Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. Injection of 3-nitropropionic acid (3-NP) is a widely used experimental model for induction of HD. The current study aimed to inspect the potential neuroprotective properties of azilsartan (Azil), an angiotensin II type 1 receptor blocker (ATR1), in 3-NP-induced striatal neurotoxicity in rats. Rats were randomly allocated into five groups and treated for 14 days as follows: group I received normal saline; group II received Azil (10 mg/kg, p.o.); group III received 3-NP (10 mg/kg, i.p); group IV and V received Azil (5 or 10 mg/kg, p.o, respectively) 1 h prior to 3-NP injection. Both doses of Azil markedly attenuated motor and behavioural dysfunction as well as striatal histopathological alterations caused by 3-NP. In addition, Azil balanced striatal neurotransmitters levels as evidenced by the increase of striatal gamma-aminobutyric acid content and the decrease of glutamate content. Azil also amended neuroinflammation and oxidative stress via modulating IĸB/NF-ĸB and KEAP1/Nrf2 downstream signalling pathways, as well as reducing iNOS and COX2 levels. Moreover, Azil demonstrated an anti-apoptotic activity by reducing caspase-3 level and BAX/BCL2 ratio. In conclusion, the present study reveals the neuroprotective potential of Azil in 3-NP-induced behavioural, histopathological and biochemical changes in rats. These findings might be attributed to inhibition of ATR1/NF-κB signalling, modulation of Nrf2/KEAP1 signalling, anti-inflammatory, anti-oxidant and anti-apoptotic properties.

Effect of azilsartan on myocardial remodeling after acute myocardial infarction.

PURPOSE: To investigate the effect of azilsartan on myocardial remodeling after acute myocardial infarction (AMI). METHODS: A total of 200 AMI patients under percutaneous coronary intervention (PCI) were selected from the Affiliated Huaian No.1 People's Hospital of Nanjing Medical University from Jan 2021 to Dec 2021. The subjects were randomly divided to take either azilsartan or benazepril. Serum C1q tumor necrosis factor-associated protein 1 (CTRP1) levels were detected in all subjects after admission, and the indices of left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) were measured by using echocardiography. At the follow-up of 6 months and 1 year after PCI, the differences in CTRP1 and echocardiogram indices between the two groups were compared, and the influencing factors of myocardial remodeling after acute myocardial infarction were analyzed. RESULTS: The levels of LVEDV and CTRP1 in all subjects at 6 months and 1 year after PCI were lower than those before discharge, and the LVEDV in the azilsartan group at 6 months and 1 year after PCI was lower than that in the benazepril group. An improvement in myocardial remodeling was obviously observed within 6 months after PCI, but the effect declined over time. CONCLUSIONS: Azilsartan can improve myocardial remodeling after acute myocardial infarction. CTRP1 may become an effective target for the prevention and treatment of myocardial remodeling after acute myocardial infarction.

Azilsartan prevents muscle loss and fast- to slow-twitch muscle fiber shift in natural ageing sarcopenic rats.

Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4-6 months and 18-21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments.

Sex-based differences in left ventricular mass reduction across angiotensin II receptor blockers in patients with heart failure with preserved or mildly reduced ejection fraction.

Although angiotensin II receptor blockers (ARBs) are more effective in women for either reduction of blood pressure or heart failure (HF), the gender disparities and the impact of class/drug effects on ARBs in relation to cardiac hypertrophy and HF remain unclear. We aimed to investigate the sex-based and drug-specific differences in left ventricular (LV) mass reduction with ARBs. We employed the cohort of 193 hypertensive patients with HF and an LV ejection fraction of ≥ 45% treated with azilsartan or candesartan once daily for 48 weeks as a sub-analysis of the J-TASTE trial. After exclusion of patients without LV mass data nor the drugs, 170 patients were finally enrolled (azilsartan: male, n = 43, female, n = 39 and candesartan: male, n = 52; female, n = 36). We investigated the sex-based differences of the primary endpoint of the change in LV mass as assessed by echocardiography from baseline to the end of the study (48 weeks), and the secondary endpoint of the incidence of the composite cardiovascular endpoint (death from cardiovascular disease or hospitalization for heart failure). In the male stratum, the ratio of patients with > 10% LV mass reduction at 48 weeks was higher in the azilsartan group than candesartan group (40 vs. 19%, p = 0.029). There was no significant difference in LV mass reduction between two groups in the female stratum. There were no differences of the onset of the secondary endpoints between male and female groups, and azilsartan and candesartan groups. The event-free survival rate of the composite cardiovascular endpoints tended to be lower in patients with ≤ 10% than > 10% LV mass reduction (95.3 vs. 100% at 48 weeks, log-rank p = 0.11). In patients with HF, the effectiveness of either azilsartan or candesartan in achieving > 10% LV mass reduction depends on sex. Male is more sensitive to azilsartan than candesartan to achieve cardiac hypertrophy in HF patients.

A rare case of dialysis associated reaction presenting with urticarial vasculitis and haemoglobinuria.

Dialysis associated reactions presenting with urticarial vasculitis is rarely reported in medical literature. We report a 61-year-old gentleman who developed sudden onset dyspnea with diffuse erythema within 20 min of haemodialysis. Patient was started on Azilsartan 3 days prior to this clinical event. Labs revealed features of hemolysis and urine was positive for hemoglobinuria. All dialysis related factors responsible for this reaction were ruled out. Due to non-resolution of skin rash, skin biopsy was attempted which revealed fibrinoid necrosis of occasional vessels with predominant lymphocytic infiltration suggestive of drug induced urticarial vasculitis. Complement levels were normal. He was managed with steroids, anti-histaminic, discontinuation of azilsartan and change of dialyzer membrane. This case highlights a rare dermatological presentation of Type A dialysis associated reaction involving azilsartan with differential diagnosis and treatment strategies.

[Sartans in the treatment of arterial hypertension: focus on telmisartan and azilsartan. A review].

The activity of the renin-angiotensin-aldosterone system is one of the main pathogenetic mechanisms underlying cardiovascular diseases at all stages of the cardiovascular continuum. This article discusses the role of telmisartan and azilsartan as the most powerful sartans in modern cardiology. Azilsartan and especially telmisartan have a significant organoprotection and are superior to other antihypertensive drugs in terms of lowering blood pressure. However, the effect of azilsartan on hard endpoints has not been studied while the efficacy of telmisartan on hard endpoints has been evaluated in plenty clinical trials including 3 large randomized clinical trials with several thousand patients. The article also presents calculations showing the better cost-effectiveness of telmisartan compared to azilsartan.

Safety and efficacy of azilsartan in paediatric patients with hypertension: a phase 3, single-arm, open-label, prospective study.

BACKGROUND: Azilsartan is an angiotensin II receptor blocker indicated for the treatment of adult hypertension. A previous single-dose study suggested that azilsartan may also be a promising agent for paediatric hypertension. However, the long-term safety and efficacy of azilsartan in children have not been established. METHODS: We conducted a phase 3, single-arm, open-label, prospective study to evaluate the safety and efficacy of azilsartan in pediatric patients with hypertension. Twenty-seven patients aged 6-15 years were treated with once-daily azilsartan for 52 weeks. The starting dose was 2.5 mg for patients weighing < 50 kg (N = 22) and 5 mg for patients weighing ≥ 50 kg (N = 5), with doses titrated up to a maximum of 20 and 40 mg, respectively. RESULTS: Azilsartan showed acceptable tolerability at doses up to 20 mg in patients weighing < 50 kg and 40 mg in those weighing ≥ 50 kg. Most drug-related adverse events (AEs) were mild, with one patient (3.7%) experiencing a severe and serious drug-related AE (acute kidney injury). One patient (3.7%) had a mild increase in serum creatinine level, which resolved after treatment discontinuation. The blood pressure-lowering effect of azilsartan was observed as early as Week 2. Overall, approximately half of the patients achieved their target blood pressure at the end of azilsartan treatment. CONCLUSIONS: Our study suggests that azilsartan has an acceptable safety profile in hypertensive patients aged 6-15 years. Azilsartan may be a promising agent for treating paediatric hypertension.

Inhibition of NF-kB/IL-6/JAK2/STAT3 Pathway and Epithelial-Mesenchymal Transition in Breast Cancer Cells by Azilsartan.

Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2, and increased the mRNA level of bax. Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways.

Selective formation of a phenathridine derivative by photodegradation of azilsartan.

Photodegradation of azilsartan produces a phenanthridine derivative, with its molecular structure determined by 1H and 13C NMR spectroscopy. This structure is confirmed by single-crystal X-ray diffraction and alternative synthesis. The phenanthridine ring formation is explained through the ring closure of an imidoylnitrene intermediate produced by decarboxylation of the 5-oxo-1,2,4-oxadiazole ring (oxadiazolone).

Cardioprotective effects of azilsartan compared with that of telmisartan on an in vivo model of myocardial ischemia-reperfusion injury.

Azilsartan is found to be more potent than other angiotensin receptor blockers in reducing blood pressure. However, its effect on the heart following myocardial infarction remains to be established. For the first time, we investigated the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonistic and cardioprotective properties of azilsartan. Computational modeling studies of interactions between azilsartan and PPAR-γ revealed azilsartan as an agonist of PPAR-γ and showed the mechanism of azilsartan in cardioprotection. Our study compared the cardioprotective potential of telmisartan to that of azilsartan in a murine model of myocardial ischemia-reperfusion injury by comparing their antioxidant, ant apoptotic, anti-inflammatory, mitogen-activated protein kinase (MAPK)-modulating ability, and PPAR-γ agonistic activity. Male Wistar rats were grouped into four to receive vehicle (dimethyl sulfoxide [0.05%] 2 ml/kg) telmisartan (10 mg/kg p.o.), azilsartan (10 mg/kg p.o.) or azilsartan with specific PPAR-γ blocker, GW 9662 for 28 days. Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion. Telmisartan and azilsartan pretreatment significantly nearly normalized cardiac parameters and preserved structural changes. Both drugs inhibited oxidative burst, inflammation, as well as cell death by modulating apoptotic protein expression along with reduction in 4',6-diamidino-2-phenylindole/terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. An increment in pro-survival kinase ERK paralleled with a reduction in p38 and JNK was also revealed by MAPK pathway studies, after administration of these drugs. Interestingly, the aforementioned changes induced by both drugs were reversed by administration of the specific PPAR-γ antagonist, GW9662. However, we found that azilsartan upregulated PPAR-γ to a lesser extent as compared to telmisartan and the latter may be preferred in hypertensive patients at risk of myocardial infarction.