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The relationship between cardiovascular and renal pathologies is well recognized in advanced nephropathy and heart failure, but in early disease it has received less attention. Consequently, microalbuminuria screening and interventions that treat early nephropathy remain under-utilized cardioprotective strategies in the hypertensive patient. Agents that delay the progression of renal disease are likely to be cardioprotective by lessening the systemic consequences of renal dysfunction and may have additional cardioprotective effects by exerting beneficial effects on endothelia elsewhere in the body and within the heart. A critical driving factor within both renal and wider cardiovascular pathologies is overactivation of the renin-angiotensin-aldosterone system (RAAS). Accordingly, RAAS-directed antihypertensive agents including both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been demonstrated to have renoprotective effects. In major prospective trials, two ARBs, losartan and irbesartan, have been demonstrated to be renoprotective in patients with frank proteinuria, and one ARB, irbesartan, has been shown to have renoprotective properties in patients with microalbuminuria. For patients with incipient or frank renal dysfunction, an aggressive RAAS-based approach to hypertension management, combining potent blood pressure control with proven renoprotection, may therefore constitute a key component of therapy targeted towards long-term cardioprotection.
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The db/db mice serve as a good model for type 2 diabetes characterized by hyperinsulinaemia and progressive hyperglycaemia. There are limited and conflicting data on the cardiovascular changes in this model. The aim of the present study was to characterize the cardiovascular and autonomic phenotype of male db/db mice and evaluate the role of angiotensin II AT(1) receptors. Radiotelemetry was used to monitor 24 h blood pressure (BP) in mice for 8 weeks. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and their variabilities. In 8-week-old db/db mice, the MAP and BP circadian rhythms were not different from age-matched control mice, while HR and locomotor activity were decreased. With ageing, MAP gradually increased in db/db mice, and the 12 h light values did not dip significantly from the 12 h dark periods. In 14-week-old mice, MAP was increased during light (101 +/- 1 versus 117 +/- 2 mmHg, P < 0.01; control versus db/db mice) and dark phases (110 +/- 1.7 versus 121 +/- 3.1 mmHg, P < 0.01; control versus db/db mice). This increase in MAP was associated with a significant increase in plasma angiotensin-converting enzyme activity and angiotensin II levels. Chronic treatment with losartan (10 mg kg(-1) day(-1)) blocked the increase in MAP in db/db mice, with no effect in control animals. Spectral analysis was used to monitor autonomic cardiovascular function. The circadian rhythm observed in systolic arterial pressure variance and its low-frequency component in control mice was absent in db/db mice. There were no changes in HR variability and spontaneous baroreflex sensitivity between control and db/db mice. The results document an age-related increase in MAP in db/db mice, which can be reduced by antagonism of angiotensin II AT(1) receptors, and alterations in autonomic balance and components of the renin-angiotensin system.
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With 4% discounting, prevention of stroke was associated with a gain of 3.7 life-years. As a consequence, losartan treatment was associated with 0.059 life-year gained (LYG) per patient treated with losartan. Losartan reduced stroke-related costs by 1,076 Euros (US $1,349) per patient. After inclusion of study medication cost, net cost per patient was 51 Euros ($64) higher for losartan than atenolol. The net cost per LYG was 864 Euros ($1083), which is below the Dutch pharmacoeconomic threshold of 20,000 Euros/LYG (~$25,000/LYG) for accepting interventions. The corresponding probability of a cost-effectiveness ratio below this Dutch threshold was 0.95. Discounting money and health following the new Dutch guideline resulted in an even more favorable cost-effectiveness for losartan.
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After myocardial infarction, angiotensin II (AngII) promotes ventricular remodeling and deposition of extracellular matrix (ECM), e.g., collagen type 1 and 3. Whether AngII regulates the expression of small leucine-rich proteoglycans (SLRP) which are important modulators of collagen fibrillogenesis and are induced after experimental myocardial infarction in rats is not known. The aim of the present study was therefore to analyse in cultured cardiac fibroblasts the expression and secretion of the SLRP biglycan in response to AngII.
It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.
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ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.
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Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT₁ receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT₁ receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1β and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds.
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Unilateral ureteral obstruction (UUO) could induce increased renal angiotensin II (ANG II), which enhances apoptosis of renal tubular cells and renal tissue loss. Systemic ANG II is also increased in UUO. There are no data available about whether UUO can induce apoptosis of circulating lymphocytes or not.
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In the in vitro experiment, at the excretion rate of 1 microl/h for 336 h, 15 microl/h for 96 h, and 30 microl/h for 120 h, the decrease in each pump weight was used to estimate the actual excretion volume. In the in vivo experiments, the iPRECIO was chronically implanted in rats, angiotensin II was infused, and arterial pressure (AP) was monitored.
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Chronic infusions of initially subpressor doses of angiotensin II (ANG II) lead to progressive hypertension over a 2-wk period and to augmented intrarenal ANG II levels. The present study was performed to investigate total renal blood flow (RBF) and medullary blood flow (MBF) autoregulatory behavior and pressure-natriuresis in ANG II-infused hypertensive rats and how these are modified by concomitant treatment with an ANG II AT(1) receptor antagonist. ANG II-infused rats (n = 27) were prepared by administration of ANG II at 60 ng/min via osmotic minipump for 13 days. Twelve of the ANG II-infused hypertensive rats were treated with losartan in the drinking water (30 mg. kg.(-1) day(-1)). Rats were anesthetized with pentobarbital sodium (50 mg/kg, ip) and prepared for renal function measurements. An aortic clamp was placed above the junction of the left renal artery to reduce renal arterial pressure. Autoregulatory responses for renal plasma flow, overall RBF, and glomerular filtration rate were impaired in ANG II-infused hypertensive rats; however, MBF autoregulation was not disrupted. Most strikingly, pressure-natriuresis was markedly suppressed in ANG II-infused hypertensive rats. Chronic treatment with losartan prevented the impairment of the pressure-natriuresis relationship caused by chronic ANG II infusion. These findings demonstrate that chronic ANG II infusion leads to marked impairment of sodium excretion and suppression of the pressure-natriuresis relationship, which may contribute to the progressive hypertension that occurs in this model. These renal effects are prevented by simultaneous treatment with an AT(1) receptor blocker.
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We evaluated the renoprotective effects of adding aliskiren to treatment with losartan in hypertensive patients with type 2 diabetes and nephropathy. A total of 599 patients were randomized to six months of treatment with placebo or aliskiren in addition to losartan 100 mg and optimal antihypertensive therapy. The primary outcome was a reduction in the urinary albumin-creatinine ratio. Aliskiren 300 mg daily reduced the mean urinary albumin-creatinine ratio by 20% (p < 0.001) compared with placebo. The number of adverse events was similar between groups. Aliskiren is renoprotective independently of its blood pressure lowering effect.
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We previously demonstrated that type 1A angiotensin II (Ang II) receptor (AT1A) is the predominant renal subtype and is upregulated by a low sodium diet. We have now tested the hypothesis that upregulation of AT1A mRNA induced by sodium deficiency is renal specific and is mediated by activation of type 1 Ang II receptor (AT1). Male Wistar rats were divided into four groups (n = 5 each) and treated for 2 weeks with normal sodium diet (0.5%), normal sodium plus 3 mg/kg per day losartan, low sodium diet (0.07%), or low sodium diet plus losartan. At the end of the 2 weeks, body weight and mean arterial pressure were not different among the four groups (P > .05). Plasma renin activity was elevated by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). Northern blot analysis showed that the ratio of renal AT1A to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was increased by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). In contrast, the ratio of adrenal AT1A to GAPDH mRNA was increased only by sodium restriction versus three other groups (P < .05). Thus, sodium deficiency increases AT1A mRNA in both kidney and adrenal gland, while Ang II receptor blockade by losartan prevents low sodium-induced AT1A mRNA only in adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)
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Four weeks after abdominal aorto-caval (AV) shunting or sham operation in rats, the hearts were retrogradely perfused in vivo and the left ventricles contracted isovolumetrically at 300 beats/min. Sympathetic nerve stimulation (SNS) was performed in the baseline state and repeated with an infusion of the angiotensin II (A-II) type 1 receptor (AT(1)-R) blocker, losartan, the A-II type 2 receptor (AT(2)-R) blocker, PD123319, or A-II. Norepinephrine (NE) overflow and left ventricular (LV) inotropic responses during baseline SNS were lower in the AV shunt rats. Losartan did not change the NE overflow or the LV inotropic responses to SNS in the sham rats, but did increase them in the AV shunt rats. PD123319 changed neither parameter in the sham rats, but decreased both in the AV shunt rats. A-II enhanced the NE overflow but attenuated the LV inotropic responses to SNS in the sham rats, but attenuated both in the AV shunt rats.
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Angiotensin receptor antagonists are effective drugs for the treatment of mild to moderate hypertension which have a side effect profile similar to placebo. Their role in the management of hypertension remains to be defined, but they are of particular use to patients who are intolerant of ACE inhibitors because of cough. It is uncertain at the present time whether the benefits of ACE inhibition in other disorders such as congestive heart failure and following myocardial infarction will be similar for angiotensin receptor blockers.
Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl, show severe hypertension, organ damage, and early death. Preventive treatment with angiotensin II type 1 (AT1) receptor antagonists is known to be effective. Previously, we found that angiotensin converting enzyme (ACE) inhibition could reduce cerebral edema when treatment was started after manifestation of either proteinuria or cerebral edema. In this study AT1 receptor blockade was started at the same time points to evaluate whether this had an effect superior to ACE inhibition. SHRSP drank 1% NaCl. Group 1 served as controls. Group 2 and 3 rats were started on losartan and enalapril after proteinuria exceeded 40 mg/day. Group 4 and 5 rats were started on losartan and enalapril after the first observation of cerebral edema with T2-weighted magnetic resonance imaging scans. In controls, median survival was 54 days (range, 35 to 80 days) after the start of salt loading. With early-onset losartan and enalapril, survival increased to 305 days (range, 184 to 422 days) and 320 days (range, 134 to 368 days) (both P < .01 v group 1). Cerebral edema formation was prevented in all but two rats, one from each treatment modality. Development of proteinuria was markedly reduced. With late-onset treatment with losartan and enalapril, survival was 290 days (range, 120 to 367 days) and 264 days (range, 154 to 319 days) (both P < .01). Both losartan and enalapril decreased cerebral edema to baseline levels. Ultimately cerebral edema reoccurred, despite continued treatment, in 75% of the rats. Systolic blood pressure did not decrease after losartan treatment, but, similarly to early-onset treatment, decreased transiently after enalapril treatment. Cerebral edema and proteinuria were prevented and reduced in SHRSP treated with either an AT1 receptor antagonist or an ACE inhibitor. Survival was markedly and similarly prolonged by both treatments, whether initiated directly before or after development of cerebral edema. In rats where treatment was initiated after manifestation of cerebral edema, both cerebral edema and proteinuria reappeared despite continued treatment. Apparently, when hypertension is sustained, reappearance of target organ damage may not be entirely dependent on angiotensin.
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The relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in patients on optimized beta-blocker therapy was reliable, but this relationship was unreliable in non-optimized heart failure patients.
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In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men.
We examined whether the level of highsensitivity C-reactive protein (hsCRP), a marker of low-grade inflammation, predicted the response of clinic and ambulatory blood pressure (BP) to antihypertensive treatment.
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Angiotensin II (Ang II) stimulation has been shown to regulate proliferation of skin fibroblasts and the production of extracellular matrix, which are very important processes in skin wound healing and fibrosis; however, there is little knowledge about the mechanisms involved in this process. We investigated the molecular aspects of this system with regards to Ang II in human dermal fibroblasts (HDF) and its potential role in fibrosis. Fibroblasts derived from human skin were subjected to examine differential relative gene and protein expression after transfection with specific reporter expression vectors and Ang II in vitro. In growth-arrested HDFs, Ang II treatment for 20 min caused acute activation of Smad2 phosphorylation, Smad overexpression and Smad-dependent gene transcription. The angiotensin type 1 (AT1) antagonist losartan diminished Ang II-induced Smad activation. The blockade of endogenous transforming growth factor-beta1 did modify the activation of Smad caused by Ang II. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 diminished Ang II-induced Smad2 phosphorylation. Transient transfection with Smad7, which interferes with receptor-mediated activation of Smad2, diminished Ang II-induced connective tissue growth factor promoter activation, gene and protein expression and fibronectin, type I procollagen and type III procollagen overexpression, showing that Smad activation is involved in Ang II-induced dermal fibrosis. Our results show that Ang II activation of Smad2 occurs via the AT1 receptor, but not the AT2 receptor. Activation of Smad2 required p38 MAPK but not p42/p44 MAPK or the epidermal growth factor receptor.
Wistar rats were ramdomly assigned to receive: (1) 96 degrees ethanol; (2) oral indometacin, (3) solid food (pellets) during two hours and subcutaneous indometacin (production of ulcers in the gastric antrum), (4) Carrageen footpad edema.
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Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed.
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Sixty Wistar rats were divided into 3 groups: Losartan treatment group, diabetes mellitus (DM) model group, and control group. All were treated accordingly for 4 weeks. 24 hours urine protein count, creatinin clearance rate (Ccr), mean arterial pressure (MAP), kidney weight/body weight, ET-1 in blood and urine, IV collagen and fibronectin (FN) in kidney tissue were determined at 1, 2, 4 weeks.
Data on the prices and availability of 47 medicines were collected from 50 public and 36 private sector medicine outlets in six regions of Shaanxi Province, Western China using a standardized methodology developed by the World Health Organization and Health Action International from September to October 2010. Medicine prices were compared with international reference prices to obtain a median price ratio. Affordability was measured as the number of days' wages required for the lowest-paid unskilled government worker to purchase standard treatments for common conditions.
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Combinations of antiproteinurics, including angiotensin I-converting enzyme inhibitors + angiotensin II receptor antagonist + statins, are promising choices in the treatment of steroid-resistant nephrotic syndrome. We aimed to investigate the effects of high doses of immunoglobulin in addition to these combinations in rats with adriamycin-induced nephrosis. The study included 40 rats allocated into five groups: control, nephrotic syndrome without treatment, dual therapy (DT) with enalapril + losartan, triple therapy (TT) with enalapril + losartan + simvastatin, and quadruple therapy (QT) with enalapril + losartan + simvastatin + a high dose of immunoglobulin. The proteinuria levels were not statistically different between DT, TT and QT groups at weeks 5, 8, 12 and 16. At week 16, serum creatinine levels in the QT group were significantly lower than those in the control, DT and TT groups. The glomerulosclerosis index in the DT group was significantly lower than in the TT and QT groups. The scores for interstitial fibrosis and TGF-beta staining were similar among treatment groups. In conclusion, we showed that quadruple therapy including immunoglobulin had a beneficial effect on renal function in the late phase, but it had no additional effects in reducing proteinuria or in glomerulosclerosis score in experimental nephrotic syndrome. Further studies with angiotensin I-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs) and immunoglobulin combinations would offer some benefits in the treatment of nephrotic syndrome.
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all immunized animals produced antibodies against the particular peptides. The systolic blood pressure was decreased in the SHR immunized with peptide-ATR12181 compared with the control. However, no changes were observed in the SHR immunized with other two peptides. The Wistar rats immunized with the three peptides did not show any changes in blood pressure. The media/lumen area ratio of the mesenteric artery was reduced in SHR immunized with ATR12181 and similar to that of the SHR treated with losartan. The antibody from SHR immunized with ATR12181 had no effect on the proliferation of VSMC. But it could inhibit the proliferation caused by angiotensin II and its effect at the titre of 1:40 was similar to that of 1µmol/l losartan.
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In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes.