- The Angiotensin Type 2 Receptor In Human Adrenocortical Zona Glomerulosa And In Aldosterone-Producing Adenoma: Low Expression And No Functional Role. [Journal Article]
- CSClin Sci (Lond) 2018 Feb 07
- The angiotensin II type 2 receptor (AT2R) and the angiotensin-(1-7) receptor (MasR) play a cardiovascular protective role by counter-regulating angiotensin II type 1 receptor (AT1R)-mediated effects,...
The angiotensin II type 2 receptor (AT2R) and the angiotensin-(1-7) receptor (MasR) play a cardiovascular protective role by counter-regulating angiotensin II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of C21, an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system blunts aldosterone synthase in the normal adrenal cortex and APA.
- Dose-Effect of Irbesartan on Cyclooxygenase-2 and Matrix Metalloproteinase-9 Expression in Rabbit Atherosclerosis. [Journal Article]
- JCJ Cardiovasc Pharmacol 2018; 71(2):82-94
- Irbesartan has previously shown antiatherosclerotic effects on human carotid atherosclerotic plaques. Our study aimed to assess the dose-effect of irbesartan on cyclooxygenase-2 (COX-2) and matrix me...
Irbesartan has previously shown antiatherosclerotic effects on human carotid atherosclerotic plaques. Our study aimed to assess the dose-effect of irbesartan on cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) in rabbit atherosclerotic aorta. New Zealand rabbits were randomly divided into 6 groups: normal control (NC), high cholesterol (HC), low-dose (10 mg·kg·day), medium-dose (20 mg·kg·d), and high-dose (30 mg·kg·d) irbesartan and celecoxib (20 mg·kg·d). Except for the NCs, rabbits were fed a HC diet for 14 weeks to induce atherosclerosis. Aortic atherosclerotic lesions and messenger RNA and protein expression of COX-2, MMP-9, and nuclear factor-κB (NF-κB) were subsequently measured. The surface area of aortic atherosclerotic lesions was visibly larger in the HC group than in NCs (P < 0.01), but showed considerable reduction with medium- and high-dosage irbesartan and celecoxib treatments (P < 0.01). In medium- and high-dosage irbesartan and celecoxib groups, COX-2 and MMP-9 expression and NF-κB activity were significantly lower than in the high-cholesterol group (P < 0.01). No significant differences in treatment effects were observed between the high-dosage irbesartan and celecoxib groups (P > 0.05). Our results indicate that medium and high doses of irbesartan and celecoxib have antiatherosclerotic effects in aortic plaques via inhibition of COX-2 and MMP-9 by suppressing NF-κB activation. High-dose irbesartan has effects similar to celecoxib.
- Predicted environmental concentration and fate of the top 10 most dispensed Australian prescription pharmaceuticals. [Journal Article]
- ESEnviron Sci Pollut Res Int 2018 Feb 04
- A basic environmental risk assessment was carried out for the top 10 dispensed pharmaceuticals in Melbourne, Australia, in contrast to the more commonly assessed measure of the most used drugs by phy...
A basic environmental risk assessment was carried out for the top 10 dispensed pharmaceuticals in Melbourne, Australia, in contrast to the more commonly assessed measure of the most used drugs by physical mass. This allowed for the evaluation of compounds that had not previously been the subject of risk assessment. Estimations of the possible fate and behaviour of the target pharmaceuticals in sewage treatment plants were also made. The predicted removal rates of most drugs within standard sewage treatment were expected to be low, with the exception of the statins, which had high removal rates. Each pharmaceutical was predicted to be present in Melbourne wastewater at the nanogram per litre range or lower. All compounds were predicted to be of low toxicity risk, although it was not possible to model mixture effects. Atorvastatin and Irbesartan were also found to possess the potential to possibly bioaccumulate in the aquatic food chain but not to the extent that would require regulation or labelling.
- Irbesartan prevents sodium channel remodeling in a canine model of atrial fibrillation. [Journal Article]
- JRJ Renin Angiotensin Aldosterone Syst 2018 Jan-Mar; 19(1):1470320318755269
- CONCLUSIONS: Irbesartan significantly increased INadensities, which contributed to improving intra-atrial conduction and prevented the induction and promotion of AF in atrial pacing dogs.
- Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions. [Journal Article]
- PRPharm Res 2018 Jan 09; 35(2):29
- CONCLUSIONS: Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.
- Synthesis of 2-Aminoimidazolones and Imidazolones by (3 + 2) Annulation of Azaoxyallyl Cations. [Journal Article]
- OLOrg Lett 2018 Feb 02; 20(3):499-501
- The first examples of (3 + 2) annulations between azaoxyallyl cations and cyanamides and nitriles to give the corresponding 2-aminoimidazolones and imidazolones are reported. On the basis of the isol...
The first examples of (3 + 2) annulations between azaoxyallyl cations and cyanamides and nitriles to give the corresponding 2-aminoimidazolones and imidazolones are reported. On the basis of the isolation of unexpected imidate products with certain substrates, it is proposed that the reaction proceeds via fast kinetic O-alkylation followed by rearrangement to the thermodynamically favored 2-aminoimidazolones and imidazolones. The method was applied to the formal synthesis of the antihypertensive drug irbesartan.
- Predictors of Mortality in Patients With Atrial Fibrillation (from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE A]). [Journal Article]
- AJAm J Cardiol 2018 Mar 01; 121(5):584-589
- The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbes...
The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4 < 25 kg/m2, 95% CI 1.3 to 1.6), diabetes mellitus, Latin American ethnicity (HR 1.4, 95% CI 1.1 to 1.6), previous stroke or transient ischemic attack, peripheral artery disease, increased resting heart rate (HR 1.3, 95% CI 1.1 to 1.4 per 30 bpm), lower diastolic blood pressure, coronary artery disease, heart failure, left ventricular systolic dysfunction, hemoglobin level of <13 mg/dl, and reduced estimated glomerular filtration rate. In conclusion, in this large clinical trial cohort of patients with AF, treatment with clopidogrel plus aspirin versus aspirin monotherapy did not affect all-cause mortality, vascular death, or nonvascular death. Novel independent predictors of increased mortality included lower diastolic blood pressure and Latin American ethnicity.
- Sorption of citalopram, irbesartan and fexofenadine in soils: Estimation of sorption coefficients from soil properties. [Journal Article]
- CChemosphere 2018; 195:615-623
- The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic,...
The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic, and citalopram cationic and neutral), in seven different soils was studied. The measured sorption isotherms were described by Freundlich equations, and the sorption coefficients, KF(for the fixed n exponent for each compound), were related to the soil properties to derive relationships for estimating the sorption coefficients from the soil properties (i.e., pedotransfer rules). The largest sorption was obtained for citalopram (average KFvalue for n = 1 was 1838 cm3 g-1) followed by fexofenadine (KF = 35.1 cm3/nμg1-1/ng-1, n = 1.19) and irbesartan (KF = 3.96 cm3/nμg1-1/ng-1, n = 1.10). The behavior of citalopram (CIT) in soils was different than the behaviors of irbesartan (IRB) and fexofenadine (FEX). Different trends were documented according to the correlation coefficients between the KFvalues for different compounds (RIRB,FEX = 0.895, p-value<0.01; RIRB,CIT = -0.835, p-value<0.05; RFEX,CIT = -0.759, p-value<0.05) and by the reverse relationships between the KFvalues and soil properties in the pedotransfer functions. While the KFvalue for citalopram was positively related to base cation saturation (BCS) or sorption complex saturation (SCS) and negatively correlated to the organic carbon content (Cox), the KFvalues of irbesartan and fexofenadine were negatively related to BCS, SCS or the clay content and positively related to Cox. The best estimates were obtained by combining BCS and Cox for citalopram (R2 = 93.4), SCS and Cox for irbesartan (R2 = 96.3), and clay content and Cox for fexofenadine (R2 = 82.9).
- Renin angiotensin-aldosterone system (RAAS) blockers usage among type II diabetes mellitus patients-A Retrospective Study. [Journal Article]
- DMDiabetes Metab Syndr 2017 Dec 21
- CONCLUSIONS: RAAS blockers usage among T2DM patients was higher in primary care versus tertiary care settings. Majority of the patients did not receive optimal dose of RAAS blockers.
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- [Choice of Angiotensin Receptor Blocker at Various Stages of the Cardiovascular Continuum]. [Journal Article]
- KKardiologiia 2017; 57(10):45-55
- We present in this paper modern views on components, physiological and pathophysiological effects of the renin-angiotensin system, pathways of its hyperactivation at various stages of the cardiovascu...
We present in this paper modern views on components, physiological and pathophysiological effects of the renin-angiotensin system, pathways of its hyperactivation at various stages of the cardiovascular continuum. Special emphasis is made on angiotensin receptor blockers (sartans). Basing on results of analysis of randomized clinical trials of these agents we have outlined clinical situations in which prescription of one or another drug from this group is preferable. For patients with multiple risk factors of cardiovascular complications preferable agent is telmisartan, for patients with nephropathy - irbesartan, for survivors of acute myocardial infarction - valsartan, while for patients with clinical signs of chronic heart failure with low ejection fraction 3 agents can be designated as preferrable - losartan, valsartan, and candesartan.