Losartan Research Articles

UK MHRA recalls contaminated losartan, irbesartan batches

UK MHRA recalls contaminated losartan, irbesartan batches

Amlodipine interfere in serum albumin binding of loasrtan and its active metabolite losartan carboxylic acid (EXP- 1734): Contra-contemporary in vitro approaches

The combination therapy of Losartan (LOS) and amlodipine (AMLO) has proven to be beneficial as compared to either individual drug monotherapy. Nonetheless, the mechanism of a beneficial effect is yet to be established. Conversely, displacement in protein binding may lead to change in free drug concentration. The selected analytes were effectively separated on Thermo β-basic C18 (100×4.6 mm, 5 µm) using mobile phase consisting of 20 mM monobasic potassium phosphate and 0.2 % TEA with acetonitrile and iso-propyl alcohol in gradient mode. The in vitro protein binding experiments were performed under simulated physiological conditions using ultrafiltration as drug-protein binding model and displacement interactions were observed. Amlodipine, losartan and LCA bind more than 95 % to recombinant human serum albumin (rHSA), when studied individually, whereas, protein binding of LCA and Losartan carboxylic acid (LCA) were not affected when spiked concomitantly with AMLO, whereas, binding of Amlodipine to rHSA was decreased by 15-20 % under similar conditions at supra pharmacological concentration level of LOS and LCA. In in-vitro experiments about three to five fold increase in free AMLO concentration was observed in ultrafiltrate in presence of LOS and LCA. The albumin binding capacity of all the analytes was reduced nearly seven to eight-fold in the case of Glycosylated Human serum albumin (Gly-HSA). The in vitro protein binding studies with Gly-HSA have shown alteration in the corresponding albumin binding of AMLO, LOS and LCA.

UV-Vis LED-assisted photo-Fenton process for mineralization of losartan and hydrochlorothiazide: optimization using desirability function.

This study presents the results obtained for the optimization of the mineralization of losartan (LOS) and hydrochlorothiazide (HCTZ) using the photo-Fenton process with a UV-Vis LED. Experimental design optimization employing a Doehlert matrix and a global desirability function enabled simultaneous evaluation of multiple responses, with factor fitting providing the best conditions that maximized the mineralization efficiency: Fe2+ at 10 mg L-1 and H2O2 at 100 mg L-1. High rates of mineralization of LOS and HCTZ were obtained, with dissolved organic carbon (DOC); removal of almost 75% after 90 min was observed for both pharmaceuticals. The kinetic model showed that the mineralization followed two regimes in the first minutes, with a fast progression followed by slower activity. The energy consumption calculated for mineralization of LOS and HCTZ at a concentration of 20 mg L-1 using the UV-Vis LED-assisted photo-Fenton process, at 60 min, was 130 kWh m-3. The desirability function provides a useful tool for finding optimal experimental conditions for the treatment of effluents with different characteristics. The UV-Vis LED was shown to be a good light source in the photo-Fenton process.

Treatment of two sartan antihypertensives in water by photo-electro-Fenton using BDD anodes: Degradation kinetics, theoretical analyses, primary transformations and matrix effects

Degradation of two representative antihypertensives, losartan (LOS) and valsartan (VAL) in water by photo-electro-Fenton (PEF), using a BDD anode in presence of sulfate anion was evaluated. PEF showed a fast elimination of these pollutants (>95% at 30 and 60 min of treatment for LOS and VAL, respectively). The main elimination route was the attacks of radicals produced in the system, having pseudo-first-order rate constants of 0.154 and 0.054 min−1 for LOS and VAL, correspondingly. Theoretical analyses of atomic charges were performed to rationalize the antihypertensives reactivity toward the electrogenerated degrading agents. Afterwards, the primary transformation products were assessed. The transformation products revealed that the degrading species attack the biphenyl-tetrazole, imidazole, and alcohol moieties on LOS. Meanwhile, carboxylic and amide groups, plus the central nucleus, were modified on VAL. These moieties corresponded well with the electron-rich sites indicated by the theoretical calculations. Also, the PEF process removed between 33 and 38% of total organic carbon after 5 h of electrolysis. Finally, it was considered LOS treatment in presence of oxalic acid (a typical organic waste of pharmaceutical industry), in addition to the pollutant degradation in effluents from municipal sewage treatment plants by PEF at pH ∼5. Oxalic acid accelerated LOS degradation. Meanwhile, in the effluent, the process led to 64% of LOS removal after 120 min of treatment, indicating the high potentiality of PEF to degrade antihypertensives in water containing organic and inorganic substances.

Development of a Novel Nanocomposite Based on Reduced Graphene Oxide/Chitosan/Au/ZnO and Electrochemical Sensor for Determination of Losartan

Background: Hypertension is a major risk for morbidity and mortality, while hypertension is associated with cardiovascular disease and organ damage. Recent research efforts have focused on the development of highly selective angiotensin receptor blockers. In which losartan (LOS) is considered as a new generation of an effective oral drug product against arterial hypertension. Therefore, the determination of drugs in biological fluids, pharmaceuticals (tablets), and wastewater is of critical importance for clinical applications, forensics, quality control, and environmental protection that call for the development of analytical methods. Many ranges of methods such as spectroscopic methods and chromatographic techniques have been developed to determine LOS in pharmaceutical formulations and biological fluids. However, there are crucial interference problems in these methods. For these reasons, more sensitive, desirable, portable, low-cost, simple, and selective nanocomposite-based sensors are needed in terms of health safety. Nanomaterials such as reduced graphene oxide, chitosan, and metal nanoparticles are used to improve the sensitivity in the development of electrochemical sensors. Objective: In this study, a novel reduced graphene oxide (RGO), chitosan (Chit), gold (Au), and zinc oxide (ZnO) nanocomposite (RGO/Chitosan/Au/ZnO) was synthesized and used to develop a sensitive and efficient electrochemical sensor for LOS detection. Methods: Modification of electrode by RGO/Chit/Au/ZnO nanocomposite was performed in four stages with GO (at -2.0 V for 150 s), Chitosan (at -3.0 V for 300 s), Au nanoparticles (at -0.4 V for 400 s), and Zn nanoflowers like (at -0.7 V for 1200 s). The RGO/Chitosan/Au/ZnO nanocomposite was characterized by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR). Cyclic Voltammetry (CV) and Differential Pulse Voltammetry (DPV) were used to detect LOS, and the influence of pH value, scan rate, accumulation potential, and time also losartan concentration on the performance of ZnO/Au/Chitosan/RGO/GCE were investigated. In order to investigate the selectivity of the modified electrode for the determination of LOS, the effect of possible interfering species was evaluated and showed that these species are not interferences. Also, the reproducibility of the modified electrode was investigated and implying that the RGO/Chit/Au/ZnO nanocomposite was highly reproducible. Results: The modified electrode was used as a sensor for the selective and sensitive determination of LOS with a detection limit of 0.073 μM over the dynamic linear range of 0.5μM to 18.0 μM. In addition, electrochemical oxidation of LOS was well recovered in pharmaceutical formulations. Conclusion: LOS is used to treat high blood pressure, taking into account the oxidation of this compound, the use of electrochemical based sensors, ideally suited to a specific chemical species, can be fully selectable and High-sensitivity answer is very important. In this study, the electrodes with RGO/Chit/Au/ZnO nanocomposite were modified by the electrochemical method. Nanocomposites were characterized by various methods such as FE-SEM, FT-IR, XRD, Raman, and XPS. The electrocatalytic activity of the modified electrode was then investigated for measuring LOS. According to the results of the modified electrode, high sensitivity, reproducibility, and selectivity have been shown to oxidize this composition.

Simultaneous Determination of Losartan and Rosuvastatin in Rat Plasma Using Liquid Chromatography–Tandem Mass Spectrometric Technique for Application into Pharmacokinetic and Drug–Drug Interaction Studies

The combined therapy benefits of losartan and rosuvastatin, within the vascular injury, have been well characterized. Nonetheless, the pharmacokinetic interactions between such therapeutic agents have not been yet figured out, making the need for a sensitive analytical technique to be of great significance. In view of this, a highly selective, sensitive, and well-validated liquid chromatography–tandem mass spectrometric technique has been developed for the simultaneous estimation of losartan (LOS) and rosuvastatin (ROS) within the rat plasma using simvastatin as an internal standard. The proposed technique adopted a simple plasma protein preparation by acetonitrile for the extraction and purification of the drug-plasma samples obtained from the rat animal models. A separation process on the Agilent™ Eclipse-Plus® (C18, 0.46 × 15 cm, 3.5 μm) columns was conducted using gradient mobile phase system comprising of water/0.1%w/v formic acid and acetonitrile at 0.9 mL min−1 flow rate. Precursor quantification into production was performed using the multiple reaction monitoring within the positive-ionization mode. Method linearity was obeyed within 1–5000 ng mL−1 for both LOS and ROS, while the validation process was performed according to the guidelines adopted by the US-FDA bioanalytical framework. The pharmacokinetic interactions after oral co-administration of both drugs furnished significant changes within their respective pharmacokinetic parameters including peak-plasma concentration, elimination t1/2, AUC, volume of distribution, and plasma clearance. Additionally, a mutual competitive displacement for each drug from their plasma albumin bindings showed a significant impact on drug's pharmacokinetic profile and was demonstrated through molecular modeling investigations. Finally, the presented study laid an evidence for a two-way pharmacological synergism with the combined therapy of LOS and ROS via increased hepatic influx of ROS and peak-plasma concentration of EXP3174, the LOS more potent metabolite. Therefore, the proposed method provides a useful tool for the drug–drug interaction investigations being valuable for prospective bioequivalence studies and therapeutic drug monitoring.

Losartan and azelastine either alone or in combination as modulators for endothelial dysfunction and platelets activation in diabetic hyperlipidemic rats

The present study aimed mainly to demonstrate the effect of the antihistamine azelastine (AZ) and Angiotensin receptor blocker ( ARB), represented by losartan (LOS) either alone or in combined form on certain metabolic aspects, endothelial dysfunction and platelets activation markers in diabetic hyperlipidemic rat model. Rats were randomly classified to five groups: One group fed normal chow diet (NC). Four groups received alloxan and CCT-diet. One group received no treatment (DHC while the other three groups received AZ, LOS and their combination form, respectively for 8weeks. Serum and tissue samples were collected for biochemical and histological evaluations. DHC rats demonstrated significant hyperglycaemia, dyslipidemia, disturbances in endothelial and platelet activation markers. AZ or LOS administration demonstrated hypoglycaemic and hypolipidemic effects. VCAM-1 and sE-selectin (Endothelial function markers) along with CD63 (Platelet activation marker) showed significant decrease as compared to control group. AZ administration exerted little prominent effects than that of LOS, while their combination demonstrated remarkable changes compared to monotherapy. Histopathological findings were in agreement to certain extent with the biomarkers results. Both drug categories may be expressed as suitable therapeutic tools for atherosclerotic complications either alone or along with other hypolipidemic drugs.

Reversion of cardiovascular remodelling in renovascular hypertensive 2K-1C rats by renin-angiotensin system inhibitors.

Evaluate whether the RAS dual blockade would induce additional beneficial effects on cardiovascular remodelling when compared to monotherapy in renal hypertensive two kidneys-one clip (2K-1C) rats. Hypertensive 2K-1C and normotensive (2K) rats were treated for 14days with submaximal doses of losartan (LOS), enalapril (ENA), losartan plus enalapril (LOS+ENA) or vehicle (water). Blood pressure and some parameters of cardiovascular remodelling were evaluated. Systolic blood pressure (SBP) was higher in 2K-1C (209±3mmHg, P<.05) than in 2K (113±1mmHg) rats. There was an additional effect in 2K-1C treated with LOS+ENA (153±9mmHg) on lowering SBP when compared to LOS (184±12mmHg) or ENA (177±9mmHg). None of the treatments had effect on SBP in 2K rats. In 2K-1C, cardiomyocyte hypertrophy was reduced by all treatments, although the cardiac hypertrophy indexes remained unchanged. 2K-1C aortas presented medial thickening that was partially reduced by the treatments. Intimal hyperplasia observed in 2K-1C (15.56±0.89µm vs 8.24±0.80µm) was reversed by ENA (9.52±0.45µm) or LOS+ENA (8.17±0.53µm). Collagen deposition was increased in 2K-1C hearts (1.77±0.16 vs 1.28±0.09) and aortas (8.1±0.6 vs 5.2±0.2). Treatment with LOS reduced (1.12±0.14%) and ENA (0.81±0.11%) or LOS+ENA (0.86±0.11%) additionally diminished collagen only in 2K-1C hearts. Submaximal doses of ACEi and/or ARB have inhibitory actions on cardiac remodelling and vascular hypertrophy not entirely dependent on their effects on blood pressure normalization in renovascular hypertensive rats. Combined therapy produced additional reduction in blood pressure than monotherapy despite a similar inhibition on cardiovascular remodelling.

The therapeutic potential of losartan in lung metastasis of colorectal cancer.

Colorectal cancer (CRC) is a common cancer with a high incidence rate. Components of the renin-angiotensin system (RAS) have been reported to be dysregulated in several malignancies including CRC. Here, we have explored the potential anti-metastatic effects of a RAS inhibitor, losartan, in an experimental model of lung metastasis in CRC. A murine model of lung metastasis of CRC was used, which involved the intravenous injection of CT26 cells via a tail vein. Four experimental groups comprised: an untreated group; a group that received 5-FU which was administered intraperitoneally; a losartan group and a combination group that received 5-FU plus losartan. We evaluated the anti-inflammatory effects of losartan by histopathological method, and the measurement of oxidative or antioxidant markers including malondialdehyde (MDA) and total thiol (T-SH) tissue levels, superoxide dismutase (SOD) and catalase activity. We found that losartan inhibited lung metastasis of CRC and there was a reduction of the IL-6 expression level in the tissue sample. It was also associated with reduced levels of the anti-angiogenic factor vascular endothelial growth factor (VEGF). Furthermore, we found that losartan induced oxidative stress as assessed by an elevation of MDA level, reduction of T-SH, SOD and catalase activities in lung tissue. Our findings demonstrated that losartan ameliorates angiogenesis, inflammation and the induction of oxidative stress via angiotensin II type I receptor (AT1R). This may shine some lights on targeting the RAS pathway as a potential therapeutic approach in the treatment of metastatic CRC patients.

MO033THE DUAL ETAR/AT1R BLOCKER SPARSENTAN SLOWS RENAL DISEASE, IMPROVES LIFESPAN, AND ATTENUATES HEARING LOSS IN ALPORT MICE: COMPARISON WITH LOSARTAN

Abstract Background and Aims In Alport syndrome (AS), endothelin type A receptor (ETAR) activation plays a role in both renal and inner ear pathologies. Currently, angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor (AT1R) blockers are the standard of care for patients with AS; however, these drugs have not been shown to improve hearing. Previously, we showed that sparsentan (SP), a dual ETAR/AT1R inhibitor, prevented increases in proteinuria, fibrosis, glomerulosclerosis, and glomerular basement membrane dysmorphology. The AS mouse model lifespan was extended when SP treatment was started at 3 weeks (W) of age (pre-proteinuric). Here we compare the effect of SP and the AT1R blocker losartan (LS) on lifespan and proteinuria in AS mice treated from 4 W, and on hearing loss and associated inner ear pathology in AS mice treated from 3 W to 8.75 W. Method Wild type (WT) and AS mice were treated daily with vehicle (V), 60, 120, or 200 mg/kg SP (SP60, SP120, or SP200) by oral gavage, or 20 mg/kg LS by daily oral gavage from 3-4 W of age and in drinking water at 10 mg/kg from 4-8.75 W. Three studies were conducted: early intervention for hearing from 3-8.75 W (V, SP120, and LS, n=5) or for assessment of laminin α2, laminin α5, and collagen IVα1 expression in stria vascularis from 3-7 W (V, SP200, and LS, n=7), and for lifespan with treatment from 3 W (V, n=10) or from 4 W (LS, SP60, or SP120, n=5). Urinary protein/creatinine (UP/C) was assessed weekly during the lifespan study. In the hearing study, the auditory brainstem response (ABR) assessed hearing ability and sensitivity to noise at 8-9 W (n=5). The cochleae were preserved and transmission electron microscopy was used to assess severity of strial pathology and to measure strial capillary basement membrane (SCBM) thickness (n=5-7). Accumulation of extracellular matrix in SCBM was determined in mice treated with V, SP200, or LS by immunofluorescence microscopy using antibodies to laminin α2, laminin α5, or collagen IVα1. Results In AS mice treated with SP from 4 W, SP120 significantly (P&amp;lt;0.05) increased median lifespan by 34 days compared to LS-treated mice, and by 50.5 days compared to V-treated mice (Figure 1). AS mice treated with SP60 or LS initiated at 4 W did not have a significant difference in lifespan compared to V. At 8 W, SP120 but not SP60 or LS significantly (P&amp;lt;0.05) attenuated the increase in UP/C compared to V (UP/C mg/mg mean±SD 8 W: 47±16 V; 31±6 LS; 61±44 SP60; 20±3 SP120). Notably, development of UP/C at 11 W in AS-SP120 mice was significantly attenuated (P&amp;lt;0.05) compared to that in AS-LS mice (UP/C mg/mg mean±SD 11 W: 58±8 LS; 77±51 SP60; 18±10 SP120). In hearing studies, although both SP120 and LS significantly (P&amp;lt;0.05) prevented SCBM thickening compared to AS-V mice (mean SCBM width±SD nm: 57.8±2.1 WT-V; 67.6±5.5 AS-V; 54.7±2.4 AS-SP120; 55.0±5.9 AS-LS), post-noise ABR thresholds at 16 kHz were significantly improved only in AS-SP120 mice compared to AS-V mice (*P&amp;lt;0.05; Figure 2). AS-LS post-noise hearing did not differ from that of AS-V mice. Moreover, SP200 tended to ameliorate increases in expression levels of laminin α2, laminin α5, and collagen IVα1 to a greater extent than LS in the SCBM of AS mice. Finally, dysmorphology of the stria vascularis was noted in LS but not SP120-treated AS mice. Conclusion SP120 provided significant nephroprotection in AS mice when treatment was started at 4 W, significantly extending lifespan beyond that of mice treated with LS while delaying the development of proteinuria. SP120 treatment in AS mice reduced the SCBM width. Moreover, SP120 treatment significantly attenuated noise-induced hearing loss in AS mice whereas LS was without effect. These pre-clinical studies, if successfully translated to the clinic, may suggest that sparsentan offers a novel, dual-therapeutic approach in AS by reducing both renal injury and hearing loss.

P0685RENAL SUBCAPSULAR ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (ASC) ADMINISTRATION, ASSOCIATED TO LOSARTAN TREATMENT, PREVENTED THE PROGRESSION OF RENAL DAMAGE IN AN EXPERIMENTAL MODEL OF CHRONIC KIDNEY DISEASE (CKD)

Abstract INTRODUCTION / AIMS Chronic kidney disease (CKD) is considered a public health problem with epidemic proportions worldwide. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to the establishment of a chronic self-sustained renal inflammation, are the main factors which contribute to the progression of CKD, leading to tissue fibrosis and loss of function. Consequently, RAAS inhibitors, such as the AT-1 receptor antagonist, Losartan, are among the most currently employed therapeutic strategies to slow down CKD progression, although the renoprotection afforded by these drugs is not complete. The association of anti-inflammatory and immunosuppressive drugs to RAAS inhibition is limited to the treatment of specific nephropathies, and its safety is still not entirely known. In this context, experimental application of mesenchymal stem cells (mSC) as a treatment to control renal inflammation and fibrosis have been showing promising results in studies with animal models of CKD. The aim of the present study was to analyze the renoprotective effects of subcapsular application of adipose-tissue derived mSC (ASC), associated to Losartan treatment, in rats submitted to 5/6 nephrectomy, after the establishment of CKD. METHODS ASC were isolated from gonadal adipose tissue from male Wistar rats, cultured until P4 and characterized by flow cytometry and in vitro differentiation. Male Wistar rats underwent 5/6 nephrectomy and were followed for 15 days to confirm the establishment of the nephropathy (CKD 15d). After this period, animals underwent a new surgery in which they received a subcapsular injection of 10 μL of sterile PBS (vehicle), or 2x106 ASC diluted in 10 μL of sterile PBS. Part of these animals were than treated orally with 50 mg/kg/day of Losartan (LOS) for further 15 days (groups CKD + LOS 30d and CKD + LOS + ASC 30d). A group of animals that received only subcapsular vehicle were kept untreated for the same period (CKD 30d). Sham-operated rats, euthanized at days 15 (Sham 15d) and 30 (Sham 30d), were used as controls. Survival rate, body weight (BW), systolic blood pressure (BP), 24h urinary protein (24h UPE) and albumin (24h UAE) excretion, serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations, percentage (GS%) and index (GSI) of glomerulosclerosis, percentage of tubulointerstitial fibrosis (INT%) and renal infiltration by macrophages (CD68) were assessed 15 and 30 days after 5/6 nephrectomy. The obtained results are presented as Mean ± SE. Differences among groups were analyzed by one-way ANOVA. RESULTS The renal subcapsular application of ASC after the establishment of severe CKD improved the renoprotection obtained with the classic treatment with LOS. The association of LOS + ASC significantly improved animal’s survival, reduced blood pressure, proteinuria and albuminuria, prevented the development of glomerular structural damage and interstitial fibrosis, and inhibited renal inflammation by normalizing renal macrophage infiltration in the CKD + LOS + ASC group. CONCLUSIONS Our preliminary results demonstrate that the application of ASC, associated to the oral administration of LOS exerted additional renoprotection in the 5/6 renal ablation model, compared to LOS monotherapy. These findings suggest that ASC therapy could be employed as a therapeutic additive together with the traditional RAAS blockade, to detain the progression of CKD.

Analytical Methods for the Determination of Sartans in Pharmaceutical Formulations and Biological Fluids: A Review

Background:Sartans are mostly used as a part of combination with additional medicines in the therapy of essencial hypertension. Preferred combinations are ARB and thiazide diuretics (Hydrochlorothiazide (HCT) and Chlorthalidone (CHL)) or ARB and calcium antagonists. The number of sartans mostly prescribed by specialists is only seven - Candesartan (CDS), Eprosartan (EPS), Irbesartan (IBS), Losartan (LOS), Olmesartan (OMS), Telmisartan (TMS) and Valsartan (VLS).Methods:The widespread use of sartans in the treatment of hypertension requires reliable methods of analysis. Bulk drugs and pharmaceutical preparations should be analyzed to ensure the quality of the medicinal products reaching patients. On the other hand, the analysis of drugs in biological fluids aims to trace and improve patient care by adjusting the therapeutic doses of drugs. According to our knowledge, a review devoted to the analysis of sartans was published in 2014.Results:Spectral methods are widely used in the analysis of bulk drugs and pharmaceutical dosage forms due to their relatively simple procedures, low reagent and sample consumption, speed, precision and accuracy combined with accessibility and comparatively low cost of common apparatus. Many papers for determination of sartans in bulk drugs and pharmaceutical preparations based on liquid chromatographic techniques were published in the available literature. Among these methods, HPLC takes the leading place but UPLC and HPTLC are also present.Conclusion:The widespread use of sartans in the treatment of hypertension requires reliable methods of analysis. Bulk drugs and pharmaceutical preparations should be analyzed to ensure the quality of the medicinal products reaching patients. On the other hand, the analysis of drugs in biological fluids aims to trace and improve patient care by adjusting the therapeutic doses of drugs. Since 2014, many articles have been published on the sartans analysis and this provoked our interest to summarize the latest applications in the analysis of sartans in pharmaceutical formulations and biological media. Articles published from 2014 to 2018 are covered.

Electrochemical Behavior and Voltammetric Determination of Losartan Using Carbon Ceramic Electrode Modified with Room Temperature Ionic Liquid

Herein, an electrochemical sensor has been proposed for the determination of losartan (LOS) in pharmaceutical formulations. A room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM.PF6) was applied to fabricate a modified carbon ceramic electrode (IL-CCE). The electrochemical studies were performed by the cyclic and linear sweep voltammetry (CV and LSV), chronoamperometry and electrochemical impedance spectroscopy (EIS) techniques. The anodic peak currents were increased with the LOS concentration and indicated a linear dynamic range from 20 to 200 μM and a detection limit of 11.7 μM (S/N = 3) under the optimized conditions. Satisfactory results were obtained by analysis of LOS in pharmaceutical tablets.

LONG-TERM STUDY OF ERYTHROPOIETIN, LOSARTAN, AND COMBINATION IN STREPT- OZOTOCIN-INDUCED DIABETIC RATS

Recombinant human erythropoietin(rHuEPO) has emerged as a newrenoprotectiveagent against variousacutekidney injuries. ExperiencewithrHuEPO in chronic kidney injuriesis so far limited and conflictingresultswere obtained. In the presentstudy,we addressed to evaluate thelong-termrenal effects of rHuEPO indiabeticnephropathy (DN) of rats inrelationto novel hypoxia theory andendogenousEPO secretion. WecomparedrHuEPO to a standarddrug,losartan (LSR), and the possibilityof add-on therapy was alsotested.Thirty-four male SpragueDawleyrats were randomly dividedintofive groups: control-naive group,untreateddiabetic group, EPO- treated diabetic group (150 U/kg,S.C., TIW), LSR-treated diabeticgroup (5 mg/kg/day), and EPO-LSRtreateddiabetic group. Drug treatmentwas started one week afterstreptozotocin(STZ) injection andcontinuedfor twenty-eight weeks.STZ-treateddiabetic rats developedprogressivealbuminuria, renal dysfunction,and significant glomerularchange28 weeks after induction ofdiabetes.Chronic administration ofrHuEPOalone or in combination withLSRto the STZ-induced diabetic ratdidnot show beneficial effect on DNevolution,inspite of improving diabetic-renalhypoxia. The best beneficialeffect on DN evolution was obtainedby LSR sole therapy based onrenalfunction evaluation, albuminu- ria, and renal histopathology. Interestingly,administration of LSR eitheraloneor in combination with rHuEPOinSTZ-induced diabetic rats significantlyabolished increased plasmaendogenousEPO. In conclusion, thisstudyhas questioned the renoprotectiverole of low-dose rHuEPO inthesetting of DN and confirmed thatthislow-dose rHuEPO used had adverseeffects on blood pressure andincreasedhematocrit level.

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.

Green preparation of dual-template chitosan-based magnetic water-compatible molecularly imprinted biopolymer

In the current study, a green method was used for the fabrication of dual-template chitosan-based magnetic water-compatible molecularly imprinted biopolymer in water without using organic and toxic reagents and then, its application as a sorbent for the simultaneous pre-concentration and determination of valsartan (VAL) and losartan (LOS) from urine samples followed by HPLC-UV.Chitosan was used as a multi-functional monomer due to its unique properties in terms of non-toxic, cost-effectiveness, readily available, biocompatible, biodegradable and easy to polymerize in mild condition. The proposed sorbent represents the exceptional properties in terms of green synthesis, high magnetic strength, bio-compatibility, high selectivity, fast equilibrium adsorption as well as high adsorption capacity. In the optimized conditions, the developed MMIP-DMSPE-HPLC/UV method showed a wide linear range of 5.0 − 1500.0 μg L−1 for VAL and 8.0 − 1500 μg L−1 for LOS and low LODs of 1.4 and 2.3 μg L−1 for VAL and LOS, respectively with RSD% values less than 5.0, (n = 5). The obtained recoveries were 95.6–100.2 % for VAL and 92.0–98.1 % for LOS which showed the applicability of green, water-compatible and bio-compatibility of the proposed method for neat and selective extraction of VAL and LOS from complicated urine samples.

UV-assisted chemical oxidation of antihypertensive losartan in water

Population growth and deteriorating health issues have led to an increase in the consumption of angiotensin receptor blockers (ARBs), such as losartan (LOR), for treating high blood pressure and, as a result, to the frequent detection of these drugs in water and wastewater. The present study focuses on the oxidation of LOR by UV photolysis, UV(/Fe2+)-activated persulfate (PS) and hydrogen peroxide (H2O2) systems. The effects of operating parameters including pH value, reaction time, concentration of oxidant and activator on the efficacy of treatment were studied. The target compound degradation by direct UV photolysis, UV/PS and UV/H2O2 systems proved to be efficient and followed a pseudo-first-order kinetic model. The application of UV/oxidant systems even at lower PS or H2O2 concentrations resulted in more than 95% of LOR degradation in 10 min. In addition, the use of UV/Fe2+-activated oxidant systems led to a further increase in the kobs by improving the LOR oxidation in aqueous solution. The effectiveness of LOR mineralization based on total organic carbon (TOC) removal was also considered. The optimized results of the studied systems obtained in ultrapure water were used in groundwater to assess the effectiveness of LOR decomposition in more complex environmental matrix. Moreover, the acute toxicity of LOR solutions before and after the UV/Fe2+-activated PS and H2O2 oxidation to luminous bacteria (Vibrio fischeri) was investigated.

Renohemodynamic Effects of Combined empagliflOzin and LosARtan

Renohemodynamic Effects of Combined empagliflOzin and LosARtan

Renin angiotensin system blockage by losartan neutralize hypercholesterolemia-induced inflammatory and oxidative injuries

ABSTRACT Objectives: This study explores the protective role of losartan (LT) against oxidative and inflammatory damages in different physiological systems including heart, liver, and kidney tissue in hypercholesterolemic rats. Methods: After induction of hypercholesterolemia by high cholesterol diet for 6 weeks, LT was administered for 4 weeks. In serum, the levels of lipoproteins, aminotransferases, creatine kinases, urea, apoptosis, and inflammatory markers were measured. In cardiac, hepatic, and renal tissues, lipid peroxidation product and GSH as well as antioxidant enzymatic activities were assayed. Finally, histopathological assessment evaluated the structural damage in cardiac, hepatic, and renal tissues. Results: Serum markers of cardiac, hepatic, and renal toxicities including creatine kinases, aminotransferases, and urea were attenuated by LT in hypercholesterolemic animals. Moreover, LT markedly corrected the elevated levels of lipoproteins, apoptosis, and inflammatory biomarkers. Hypercholesterolemia-induced lipid peroxidation, low GSH levels, and diminished activities of antioxidant enzymes were prominently improved in LT treated animals. Histopathological alterations by hypercholesterolemia in heart, liver, and kidney tissues were ameliorated by LT. Conclusion: This study confirmed the pathological enrollment of renin–angiotensin system in hypercholesterolemia-associated metabolic alterations. LT had a significant cardiac, hepatic, and renal protective role against these impairments through down-regulation of oxidative damage, inflammation and necrosis.

Management of Dilated Cardiomyopathy with Enalapril and Losartan

Management of Dilated Cardiomyopathy with Enalapril and Losartan