Losartan Research Articles

Angiotensin II Increases JNK and IRS‐1ser307 Activity via NAD(P)H and Inhibits Insulin Signaling in Rats with Insulin Resistance Induced by Low Salt Diet

Low salt diet (LS) increases angiotensin II (AII), which may enhance JNK and IRS1ser307 phosphorylation (PP) decreasing insulin signaling (INS‐S). AII stimulate ROS production through activation of NAD(P)H oxidase (NAD). However, whether AII, oxidative stress (OX) and inflammatory signaling (IS) are involved in INS resistance induced by LS is not established.ObjectiveEvaluate if losartan (LOS) improves INS resistance by decreasing OX, JNK and IRS1ser307 PP.MethodsRats were fed a LS (0.15% NaCl) or normal salt diet (NS: 1.3%) since weaning. Groups: NS, NS+LOS, LS and LS+LOS. NAD activity (subunits p47 and gp91PHOX), tissue AII, blood glucose (G), plasma INS, HOMA, INS‐S and IS, AII type 1 (AT1) receptor gene and protein expression were evaluated.Results(P<0.05, n=8): INS level, HOMA index, muscle AII and NAD subunits PP were greater in LS (p47: 10,066±975, gp91: 740±106) than in NS (p47: 5,783±801, gp91: 416±70 AU). G and NAD activity were lower in LS+LOS than in LS. INS receptor and Akt PP were greater and JNK (58±3) and IRS1ser307 PP (47±3 AU) were lower in the muscle of LS+LOS than in LS. IkB‐α PP was lower in LS (50±3) than in NS (100±3 AU) suggesting an activation of IS in LS. AT1 did not differ among groups.ConclusionsINS resistance induced by LS is associated with alterations in regulation of INS‐S, activated IS (JNK and IkB‐α), and higher tissue AII and NAD activity. In LS, LOS improves INS‐S by decreasing OX, JNK and IRS1ser307 PP, indicating that LOS may has anti‐inflammatory properties. AII may be a pathway that connects IS, OX and INS resistance in LS.Funded by FAPESP

Increased expression of CAPON (Carboxy‐terminal PDZ ligand of nNOS) within the paraventricular nucleus (PVN) of rats with heart failure (HF).

Activation of NMDA receptor initiates a Ca2+ influx that stimulates the production of NO by neuronal nitric oxide synthase (nNOS). A physical coupling of the NMDA receptor and nNOS occurs by an intermediary adaptor protein PSD95 (post synaptic density 95). CAPON, a protein rich in PVN competes with PSD95 for interaction with nNOS. Previously, we showed a decreased expression of nNOS and enhanced expression of NMDA NR1 within the PVN of rats with HF. To further elucidate the underlying mechanism of upregulation of NMDA NR1 with a concomitant downregulation of nNOS, we measured the levels of CAPON in left coronary ligation‐induced HF model of rats. CAPON expression is augmented by 22% in rats with HF. Previously we showed that Angiotensin II receptor (AT1) blocker, losartan (LOS) treatment in rats with HF normalized the changes in expression of NR1 and nNOS protein in the PVN. Consistent with these data, LOS treatment (10 mg/kg/day in the drinking water for three weeks) in rats with HF normalized protein expression of the CAPON in the PVN. Studies in neuronal NG108‐15 hybrid cell line treated with Ang II (6.25–100 μM) for 24h revealed 30% increase in CAPON expression at highest dose as compared to untreated cell samples. Co‐treatment with LOS (1μM) for 24h significantly, ameliorates the increased CAPON expression to Ang II. Immunostaining revealed colocalization of CAPON and nNOS in NG108 cell line as well as in PVN. These data suggest that perhaps the disparate changes in NR1 (upregulation) and nNOS (downregulation) may be due to an over expression of CAPON and this over expression of CAPON may be mediated by increased Ang II influence in rats with HF.

Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan

St. Elisabeth and Barbara Hospital 5, Mauerstrabe, Halle/Saale, Germany, 06110 Alpha Medical 49, Vlcie hrdlo, Slovakia, 81207 Children Hospital 1, Limbova, Bratislava, Slovakia, 83340 St. Elisabeth University of Health and Social Sciences 1, Namestie, maja, Bratislava, Slovakia, 81100 University of Wurzburg 6, Oberdurrbacher Strabe, Wurzburg, Germany, 97080 Slovak Medical University 12, Limbova, Bratislava, Slovakia, 83303

Comparison of the influence of angiotensin-converting enzyme inhibitor lisinopril and angiotensin II receptor antagonist losartan in patients with idiopathic membranous nephropathy and nephrotic syndrome

In this prospective study, the effects of an angiotensin-converting enzyme inhibitor [lisinopril (LIS)] and an angiotensin II receptor antagonist [losartan (LOS)] were compared in nephrotic patients with idiopathic membranous nephropathy. Twenty-seven patients (13 males, mean age +/- SD 51.3 +/- 15.4 years) were treated with LIS (13 patients, six males, mean age 52.1 +/- 15.3 years) or LOS (14 patients, seven males, mean age 50.5 +/- 15.5 years) for 12 months. At baseline and after the treatment period, serum albumin, total cholesterol, estimated glomerular filtration rate (GFR), 24 h proteinuria and mean arterial pressure were determined. Proteinuria (g/24 h) was significantly reduced in both groups (LIS from 4.82 +/- 1.26 to 1.75 +/- 0.64, p < 0.0001; LOS from 4.55 +/- 1.09 to 2.54 +/- 1.94, p = 0.002) (all results +/- SD). Serum albumin levels (g/dl) increased significantly in both groups (LIS 2.27 +/- 0.41 to 3.17 +/- 0.63, p < 0.0001; LOS 2.93 +/- 0.40 to 3.55 +/- 0.44, p < 0.0001). GFR (ml/min x 1.73 m(2)) did not change significantly in either group (LIS 55 +/- 17 to 56 +/- 17, p = 0.65; LOS 64 +/- 18 to 59 +/- 16, p = 0.13). Total cholesterol (mg/dl) was significantly reduced only in the lisinopril group (LIS 347 +/- 81 to 266 +/- 64, p < 0.0001; LOS 306 +/- 58 to 263 +/- 77, p = 0.138). Mean arterial pressure (mmHg) was reduced in both groups (LIS 107 +/- 12 to 95 +/- 6, p < 0.0001; LOS 104 +/- 10 to 96 +/- 5, p = 0.003). In the comparison between the two groups, serum albumin levels were higher in the losartan group at baseline (p < 0.0001) and after 12 months (p = 0.029). There were no significant differences between the baseline and end-of-study values for the rest of the studied parameters. Treatment with lisinopril and losartan in nephrotic patients with idiopathic membranous nephropathy results in similar (and significant) effects on renal function, hypoalbuminaemia, proteinuria and blood pressure.

Effect of losartan on expression of PTHrP and PTH1R induced by high glucose in NRK-52E cells

To study the effect of losartan on high glucose up-regulated expression of parathyroid hormone-related peptide (PTHrP) and its type 1 receptor (PTH1R) in NRK-52E cells. The expression of PTHrP and PTH1R were detected by RT-PCR and Western blot in control group (0 mmol/L glucose) ,normal glucose group (5 mmol/ L glucose) ,moderately high glucose group (16.7 mmol/L glucose) ,high glucose group (25 mmol/L glucose) ,and after intervention by 10 μmol/L losartan for 72 h (only Western blot). The expression of PTHrP and PTH1R were up-regulated by high glucose (PTHrP mRNA : 0. 66 ± 0.08, 0. 84 ± 0. 13,1.57 ± 0. 15, and 1.73 ± 0.21 ; PTHrP protein :0.63±0.12,0.68±0.06,1.02±0. 11, and 1.04±0.08 ; PTH1R mRNA :0.26±0. 08,0.28±0.07,2.35± 0. 10,and 2.47±0. 05 ; PTH1R protein:0. 88±0. 05,0. 87±0. 10, 1.05±0. 11, and 1.12±0. 09) ,and losartan inhibited the effects of high glucose (PTHrP 0.74±0. 15, PTH1R 0.98±0.06, both P<0.01). The results suggest that losartan could inhibit the expression of FTHrP and PTH1R induced by high glucose in NRK-52E. Key words: PTHrP; PTH1R; Losartan; NRK-52E cells; High glucose

Experimental study of abating oxidative damage after acute myocardium infarction by Losartan

Objective To investigate the effects of Losartan abating inflammatory factors after myocardium infarction and the possible mechanisms. Methods Losartan was given to the rats with myocardiac infarction by left anterior decending coronary artery ligation. After 4 and 8 weeks. cardiac remodeling was observed through right ventricular weight index (RVWI) 、left ventricular weight index (LVWI), The activity of superoxide dismutase (SOD) and copper-zinc SOD (CuZu-SOD) in left ventricular and hydrogen peroxide ( H2O2 ) in serum were measured. Results Compared with controls, the rat model of myocardiac infarction induced RVWI, LVWI increase (P ＜ 0.01 ). The activity of SOD 、CuZu-SOD in left ventricular decrease and H2O2 in serum increase.SOD、CuZu-SOD activity increase and content of H2O2 in serum decrease( each P ＜0.01). Losartan attenuated RVWI, LVWI (each P ＜ 0.01 ) and decreased content of the HC 、 collagen and IL-6 ( each P ＜ 0.01 ). Conclusion Losartan abate oxidative damage and improve cardiac remodeling after acute myocardiac infarction. Key words: Losartan; Myocardium infarction; Inflammatory factors; Cardiac remodeling

High-Dose Is Better Than Low-Dose Losartan in Some Patients with CHF

In several studies, high-dose angiotensin-receptor blockers (ARBs), either alone or in combination with angiotensin-converting–enzyme (ACE) inhibitors, have lowered cardiovascular morbidity and mortality in patients with congestive heart failure and reduced left ventricular ejection fraction (LVEF). Because the effects of different ARB dosing regimens are unknown, manufacturer-sponsored researchers randomized …

Rapid determination of losartan and losartan acid in human plasma by multiplexed LC–MS/MS

A rapid LC-MS/MS method has been developed and validated for the determination of losartan (LOS) and its metabolite losartan acid (LA) (EXP-3174) in human plasma using multiplexing technique (two HPLC units connected to one MS/MS). LOS and LA were extracted from human plasma by SPE technique using Oasis HLB cartridge without evaporation and reconstitution steps. Hydroflumethiazide (HFTZ) was used as an internal standard (IS). The analytes were separated on Zorbax SB C-18 column. The mass transition [M-H] ions used for detection were m/z 421.0 --> 127.0 for LOS, m/z 435.0 --> 157.0 for LA, and m/z 330.0 --> 239.0 for HFTZ. The proposed method was validated over the concentration range of 2.5-2000 ng/mL for LOS and 5.0-3000 ng/mL for LA with correlation coefficient > or = 0.9993. The overall recoveries for LOS, LA, and IS were 96.53, 99.86, and 94.16%, respectively. Total MS run time was 2.0 min/sample. The validated method has been successfully used to analyze human plasma samples for applications in 100 mg fasted and fed pharmacokinetic studies.

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma

We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the anti-hypertensive drug losartan (LOS). We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumor-associated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C. Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.

NADPH oxidase-derived reactive oxygen species involved in angiotensin II-induced monocyte chemoattractant protein-1 expression in mesangial cells

To investigate the origin of oxidative stress induced by angiotensin II (AngII) in human mesangial cells and the role of reactive oxygen species (ROS) in AngII-induced monocyte chemoattractant protein-1 (MCP-1) expression. MCP-1 expression was determined by real time RT-PCR. ROS production was measured by DCFDA fluorescence. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was examined by lucigenin chemiluminescence. p47phox and p67phox translocation was assayed by Western blot. Twenty-four male mice were randomly divided into three groups: the control, the AngIIinfusion [AngII 400 ng/(kg.min)], and the apocynin treatment. AngII was infused by subcutaneously osmotic minipump for 14 days. Urinary albumin and 8-isoprostane excretion were measured by ELISA. In cultured human mesangial cells, AngII induced the MCP-1 expression in a dose-dependent manner with 3.56 fold increase as compared with the control. AngII increased intracellular ROS production as early as 3 min with the peak at 60 min and was in a time and dose-dependent. Incubation with different dosages of AngII (1 nmol/L, 10 nmol/L, and 100 nmol/L AngII) for 60 min, ROS production increased at 1.82, 2.92, and 4.08 folds respectively. AngII-induced ROS generation was sensitive to diphenyleneiodonium sulfate (DPI, 10 micromol/L) and apocynin (500 micromol/L), two structurally distinct NADPH oxidase inhibitors. In contrast, inhibitors of other oxidant-producing enzymes, including the mitochondrial complex Iinhibitor rotenone, the xanthine oxidase inhibitor allopurinol, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguiaretic acid, the cytochrome P450 oxygenase inhibitor ketoconazole and the nitric oxide synthase inhibitor G-nitro-L-arginine methyl ester were without an effect. AngII-induced ROS generation was inhibited by the AT1 antagonist losartan (10 micromol/L) but not the AT2 antagonist PD123319 (10 micromol/L). AngII treatment induced translocation of cytosolic of p47phox and p67phox to the membrane. The antioxidants almost abolished AngII-induced MCP-1 expression. AngII infusion increased urinary and p67 translocation by 2.69-, 2.97-, and 2.67-fold, respectively. NADPH oxidase-derived ROS is involved in AngII-induced MCP-1 expression. Inhibition of NADPH oxidase alleviates AngII-induced renal injury.

Antagonist of the Type-1 ANG II receptor prevents against LPS-induced septic shock in rats

Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model. We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)). We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation. Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.

The importance of aldosterone suppression in the restoration of cerebrovascular myogenic function in SHRsp during post stroke Captopril and Losartan treatment

Treatment of Kyoto Wistar stroke prone spontaneously hypertensive rats (SHRsp) with Captopril (CAP) or Losartan (LOS) after hemorrhagic stroke (HS) restores pressure dependent constriction (PDC) in middle cerebral arteries (MCAs) . We assessed the importance of aldosterone (ALD) suppression during both treatments. Plasma ALD was elevated in SHRsp with HS over prestroke levels (3.9 ± 0.8 nM vs 0.15 ± 0.09 nM). SHRsp with HS were treated orally with 50mg/kg/day CAP or 35 mg/kg/day LOS for 28 days. During the last 10 days of treatment ALD (0.66 μg/hr) or vehicle was infused via an osmotic pump . CAP and LOS treatment suppressed plasma ALD (0.23 ± 0.07 and 0.075 ± 0.044 nM respectively), whereas supplementation elevated ALD (6.27±1.75 and 4.49 ± 0.80 nM respectively). ALD supplementation did not alter BP. After 28 days of CAP or LOS treatment, MCAs from SHRsp with HS (studied using a pressure myograph) regained PDC and the ability to constrict in response to protein kinase C activation (1μM phorbol dibutyrate) and elevated [K+]o depolarization. ALD supplementation prevented these changes in CAP but not LOS treated SHRsp. Elevation in plasma ALD enhance the deterioration of myogenic function. We believe that poststroke treatment with LOS (vs CAP) promotes systemic beneficial effects that permit the restoration of cerebrovascular function even under conditions of where plasma ALD is elevated.

High Salt Exacerbates Proteinuria in Chronic Angiotensin‐II Infused Rats.

This study examined the effect of a high salt (HS) diet on systolic blood pressure (SBP) and proteinuria in chronic Ang II‐infused hypertensive rats with and without RAS blockade with an Ang II type I receptor blocker, losartan (LOS). Male Sprague‐Dawley rats divided into four groups: 1) Sham+HS [n=5]; 2) Ang II [n=3]; 3) AngII+HS [n=5]; 4) Ang II+HS+LOS [n=5] were infused with Ang II (80 ng/min) for 14 days, fed with HS diet (8% NaCl) and treated with LOS (30 mg/L, drinking water). SBP progressively increased in Ang II and Ang II+HS rats up to 228±9mmHg and 228±10mmHg, respectively, compared to Sham+HS (128±7mmHg). Losartan attenuated the increases in SBP during the two‐weeks of treatment (144±9mmHg). Rats receiving Ang II+HS showed marked proteinuria measured in 24h‐urine collections (79±26mg/day) which was greater than in the Ang II group. Proteinuria decreased in the Ang II+HS+LOS, but not to levels of Sham+HS (29±2mg/day vs. 18±1mg/day), indicating a partial beneficial effect of LOS on proteinuria. The lack of difference between SBP in rats with Ang II‐induced hypertension and those that also received HS suggest that HS does not exert an additive effect on SBP. However, the presence of marked proteinuria in Ang II+HS rats indicates that HS might contribute to glomerular kidney damage independently of SBP and Ang II effects suggesting a direct action on glomerular protein barrier.Support from NIH and Merck &amp; Co., Inc.

Angiotensin II and Oxidative Stress Increases JNK and IRS‐1ser307 Activity and Inhibits Insulin Signal Transduction in Rats with Insulin Resistance Induced by Low Salt Intake

Low salt diet (LS) increases angiotensin II (AII) and oxidative stress (TBARS), which may enhance JNK and IRS1ser307 phosphorylation (PP) decreasing insulin signaling (INS‐S).ObjectiveTo evaluate if losartan (LOS) improves INS resistance by decreasing JNK and IRS1ser307 PP.MethodsTwelve‐week‐old rats were fed a LS (0.15% NaCl) or normal salt diet (NS: 1.3%) since weaning. Groups: LS+LOS (30mg/kg/day), LS+vehicle, NS+LOS and NS+vehicle. Blood pressure (BP), blood glucose (G), plasma INS and TBARS, HOMA, and tissue AII were evaluated. The INS‐S and inflammatory signaling (IS) were determined by Western blot and immunoprecipitation. AT1 receptor gene expression was determined by RT‐PCR.Results (mean±SEM, P&lt;0.05, n=8)BP and AT1 did not differ among groups. INS, HOMA and TBARS were higher in LS (INS: 712±60) than in NS (257±40 pmol/l). G and TBARS were lower and INS was higher in LS+LOS (TBARS: 4±0.5) than in LS (6±1 nmol/ml). Liver AII was higher in LS than in NS. INS receptor and Akt PP were higher and JNK (120±3) and IRS1ser307 PP (100±6 AU) were lower in the liver of LS+LOS compared to LS. IkBα PP was lower in LS (20±2) than in NS (100±4 AU) suggesting an activation of IS in LS. Similar results were observed in the muscle.ConclusionsINS resistance induced by LS is associated with alterations in regulation of INS‐S, activated IS, and higher tissue AII and TBARS. In LS, LOS improves INS‐S by decreasing JNK and IRS1ser307 PP with no change in BP.FAPESP

Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production

Expression of nuclear angiotensin II type 1 (AT(1)) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist (125)I-[Sar(1),Thr(8)]-ANG II ((125)I-sarthran) with the AT(1) antagonist losartan (LOS) or the AT(2) antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (> or =70%) and PM (> or =80%) sites while LOS competition predominated in medullary NUC (> or =75%) and PM (> or =70%). Immunodetection with an AT(2) antibody revealed a single approximately 42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT(2) in the tubulointerstitium, AT(1) in the medulla and vasa recta, and both AT(1) and AT(2) in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-l-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT(2) receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.

Simultaneous Determination of Losartan and Hydrochlorothiazide in Human Plasma by LC/MS/MS with Electrospray Ionization and Its Application to Pharmacokinetics

A method based on a simple liquid-liquid extraction (LLE) followed by high-performance liquid chromatography with negative ion electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of losartan (LOS) and hydrochlorothiazide (HCTZ) in human plasma, using valsartan (VAL) and chlorthalidone (CHTD) as an internal standard, respectively. The acquisition was performed in multiple reactions monitoring (MRM) and the limit of quantification was 4 ng/mL for both LOS and HCTZ. The method was linear in the studied range (4–800 ng/mL for LOS and 4–500 ng/mL for HCTZ). The intra-assay precisions ranged from 2.6–11.9% for LOS and 1.4–8.2% for HCTZ, while the inter-assay precisions ranged from 1.0–8.0% for LOS and 2.5–7.7% for HCTZ. The intra-assay accuracies ranged from 91.3 to 107.6% for LOS and 91.5 to 105.8% for HCTZ, while the inter-assay accuracies ranged from 99.9 to 106.4% for LOS and 97.4 to 101.4% for HCTZ. The analytical method was applied to a bioequivalence study, in which 28 healthy adult volunteers (14 men) received single oral doses (100 mg LOS + 25 mg HCTZ) of reference and test formulations, in an open, two-period, balanced randomized, crossover protocol. Based on the 90% confidence interval of the individual ratios for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference Hyzaar® formulation with respect to the rate and extent of absorption of both LOS and HCTZ.

Bioavailability and Interaction Potential of Atorvastatin and Losartan on Co-administration in Healthy Human Subjects

A randomized, open-label, balanced, three-treatment, three-sequence, three-period single dose crossover pharma- cokinetic interaction study was conducted to evaluate the potential of interaction between Atorvastatin (AT) and Losartan (LS). Subjects were administered either 40 mg AT or 100 mg LS or combination of both in either of the periods. Blood samples were collected at regular intervals to measure the plasma concentrations of AT, O-hydroxy atorvastatin (O-HAT), LS and its carboxylic acid metabolite (LS-CA) for pharmacokinetic analysis. Co-administration of AT and LS was well tolerated without any significant change in area under the curve (AUC) of either of the drugs or their respective metabolites. There was an increase in C max (ng/mL) of AT, O-HAT, LS, and LS-CA by 29% (38.8(±20.9) to 47.8(±18.4)), 86% (15.7±(10.6) to 29.8(±19.1)), 51% (503.0(±246.0) to 793.0(±376.0)) and 21% (971.0(±245.0) to 1189.0(±323.0)), respectively in combination treatment. Both AT and LS are substrates of P-glycoprotein (P-gp) and CYP3A4, and reported to be completely absorbed from gastrointestinal tract. Hence, this change in the rate of absorption appears to be due to transient saturation of P-gp and/or CYP3A4 during initial absorption phase in the gut wall prior to reaching in portal vein circulation. The increase in C max of both drugs may not be clinically signifi- cant to call for dosage adjustment.

Losartan/Hydrochlorothiazide Fixed Combination Versus Amlodipine Monotherapy in Korean Patients With Mild to Moderate Hypertension

Background and ObjectivesThe antihypertensive efficacy and tolerability of losartan (LST) in fixed combination with hydrochlorothiazide (HCTZ) has not been compared to those of amlodipine monotherapy in Asians. This is an important comparison to draw, because Asians have been suggested to respond more favorably to calcium channel blockers and less favorably to angiotensin-converting enzyme inhibitors in comparison to Westerners. We sought to compare these two regimens in Korean patients with mild to moderate hypertension.Subjects and Methods174 patients were randomized to receive LST 50 mg once daily, which could be titrated to LST/HCTZ 50/12.5 mg at 4 weeks, followed by 100/25 mg at 8 weeks; or to receive amlodipine besylate 2.5 mg once daily, which could be titrated to 5 mg at 4 weeks, followed by 10 mg at 8 weeks to achieve diastolic blood pressure <90 mmHg.ResultsAt 12 weeks, the differences between the LST/HCTZ and amlodipine groups with regard to diastolic and systolic blood pressure were 1.2 mmHg (95% confidence interval: -1.1 to 3.4) and -0.5 mmHg (95% confidence interval: -4.3 to 3.4), respectively. The rates of achieving systolic blood pressure <140 mmHg were 66.7% in the LST/HCTZ group and 75.9% in the amlodipine group (p=0.20). The rates of drug-related adverse events were 15.6% in the LST/HCTZ group and 11.9% in the amlodipine group (p=0.49).ConclusionThe two regimens, with a relatively higher dose of LST/HCTZ compared to that required in Westerners, produced equivalent blood pressure reduction and were comparably well tolerated in Korean patients with mild to moderate hypertension.

Aliskiren Combined with Losartan in Diabetes and Nephropathy

Aliskiren Combined with Losartan in Diabetes and Nephropathy

Losartan, alone or in combination with hydrochlorothiazide, lowers BP in patients who are hypertensive and obese,

Losartan, alone or in combination with hydrochlorothiazide, lowers BP in patients who are hypertensive and obese,