Angiotensin Receptor Blocker Telmisartan Research Articles

Effects of two different angiotensin receptor blockers on blood glucose level and HbA1c in type-2 diabetes mellitus patients with hypertension

Diabetes mellitus is a common metabolic disorder characterized by chronic hyperglycemia and disturbance of carbohydrate, fats, and protein metabolism. Type 2 diabetes mellitus results from reduced insulin secretion, decreased glucose utilization, and increased glucose production, which results in hyperglycemia. Hypertension further increases the risk of cardiovascular diseases, including coronary heart disease (CHD), congestive heart failure (CHF), ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease (PAD). Angiotensin receptor blockers (ARBs) are very effective antihypertensive drugs. This study was done to find the effects of two different angiotensin receptor blockers on various biochemical markers in type-2 diabetes mellitus patients.MethodsThis was a prospective interventional study, comparing two ARBs Azilsartan and telmisartan, involving 76 patients with type 2 diabetes mellitus and hypertension.ResultsBoth drugs controlled blood pressure equally. The study showed that improvement in fasting plasma glucose was more with Azilsartan as compared to Telmisartan but their mean difference is not statistically significant (p > 0.05). The improvement in post-prandial plasma glucose and HbA1C was more with Telmisartan as compared to Azilsartan but only mean HbA1C was statistically significant (p < 0.05).ConclusionsTelmisartan has a better impact on HbA1c reduction than Azilsartan, as a part of the pleotropic effect of ARBs.

Angiotensin Receptor Blocker-Related Sprue-like Enteropathy: Review of Food and Drug Administration Adverse Event Reporting System.

Sprue-like enteropathy (SE) related to olmesartan use was first reported in 2012. In 2017, the manufacturer of Benicar paid $300 million for 2300 claims for olmesartan-related SE. A study in 2019 suggested that SE was related to olmesartan and with the possibility of angiotensin receptor blocker (ARB) class effect. To further characterize this condition, our group examined reports of ARB-related SE to Food and Drug Administration Adverse Event Reporting System (FAERS). All reports of ARB-related SE from January 2017 to December 2021 were downloaded from the FAERS database. Gastrointestinal adverse events including SE were reviewed. Reporter categories included physicians, pharmacists, other health care professionals, consumers, and attorneys. A total of 106 590 reports of ARB-related adverse effects were analyzed. Sprue-like enteropathy was identified in 4337 cases (4.1% of total reports). Of these, 4240 cases (98.0%) of ARB-related SE were reported in patients using products with olmesartan, and 97 cases of SE were reported for all other ARBs (eprosartan, losartan, telmisartan, irbesartan, valsartan, and candesartan). Reports of olmesartan-related SE increased rapidly in 2017, continued at a high rate in 2018 and 2019, and essentially stopped in 2020 and 2021. Reports to FAERS for ARB-related SE are mostly related to olmesartan. There was a steep decline in reports of olmesartan-related SE following the lawsuit with potential of lawyer interference. There are reports of SE related to ARBs other than olmesartan, with increased physician awareness and the potential to discover a class effect with future studies.

Biomarker-Guided Drug Repurposing and Molecular Validation of Angiotensin-2 Receptor Type-1 in Brain Tumor

Glioma, the most frequent and malignant brain tumor, is one of the most lethal forms of cancer. Among a wide range of aberrantly expressed genes, Angiotensin-2 Receptor Type-1 (AGTR1) is reported to be up-regulated in glioma and associated with aggressive tumor traits and progression. The current study evaluates the anticancer potential of commonly used angiotensin receptor blocker (ARB) telmisartan. A total of eleven, Food and Drug Administration (FDA) approved ARBs were selected, and eight drugs were docked against the AGTR1 receptor. The antihypertensive drug with the highest docking score was selected for in vitro experimentation. Half maximal inhibitory concentration was determined and subsequently applied to patient-derived glioma cell lines. Quantitative gene expression post-drug treatment was determined through real-time polymerase chain reaction (PCR). In vitro growth inhibitory assays revealed that telmisartan at a dose of 45±0.06 μM was able to inhibit 50% of the cell population in malignant glioma U87 cell lines. The PCR results show that AGTR1 expression in the untreated sample was high, as evidenced by 2-ΔΔCt values (342.4, 138.5, 1467.3) for sample IK148-Glioblastma multiform (GBM), IK163-low grade glioma (LGG), and IK231-Medulloblastoma (MDB), respectively. The comparison was made with positive control U-87 cell lines. Following the drug treatment, an increase in the cycle threshold (Ct) mean value for AGTR1 was observed, coinciding with a decrease in mean fold changes of 0.06±0.8, 0.5±2.0, and 0.02±0.02 for GBM, LGG, and MDB samples, respectively. Based on the findings of this study, it can be concluded that telmisartan exhibits successful inhibitory effects against AGTR1 expression in glioma cell lines.

Editor's Summaries of the Articles Published in This Issue of Precision Medicine Communications

In this issue, Rafiq et al, investigated noncancerous FDA-approved drugs for repurposing through molecular docking studies in Breast Cancer patients after their target cystic fibrosis transmembrane conductance regulator protein (CFTR) detection in breast cancer patients. Konain and colleagues evaluate the anticancer potential of commonly used angiotensin receptor blocker (ARB) telmisartan and validate it through molecular techniques, Bangash and friends investigate whether the efficacy and adverse effects of fluvoxamine are associated with polymorphism in the CYP2D6 gene in patients with depression; Mubarak and colleagues reviewed studies aimed at investigating resistance to Carbamazepine in epilepsy patients influenced by the polymorphism of genes encoding metabolic enzymes and drug transporters, while Riaz and Chen provide general information about Type 2diabetes mellitus, treatment challenges, and pharmacogenetic aspects of metformin pharmacotherapy in type 2 diabetes mellitus.

Studying Telmisartan Plasma Exposure, Kidney Distribution, Receptor Occupancy, and Response in Patients With Type 2 Diabetes Using [11 C]Telmisartan.

The angiotensin receptor blocker telmisartan slows progression of kidney disease in patients with type 2 diabetes (T2D), yet many patients remain at high risk for progressive kidney function loss. The underlying mechanisms for this response variation might be attributed to differences in angiotensin-1 receptor occupancy (RO), resulting from individual variation in plasma drug exposure, tissue drug exposure, and receptor availability. Therefore, we first assessed the relationship between plasma telmisartan exposure and urinary-albumin-to-creatinine-ratio (UACR) in 10 patients with T2D and albuminuria (mean age 66 years, median UACR 297 mg/g) after 4 weeks treatment with 80 mg telmisartan once daily. Increasing telmisartan exposure associated with a larger reduction in UACR (Pearson correlation coefficient (PCC)=-0.64, P=0.046, median change UACR: -40.1%, 95% confidence interval (CI): -22.9 to -77.4%, mean telmisartan area under the curve (AUC)=2927.1 ng·hour/mL, 95% CI: 723.0 to 6501.6 ng·hour/mL). Subsequently, we assessed the relation among plasma telmisartan exposure, kidney distribution, and angiotensin-1 RO in five patients with T2D (mean age 60 years, median UACR 72 mg/g) in a separate positron emission tomography imaging study with [11 C]Telmisartan. Individual plasma telmisartan exposure correlated with telmisartan distribution to the kidneys (PCC=0.976, P=0.024). A meaningful RO could be calculated in three patients receiving 120 mg oral telmisartan, and although high exposure seems related to higher RO, with AUC0-last of 31, 840, and 274 ng·hour/mL and corresponding RO values 5.5%, 44%, and 59%, this was not significant (P=0.64). Together these results indicate, for the first time, a relationship among interindividual differences in plasma exposure, kidney tissue distribution, RO, and ultimately UACR response after telmisartan administration.

Comparative Efficacy of Antihypertensive Drugs in Dogs: A Systematic Review

Systemic arterial hypertension is a health condition causing target organ damage (TOD) in dogs. Early and effective treatment is essential to prevent hypertensive emergencies and to reduce the risk of TOD. This study investigated the diseases underlying hypertension and compared the short-term efficacy of antihypertensive drugs in dogs. We evaluated the medical records of client-owned dogs treated with antihypertensive drugs between 2017 and 2018. The study included 75 dogs diagnosed with systemic arterial hypertension (systolic blood pressure ≥150 mmHg). The dogs were classified based on treatment with the following antihypertensive drugs: calcium channel blocker amlodipine, angiotensin-converting enzyme inhibitor ramipril, and angiotensin receptor blocker telmisartan, either as monotherapy or combination therapy (telmisartan + amlodipine or ramipril + amlodipine). Systolic blood pressure was measured using an indirect Doppler method over 4 weeks. Naturally acquired hyperadrenocorticism was the most common disorder to be diagnosed in conjunction with systemic hypertension. In the telmisartan group, the systolic blood pressure decreased more rapidly for 3 weeks compared to ramipril. The combination of telmisartan and amlodipine showed the greatest decrease in systolic blood pressure throughout the 4-week treatment period. This study is meaningful as it suggests guidelines for the use of various antihypertensive drugs in dogs.

Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial.

BackgroundAngiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation.MethodsThis is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed).FindingsA pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79–4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08–2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79–3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44–1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported.InterpretationOur study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19.

Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms

Currently there is no drug therapy for abdominal aortic aneurysm (AAA). To test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. A randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019. Telmisartan, 40 mg, or identical placebo. The primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life. Of 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n = 107) or placebo (n = 103). Of patients included in the intention-to-treat analysis (telmisartan: n = 106, placebo: n = 101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P < .001) and diastolic (7.0; 4.3-9.8 mm Hg; P < .001) blood pressure levels compared with participants receiving placebo. A total of 188 participants (91%) received at least 2 ultrasonographic scans and 133 participants (64%) had at least 2 CT scans. There was no significant difference in ultrasonographic-assessed AAA growth rates among those assigned telmisartan (1.68 mm/y) or placebo (1.78 mm/y): mean difference, -0.11 mm/y (95% CI, -0.60 to 0.38 mm/y; P = .66). Telmisartan had no significant effects on AAA growth assessed by CT-measured AAA diameter (mean difference, -0.01 mm/y; 95% CI, -0.02 to 0.01 mm/y; P = .23) or volume (mean difference, -0.02 cm3/y; 95% CI, -0.04 to 0.00 cm3/y; P = .11), AAA-related events (relative risk, 1.35; 95% CI, 0.54-3.35; P = .52), or health-related quality of life (mean difference in physical component score at 24 months, 0.4; 95% CI, 0.4-0.4; P = .80). Hypotensive symptoms (eg, syncope) were twice as common among participants receiving telmisartan compared with placebo (28 [26%] vs 13 [13%]; P = .02), but overall adverse event rates were otherwise similar for both groups. This underpowered study did not show a treatment effect for telmisartan on small AAA growth. Future trials will need to ensure adequate sample size and duration of follow-up. anzctr.org.au Identifier: ACTRN12611000931976; ClinicalTrials.gov Identifier: NCT01683084.

Evaluation of antidepressant effect of angiotensin receptor blocker telmisartan in albino mice

Background: Depression and hypertension are common morbidities which are seen in elderly and also one leads to the other. Present antidepressant drugs are known for its side effects and there is a necessary for newer drugs with lesser adverse effects. Telmisartan being a widely used antihypertensive drug and with multiple additional properties like peroxisome proliferator-activated receptor gamma activity along with blunting of renin-angiotensin-aldosterone system can be a potential drug for depression. Hence this study is aimed to evaluate the antidepressant activity of angiotensin receptor blocker telmisartan in animal models.Methods: As per protocol submitted to ethics committee, 24 male albino mice weighing between 20-30grams of either sex were selected and divided into 4 groups consisting of 6 each. They were housed in cages with food and water ad libitum. Animals were kept in ambient temperature and humidity, with a 12-hour light and 12-hour dark cycle. Group 1 and group 2 were administered distilled water and fluoxetine 10 mg/kg respectively only on day 15, whereas group 3 and group 4 received telmisartan per orally 1 mg/kg and 2 mg/kg respectively for 15 days once daily. All animals were tested on day 15 using tail suspension test for antidepressant effect.Results: There was significant reduction in the immobility time in telmisartan group when compared to the control group and this time was comparable with the immobility time of standard drug fluoxetine. Decrease in immobility time was found to statistically significant by using one-way ANOVA followed by Bonferroni post hoc test.Conclusions: As evident from our study, telmisartan can be a newer target for antidepressant effect.

Abstract B06: The angiotensin receptor blocker and partial PPARγ agonist telmisartan inhibits the growth of pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy, partly due to the presence of a dense-fibrotic stroma and adaptive metabolism. Telmisartan is an angiotensin II type receptor 1 (AT1) antagonist with partial peroxisome proliferator-activated receptor gamma (PPARγ) agonistic activity used for treatment of hypertension. The aim of this study was to determine the effects of telmisartan on the viability of PDAC cells and tumor progression. In panels of 4 murine and 8 human PDAC cells, the telmisartan IC50 was lower in cells with a low steady-state expression of PPARγ and a mesenchymal cell morphology. In contrast, losartan—a selective AT1 inhibitor—did not affect the viability of PDAC cells. The siRNA knockdown of PPARγ enhanced the sensitivity of telmisartan and stimulated epithelial-mesenchymal transition, which was accompanied by an increase in Wnt signaling. PPARγ regulates glucose metabolism and autophagy. We thus assessed effects of telmisartan on bioenergetics and autophagy of PDAC cells. In PPARγ-knockdown and -scrambled cells telmisartan significantly reduced glucose uptake, without affecting ATP production, but increased respiratory capacity, which can maintain the production of ATP during hypoglycemia. Immunoblotting revealed that PPARγ knockdown compared to scramble cells had increased levels of phosphorylated-AMP-activated protein kinase (p-AMPK) and increased expression of LC3A/B—structural proteins of autophagosomal membranes—which implies higher levels of autophagy. We also compared effects of telmisartan treatment on LC3A/B expression to well-established autophagy modulators, chloroquine and verapamil. Under nutrient-rich conditions and as expected, chloroquine and verapamil treatment induced LC3A/B accumulation, consistent with active autophagic flux in these cells. Telmisartan treatment decreased the levels of LC3A/B in both scramble and PPARγ knockdown cells and decreased the formation of LC3A/B positive granules in other PDAC cell lines. Telmisartan can also induce the accumulation of the signal adaptor protein p62 (SQSTM1), even in the presence of verapamil, which is also consistent with autophagy inhibition. Telmisartan did not prevent the accumulation LC3A/B in the presence of chloroquine, implying that telmisartan acts after the autophagosome-lysosome fusion step. To assess the effects of telmisartan in vivo, we used an orthotopic PDAC model. Telmisartan monotherapy inhibited the growth of primary tumors, decreased the incidence of liver metastasis, and significantly improved the survival of mice. Hence, telmisartan can reduce autophagy and the viability of PDAC cells, and PDAC progression. Because telmisartan is an FDA-approved drug, our findings provide the scientific rationale for testing its efficacy in the prevention of PDAC progression. Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Mark Duquette, Alba Luengo, Daniel Schanne, Andrew S. Liss, Matthew G. Vander Heiden, Rakesh K. Jain, Yves Boucher. The angiotensin receptor blocker and partial PPARγ agonist telmisartan inhibits the growth of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B06.

Angiotensin Receptor Blockers for Erectile Dysfunction in Hypertensive Men: A Brief Meta-Analysis of Randomized Control Trials.

Erectile dysfunction is common in adult men, particularly those with hypertension and diabetes. The present study determines the effectiveness of angiotensin receptor blocker (ARB) drugs on erectile function in hypertensive male adults. For this purpose, CENTRAL and MEDLINE and reference lists of the articles were searched. The randomized controlled trials (RCTs) were selected that compared ARBs with conventional therapy or no treatment in men of any ethnicity who were presented with hypertension and/or diabetes. A total four trials that had 2,809 men were included. Three trials reported adequate random sequence allocation, two reported adequate blinding. Attrition bias is low in one of the included studies. All three studies are of low risk of selective reporting bias. There was an improvement in sexual activity with ARBs (valsartan) (mean difference (MD): 0.71, 95% Confidence Interval (CI) 0.66 to 0.76, I2 statistic = 0%). However, the erectile functions did not increase significantly in ARBs (losartan or telmisartan) treated men as compared to control or placebo (n = 203 vs n = 232; MD: 1.36; 95% CI: −0.97 to −3.69; I2 statistic = 80%). These results suggested that ARBs significantly improved sexual activity among hypertensive men. However, the erectile function was not significantly improved in ARBs treated men as compared to the control or placebo-treated. There were limited studies available. Hence, additional studies are needed to support findings from this review. ARBs should be considered when prescribing antihypertensive drugs to men.

Telmisartan protects chronic intermittent hypoxic mice via modulating cardiac renin-angiotensin system activity

BackgroundTo explore the effects of chronic intermittent hypoxia (CIH), which mimics sleep apnea syndrome, on the cardiac renin angiotensin system (RAS), and to investigate the cardiac protection of an angiotensin receptor blocker (ARB)telmisartan (TERT) against CIH.Methods32 healthy male C57B6J mice were randomly divided into CIH, ARB, blank and air control groups. CIH lasted for 12 weeks. Cardiac angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE 2) and angiotensin II (Ang II) were evaluated by immunohistochemistry. Myocardial apoptosis were assessed by TUNEL assay and myocardial cell ultrastructure were observed under transmission electron microscope.ResultsCardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment.ConclusionsCIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts.

Modulation of brain ACE and ACE2 may be a promising protective strategy against cerebral ischemia/reperfusion injury: an experimental trial in rats.

The brain renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression. We evaluated the protective effects of the angiotensin receptor blocker (ARB) telmisartan and the angiotensin-converting enzyme 2 (ACE2) activator xanthenone on experimental cerebral ischemia/reperfusion (I/R) injury. Rats were divided into a sham control, a cerebral I/R control, a standard treatment (nimodipine, 10mg/kg/day, 15days, p.o.), three telmisartan treatments (1, 3, and 10mg/kg/day, 15days, p.o.), and three xanthenone treatments (0.5, 1, and 2mg/kg/day, 15days, s.c.) groups. One hour after the last dose, all rats except the sham control group were exposed to 30-min cerebral ischemia followed by 24-h reperfusion. Brain ACE and ACE2 activities and the apoptotic marker caspase-3 levels were assessed. Glutathione (GSH), malondialdehyde (MDA), and nitric oxide end products (NOx) as oxidative markers and tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-10 as immunological markers were assessed. Histopathological examination and immunohistochemical evaluation of glial fibrillary acidic protein (GFAP) were performed in cerebral cortex and hippocampus sections. Telmisartan and xanthenone in the higher doses restored MDA, NOx, TNF-α, IL-6, caspase-3, ACE, and GFAP back to normal levels and significantly increased GSH, IL-10, and ACE2 compared to I/R control values. Histopathologically, both agents showed mild degenerative changes and necrosis of neurons in cerebral cortex and hippocampus compared with I/R control group. Modulation of brain RAS, either through suppression of the classic ACE pathway or stimulation of its antagonist pathway ACE2, may be a promising strategy against cerebral I/R damage.

Angiotensin receptor blocker telmisartan inhibits cell proliferation and tumor growth of cholangiocarcinoma through cell cycle arrest

Cholangiocarcinoma (CCA) is at an advanced stage at the time of its diagnosis, and developing a more effective treatment of CCA would be desirable. Angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan may inhibit cancer cell proliferation, but the mechanisms by which telmisartan affects various cancers remain unknown. In this study, we evaluated the effects of telmisartan on human CCA cells and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on CCA cells using two cell lines, HuCCT-1 and TFK-1. In our experiments, telmisartan inhibited the proliferation of HuCCT-1 and TFK-1 cells. Additionally, telmisartan induced G0/G1 cell cycle arrest via blockade of the G0 to G1 cell cycle transition. Notably, telmisartan did not induce apoptosis in HuCCT-1 cells. This blockade was accompanied by a strong decrease in cell cycle-related protein, especially G1 cyclin, cyclin D1, and its catalytic subumits, Cdk4 and Cdk6. Telmisartan reduced the phosphorylation of EGFR (p-EGFR) and TIMP-1 by using p-RTK and angiogenesis array. Furthermore, miRNA expression was markedly altered by telmisartan in HuCCT-1. Telmisartan inhibits tumor growth in CCA xenograft model in vivo. In conclusion, telmisartan was shown to inhibit human CCA cell proliferation by inducing cell cycle arrest.

Angiotensin receptor blocker telmisartan: efficacy, safety and relevance of clinical application

Angiotensin receptor blocker telmisartan is a modern and effective antihypertensive drug which has advantages in comparison with other drugs of the group of angiotensin receptor blockers. Long half-life retains its effect is significant more than 24 hours, which is especially important for blood pressure control in the dangerous morning hours. Telmisartan is excreted by the kidneys less than 2%, making its use safe in patients with renal pathology. High antihypertensive efficacy combined with its excellent tolerability. Telmisartan has the greatest affinity to PPARg-receptors, which is especially important when selecting antihypertensive therapy in patients with arterial hypertension and metabolic disorders, insulin resistance, metabolic disorders. A considerable number of studies showing the effectiveness of treatment with telmisartan in patients with cardiovascular disease, diabetes, metabolic syndrome, nephropathy. The article presents the results of a study of therapeutic equivalence of generic drug is telmisartan, which showed a high bioequivalence to original brand-name formulation and was according to the indications: hypertension and decrease cardiovascular morbidity and mortality in patients aged 55 years and older with a high risk of cardiovascular disease. The results of our observations show comparable antihypertensive efficacy of the original and generic products and well tolerated by the results of questioning of patients.

Блокатор рецепторов ангиотензина телмисартан: эффективность, безопасность и актуальность клинического применения

Angiotensin receptor blocker telmisartan is a modern and effective antihypertensive drug which has advantages in comparison with other drugs of the group of angiotensin receptor blockers. Long half-life retains its effect is significant more than 24 hours, which is especially important for blood pressure control in the dangerous morning hours. Telmisartan is excreted by the kidneys less than 2%, making its use safe in patients with renal pathology. High antihypertensive efficacy combined with its excellent tolerability. Telmisartan has the greatest affinity to PPARg-receptors, which is especially important when selecting antihypertensive therapy in patients with arterial hypertension and metabolic disorders, insulin resistance, metabolic disorders. A considerable number of studies showing the effectiveness of treatment with telmisartan in patients with cardiovascular disease, diabetes, metabolic syndrome, nephropathy. The article presents the results of a study of therapeutic equivalence of generic drug is telmisartan, which showed a high bioequivalence to original brand-name formulation and was according to the indications: hypertension and decrease cardiovascular morbidity and mortality in patients aged 55 years and older with a high risk of cardiovascular disease. The results of our observations show comparable antihypertensive efficacy of the original and generic products and well tolerated by the results of questioning of patients.

Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention.

ObjectiveExamining the Retinal Renin Angiotensin System (RRAS) in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR) model.MethodVitreous of ROP patients (n = 44, median age 5.5 months) was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS).ResultsMultifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan), ACEI (lisinopril) and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels.ConclusionThis study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model.

Abstract B41: The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. PDAC is highly resistant to chemotherapy, which impels search for novel approaches for treatment. Our group has previously shown in PDAC models that the angiotensin II type 1 receptor (AT1R) blocker losartan decreases desmoplasia and solid stress, which enhances blood flow, and improves the delivery and effectiveness of cytotoxic agents (Chauhan et al, Nature Comm 2013). In contrast to losartan, which had no effects on the growth of primary PDAC, we recently found that the AT1R blocker telmisartan significantly reduces the growth of PDAC. In addition to inhibiting AT1R activity telmisartan is also a partial agonist of Peroxisome Proliferator Activated Receptor γ (PPARγ). We determined in a panel of PDAC cell lines the effects of telmisartan on cellular viability. Our findings suggest that the sensitivity to telmisartan treatment correlates with low steady-state expression of PPARγ and a mesenchymal morphology. Furthermore, telmisartan induced a transcriptional profile distinct from the response to the direct PPARγ agonist pioglitazone. In support of our correlative results, the genetic knockdown of PPARγ increased the sensitivity to telmisartan and stimulated epithelial to mesenchymal transition (e.g. decreased expression of E-cadherin, increased expression of the mesenchymal markers Snail and N-cadherin). We also tested the effects of telmisartan in orthotopically implanted and genetically engineered mouse models of PDAC. Telmisartan inhibited the growth of primary tumors, decreased the incidence of metastasis and improved mice survival. In summary, our findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice. Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher.{Authors}. The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B41.

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.

BackgroundExperimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.Methods/DesignTelmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.DiscussionCurrently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.Trial registrationAustralian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976, registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084, registered on 5 September 2012.

Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

Background and ObjectiveSodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.Research Design and MethodsWe induced diabetes using a low dose streptozotocin protocol in 7–8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).ResultsDiabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.ConclusionHence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.