Administration Of Telmisartan Research Articles

Telmisartan/17β-estradiol mitigated cognitive deficit in an ovariectomized rat model of Alzheimer's disease: Modulation of ACE1/ACE2 and AT1/AT2 ratio

AimsThe higher incidence rate of Alzheimer's disease (AD) among women has led to explorations on the association between estrogen deficiency and AD. Also, usage of antihypertensive drugs has been suggested to reduce the incidence of AD in elderly hypertensive patients. Thus, this study aimed to investigate the effects of telmisartan and/or 17β-estradiol on a cognitively impaired ovariectomized rat model of AD. Main methods75 female Wistar rats were randomly allocated into five groups. One group was sham operated and the other four groups were subjected to ovariectomy, received D-galactose and either untreated or treated with telmisartan and/or 17β-estradiol for 6 weeks. Key findingsOvariectomized rats showed cognitive impairment in Morris water maze and novel object recognition tests, increasing inflammatory biomarkers (tumor necrosis factor-α, and interleukin-1β), increasing AD biomarkers (amyloid beta1-42, and acetylcholine esterase), and over activation of classical arm of renin angiotensin system (RAS) (ACE1/Ang2/AT1) in hippocampi. Also, hippocampi histopathological examination revealed amyloid beta deposition. Whereas, administration of telmisartan and/or 17β-estradiol improved animals' behavior, alleviated histopathological alterations and reduced the level of inflammatory and AD biomarkers, modulated RAS activity favoring the novel neuroprotective arm (ACE2/Ang(1–7)/MasR). SignificanceOur findings suggest that combined administration of both drugs has synergetic neuroprotective effects; supporting their potential application in AD treatment.

Telmisartan alone or in combination with etanercept improves anemia associated with rheumatoid arthritis in rats: a possible role of anti-inflammatory and reno-protective effects.

There are conflicting data regarding angiotensin receptor blockers (ARBs) induced anemia and its beneficial anti-inflammatory effect in rheumatoid arthritis. The aim of the present study was to investigate the effect of telmisartan administration either alone or in combination with etanercept on anemia of chronic inflammatory diseases in a model of rheumatoid arthritis in rats. Rheumatoid arthritis (RA) was induced by Freund's Complete Adjuvant (FCA; 1mg/0.1ml paraffin oil), injected subcutaneously on days 0, 30 and 40. Rats with RA received dimethyl sulfoxide (DMSO), etanercept (0.3mg/kg 3 times/week; sc), telmisartan (1.5mg/kg/day; orally) or combination of etanercept and telmisartan. Arthritis parameters (footpad circumference change and paw volume change), erythrocyte indices (hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin level changes), iron profile (serum iron and serum ferritin), serum levels of erythropoietin (EPO), hepcidin, tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 were evaluated, along with measuring serum urea and creatinine levels. All treated groups showed improvement of the measured parameters in comparison to RA-control subgroup. Telmisartan either alone or in combination with etanercept significantly improved arthritis and erythrocyte indices. Telmisartan showed significant increase in EPO and decrease in hepcidin compared to etanercept. Combination group showed significant improvement in serum iron, ferritin, EPO, hepcidin, TNF-α, IL-6, urea and creatinine, compared to etanercept. Telmisartan either alone or in combination, but not etanercept alone, significantly decreased creatinine level. Telmisartan improved anemia and arthritis parameters and showed anti-inflammatory and reno-protective effects, in a rat model of rheumatoid arthritis.

The effect of therapy with olmesartan or telmisartan in patients with arterial hypertension combined with obesity

The aim: To evaluate the hemodynamic and echocardiographic parameters, the level of adiponectin and IL-6 in such patients under the influence of therapy with sartans (telmisartan or olmesartan) and atorvastatin 12 weeks later. Materials and methods: Fifty patients with arterial hypertension of II stage and 2 level, who underwent elective in-patient treatment were examined. During the next 12 weeks, they took olmesartan (1st group) or telmisartan (2nd group) in combination with atorvastatin. Results: The combined use of olmesartan or telmisartan in with atorvastatin for 12 weeks had a resulted in a significant decrease in systolic and diastolic blood pressure, heart rate and myocardial mass. After treatment with olmesartan in combination with atorvastatin, the adiponectin content in the blood increased by 41.6% (p <0.05). In the group of patients who receiving telmisartan, an increase adiponectin level was noted in 80.0% of patients and a had shown a significantly higher increase in adiponectin levels, namely for 59.4% after treatment (p <0.01). The level of IL-6 has significantly decreased, both with the administration of olmesartan (2.7 times) and telmisartan (2.6 times) (p<0.01). Conclusions: Telmisartan, in comparison with olmesartan, significantly reduces the size of the left ventricular and left atrium myocardium, and decreased left ventricular mass index. Telmisartan improves the cardio-metabolic profile of obese and hypertensive patients by increase of adiponectin concentrations and decrease of IL-6 levels.

Long term effects after telmisartan administration for cardiovascular-renal axis disorder in cats

Long term effects after telmisartan administration for cardiovascular-renal axis disorder in cats

Angiotensin II Receptor Type 1 Antagonists Modulate Vascular Smooth Muscle Cell Proliferation and Migration via AMPK/mTOR

The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) in the vascular wall are crucial pathological events involved in cardiovascular impairments including hypertension, heart failure, and atherosclerosis. At the molecular level, the mammalian target of rapamycin (mTOR)-ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway is essential to potentiate VSMC proliferation and migration. Although angiotensin II receptor type 1 ­(AT1-R) antagonists such as valsartan and telmisartan have a significant cardiovascular protective effect, the molecular basis of this class of drugs in VSMC proliferation and migration remains elusive. By using cultured VSMCs, adenosine monophosphate-activated protein kinase (AMPK) α2 knockout mice, and hypertensive rat models, this study investigated whether AT1-R antagonists can inhibit the mTOR-p70S6K signaling pathway in VSMCs and the vascular wall. Valsartan activated AMPK, which in turn suppressed reactive oxygen species production and consequently attenuated VSMC proliferation and migration. In vivo, a clinical dose of telmisartan significantly inhibited the mTOR-p70S6K signaling pathway in the vascular wall of wild-type but not AMPKα2^–/– mice. Furthermore, spontaneously hypertensive rats had significantly elevated phosphorylation of mTOR and p70S6K in the aorta compared to Wistar-Kyoto rats, which were reduced by telmisartan administration. These data suggest that AT1-R antagonists inhibit VSMC proliferation and migration via their regulation of AMPK, mTOR, and p70S6K, which contribute to the cardioprotective effects of these drugs.

BLOOD PRESSURE LOWERING EFFICACY OF TELMISARTAN, AZILSARTAN, OLMESARTAN TAKING ON THE MORNING OR AT BEDTIME IN PATIENTS WITH MILD TO MODERATE ARTERIAL HYPERTENSION

Objective: Aim study was compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of olmesartan, azilsartan, telmisartan on 24-h BP. Design and method: 126 patients (57 men, 69 women) was included in 12-week study with evaluated the efficacy and safety of olmesartan 20–40 mg (n = 40), azilsartan 40–80 mg (n = 41), telmisartan 40–80 mg (n = 45), dosed a.m. or p.m., in patients with grade 1–2 hypertension. Mean ages 51,80 ± 1,31, BMI - 28,81 ± 0,39 kg/m2. Mean 24SBP – (135,60 ± 0,96) mmHg., 24DBP – (82,41 ± 0,84) mmHg., 24HR – (71,88 ± 0,89) b.p.m. Results: Mean 24-h SBP/DBP change from baseline to Weeks 12 in olmesartan group was benefit (−11,09 ± 2,30/8,38 ± 2,58 mmHg) in p.m. compared (−4,06 ± 2,25/3,38 ± 2,31mmHg) in a.m., p < 0,01 between evening and morning administration. Mean 24-h SBP/DBP change in azilsartan group was comparable in p.m. (−13,06 ± 2,65/9,76 ± 1,73 mmHg) and a.m. (−12,71 ± 1,62/7,00 ± 1,50 mmHg) in a.m., p > 0,05 between evening and morning. Mean 24-h SBP/DBP change from baseline to Weeks 12 in telmisartan group was benefit (−16,48 ± 2,86/12,56 ± 2,80 mmHg) in a.m. compared (−4,93 ± 1,53/5,40 ± 1,89 mmHg) in p.m., p < 0,01 between morning and evening administration. All treatments were well tolerated. At 24-h BP, with the administration of olmesartan, azilsartan and telmisartan, the target blood pressure levels were 71.80%, 71.05% and 75.61% respectively. Thus, all three drugs have equally effectively. Conclusions: Taking telmisartan more significantly reduced the 24-h BP in the morning compared with the evening adminisrtation, olmesartan lowered 24-h BP better in the evening administration, and the use of azilsartan equally decreased 24-h BP, regardless of the time of taking the drug.

Effects of UGT1A1 Polymorphism, Gender and Triglyceride on the Pharmacokinetics of Telmisartan in Chinese Patients with Hypertension: A Population Pharmacokinetic Analysis.

Telmisartan is an angiotensin receptor blocker used for the treatment of hypertension. The effects of gender and uridine diphosphate-glycosytransferase 1A1 (UGT1A1) genetic polymorphisms (rs4124874, rs4148323, and rs6742078) on telmisartan plasma concentration and blood pressure in Chinese patients with hypertension have been reported previously. In this study, we aimed to develop a population pharmacokinetic (PopPK) model to quantify the effects of gender and UGT1A1 polymorphisms on the pharmacokinetics of telmisartan. Population pharmacokinetic analyses were performed using data collected prospectively from 58 Chinese patients with mild to moderate essential hypertension (aged 45-72years; 36 men, 22 women) receiving 80mg/day telmisartan orally for 4weeks. Blood samples were collected in heparinized tubes at 0, 0.5, 1, and 6h on day28 after telmisartan administration. The plasma concentrations and UGT1A1 genetic variants were determined by high-performanceliquid chromatography-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, respectively. A two-compartment pharmacokinetic structural model with first-order elimination and absorption best described the pharmacokinetic characteristics of telmisartan. Gender and triglyceride influenced the apparent oral clearance (CL) of telmisartan. UGT1A1 (rs4124874) affected the bioavailability (F1) of telmisartan. Lower CL and bioavailability resulted in higher plasma concentrations being observed in female subjects with UGT1A1 CC or CA genotype and high triglyceride. A PopPK model of telmisartan was established to confirm that UGT1A1 genotype, gender and triglyceride can affect the pharmacokinetics of telmisartan in Chinese patients with hypertension. Our findings can provide relevant pharmacokinetic parameters for further study of telmisartan.

Вплив блокаторів рецепторів ангіотензину II на зміни артеріального тиску при добовому моніторуванні залежно від ранкового або вечірнього прийому

The aim – to evaluate the effect of angiotensin II receptor blockers olmesartan, azilsartan and telmisartan when administered in the morning or evening hours on blood pressure (BP) indices during daily monitoring in patients with arterial hypertension (AH).Materials and methods. The study involved 126 patients with mild to moderate hypertension who were selected to compare the effect of angiotensin II receptor blockers – olmesartan, azilsartan and telmisartan – in the morning and evening hours. They were divided into 6 groups: 20 patients taking olmesartan at a dose of 20–40 mg in the morning, 20 patients taking olmesartan at a dose of 20–40 mg in the evening, 21 patients taking azilsartan at a dose of 40–80 mg in the morning, 20 patients taking azilsartan at a dose of 40–80 mg in the evening, 22 patients taking telmisartan at a dose of 40–80 mg in the morning, 23 patients taking telmisartan at a dose of 40–80 mg in the evening. Patients underwent primary examination and repeated one – after 3 months of therapy.Results and discussion. Evening reception of olmesartan, compared with morning one, led to a more pronounced decrease in diurnal systolic blood pressure (SBT) – (11.09±2.30) vs (4.06±2.25) mm Hg (p&lt;0.01). Changes in diurnal diastolic blood pressure (DBP) were statistically insignificant, although its decrease during evening reception was more significant compared to decrease during morning reception ((8.38±2.58) mm Hg versus (3.38±2.31) mm Hg). Changes in daily blood pressure against reception of azilsartan in the evening and morning hours were statistically significant, but did not differ from each other ((13.06±2.65)/(9.76±1.73) vs. (12.71±1.62)/(7.00±1.50) mm Hg). Reduction of diurnal blood pressure at the background of telmisartan administration was statistically significantly more pronounced in the morning than in the evening intake ((16.48±2.86)/(12.56±2.80) vs. (4.93±1.53)/(5.40±1.89) mm Hg, p&lt;0.01). Thus, morning reception more significantly lowered the average daily blood pressure against the background of taking telmisartan, and the evening reception – against the background of taking olmesartan. Azilsartan equally reduced the blood pressure both at evening and morning admission. The rate of achievement of target BP at daily monitoring against the background of the administration of olmesartan, azilsartan and telmisartan was 71.80; 71.0 and 75.61 %, respectively.Conclusions. Admission of telmisartan more significantly reduced the average daily blood pressure in morning hours compared to evening hours, olmesartan better lowered the average daily blood pressure when taken in the evening, and the use of azilsartan equally affected the decrease in blood pressure regardless of the time of taking the drug.

Aldosterone mediates angiotensin II‐induced myocardial fibrosis and hypertrophy via steroidogenic acute regulatory protein and aldosterone synthase

ObjectiveAldosterone produced in the adrenal glands through angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. The purpose of this study was designed to test the hypothesis that Ang II causes cardiac morphological changes through the steroidogenic acute regulatory protein (StAR)/aldosterone synthase (AS)‐dependent aldosterone synthesis primarily initiated in the heart.MethodsSprague‐Dawley rats were observed for a 28‐day period and randomized to the following groups: untreated Ang II infusion with osmotic pumps (500 ng/kg/min), dietary Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day), dietary aldosterone receptor blocker, spironolactone (100 mg/kg/day) and adrenalectomy before Ang II infusion. Rats received saline infusion were served as the Sham controls.ResultsRelative to the Sham animals, Ang II infusion significantly increased protein levels including Ang II AT1 receptors, StAR and AS as well as their tissue expression in the adrenal glands and heart, as identified by Western blot assay and immunohistochemical staining. Administration of telmisartan, significantly down‐regulated the protein level and expression of StAR and AS, but these changes were not altered by treatment with spironolactone, suggesting that Ang II AT1 receptors are involved as an upstream regulator and the blockade of aldosterone receptor does not affect the AT1/StAR/AS signaling. Following activation of these signaling cascades, Ang II infusion further augmented migration of macrophages, protein level of TGFβ1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, in coincidence with enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by either telmisartan or spironolactone treatment (all P&lt;0.05 vs. Ang II group). However, removing adrenal glands by adrenalectomy did not fully suppress Ang II‐induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in the pathogenesis of Ang II induced cardiac injury.ConclusionsMyocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue‐specific activation of aldosterone synthesis, which are primarily mediated via AT1/StAR/AS signaling pathways. Understanding these maladaptive responses to Ang II could lead to the development of novel therapeutic strategy.Support or Funding InformationThis study was supported in part by grants from the Mercer University School of Medicine, the Medcen Community Health Foundation, Georgia and the National Natural Science Foundation of China (81470436).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization

Telmisartan is a well-known anti-hypertensive drug acting as an angiotensin 2 receptor blocker (ARB), but it also possesses partial PPARγ agonistic activity and induces insulin sensitivity. In the present study, we investigated the effects of telmisartan on macrophage polarization in association with its browning capacity, because PPARγ plays a key role in M2 polarization and in the browning of white adipocytes. Telmisartan induced M2 marker expression in murine macrophages concentration dependently, which was confirmed by flow cytometry. Both PPARγ and PPARδ activations appear to be responsible for telmisartan-induced M2 polarization. Telmisartan-treated conditioned medium (Tel-CM) of RAW264.7 cells and of bone marrow derived macrophages (BMDM) induced the expressions of browning markers in fully differentiated white adipocytes with reduced lipid droplets, and increased oxygen consumption rate and mitochondrial biogenesis. Levels of catecholamines (CA) released into the conditioned medium as well as intracellular tyrosine hydroxylase (TH) mRNAs were found to be increased by telmisartan, and browning effects of Tel-CM were lessened by β3 receptor antagonist (L-748,337), suggesting CA secreted into CM play a role in Tel-CM-induced adipocyte browning. Acute administration of telmisartan (2 weeks, p.o.) to C57BL/6J mice increased the expressions of browning markers and M2 markers in white adipose tissues, whereas macrophage depletion by clodronate liposome pretreatment attenuated the telmisartan-induced expressions of browning markers. Together, telmisartan was observed to induce the browning of fully differentiated white adipocytes, at least in part, via PPAR activation-mediated M2 polarization.

Evaluation of effect over time after oral administration of telmisartan for chronic kidney disease in cats

Angiotensin receptor blockers, such as telmisartan, are considered effective in the treatment of hypertension and proteinuria due to chronic kidney disease (CKD) in cats. It selectively blocks the AT1 receptor and does not affect the AT2 receptor, thus effectively blocking the activity of the renin angiotensin aldosterone system. This study aims to compare over time the changes in various indicators, including systemic hypertension and proteinuria, before and after the administration of telmisartan in cats with CKD. Decrease in blood pressure (BP) (p&lt;0.001) and urine protein to creatinine (UP/C) ratio (p&lt;0.001) were found to be statistically significant over time after the administration of telmisartan. BP and the UP/C ratio were 160 ± 22.2 and 0.50 ± 0.647 before telmisartan administration (Day 0), 150 ± 21.0 and 0.27 ± 0.487 on the 30th day (Day 30), 150 ± 17.0 and 0.25 ± 0.376 on the 60th day (Day 60), and 140 ± 17.8 and 0.15 ± 0.233 on the 90th day (Day 90) after administration, respectively. BP and UP/C were statistically significantly lower in cats with CKD over time at each time point from Day 0 to Day 90 at 30 day intervals. Especially after 90 days of telmisartan administration, the improvement of BP and UP/C were estimated to be about 20 mmHg and 0.35, respectively. In conclusion, the oral administration of telmisartan to cats with CKD is effective in improving BP and proteinuria, which has a positive effect on long-term survival in cats with CKD.

Telmisartan regulates the development of cerebral ischemia by alleviating endoplasmic reticulum stress.

Recent studies have shown that telmisartan (TMS) is effective for the protection against ischemia/brain damage in rat models. However, the specific underlying mechanism is poorly understood. In line with previous results, our data showed that TMS improves CBF and physiological variables, including pH, pCO2, pO2. Through CD31 immunofluorescence staining, reduction of blood vessel density was found in MCAO group, but TMS treatment could enhance the cerebral vascular density in the ischemic area. Meanwhile, TMS treatment could enhance the number of BrdU/lectin double-positive cells. Furthermore, the reduction of nestin-positive cells was identified in the brain of MCAO rats, while the number of nestin-positive cells was significantly increased after TMS administration. Furthermore, the expression of ERS-related proteins, including GRP78, CHOP/GADD153, Caspase12 was increased after MCAO, but was decreased after administration of TMS, thereby enhancing angiogenesis and neuron regeneration.

Telmisartan attenuates kidney apoptosis and autophagy-related protein expression levels in an intermittent hypoxia mouse model

PurposeObstructive sleep apnea (OSA) is associated with renal impairs. As a novel pathophysiological hallmark of OSA, chronic intermittent hypoxia (CIH) enhances apoptosis and autophagy. The present study aims to evaluate the effect of telmisartan on CIH-induced kidney apoptosis and autophagy in a mouse model of OSA.Materials and methodsMice were randomly allocated to normoxia, CIH, and CIH+telmisartan groups (n = 12 in each group). The CIH exposure duration was 12 weeks. Mice in the CIH+telmisartan group received telmisartan administration. The terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and western blotting of Bax and cleaved caspase-3 were conducted for evaluating apoptosis in kidney tissue. While the autophagy-related proteins, beclin-1 and LC3, were also observed via western blotting.ResultsThe percentage of apoptotic cell in the CIH group was significantly higher than that of normoxia group; meanwhile, Bax and cleaved caspase-3 protein levels were increased in the CIH group than those of normoxia group (all p < 0.05). Compared with the normoxia group, mice in the CIH group had greater autophagy-related proteins (beclin-1 and LC3) expression. When compared to the CIH group, both the renal apoptosis and autophagy in the CIH+telmisartan group were decreased.ConclusionThe CIH accelerates renal apoptosis and autophagy levels. Telmisartan ameliorating those levels suggests that it might prevent renal impairs from the CIH in OSA patients.

Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs

IntroductionThis study examined whether the angiotensin II receptor blocker telmisartan had inhibitory effects on drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs. AnimalsFive healthy laboratory beagles were used in this study. MethodsEach dog received amlodipine (0.5 mg/kg, q12h, PO) alone for 14 days. Starting on the next day, animals received both amlodipine and telmisartan (1.0 mg/kg, q24h, PO) for 84 days. Systolic blood pressure, heart rate, plasma biochemical variables (blood urea nitrogen, creatinine, and electrolytes), plasma renin activity, and 24-h urinary aldosterone elimination (U-Aldo) were measured before amlodipine administration; at day 0; and at days 1, 7, 14, 28, 56, and 84 of telmisartan treatment. ResultsTelmisartan was associated with significant decreases in systolic blood pressure on day 56 (p=0.046), whereas heart rate did not significantly change during this treatment (p=0.061). Plasma renin activity was significantly increased on days 1, 7, 28, 56, and 84 during telmisartan administration (all p=0.04). No change in median U-Aldo was detected following telmisartan administration (p=0.241). When U-Aldo was evaluated in individual animals, two dogs displayed evidence of aldosterone breakthrough. ConclusionsTelmisartan administration did not suppress RAAS activation. The appearance of aldosterone breakthrough supports the incomplete blockade of RAAS activation.

Application of Liquid Chromatography with Fluorimetric Detection for the Determination of Urinary Pentosidine in Type 2 Diabetes Mellitus Patients: Effect of Telmisartan Administration on Podocyturia and Relationship with Metabolic Control

The beneficial effects of a short period of Telmisartan administration were successfully assessed trough pentosidine urinary levels (uPen) and urinary podocyte excretion (UPE), in type 2 diabetes mellitus (DM2) patients. Patients with podocyturia received Telmisartan treatment (80 mg/day) for two months. uPen were quantified pre and post treatment using HPLC with fluorimetric detection and in-lab synthesized standard. Immunofluorescence method for podocalyxin was used to evaluate urinary excretion of podocytes. uPen and UPE significantly decrease after treatment (p&amp;lt;0.01255 and p&amp;lt;0.005 respectively), as well as serum total cholesterol and LDL levels (p&amp;lt;0.001). These results suggest that podocyte protection by Telmisartan even in the face of deficient metabolic control could be an important matter in the prevention and progression of diabetic nephropathy. This study also strengthens evidence of the promising role of pentosidine as prognostic and diagnostic markers in diabetic nephropathy

Evaluation of the anti-inflammatory effect of telmisartan as an adjuvant therapy to nsaid in the management of knee osteoarthritis; a clinical prospective study

Osteoarthritis (OA)is a degenerative joint disease caused by gradual loss of cartilage. Telmisartan is an Angiotensin II receptor antagonist,and act as a partial agonist on the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ),that has been reported to exert anti-inflammatory effects. This study was designed to evaluate the potential anti-inflammatory effect oftelmisartan in patients with knee OA.42 patients with painful knee OA were allocated into 2 groups,group (1): patients treated with naproxen tablets (500 mg/12 hr),telmisartan tablets (40 mg/day) and omeprazole (20 mg/day) for 3 months,while group (2): patients treated with naproxen tablets (500 mg/12hr) and omeprazole (20 mg/day) for 3 months. The serum levels of IL-1β,high-sensitivity C-reactive protein (hs-CRP),TNF-α anderythrocyte sedimentation rate (ESR) were measured before and after 3 months of treatment.Telmisartan when used in combination with naproxen resulted in significant decrease in serum levels of IL-1β and hs-CRP,higher than that produced by naproxen when used alone. The mean TNF-α level and ESR was decreased non-significantly in both study groups. Administration of telmisartan as an adjuvant therapy to naproxen in knee OA patients produced a significant decrease in the serum levels of IL-1β and hs-CRP,though no clear effect on TNF-α and ESR was noticed after 3 months treatment. Accordingly,many promising preventive strategies emerged from the available results since telmisartan relatively reduce the inflammatory burden in OA patients.

Cerebral ischemia induced inflammatory response and altered glutaminergic function mediated through brain AT1 and not AT2 receptor

In the present study, we investigated the effects of angiotensin (Ang II) receptor blockers in cerebral ischemia by administration of telmisartan (AT1 blocker) and/or PD123319 (AT2 blocker) in global ischemic mice model. The neuroprotective effect of AT antagonists was evaluated through monitoring muscle co-ordination and cerebral blood perfusion in ischemic mice. Gene expression studies (NF-κB, GSK-3β, EAAT-2, AT1 & AT2 receptors) and staining of brain regions with cresyl violet, GFAP, synaptophysin and NSE methods were carried out in to understand the molecular mechanisms. Further, the brain glutamate, cytokines, and Ang II peptide levels were evaluated and their correlation with EAAT-2 mRNA expression was performed. Our results indicate that the induction of ischemia elevates brain Ang II, cytokines, and glutamate levels and reduced muscle co-ordination and cerebral blood perfusion. The expressions of NF-κB, GSK-3β and AT1 were significantly increased, whereas, EAAT-2 expression was decreased. Blocking of AT1 receptors by telmisartan (TM) reversed the detrimental responses of cerebral ischemia and restored the cerebral blood flow denoting blockade of Ang II/AT1 pathway is beneficial in ischemia, whereas, blockade of AT2 receptors by PD123319 (PD) increased the ischemic injury in mice. This vulnerable effect of PD may be attributed through augmenting the Ang II/AT1 dependent cytokines mediated glutamate transporter (EAAT-2) dysfunction. Interestingly, the beneficial effects of AT1 blocker was remarkably antagonized by AT2 blocker in most of the parameters studied in ischemic conditions. Also, the expression of AT2 receptors was significantly increased compared to that of AT1 receptors upon ischemic induction. It denotes that the endogenous Ang II predominantly acts on AT2 receptor, thereby promoting its own mRNA transcription. Hence, the increased expression of AT2 receptors in ischemic condition could be used as target protein for therapeutic benefit.

EVALUATION OF THE ANTI-INFLAMMATORY EFFECT OF TELMISARTAN AS AN ADJUVANT THERAPY TO NSAID IN THE MANAGEMENT OF KNEE OSTEOARTHRITIS; A CLINICAL PROSPECTIVE STUDY

Background: Osteoarthritis (OA) is a degenerative joint disease caused by gradual loss of cartilage. Telmisartan is an angiotensin II receptor antagonist, and act as a partial agonist on the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), that has been reported to exert anti-inflammatory effects. Objective: To evaluate the potential anti-inflammatory effect of telmisartan in patients with knee OA. Methods: Forty-two patients with painful knee OA were allocated into 2 groups, group (1): patients treated with naproxen tablets (500 mg/12 hr), telmisartan tablets (40 mg/day) and omeprazole (20 mg/day) for 3 months, while group (2): patients treated with naproxen tablets (500 mg/12 hr) and omeprazole (20 mg/day) for 3 months. The serum levels of IL-1β, high-sensitivity C-reactive protein (hs-CRP), TNF-α and erythrocyte sedimentation rate (ESR) were measured before and after 3 months of treatment. Results: Telmisartan when used in combination with naproxen resulted in significant decrease in serum levels of IL-1β and hs-CRP, higher than that produced by naproxen when used alone. The mean TNF-α level and ESR was decreased non-significantly in both study groups. Conclusion: Administration of telmisartan as an adjuvant therapy to naproxen in knee OA patients produced a significant decrease in the serum levels of IL-1β and hs-CRP, though no clear effect on TNF-α and ESR was noticed after 3 months treatment. Accordingly, many promising preventive strategies emerged from the available results since telmisartan relatively reduce the inflammatory burden in OA patients. The dose and duration of telmisartan treatment in this study did not indicate a risk of hypotension. Keywords: Telmisartan, naproxen, osteoarthritis, cytokines Citation: Hmood SA, Mohammed MM, Kamal YM, Jasim NA. Evaluation of the anti-inflammatory effect of telmisartan as an adjuvant therapy to NSAID in the management of knee osteoarthritis; a clinical prospective study. Iraqi JMS. 2018; Vol. 16(1): 100-110. doi: 10.22578/IJMS.16.1.14

Telmisartan ameliorates vascular endothelial dysfunction in coronary slow flow phenomenon (CSFP).

Coronary slow flow phenomenon (CSFP) is a coronary microvascular disorder with an increasing morbidity, and currently, available therapies are of limited clinical value for its cure. Hence, it is urgent to find a novel approach to CSFP treatment. Several studies show that endothelial dysfunction plays a critical role in the aetiology of CSFP. Telmisartan (TMST) is a clinically available anti-hypertensive medicine and has shown its potential properties for improving vascular endothelial function. Thus, we aimed to investigate the effect of TMST on endothelial dysfunction in CSFP, Endothelial-dependent flow-mediated vasodilation, serum levels of nitric oxide, adiponectin, and endothelin-1 were surveyed before and after 3months of TMST treatment. And the percentages of vasodilator response to acetylcholine (Ach) were detected after 12weeks of TMST treatment. Compare with pretreatment, flow-mediated vasodilation, nitric oxide, and adiponectin were substantially improved after TMST treatment; meanwhile, endothelin-1 was decreased in the TMST group (all P<.01). Compared with the model group, the vasodilator response to Ach was enormously increased after TMST intervention. Additionally, administration of SU11274 or GW9662 would partially reverse the protective effects of TMST on accumulative concentration-vasodilator responses to Ach (P<.01). We demonstrated that administration of TMST could remarkably increase the mRNA and/or protein levels of hepatocyte growth factor, mesenchymal-epithelial transition factor, peroxisome proliferation-activated receptor γ, whereas dramatically diminish mRNA and/or protein levels of p-JNK1/2, mitogen-activated protein kinase, and nuclear factor kappa B (P<.05). Our results thus implicate that TMST ameliorates endothelial dysfunction in CSFP. It is suggested that TSMF may play an important role in the medication of CSFP.

Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice

Traumatic brain injury (TBI) causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group) underwent sham or unilateral controlled cortical impact (CCI) injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. Expressions of several genes important for brain glucose utilization were determined by qRT-PCR. In results, (1) mRNA levels of three key enzymes in glucose metabolism [hexo kinase (HK) 1, pyruvate kinase, and pyruvate dehydrogenase (PDH)] were all increased 6 h after injury in the contralateral cortex, followed by decreases at subsequent times in the ipsilateral cortex and hippocampus; (2) capillary glucose transporter Glut-1 mRNA increased, while neuronal glucose transporter Glut-3 mRNA decreased, at various times in the ipsilateral cortex and hippocampus; (3) astrocyte lactate transporter MCT-1 mRNA increased, whereas neuronal lactate transporter MCT-2 mRNA decreased in the ipsilateral cortex and hippocampus; (4) HK2 (an isoform of hexokinase) expression increased at all time points in the ipsilateral cortex and hippocampus. GPR81 (lactate receptor) mRNA increased at various time points in the ipsilateral cortex and hippocampus. These temporal alterations in gene expression corresponded closely to the patterns of impaired brain glucose utilization reported in both TBI patients and experimental TBI rodents. The observed changes in hippocampal gene expression were delayed and prolonged, when compared with those in the cortex. The patterns of alterations were specific to different brain regions and exhibited different recovery periods following TBI. Oral administration of telmisartan (1 mg/kg, for 7 days, n = 10 per group) ameliorated cortical or hippocampal mRNA for Glut-1/3, MCT-1/2 and PDH in CCI mice. These data provide molecular evidence for dynamic alteration of multiple critical factors in brain glucose metabolism post-TBI and can inform further research for treating brain metabolic disorders post-TBI.