Losartan Research Articles

UPLCMS Method Development and Validation of Amlodipine, Hydrochlorthiazide and Losartan in Combined Tablet Dosage Form

A simple, rapid, sensitive and specific UPLCMS method was developed and validated following ICH guidelines for simultaneous estimation of tablet dosage form containing amlodipine (AMLO) hydrochlorothiazide (HCT) and losartan (LOSAT) using telmisartan (TELMI) as an internal standard (IS). The separation was achieved using Waters ACQUITY BEH C18 (1.7 μm, 2.1 × 50 mm) column with gradient mode, mobile phase containing acetonitrile (A) & 1% ammonium acetate (B) pH adjusted to 2.8 with trifluoro acetic acid with gradient mode. The flow rate was 0.4 mL·mL﹣1 and the injection volume 2 μl. The retention time for amlodipine, hydrochlorothiazide and losartan was found to be 3.7, 2.5 and 3.9 min, respectively. The developed method was found to be linear over the concentration range of 50 - 300 ng·mL﹣1, 125 - 750 ng·mL﹣1 and 500 - 3000 ng·mL﹣1 for AMLO, HCT and LOSAT respectively. The signal intensities obtained in ion mode for amlodipine, hydrochlorothiazide, losartan and telmisartan (IS) they were found to be much higher positive ion mode (M+)﹣ parent ion at m/z, 409.02, 297.97, 422.91 and 515.03, respectively, in QUATTROZQ full scan mass spectra.

Simultaneous analysis of losartan, its active metabolite, and hydrochlorothiazide in human plasma by a UPLC-MS/MS method

A selective and sensitive ultra performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of losartan (LOS), EXP-3174, which is an active metabolite LOS carboxylic acid, and hydrochlorothiazide (HCTZ) in human plasma. Solid-phase extraction was carried out on Oasis HLB cartridges with 100 $\mu $L of plasma to give an extraction recovery in the range of 88.5%-102.5% for the three analytes. Chromatography on a BEH C18 column afforded baseline separation of all the analytes within 2.4 min using 1.0% formic acid in water and acetonitrile (15:85, v/v) as the mobile phase. Quantitation was performed with multiple reaction monitoring in the negative ionization mode. The response of the method was linear over a dynamic range of 0.5-500, 1.0-750, and 0.25-150 ng/mL for LOS, EXP-3174, and HCTZ, respectively. Extent of signal suppression/enhancement was examined through postcolumn infusion. The effect of matrix components was evaluated by postextraction spiking and calculation of the slope of calibration lines. The method was successfully applied to a bioequivalence study of 50 mg losartan and 12.5 mg hydrochlorothiazide tablet formulation in 65 healthy human subjects. Reproducibility of the method was shown by reanalysis of 213 incurred samples.

The Blocking on the Cathepsin B and Fibronectin Accumulation in Kidney Glomeruli of Diabetic Rats.

Hyperglycemia results in the activation of tissue angiotensin II. Angiotensin II stimulates the synthesis of ECM proteins and causes a decrease activity of proteolytic enzymes. The aim of this study was to assess the impact of multilevel blocking of the RAAS, cathepsin B activity, and fibronectin accumulation in the glomerular in the rats diabetes model. Sixty male Wistar rats were initially included. Diabetes was induced by intravenous administration of streptozotocin. The animals were randomized to six groups of ten rats in group. Rats in the four groups were treated with inhibitors of the RAAS: enalapril (EN), losartan (LOS), enalapril plus losartan (EN + LOS), and spironolactone (SPIR); another group received dihydralazine (DIH) and the diabetic rats (DM) did not receive any drug. After six weeks, we evaluated blood pressure, 24 h urine collection, and blood for biochemical parameters and kidneys. In this study, fluorometric, ELISA, and immunohistochemical methods were used. Administration of EN + LOS increased activity of cathepsin B in homogenates of glomeruli compared to DM. Losartan treatment resulted in reduction of the ratio kidney weight/body weight compared to untreated diabetic rats. SPIR resulted in the increase activity of cathepsin B in the homogenate of glomeruli. The values of cathepsin B in the plasma of rats in all studied groups were similar and showed no tendency.

Clinical analysis on losartan potassium and hydrochlorothiazide tablets treating type 2 diabetes mellitus with hypertention

Objective To observe the clinical curative effect and safety of losartan potassium and hydrochlorothiazide tablets on treating type 2 diabetic mellitus with hypertension.Methods 86 patients with type 2 diabetic mellitus and hypertension were divided into the test group and the control group with the method of randomized controlled trials according to randomized controlled table.The control group was treated with losartan potassium tablets and hydrochlorothiazide tablets.The test group was treated with losartan potassium and hydrochlorothiazide tablets.Finally,the clinical curative effects were compared.Results In the total efficiency,the test group was 95.35％,the control group was 81.40％,the test group was significantly better than the control group (P ＜ 0.05).Systolic blood pressure and diastolic blood pressure before treatment had no statistical significant difference (P ＞ 0.05).Systolic blood pressure and diastolic blood pressure after treatment of the two group was lower than that before treatment (P ＜ 0.05).Systolic blood pressure and diastolic blood pressure of the test group was lower than that of the control group (P ＜ 0.05),FPG and P2hBG after treatment of the control group increased,the other groups had no significant changes.The test group was better than the control group (P ＜ 0.05).Conclusion Losartan potassium and hydrochlorothiazide tablets on treating type 2 diabetic mellitus with hypertension has efficient,fast and strong curative effect,with higher safety and less adverse reactions.Losartan potassium and hydrochlorothiazide tablets has less influence on blood glucose.It can improve patients' drug therapy compliance. Key words: Type 2 diabetic mellitus; Hypertension; Losartan potassium tablets; Hydrochlorothiazide tablets; Losartan potassium and hydrochlorothiazide tablets

Simultaneous Determination and Pharmacokinetic Study of Losartan, Losartan Carboxylic Acid, Ramipril, Ramiprilat, and Hydrochlorothiazide in Rat Plasma by a Liquid Chromatography/Tandem Mass Spectrometry Method.

The monitoring of the plasmatic concentrations of cardiovascular drugs is crucial for understanding their pharmacokinetics and pharmacodynamics. A simple, sensitive, specific, and high-throughput liquid chromatography/tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous estimation and pharmacokinetic study of losartan (LOS), losartan carboxylic acid (LCA), ramipril (RAM), ramiprilate (RPT), and hydrochlorothiazide (HCZ) in rat plasma using irbesartan (IBS) and metolazone (MET) as internal standards (ISs). After solid phase extraction (SPE), analytes and ISs were separated on an Agilent Poroshell 120, EC-C18 (50 mm × 4.6 mm, i.d., 2.7 μm) column with a mobile phase consisting of methanol/water (85:15, v/v) containing 5 mmol/L ammonium formate and 0.1% formic acid at a flow rate of 0.4 mL/min. The precursor → product ion transitions for the analytes and ISs were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) mode and switching the electrospray ionization (ESI) mode during chromatography from positive (to detect LOS, LCA, RAM, RPT, and IBS) to negative (to detect HCZ and MET). The method was validated as per the FDA guidelines and it exhibited sufficient specificity, accuracy, and precision. The method was found to be linear in the range of 3–3000 ng/mL for LOS and LCA, 0.1–200 ng/mL for RAM and RPT, and 1–1500 ng/mL for HCZ. The described method was successfully applied to the preclinical pharmacokinetic study of analytes after oral administration of a mixture of LOS (10 mg/kg), RAM (1 mg/kg), and HCZ (2.5 mg/kg) in rats.

High-Salt Intake Induces Cardiomyocyte Hypertrophy in Rats in Response to Local Angiotensin II Type 1 Receptor Activation

Many studies have shown that risk factors that are independent of blood pressure (BP) can contribute to the development of cardiac hypertrophy (CH). Among these factors, high-salt (HS) intake was prominent. Although some studies have attempted to elucidate the role of salt in the development of this disease, the mechanisms by which salt acts are not yet fully understood. Thus, the aim of this study was to better understand the mechanisms of CH and interstitial fibrosis (IF) caused by HS intake. Male Wistar rats were divided into 5 groups according to diet [normal salt (NS; 1.27% NaCl) or HS (8% NaCl)] and treatment [losartan (LOS) (HS+LOS group), hydralazine (HZ) (HS+HZ group), or N-acetylcysteine (NAC) (HS+NAC group)], which was given in the drinking water. Tail-cuff BP, transverse diameter of the cardiomyocyte, IF, angiotensin II type 1 receptor (AT1) gene and protein expression, serum aldosterone, cardiac angiotensin II, cardiac thiobarbituric acid-reactive substances, and binding of conformation-specific anti-AT1 and anti-angiotensin II type 2 receptor (AT2) antibodies in the 2 ventricles were measured. Based on the left ventricle transverse diameter data, the primary finding was the occurrence of significant BP-independent CH in the HS+HZ group (96% of the HS group) and a partial or total prevention of such hypertrophy via treatment with NAC or LOS (81% and 67% of the HS group, respectively). The significant total or partial prevention of IF using all 3 treatments (HS+HZ, 27%; HS+LOS, 27%; and HS+NAC, 58% of the HS group, respectively), and an increase in the AT1 gene and protein expression and activity in groups that developed CH, confirmed that CH occurred via the AT1 in this experimental model. Thus, this study unveiled some relevant previously unknown mechanisms of CH induced by chronic HS intake in Wistar rats. The link of oxidative stress with CH in our experimental model is very interesting and stimulates further evaluation for its full comprehension.

Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro.

Co-administration of anti-hypertension and anti-diabetic drugs is common in clinical settings. In this study, we characterized the drug-drug interactions of losartan (LOS) and glimepiride (GLP) using recombinant cytochrome P450 (CYP) 2C9 enzymes (CYP2C9*1, CYP2C9*3, CYP2C9*13, and CYP2C9*16). Metabolism of losartan by recombinant CYP2C9* 1, CYP2C9*3, CYP2C9*13, and CYP2C9* 16 was inhibited by glimepiride competitively with IC50 values of 0.669 ± 0.055 µM, 0.424 ± 0.032 µM, 2.557 ± 0.058 µM, and 0.667 ± 0.039 µM, respectively. The inhibitory effect of glimepiride on losartan metabolism by CYP2C9*13 was marginal. The apparent Ki value of glimepiride with CYP2C9*3 (0.0416 ± 0.0059 µM) was significantly lower than with CYP2C9*1 (0.1476 ± 0.0219 µM) and CYP2C9*16 (0.2671 ± 0.0456 µM). On the other hand, losartan weakly inhibited the hydroxylation of glimepiride by P450 2C9 enzymes competitively. The potencies for inhibition of glimepiride hydroxylation were determined to be CYP2C9*1~CYP2C9*3~CYP2C9*16 > CYP2C9*13 by 4 µM losartan. No significant inhibition was observed when 0.5 µM losartan was used. Given these results, the potential inhibition of losartan metabolism by CYP2C9*3, CYP2C9*13, and CYP2C9*16 in vivo by glimepiride deserves further investigation. These results may provide valuable information for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.

Evaluation of pharmaceuticals in surface water: Reliability of PECs compared to MECs

Due to the current analytical processes that are not able to measure all the pharmaceutical molecules and to the high costs and the consumption of time to sample and analyze PhACs, models to calculate Predicted Environmental Concentrations (PECs) have been developed. However a comparison between MECs and PECs, taking into account the methods of calculations and peculiarly the parameters included in the calculation (consumption data, pharmacokinetic parameters, elimination rate in STPs and in the environment), is necessary to assess the validity of PECs. MEC variations of sixteen target PhACs [acetaminophen (ACE), amlodipine (AML), atenolol (ATE), caffeine (CAF), carbamazepine (CAR), doxycycline (DOX), epoxycarbamazepine (EPO), fluvoxamine (FLU), furosemide (FUR), hydrochlorothiazide (HYD), ifosfamide (IFO), losartan (LOS), pravastatin (PRA), progesterone (PROG), ramipril (RAM), trimetazidine (TRI)] have been evaluated during one hydrological cycle, from October 2011 to October 2012 and compared to PECs calculated by using an adaptation of the models proposed by Heberer and Feldmann (2005) and EMEA (2006). Comparison of PECs and MECS has been achieved for six molecules: ATE, CAR, DOX, FUR, HYD and PRA. DOX, FUR and HYD present differences between PECs and MECs on an annual basis but their temporal evolutions follow the same trends. PEC evaluation for these PhACs could then be possible but need some adjustments of consumption patterns, pharmacokinetic parameters and/or mechanisms of (bio)degradation. ATE, CAR and PRA are well modeled; PECs can then be used as reliable estimation of concentrations without any reserve.

Dynamics of morphological changes of platelet granules in patients with hypertension and high cardiovascular risk in applying losartan potassium.

Проведено кількісну оцінку ультраструк­турних змін різних типів гранул тромбоцитів у пацієнтів з артеріальною гіпертензією, а також у хворих на артеріальну гіпертензію і цукровий діабет 2-го типу при корекції артеріального тиску лозартаном. Показано, що обмежена дегрануляція у пацієнтів з артеріальною гіпертензією відбувається за рахунок екзоцитозу дельта-гранул, вміст яких нормалізується через 9 місяців антигіпертензивної терапії. Корекція артеріальної гіпертензії у хворих на цукровий діабет із застосуваням лозартану калію призводить до значного відновлення вмісту альфа-гранул, нормалізації вмісту щільних тілець та обмеження лізосомальної активності.

Impact of combined losartan/hydrochlorothiazide on proteinuria in patients with chronic kidney disease and hypertension.

It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n=51) or a combination of LS (50 mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n=51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mm Hg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.

176 Effects of Different Antihypertensive Pharmacological Treatments on the Cardiovascular Autonomic Control Evaluated by Different Experimental Approaches in Animal Model

IntroductionArterial hypertension is frequently accompanied by a lot of comorbidities, such as the changes in autonomic cardiovascular control. These changes, if not reversed, may be crucial for the development and...

The Clinical Effect and Influence on cardiac function of losartan joint tartrate metoprolol on heart function in patients with coronary heart disease（CHD） and chronic heart failure（CHF）

Objective To explore the clinical effect and influence on cardiac function of losartan joint tar-trate metoprolol on heart function in patients with coronary heart disease （ CHD ） and chronic heart failure （ CHF ） . Methods 76 patients were randomly divided into two groups with double blind method ,control group adopted tartrate metoprolol treatment ,observation group on the basis of the losartan treatment ,compared two groups of cardiac function changes and clinical curative effect .Results After treatment,changes of DP/dtmax,DP/dtmax,LVEDP were greater than those of the control group ,the difference was statistically significant （ t=9.141,75.458,9.141,75.458,all P<0.05）;compared with control group , the differences in LDH, SOD, NO were statistically significant （ t =6.951, 15.694,6.951,P<0.05）;Observation group effectiveness was 89.47%,control group effectiveness was 78.95%, the difference in efficient between the two groups have statistical significance （Ridit=16.951,P=16.951）;the rate for incidence of major adverse cardiovascular events in observation group was 7.89%;control group was 10.53%, there was no statistically significant difference in two groups （χ2 =0.695,P=0.695）.Conclusion Curative effect of losartan with tartrate metoprolol treatment of coronary heart disease （CHD） is distinct,combination may be considered in clinical application and can improve cardiac function in patients adjusting the nerve -endocrine disorder from differ-ent mechanism . Key words: Losartan; Metoprolol; Heart failure,congestive; Coronary disease

AT1 receptor blocker attenuates mechanical ventilation‐induced atrophy and oxidative stress in the diaphragm muscle (1102.39)

Background: Mechanical ventilation (MV) is a method of maintaining adequate gas exchange in patients who are unable to sustain adequate alveolar ventilation on their own. Recently, our lab demonstrated that Angiotensin II (Ang II) is a possible mechanism that causes MV‐induced diaphragm muscle atrophy. During MV, elevation of Ang II induces Reactive Oxygen Species (ROS) emission from mitochondria and results in activation of key proteases, calpain and caspase‐3, in the diaphragm. To determine Ang II is a required upstream signal for MV‐induced diaphragm muscle atrophy and contractile dysfunction, we used AT1 receptor blocker (Losartan) and ACE inhibitor (Enalapril), which prevent the elevation of plasma Ang II levels during MV.Methods: Adult female rats were randomly assigned to one of six experimental groups (n =12 each) (1) Spontaneous breathing (SB) with salin, (2) SB with Losartan (LOS), (3) SB with Enalapril (ENA), (4) MV with salin, (5) MV with LOS, (6) MV with ENA. Dependent measures included plasma Ang II levels, diaphragmatic muscle fiber cross‐sectional area, diaphragm contractile properties, and the activity of key proteases in the diaphragm.Results: ENA attenuates increased circulating Ang II levels during 12 hours prolonged MV but LOS does not. However, only LOS attenuated MV‐induced diaphragm muscle atrophy. As well as, LOS attenuated MV‐induced mitochondrial dysfunction, ROS production, and proteasome activity during.Therefore, Ang II does not appear to be a possible upstream mechanism to prevent MV‐induced diaphragm muscle atrophy. AT1 receptor blocker, losartan has an antioxidant effect and attenuates MV‐induced VIDD. Therefore, the results of our experiments could lead to human clinical trials using losartan as a therapeutic intervention to prevent VIDD.

Low‐level lead exposure increased bioavailability of nitric oxide mediated by angiotensin II and PI3K/AKT pathway in rat aorta (700.2)

We previously demonstrated that 7‐day exposure with a low concentration of lead acetate increases blood pressure (BP) and nitric oxide (NO) bioavailability, which could be a compensatory mechanism in the initial stages of lead exposure.We investigated the involvement angiotensin II and PI3K/AKT pathway in this increased NO bioavailability. Wistar rats were treated with lead (1st dose 4 μg/100g and, subsequent doses 0.05 μg/100g, i.m cover daily loss) or vehicle. After lead treatment, blood levels were of 9.98μg/dL. In aortic rings from lead‐treated rats, phenylephrine (PHE 10‐10‐10‐4M) contractile responses were reduced; L‐NAME (LN‐10µM) increased PHE responses more in lead‐treated rats than untreated rats. Wortmannin (WT‐0,1µM) and PD123319 (PD‐1µM) normalized PHE responses in treated rats, and in presence of either WT, PD or losartan (LOS) that effect of LN on reactivity from lead treated group was blunted. Lead also increased release of NO, which was blocked by LOS, WT and PD. Our results suggest the involvement of angiotensin II and PI3K/AKT pathway in increased NO bioavailability in lead rats. This might be an alternative way to increase the NO bioavailability, as a compensatory mechanism against the increased SBP in the early stages of lead exposure.Grant Funding Source: CAPES, CNPq and FAPES.

Evidence for expression and function of angiotensin II receptor type 1 in pulmonary epithelial cells

There is a growing evidence that the peptide hormone angiotensin II (ANGII) can act as an auto-/paracrine mediator to regulate epithelial ion transport processes. The present study focused on the impact of ANGII on transepithelial ion transport in pulmonary epithelia. Transcripts for the ANGII receptor type 1 (ATR1) were detected in lungs of Xenopus laevis and H441 cells (human pulmonary epithelial cell line). Native Xenopus lung preparations were used for Ussing chamber recordings and apically applied ANGII (10μM) induced a significant increase of short-circuit current (ISC: 8±2%, n=13). Pre-incubation with losartan (LOS), an antagonist of ATR1 prevented the effect of ANGII on ISC.Transcripts for ATR1 in Xenopus lungs and H441 cells were detected and an increase of ISC was observed by ANGII in native Xenopus lung epithelia. This indicates that ANGII is a potential auto-/paracrine mediator for ion transport regulation in pulmonary epithelia.

Intermittent Losartan Administration Triggers Cardiac Post-Conditioning in Isolated Rat Hearts: Role of BK2 Receptors

IntroductionThe angiotensin (Ang) and bradykinin (BK) tissue-system plays a pivotal role in post-conditioning, but the efficacy of angiotensin type 1 receptor (AT1R) blockers (ARBs) in post-ischemic strategies is still under investigation. We evaluated functional and morphological outcomes, together with activation of cytosolic RISK pathway kinases, in rat hearts subjected to losartan (LOS) or irbesartan (IRB) post-ischemic administration.MethodsIsolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Post-conditioning was obtained by intermittent (10 s/each) or continuous drug infusion during the first 3 min of reperfusion. Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (dLVP), coronary flow (CF), and left ventricular infarct mass (IM) were measured together with the activation status of RISK kinases Akt, p42/44 MAPK and GSK3β.ResultsWhen compared to hearts subjected to ischemia/reperfusion (iI/R) alone, continuous IRB or LOS administration did not significantly reduce total infarct mass (cIRB or cLOS vs. iI/R, p = 0.2). Similarly, intermittent IRB (iIRB) was not able to enhance cardioprotection. Conversely, intermittent LOS administration (iLOS) significantly ameliorated cardiac recovery (iLOS vs iI/R, p<0.01). Differences between iLOS and iIRB persisted under continuous blockade of AT2R (iLOS+cPD vs. iIRB+cPD, p<0.05). Interestingly, iLOS cardioprotection was lost when BK2R was simultaneously blocked (iLOS+cHOE vs. iI/R, p = 0.6), whereas concurrent administration of iBK and iIRB replicated iLOS effects (iIRB+iBK vs. iLOS, p = 0.7). At the molecular level, iIRB treatment did not significantly activate RISK kinases, whereas both iLOS and iBK treatments were associated with activation of the Akt/GSK3β branch of the RISK pathways (p<0.05 vs. iI/R, for both).ConclusionsOur results suggest that intermittent losartan is effective in mediating post-conditioning cardioprotection, whereas irbesartan is not. The infarct mass reduction by intermittent losartan seem mainly related on its specific ability to modulate BK2R, and only modestly associated on AT1R blocking properties.

Effect of ras-blockers and no-cycle metabolites on the renal functions of rats exposed to thyroxine injections

Dolomatov S. I., Sataieva T. P. Effect of ras-blockers and no-cycle metabolites on the renal functions of rats exposed to thyroxine injections. Journal of Education, Health and Sport. 2015;5(1):41-55. ISSN 2391-8306 . DOI: 10.5281/zenodo.13902 http://ojs.ukw.edu.pl/index.php/johs/article/view/2015%3B5%281%29%3A41-55 https://pbn.nauka.gov.pl/works/522594 http://dx.doi.org/ 10.5281/zenodo.13902 F ormerly Journal of Health Sciences. ISSN 1429-9623 / 2300-665X. Archives 2011 – 2014 http://journal.rsw.edu.pl/index.php/JHS/issue/archive Deklaracja. Specyfika i zawartośc merytoryczna czasopisma nie ulega zmianie. Zgodnie z informacją MNiSW z dnia 2 czerwca 2014 r., ze w roku 2014 nie bedzie przeprowadzana ocena czasopism naukowych; czasopismo o zmienionym tytule otrzymuje tyle samo punktow co na wykazie czasopism naukowych z dnia 31 grudnia 2014 r. The journal has had 5 points in Ministry of Science and Higher Education of Poland parametric evaluation. Part B item 1089. (31.12.2014). © The Author (s) 2015; This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland and Radom University in Radom, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 15.06.2014. Revised 05.10.2014. Accepted: 12.01.2015. EFFECT OF RAS-BLOCKERS AND NO-CYCLE METABOLITES ON THE RENAL FUNCTIONS OF RATS EXPOSED TO THYROXINE INJECTIONS S. I. Dolomatov, T. P. Sataieva Crimea State Medical University Simferopol, Russian Federation Corresponding author: Sergei Dolomatov E-mail: path888d@yandex.ru Abstract Objective. Evaluating the role of RAS and NO-dependent pathogenic mechanisms of formation of renal dysfunction in disorders of the thyroid status. Methods. First 2 groups of experimental white male outbredrats was administered thyroxine (T4) in a dose of 50 g / 100 g per body weight injected intraperitoneally on 1% starch gel base once or during 7 days. In addition, rats were administered non-selective NO-synthase inhibitor Nω-NLA. Those rats were exposed to single administration of the combined T4 (intraperitoneally, 50mg/100g body weight in 24 hours before water loading) and Nω-NLA (intraperitoneally 1 mg / 100 g body weight 30 min before water loading). As a comparison we studied a group of animals received only an equivalent dose only or T4 Nω-NLA only 1 mg / 100 g body weight in 30 min before water loading. After 7-days. of T4 administration the same rats received water solution of losartan (10 mg / l) or water solution of captopril (20 mg / l) for 24 hours after the last administration of T4. Another group of rats was treated with T4 for 7 days and afterwards was administered L-arginine in a dose 2 mg / 100 g bw per day or water solution (20 mg / l) of sodium nitrite. Rats in the control group for 7 days. was administered intragastrically gel containing no T4. Kidney function was studied in 24h after administration of T4 in terms of water 5% loading on kidneys. Results. It was found out that administaration of RAS-blockers increases creatinine clearance value after either a single or prolonged administration of T4 in rats. However, decreased renal excretion of endogenous nitrates and protein as well as prevented retention of endogenous nitrite was registered in rats only after administration of losartan after 7 days of T4 administration. Prolonged administration of T4 to the rats was accompanied by weakened renal effects of NO and activated the arginine dependent pathway of NO synthesis into the nitrite reduction, evidenced by the increase of endogenous nitrite level in blood plasma of rats treated with T4 continuously along with no pronounced corrective effect of exogenous arginine in hyperthyroid animals and elevated creatinine clearance under the influence of exogenous sodium nitrite in the hyperthyroid animals. Conclusion. Discovered effects of RAS blockers allow us to recommend this pharmacological agents as an effective way to slow down the progression of renal dysfunction inthyroid pathlogy. Keywords: rat, hyperthyroidism, renal function, RAS- inhibitors, nitrites, nitrates.

The effects of losartan on memory performance and leptin resistance induced by obesity and high-fat diet in adult male rats.

Leptin is a hormone secreted by adipose tissue and is involved not only in the regulation of feeding and energy expenditure, but also its role in memory enhancement has been demonstrated as well. The partial transfer of leptin across the blood-brain barrier in obese individuals causes leptin resistance and prevents leptin reaching brain. On the other hand, studies have shown that angiotensin antagonists such as losartan can improve memory and learning abilities. The aim of this study was to evaluate the effects of losartan on improving memory and leptin resistance induced by high fat diet in obese rats. 40 Wistar male rats were divided in 4 groups: control (C), losartan (LOS), high-fat diet (HFD) and high-fat diet and losartan (HFD and LOS). The spatial memory performances of the rats were assessed in the Morris water maze after 2 months of treatment. Then they were weighed and serum levels of leptin and triglyceride were measured. In spite of receiving high-fat diet, no significant differences in body weight were observed in the (HFD & LOS) group. In the Morris water maze trial, the (LOS) and (HFD & LOS) groups also showed a significant reduction (P <0.05) in latency and path length. In addition, a significant decrease (P <0.05) in serum levels of leptin and no significant difference in serum levels of triglyceride was observed in the (HFD & LOS) group. Losartan can improve leptin resistance induced by obesity and high fat diet. At the same time, it modulates body weight and enhances learning and memory.

Pharmacological and Non-Pharmacological Treatment in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, from steatosis to liver cirrhosis in individual who does not consume alcohol in significant amount. The prevalence of NAFLD in Indonesia was estimated around 30%, this condition related to the increased incidence of metabolic disorders. Current understanding of NAFLD pathogenesis is the third-hit theory, in which insulin resistance resulting in free fatty acid accumulation that triggers inflammation causing fibrosis and hepatocyte death, and these conditions are not followed by adequate hepatocyte proliferation. Treatment of NAFLD requires both non-pharmacologic and pharmacologic interventions. Life style intervention includes restricting calories, low saturated fat and low sugar diet, and also physical activity. Bariatric surgery remains controversial since in several study participants had experienced deterioration of disease. There are no definitive treatment for NAFLD currently. Treatment is aimed to improved insulin sensitivity, decreased oxidative stress and inflammation. Several agents use for treatment of NAFLD are insulin sensitizer (metformin and glitazones), statin, omega-3, vitamin E, ursodeoxycholic acid, orlistat, pentoxyphylline, and losartan. Keywords : NAFLD, treatment, pharmacologic, non-pharmacologic

Simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by LC–ESI-MS/MS and its application to pharmacokinetics in rats

Polypill is a fixed-dose combination that contains three or more active ingredients used as a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. A novel and accurate liquid chromatography tandem mass spectrometry method using electrospray ionization mode has been developed and validated for the simultaneous determination of amlodipine (AMD), valsartan (VAL) using losartan (LOS) as an internal standard (IS), and hydrochlorothiazide (HCT) using furosemide (FSD) as an IS. The separation was carried on Aquasil C18 (50mm×2.1mm, 5µm) reversed phase column using acetonitrile and water containing 0.1% formic acid (50:50, v/v) as the mobile phase. The method was validated in terms of linearity, accuracy and precision over the concentration range of 1–1000ng/mL. The intra and inter-day precision and accuracy, stability and extraction recoveries of all the analytes were in the acceptable range. This method can be successfully applied to the pharmacokinetic study of AMD, VAL and HCT when given as a polypill.