induced haemolysis. In the tissue-based assay using mouse isolated paced left atria, the free radical generator doxorubicin (30μM) resulted in a decrease in left atrial force over 90min. In this assay the phenol, nitroxide or ebselen antioxidant pharmacophores protected against doxorubicin-induced negative inotropy but selenocystine and benzothiophene did not. Nitrasartan (10μM) was the only novel analogue to protect against radical-induced negative inotropy. Nitrasartan also antagonised angiotensin II responses and decreased superoxide production in a concentration-dependent manner in rat isolated carotid arteries and aortae, respectively. In conclusion, nitrasartan is a dual action molecule demonstrating both AT1 receptor antagonist potency and antioxidant properties in vitro. [Copyright &y& Elsevier]

Renin-angiotensin-system (RAS) activation plays a key role in the development of hypertension and cardiovascular disease. Drugs that antagonize the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) have proven clinical efficacy in reducing blood pressure values and cardiovascular morbidity and mortality. ACE inhibitors partially inhibit plasma ACE, and angiotensin II generation. Thus, ARBs, which block selectively type 1 angiotensin II receptor (AT1R), have been developed and used in the clinical management of hypertension and cardiovascular disease. Experimental and clinical trials with ARBs indicate that this class of drug represents an effective, safe and well tolerated therapeutic option for the prevention and care of hypertension, even though there is no proven superiority as compared to ACE inhibitors except for the better tolerability. Most ARBs may not completely inhibit the AT1R at the approved clinical doses. Azilsartan medoxomil is a newly approved ARB for the management of hypertension. This ARB induces a potent and long-lasting antihypertensive effect and may have cardioprotective properties. This article reviews the current evidence on the clinical effectiveness of azilsartan in hypertension. [ABSTRACT FROM AUTHOR]

A quantitative structure activity relationship (QSAR) analysis of a set 33 benzimidazole analogues as angiotensin (AT) II AT1 receptor antagonists was performed to explore substitutional requirements for a favorable receptor drug interaction. The QSAR models were generated by using Fuzita ban analysis and Hansch analysis. Stepwise regression was performed to derive a predictive model. The predictive ability of the model developed was assessed by using a test set of 11 compounds. The internal (correlation coefficient r2) and external consistency (predictive r2) of the final Hansch QSAR model were 0.68 and 0.46, respectively. The internal (correlation coefficient r2) consistency of the Fujita-ban model was 0.572 and CH2COOH group at the seventh position is significant in increasing AII antagonistic activity. Ovality (Steric), Lumo and total energy (electronic), and Bend energy (thermodynamic) are significant descriptors that govern the AII antagonistic activity. [ABSTRACT FROM AUTHOR]

Therapy normopress and enalapril, against the background of basic therapy has shown efficacy in the development of the pathological process of regression, reduced fraction of atherogenic lipids, improve endothelial dysfunction and recovery of myocardial contractility. At the same time, more pronounced and significant dynamics found in patients with myocardial infarction treated with normopress. [ABSTRACT FROM AUTHOR]

Background and Purpose: Diet-induced hypercholesterolaemia exacerbates post-myocardial infarction (MI) ventricular remodelling and heart failure, but the mechanism of this phenomenon remains unknown. This study examined whether worsening of post-MI ventricular remodelling induced by dietary hypercholesterolaemia was related to upregulation of angiotensin II type 1 (AT1) receptor in the rat heart.Experimental Approach: MI was induced surgically in rats fed normal or high cholesterol diet. Both groups of rats were then assigned to control, atorvastatin, losartan or atorvastatin+losartan-treated subgroups and followed for 8 weeks. Left ventricular (LV) function was assessed with echocardiography. In isolated hearts, LV pressures were measured with a latex balloon and a tip catheter. AT1-receptor density was assessed in LV membranes with radioligand-binding assays.Key Results: High cholesterol diet exacerbated LV dilation and dysfunction in post-MI hearts. Atorvastatin or losartan prevented these hypercholesterolaemia-induced effects, whereas their combination was not more effective than each drug alone. AT1 receptors were upregulated 8 weeks after MI, this was further increased by hypercholesterolaemia and restored to baseline levels by atorvastatin.Conclusions and Implications: Hypercholesterolaemia exacerbated LV remodelling and dysfunction in post-MI rat hearts and upregulated cardiac AT1 receptors. All these effects were effectively prevented by atorvastatin. Thus, the pleiotropic statin effects may include interference with the renin-angiotensin system through downregulation of AT1 receptors. [ABSTRACT FROM AUTHOR]

Sartans are selective type 1 angiotensin II receptor-antagonists that are used in the treatment of arterial hypertension. Few reports are available concerning the use of sartans during pregnancy. We report two cases of adverse fetal outcome in hypertensive pregnancies exposed to sartans. In the first case, anamnios and fetal renal failure due to severe tubular dysgenesia led to termination of pregnancy in the 27th week. The second patient presented with hypocalvaria and developed fetal renal failure. The use of sartans during the two last trimesters of pregnancy should be strictly avoided. [ABSTRACT FROM AUTHOR]

Aims: This study assessed the clinical efficacy and safety of telmisartan, an angiotensin II receptor blocker with a long terminal elimination half-life and almost exclusively excreted in bile, in patients with varying severity of chronic kidney disease (CKD). Patients and methods: Adults with diastolic blood pressure (DBP) 90- 109 mmHg and stable CKD were enrolled: mild/moder- ate (creatinine clearance (CrCl) 30 - 74 ml/ minl/.73 m2), severe (CrCl <30 mIIminI/.73 m2) or requiring maintenance hemodialysis. A two- to four-week single-blind, placebo run-in period preceded once-daily telmisartan 40 mg administration for four weeks. Telmisartan 80 mg was given after four- or eight-week treatment if DBP ≥ 85 mmHg. After 12-week treatment, trough DBP!systolic blood pressure (SBP), DBP and SBP control rates, renal function and tolerability were recorded. Results: Mean changes in DBP/SBP were -10.5/-10.7 mmHg for mild/moderate CKD(n 27),-11.2/-14.9 mmHg for severe CKD (n = 27) and -15.0/-21.1 mmHg for hemodialysis patients (n = 28). DBP control rates (<90 mmHg)!SBP responses (< 140 mmHg or ≥ 10 mmHg reduction) occurred in 59.3%/66.7%, 63.0%/70.4% and 71.4%/92.9% of mild/moderate CKD, severe CKD and hemodialysis patients, respectively. mcidences of thug-related adverse events were low, and all were known adverse events of telmisartan and common to other angiotensin TI receptor blockers. At the end of treatment, a decrease in 24-h urine creatinine occurred in 5/53 (9.4%) patients. Two patients discontinued treatment prematurely due to the worsening of CKD and one due to aggravated proteinuria. Conclusion: Once-daily telmisartan provided effective and well-tolerated treatment of mild/moderate hypertension in CKD patients, with no worsening of renal function. [ABSTRACT FROM AUTHOR]

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article describes the case of severe renal failure in a 36-week old baby girl whose mother had taken Olmesartan for hypertension during her last month of pregnancy. The baby died of cardio-circulatory failure 45 days after her birth with kidneys showing severe tubular dysgenesis. Also included is information on sartans as treatment for arterial hypertension and role of renin-angiotensin components in kidney development. The study concludes that exposure to sartans during the last month of pregnancy can cause congenital malformations, renal impairment, and fetal or neo-natal death.

A gradient HPLC method was developed and validated for rapid simultaneous separation and determination of the following eight drugs of sartan and statin classes in their pure and dosage forms within 15 minutes: irbesartan (IRB), losartan (LOS), valsartan (VAL), olmesartan (OLM), rosuvastatin (ROS), atorvastatin (ATR), lovastatin (LOV), and simvastatin (SIM). Separation was carried out on a Kinetex C18 100A column (2.60 μm, 4.60 mm × 100 mm) using a gradiant binary mobile phase of 0.05M potassium dihydrogen phosphate buffer (pH 3.50 adjusted by ortho-phosphoric acid) and acetonitrile at room temperature. The flow rate was 1.00 mL/min and maximum absorption was measured using a DAD detector at 280 nm. The retention times of IRB, LOS, ROS, VAL, ATR, LOV, OLM, and SIM were recorded to be 4.72, 5.32, 6.06, 7.19, 7.96, 9.30, 11.91, and 14.66 minutes, respectively. Limits of detection were reported to be 2.01, 1.32, 1.10, 0.76, 0.21, 1.50, 0.38, and 0.55 mM for the same sequence of drugs, respectively, showing a high degree of method sensitivity. The method was then validated according to the international conference of harmonization (ICH) guidelines for the determination of the drugs in their dosage forms with highly precise recoveries. Also, a statistical comparison with reference methods was performed showing no significant differences between the proposed method and reported ones in terms of precision and accuracy. [ABSTRACT FROM AUTHOR]

Background: Drugs that block the renin-angiotensin system represent one of the most significant therapeutic interventions available for the treatment of hypertension. The angiotensin II receptor antagonists (AIIRAs), also known as sartans, are one such class of drugs that block the effects of angiotensin II by antagonizing the angiotensin II type 1 receptor. Olmesartan is the newest member of this class.Objective: The present article reviews 3 head-to-head trials directly comparing the antihypertensive efficacy of olmesartan with that of 4 other AURAS, at recommended maintenance doses, already in clinical use for the treatment of hypertension.Results: In the first study, olmesartan 10 mg/d was compared with losartan 50 mg/d in 316 patients with mild to moderate hypertension (mean baseline diastolic blood pressure [DBP], 95–114 mm Hg). Dosage was doubled at week 4 and hydrochlorothiazide was added at week 12 if blood pressure response was inadequate. Olmesartan was significantly more effective than losartan with respect to the reduction in blood pressure at weeks 2, 4, and 12, and to the responder rate at weeks 2 and 4 (with the starting dose of the respective drug). In a second study, olmesartan 20 mg/d was shown to be significantly more effective than losartan 50 mg/d, valsartan 80 mg/d, and irbesartan 150 mg/d in 588 patients with mild to moderate hypertension (mean sitting baseline DBP, 100–115 mm Hg) (P ⩽ 0.05). At week 2, the reduction in blood pressure observed with olmesartan was significantly greater than that of the comparator treatments (P ⩽ 0.05). The superiority of olmesartan was maintained at week 8. The third study involved 643 evaluable patients with moderate to severe hypertension (mean DBP, 100–120 mm Hg; mean systolic blood pressure, >150 mm Hg). Olmesartan 20 mg/d was more effective than candesartan 8 mg/d in lowering 24-hour blood pressure at week 8 (P ⩽ 0.05). Most of this treatment effect was evident after only 1 or 2 weeks, with greater reductions in blood pressure compared with candesartan.Conclusions: These data indicate that, at the doses studied, olmesartan is more effective than other AIIRAs tested at their recommended doses, in terms of reduction of cuff or 24-hour ambulatory blood pressure, in patients with essential hypertension. These differences in blood pressure reduction between these agents may be clinically relevant and have important long-term implications. Additional studies will further define the role of olmesartan in the management of cardiovascular diseases, such as atherosclerosis. [Copyright &y& Elsevier]

Background: Olmesartan medoxomil is an angiotensin II receptor antagonist that selectively and competitively inhibits the angiotensin 11 type 1 receptor.Objective: This article reviews the results of some key studies that assessed the efficacy and tolerability of olmesartan in patients with hypertension.Methods: Olmesartan has been investigated in several clinical studies. This article reports on data from 1 such study with a prospective, randomized, double-blind, placebo-controlled, parallel-group, dose-finding design in patients with mild to moderate hypertension (baseline mean sitting diastolic blood pressure, 100–114 mm Hg). The results from a meta-analysis of 7 randomized, double-blind, placebo-controlled studies are also presented.Results: In the dose-finding study, 792 patients were randomized to olmesartan (2.5–80 mg) or placebo once daily, and changes were recorded in trough mean sitting diastolic and systolic blood pressures from baseline to the end of a 12-week treatment period. For the meta-analysis, 3055 patients were randomized to treatment; 2511 received olmesartan. In the dose-finding study as well as in the meta-analysis, olmesartan (2.5–80 mg once daily) produced a dose-dependent decrease in diastolic and systolic blood pressures, and at a dose of 10 to 80 mg showed significant superiority in reducing diastolic blood pressure over placebo (P < 0.05). The 20-mg dose was considered optimal, with a responder rate of 70%. Furthermore, in a 2-year study with 462 patients, olmesartan had a good safety profile and was well tolerated. The results of the clinical studies in >3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over 2 years of treatment. [Copyright &y& Elsevier]

Background: Poor compliance with treatment and early discontinuation negatively affect long-term blood pressure control. According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, poor compliance could contribute to the lack of adequate blood pressure control in ∼-70% of patients with hypertension, even after treatment with several anti-hypertensive drugs.Objective: This article discusses blood pressure control and patient compliance with antihypertensive drugs. It then outlines the clinical pharmacokinetics and interaction profile of the novel antihypertensive olmesartan medoxomil, an angiotensin II receptor antagonist (AIIRA), and relates the findings to the recommended dosing regimen and tolerability of the drug.Conclusions: Many factors influence patient compliance, including forgetfulness, adverse effects, irregular lifestyle, and complexity of drug regimen, such as multiple drugs and, in particular, frequent dosing. Drugs that are well tolerated and easy to manage in a once-daily regimen improve compliance. In a study of different classes of antihypertensive drugs, patients taking AURAS were more likely to continue their treatment than those taking any other class of antihypertensive. Therefore, the right drug choice may contribute to patient compliance. The newest member of the AIIRAs, olmesartan medoxomil, is a long-acting antihypertensive drug with a favorable safety and tolerability profile. It is not metabolized by and does not interfere with the cytochrome P-450 enzyme system. These properties meet modern requirements for the treatment of hypertension. [Copyright &y& Elsevier]

Background: Evidence for the cardiovascular benefits of antihypertensive treatment is among the strongest in medicine. Randomized, prospective, unconfounded studies in thousands of people have shown that even small reductions in blood pressure for short periods substantially improve cardiovascular outcomes. Recent evidence has emphasized the importance of optimal blood pressure control, particularly in patients with high cardiovascular risk, such as those with type 2 diabetes mellitus.Objective: This article discusses optimal target blood pressure goals, reviews the effects of antihypertensive treatment in high-risk patients, presents current guidelines for blood pressure control, discusses the failure worldwide to achieve such control, and suggests approaches to improved treatment.Conclusions: In high-risk patients, small improvements in blood pressure control are associated with large reductions in cardiovascular risk. National and international guidelines for the management of hypertension therefore now recommend rigorous blood pressure targets. Despite extensive clinical evidence, the delivery of care for hypertension remains unsatisfactory. Hypertension is underdiagnosed and undertreated, and recommended target blood pressures are rarely achieved. Physicians appear reluctant to make changes to treatment, which would lead to more effective use of antihypertensive drugs. Overwhelming evidence supports the benefit of optimal blood pressure control in patients with hypertension. Several studies have shown that such control can be achieved, but most likely requires combination treatment. Combination treatment is likely to be successful only if drugs are well tolerated and patients are compliant. The angiotensin II receptor antagonists (sartans) have the therapeutic advantage of efficacy, excellent tolerability, and a good record of compliance. Blood pressure control can be more easily accomplished by using sartans early in treatment and by recognizing the benefits of even small reductions in blood pressure. [Copyright &y& Elsevier]