Azilsartan

Azilsartan(TAK-536) is a specific and potent angiotensin II type 1 receptor antagonist with IC50 of 2.6 nM.

Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats.[Pubmed:28190245]

Naunyn Schmiedebergs Arch Pharmacol. 2017 May;390(5):457-470.

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of blood pressure following oral administration of Azilsartan medoxomil (AZM) and/or chlorthalidone (CLT) in spontaneously hypertensive (SH) rats. The drug concentration and pharmacological effects, including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tail-cuff manometry, respectively. Sequential PK-PD analysis was performed, wherein the plasma concentration-time data was modeled by one compartmental analysis. Subsequently PD parameters were calculated to describe the time-concentration-response relationship using indirect response (IDR) PK-PD model. The combination of AZ and CLT had greater BP lowering effect compared to AZ or CLT alone, despite of no pharmacokinetic interaction between two drugs. These findings suggest synergistic antihypertensive pharmacodynamic interaction between AZ and CLT noncompetitively, which was simulated by inhibitory function of AZ and stimulatory function of CLT after concomitant administration of the two drugs. The present model was able to capture the turnover of blood pressure adequately at different time points at two different dose levels. The current PK-PD model was successfully utilized in the simulation of PD effect at a dose combination of 0.5 and 2.5 mg/kg for AZ and CLT, respectively. The developed preclinical PK-PD model may provide guidance in the optimization of dose ratio of individual drugs in the combined pharmacotherapy of AZ and CLT at clinical situations.

[Azilsartan Medoxomil Capabilities in Arterial Hypertension and Obesity].[Pubmed:28290827]

Kardiologiia. 2016 Dec;56(11):108-112.

Arterial hypertension (AH) is one of the most common cardiovascular disease. Angiotensin II (AT II), the hormone of renin-angiotensin-aldosterone system, realizes its negative effects through AT 1 receptors - application point of angiotensin receptor blockers (ARB). Due to different dissociation AT 1 receptors properties some ARBs are more effective than others. Multiply multicenter randomized and observational studies approve the effectiveness and safety of Azilsartan medoxomil in patients with AH 1-2 grade. Several preclinical studies have shown the additional properties of Azilsartan, including increase of insulin sensitivity, cardio- and nephron protection in obesity. In our clinical case we showed the positive influence of Azilsartan medoxomil on clinic and ambulatory blood pressure, 24-hour aortic stiffness parameters, longitudinal left ventricular strain in patient with AH and obesity.

Practical efficacy of olmesartan versus azilsartan in patients with hypertension: a multicenter randomized-controlled trial (MUSCAT-4 study).[Pubmed:28079534]

Blood Press Monit. 2017 Apr;22(2):59-67.

BACKGROUND: Olmesartan and Azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with Azilsartan. METHODS: Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of Azilsartan (Azilsartan, not Azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups. RESULTS: Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P<0.05, AZ group: 149/83-135/75 mmHg; P<0.05). Diastolic home blood pressure in the AZ group decreased significantly (79+/-9-74+/-7 mmHg; P<0.05), but not in the OL group (79+/-11-75+/-10 mmHg; P=0.068). However, there were no significant differences between the groups. The dosage of olmesartan and Azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P<0.05, AZ group: 20.5-23.2 mg; P<0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups. CONCLUSION: Both olmesartan and Azilsartan equally reduced blood pressures. Both olmesartan and Azilsartan showed a renoprotective effect and were well tolerated without any major adverse events.

[Hronotherapy Aspects of Efficiency Azilsartan Medoxomil in Combination Therapy in Patients With Hypertension and Metabolic Syndrome].[Pubmed:28290893]

Kardiologiia. 2016 Oct;56(10):35-40.

OBJECTIVE: Determination of the effectiveness and safety of different dosing regimens during the day (in the morning or at bedtime) combination therapy including Azilsartan medoxomil in patients with essential hypertension and metabolic syndrome (MS). DESIGN AND METHODS: The study included 60 patients with uncontrolled hypertension and MS (age median - 59 (54-65) years). Patients were randomized in two groups: group 1 (n=30) received Azilsartan medoxomil 40 mg/day, and indapamide retard 1,5 mg/day in the morning; group 2 (n=30)- Azilsartan medoxomoil 40 mg at bedtime and indapamide retard 1,5 mg in the morning. All patients at baseline, and after 4 and 12weeks assessed levels of office blood pressure (BP), heart rate (HR); at baseline and after 12 weeks was conducted ambulatory BPmonitoring (ABPM). Evaluated the main indicators of circadian blood pressure profile, as well as the central aortic pressure (CAP) and the rigidity of the vascular wall: systolic, diastolic, and mean arterial pressure in the aorta, aortic augmentation index, pulse wave velocity in the aorta, the augmentation index. Study results were processed using the program Statistica 6.1 by methods nonparametric statistics. RESULTS: Regardless of the regimen used Azilsartan destination as part of combination therapy after 4 weeks showed a significant (p<0.05) reduction in SBP and DBP. After 12 weeks of observation target blood pressure was recorded 27 (90%) patients of group 1 and 29 (96.7%)- group2. As a result of ABPM after 12 weeks of treatment in both groups showed a statistically significant (p<0.05) improvement in all parameters investigated. However, positive changes such indicators as an index time of hypertension in the day and night hours, SBP, DBP, and BP variability during the night, the morning rise of systolic as well as the speed of morning rise in SBP and DBP were more pronounced in the appointment Azilsartan medoxomil at bedtime compared to morning reception. The use of both treatment regimens provided significant (p<0.05) increase frequency registration profile dippear and reduction - non-dipper. Importantly, irrespective of the time of taking the drugs in both groups occurred significant (p <0.05), and a comparable improvement in rigidity and CAP vascular wall. CONCLUSION: When combined with essential hypertension and MS Azilsartana use of combination drug therapy provided achievement of the target values of blood pressure in the majority of patients, a significant improvement in the main indicators of ABPM, CAP, and the rigidity of the vascular wall, as well as the normalization of daily profile of blood pressure in the majority of patients, regardless of dosing regimen during the day. However, the combination of indapamide retard morning - Azilsartan medoxomil at bedtime accompanied by a significantly greater positive changes most ABPM parameters, especially at night.

The angiotensin receptor blocker, azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-I protein potentially facilitating the stabilization of atherosclerotic plaques.[Pubmed:21558880]

J Cardiovasc Pharmacol. 2011 Aug;58(2):143-8.

Increased expression of plasminogen activator inhibitor type-I (PAI-1) in vessel walls seems to accelerate atherosclerosis. Angiotensin II can increase the synthesis of PAI-1. Inhibition of this process may facilitate migration of vascular smooth muscle cells (VSMCs) stabilizing atherosclerotic plaques. To determine whether the inhibition of the angiotensin II type 1 receptor can blunt the expression of PAI-1 protein in the aortic wall, we administered Azilsartan medoxomil (AZL-M), a prodrug of an angiotensin II type 1 receptor blocker developed by the Takeda Pharmaceutical Company Limited, for 16 weeks to ApoE knockout mice on a high fat diet rendered overexpressors of PAI-1 in VSMCs. Homogenates of the pooled aortas from each group were assayed for PAI-1 by enzyme-linked immunosorbent assay. Cellularity of atherosclerotic lesions was assessed by 4',6-diamidino-2-phenylindole staining in sections of aortic lesions, and collagen content in the lesions was quantified by immunohistochemistry. Aortic wall PAI-1 was decreased by each of the 3 dosage regimens of AZL-M (0.1-10 mg/kg). Cellularity and collagen were increased in lesions from mice given AZL-M, consistent with the development of more stable plaques. Accordingly, the suppression of PAI-1 expression by AZL-M may attenuate the evolution of atherosclerotic plaques vulnerable to rupture.

Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker.[Pubmed:21986624]

J Hypertens. 2011 Dec;29(12):2476-83.

BACKGROUND: Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24-h blood pressure more effectively than maximally recommended doses of older ARBs. Although Azilsartan is considered to be an unusually potent angiotensin II type 1 (AT1) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. METHODS AND RESULTS: We investigated pleiotropic features of Azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, Azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARdelta, leptin, adipsin, and adiponectin. The effects of Azilsartan on adipocyte differentiation and gene expression were observed at concentrations of Azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, Azilsartan inhibited cell proliferation at concentrations as low as 1 mumol/l, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 mumol/l. Antiproliferative effects of Azilsartan were also observed in cells lacking AT1 receptors. In addition, Azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 h after washout of drug from the incubation media. CONCLUSION: These findings suggest that Azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT1 receptors and/or reduction in blood pressure.

In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies.[Pubmed:21123673]

J Pharmacol Exp Ther. 2011 Mar;336(3):801-8.

The angiotensin II (AII) antagonistic action of Azilsartan (AZL) [2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H -benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of (1)(2)(5)I-Sar(1)-Ile(8)-AII to human angiotensin type 1 receptors with an IC(5)(0) of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC(50) value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC(5)(0) values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC(5)(0) values of 242.5, 191.6, >10,000, and >10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC(5)(0) value of 9.2 nmol; this effect was resistant to washout (IC(5)(0) value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC(5)(0) values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC(5)(0) value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pD'(2) value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.