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60 male wistar rats weighting about 250 g were divided into 4 groups. Model group (Mo): The rats were injected with 40% CCl(4) 0.25 ml/100 g subcutaneously three times a week. Perindopril group (Pe): The rats were injected with 40% CCl(4). Perindopril, equivalent to 2 mg x kg(-1) x d(-1), was given i.g. Losartan group (Lo): The rats were injected with 40% CCl(4). Losartan, equivalent to 50 mg x kg(-1) x d(-1), was given i.g. Control group (Nc): the rats were injected with olive oil only. After 4, 6 weeks, morphological examination was based on microscopy. RT-PCR was utilized to detect gene expression of AT-1 receptor in the liver. Meanwhile, the protein expressions of AT-1 receptor, TGF-beta1 and PDGF-BB in liver tissue were examined by Western blot. The activity of matrix metalloproteinase-2 (MMP-2) was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radioimmunoassays.
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Arterial hypertension is the most frequent chronic disease and it is an important cause of morbidity and mortality in the developed world. Arterial hypertension is associated with such adverse effects as accelerated arteriosclerosis and pathological left ventricular hypertrophy, among others. The molecular mechanisms affecting left ventricular hypertrophy remain mostly unknown. The advent of proteome profiling has facilitated the elucidation of disease-associated proteins, paving the way for molecular diagnostics and the identification of novel therapeutic targets. We explored the proteomic profile of pathological left ventricular hypertrophy in comparison with normal heart in a model of rats and investigated the proteomic changes in response to different antihypertensive regimens in order to elucidate their cardioprotective effects. Here we describe in depth the protocol for this type of study.
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Effective blood pressure control was observed in both groups at 6 months, and with further improvement at 1 year. Serum potassium was significantly decreased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but not in the L+D group. Serum uric acid was significantly increased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but had minimally decreased at 1 year in the L+D group (p < 0.1). Blood glucose, renal function and lipid parameters did not change in either group.
Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-b1 expression.
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Obesity is often associated with chronic inflammatory state which contributes to the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). This study investigated the effects of single and combined administration of atorvastatin (ATOR, lipid-lowering drug) and losartan (LOS, angiotensin receptor antagonist) on metabolic disorders and inflammatory status that are implicated in the development of T2DM with the use of pioglitazone (PIO) as a standard antidiabetic drug. T2DM was induced in male rats by high-fat diet (HFD) feeding for 16 weeks. Oral administrations of ATOR (10 mg/kg), LOS (20 mg/kg), PIO (3 mg/kg), their binary combinations, or vehicle were started in the last 4 weeks. Fasting serum glucose, oral glucose tolerance, fasting serum insulin, IR, serum lipid profile, serum TNF-α and body composition index were determined. Results showed that all drugs and their combinations had positive impact effect on all measured parameters, and better results were achieved from binary drug combinations than administration of each drug alone. Combination of PIO with either ATOR or LOS provided better improvements on T2DM-associated metabolic abnormalities and inflammatory status with respect to each drug alone. However, the most pronounced effects of drugs and their combinations regarding the above parameters were attributed to LOS + PIO combination. In conclusion, this study indicates that combination of ATOR + PIO and, in particular, LOS + PIO can be used as promising effective therapies in the management of HFD-induced T2DM. This concept may be attributed to the combined effects of the respective monotherapies to improve lipid profile, insulin sensitivity, and TNF-α level.
Hypertensive patients with relatively mild LVH without either increased LV volume or concentricity have similar risk of all-cause mortality or cardiovascular events because hypertensive patients with normal LVM seem to be a low-risk group.
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Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A2/prostaglandin H2 receptors and inhibits the thromboxane A2 (TxA2) analog U46619-induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA2-induced platelet aggregation and vasoconstriction in spontaneously hypertensive rats (SHRs). Pretreatment with losartan (10 microM) significantly reduced U46619-induced, concentration-dependent washed platelet aggregation. The inhibition is specific for losartan, because another Ang II AT1-receptor antagonist, CV11974 (10 microM), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 microM) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the ACH-induced endothelium-derived contracting factor (EDCF)-mediated vasoconstriction in the aortic rings from adult SHRs. U46619 produced dose-dependent vasoconstriction in aortic vessels of SHRs, which was demonstrated to be blocked by the potent, selective TxA2/PGH2 receptor antagonist SQ29,548. Pretreatment with losartan (10(-6)-10(-5) M) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold in the presence of 1 and 10 microM losartan, respectively, without changes in maximal contraction. The active metabolite of losartan, EXP3174, at 1 microM also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT2 antagonist PD123319, nor the angiotensin-converting enzyme inhibitor lisinopril, each at concentrations of 1 microM, had any effect on the U46619-induced constriction in aortic rings. In conclusion, losartan, acting as both AT1- and TxA2/PGH2-receptor antagonists, may enhance its therapeutic profile in the treatment of hypertension and cardiovascular disease.
The study was performed to investigate the role of angiotensin II type 2 (AT2) receptors and nitric oxide in the renal sympathoinhibitory response to volume expansion (VEP).
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Captopril, L-158809 and losartan were given intraperitoneally. Main outcome features: pancreatic pathology, pancreatic myeloperoxidase activity and serum amylase activity were assessed.
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Chronic treatment with carvedilol and hydralazine significantly decreased blood pressure to a similar level but failed to normalize it, whereas both losartan and quinapril completely normalized blood pressure. Despite a blood pressure reduction in all treatment groups, only losartan, quinapril and hydralazine preserved endothelial function, while carvedilol did not. Furthermore, losartan and quinapril prevented cardiac and medial hypertrophy. The expression of atrial natriuretic factor messenger RNA paralleled the hemodynamic changes. Plasma norepinephrine levels were normalized by losartan or quinapril but remained increased after carvedilol and hydralazine treatment.
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In laboratory animals with endothelial dysfunction (nitric oxide deficiency) modeled by the introduction of NO-synthase inhibitor L-NAME, the activation of endothelioprotective effects of enalapril, lozartan, amlodipine, indapamide and nebivolol is revealed for their introduction in combination with L-arginine. This result was confirmed by the behavior of a generalizing parameter, the coefficient of endothelial dysfunction (CED) calculated using the results of tests on endothelium-dependent and -independent vasodilation.
Blood pressure was measured by telemetry in spontaneous hypertensive rats (SHRs) and the acute response to losartan (L), captopril (C), or their combination in equal amounts was measured for doses of 0, 1.25, 2.5, 5, 10, 20, and 40 mg/kg.
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Pressure overload in vivo results in left ventricular hypertrophy and activation of the renin-angiotensin system in the heart. Mechanical stretch of neonatal rat cardiac myocytes in vitro causes secretion of angiotensin II (Ang II), which in turn plays a pivotal role in mechanical stretch-induced hypertrophy. Although in vivo data suggest that the stimulus of hemodynamic overload serves as an important modulator of cardiac renin-angiotensin system (RAS) activity, it is not clear whether observed upregulation of RAS genes is a direct effect of hemodynamic stress or is secondary to neurohumoral effects in response to hemodynamic overload. Moreover, it is unclear whether activation of the local RAS in response to hemodynamic overload predominantly occurs in cardiac myocytes or fibroblasts or both. In the present study, we examined the effect of mechanical stretch on expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and Ang II receptor (AT(1A), AT(1B), and AT(2)) genes in neonatal rat cardiac myocytes and cardiac fibroblasts in vitro. The level of expression of angiotensinogen, renin, ACE, and AT(1A) genes was low in unstretched cardiac myocytes, but stretch upregulated expression of these genes at 8 to 24 hours. Stimulation of cardiac myocytes with Ang II also upregulated expression of angiotensinogen, renin, and ACE genes, whereas it downregulated AT(1A) and did not affect AT(1B) gene expression. Although losartan, a specific AT(1) antagonist, completely inhibited Ang II-induced upregulation of angiotensinogen, renin, and ACE genes, as well as stretch-induced upregulation of AT(1A) expression, it did not block upregulation of angiotensinogen, renin, and ACE genes by stretch. Western blot analyses showed increased expression of angiotensinogen and renin protein at 16 to 24 hours of stretch. The ACE-like activity was also significantly elevated at 24 hours after stretch. Radioligand binding assays revealed that stretch significantly upregulated the AT(1) density on cardiac myocytes. Interestingly, stretch of cardiac fibroblasts did not result in any discernible increases in the expression of RAS genes. Our results indicate that mechanical stretch in vitro upregulates both mRNA and protein expression of RAS components specifically in cardiac myocytes. Furthermore, components of the cardiac RAS are independently and differentially regulated by mechanical stretch and Ang II in neonatal rat cardiac myocytes.
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From 109 eligible patients with hypertension, 99 started the protocol (70 under the low-dose combination). Echocardiography indices had mutual correlation and contributed independently to the primary outcome (Cronbach's α index = 0.66). Intention-to-treat analysis showed that 60 patients [60.6%, 95% confidence interval (CI) 50.3-70.3] had reduced LVM. Echocardiographic changes were not associated with dose levels. Favorable changes in BP, uricemia and microabuminuria were seen in 77, 64 and 76 patients respectively. After 6 months there were 64 (95% CI 54-74%) patients with adequately controlled hypertension.
The paraventricular nucleus (PVN) of the hypothalamus has critical homeostatic functions, including the regulation of fluid balance and sympathetic drive. It has been suggested that altered activity of this nucleus contributes to the progression of congestive heart failure (HF). We hypothesized that forebrain influences of the renin-angiotensin-aldosterone system augment the activity of PVN neurons in HF. The rate of PVN neurons (n = 68) from rats with ischemia-induced HF was higher than that of PVN neurons (n = 42) from sham-operated controls (8.7 +/- 0.8 vs. 2.7 +/- 0.3 spikes/s, P < 0.001, HF vs. SHAM). Forebrain-directed intracarotid artery injections of the angiotensin type 1 receptor antagonist losartan, the angiotensin-converting enzyme inhibitor captopril, and the mineralocorticoid receptor antagonist spironolactone all significantly (P < 0.05) reduced PVN neuronal activity in HF rats. These findings demonstrate that the renin-angiotensin-aldosterone system drives PVN neuronal activity in HF, likely resulting in increased sympathetic drive and volume accumulation. This mechanism of neurohumoral excitation in HF is accessible to manipulation by blood-borne therapeutic agents.
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In the whole cell patch clamp recording model, Ang II stimulated ICa,L in a concentration dependent manner; the maximal effect was obtained at 100 nmol/L (n = 9). At 30 nmol/L, Ang II stimulated peak ICa,L from 11.3 +/- 0.6 pA/pF to 15.3 +/- 0.6 pA/pF (at + 10 mV, n = 9, P < 0.05). 100 nmol/L Losartan, a specific AT1 receptor inhibitor, had no effect on ICa,L (n = 9), but the effect of Ang II on ICa,L was inhibited by 100 nmol/L Losartan. Ang II on ICa,L was also inhibited by 20 mumol/L H-7, a specific protein kinase C inhibitor, whereas H-7 alone has no effect on ICa,L (n = 9).
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In the Evaluation of Losartan in the Elderly (ELITE) heart failure study, a survival benefit (primarily because of a reduction in sudden deaths) was observed in symptomatic patients treated with losartan compared with captopril.
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1. We visualized the changes in intracellular Ca2+ concentration ([Ca2+]i), using fluo-3 as an indicator, in individual smooth muscle cells within intact rat tail artery preparations. 2. On average in about 45 % of the vascular smooth muscle cells we found spontaneous Ca2+ waves and oscillations ( approximately 0.13 Hz), which we refer to here as Ca2+ ripples because the peak amplitude of [Ca2+]i was about one-seventh of that of Ca2+ oscillations evoked by noradrenaline. 3. We also found another pattern of spontaneous Ca2+ transients often in groups of two to three cells. They were rarely observed and are referred to as Ca2+ flashes because their peak amplitude was nearly twice as large as that in noradrenaline-evoked responses. 4. Sympathetic nerve activity was not considered responsible for the Ca2+ ripples, and they were abolished by inhibitors of either the Ca2+ pump in the sarcoplasmic reticulum (cyclopiazonic acid) or phospholipase C (U-73122). 5. Both angiotensin antagonists ([Sar1,Ile8]-angiotensin II and losartan) and an angiotensin converting enzyme inhibitor (captopril) inhibited the Ca2+ ripples. 6. The extracellular Ca2+-dependent tension borne by unstimulated arterial rings was reduced by the angiotensin antagonist by approximately 50 %. 7. These results indicate that the Ca2+ ripples are generated via inositol 1,4, 5-trisphosphate-induced Ca2+ release from the intracellular Ca2+ stores in response to locally produced angiotensin II, which contributes to the maintenance of vascular tone.
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Last year, in 2001, the results of several major clinical trials have been published, concerning hypertensive patients with type 2 diabetes (IRMA, RENAAL and IDNT studies) and patients with previous strokes. Angiotensin II antagonists (irbesartan and losartan) are able to reduce the rate of progression of diabetic nephropathy in hypertensive patients with type 2 diabetes. This preventive effect occurs independently of the stage of renal dysfunction (early stage in IRMA, patent nephropathy in RENAAL and advanced nephropathy in IDNT). The PROGRESS study shows that the decrease in blood pressure, in response to an ACE inhibitor/diuretic bitherapy (perindopril/indapamide), in patients with previous minor stroke or transient ischaemic attack, reduces significantly the risk of recurrent stroke.
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BPP shortened repolarization in CS and PV regions but not in SN or BB, resulting in increased dispersion of repolarization in right and decreased in left atria. Propranolol, atropine and losartan failed to alter the decrease in repolarization induced by BPP whereas apamin, nifedipine and ryanodine prevented BPP effects. Before BPP, bigeminy did not induce arrhythmias in either atrium, but after BPP, bigeminy significantly increased the incidence of arrhythmias in the right atrium.
Atorvastatin was the most frequently prescribed substance. Fifteen percent of the prescriptions originate from government sector. SLMC registration number and trade names were seen more in prescriptions originating from the private sector. Most prescriptions were legible with effort. NSAIDs were the commonest implicated in drug class duplication. Fifty three percent of prescriptions have pDDI.
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Telmisartan, an angiotensin II receptor blocker, is an effective once-daily antihypertensive agent available either alone or in fixed-dose combination with hydrochlorothiazide (HCTZ). This multicentre, prospective, randomised, open-label, blinded-endpoint (PROBE) study assessed the efficacy and safety of six weeks' treatment with telmisartan 40 mg/HCTZ 12.5 mg (n = 199) and telmisartan 80 mg/HCTZ 12.5 mg (n = 200) versus losartan 50 mg/HCTZ 12.5 mg (n = 198) in patients with mild to moderate essential hypertension. During the last six hours of the dosing interval, telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg reduced mean ambulatory diastolic blood pressure (DBP) to a greater extent than losartan 50 mg/HCTZ 12.5 mg (treatment differences 1.8 mmHg [p < 0.05] and 2.5 mmHg [p < 0.001], respectively). Telmisartan 80 mg/HCTZ 12.5 mg also lowered mean 24-hour DBP by 2.3 mmHg more than losartan 50 mg/HCTZ 12.5 mg (p < 0.001). Telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg produced greater reductions in ambulatory systolic blood pressure versus losartan 50 mg/HCTZ 12.5 mg of 2.5 mmHg and 3.4 mmHg, respectively, during the last six hours of the dosing interval (p < 0.05), and of 2.1 mmHg and 3.4 mmHg, respectively, over the entire 24-hour dosing interval (p < 0.05). All treatments were well tolerated.
The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.
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The chronopharmacodynamics of angiotension-converting enzyme (ACE) inhibitors, such as ramipril (R), enalapril (E), acetene (A), caposide-50 (C-50) and the effect of the epiphyseal neurohormone melatonin used alone and in combination with cozaar (Co) and cintome (Ci) in the randomized groups including 124 patients with arterial hypertension (AH). The ACE inhibitors were given in the morning, afternoon, and evening. Co and Ci were used in the morning. Melatonin was given at 10.00 p.m. 10-14 days before and after therapy, 24-hour monitoring (Astracard, Russia) and echocardiography (Toshiba, Japan) were performed. Analyzing the findings indicated the time-dependent hemodynamic effects of R, E, and C-50. Ci, A, and Co were found to have antihypertensive and vasodilatory effects without normalizing the chronostructure of circadian rhythms of major hemodynamic parameters. By producing antihypertensive and vasodilatory effects, melatonin leads to the recovery of circadian hemodynamic organization when used alone and in combination with Co, Ci, and ACE inhibitors.
Diastolic dysfunction is present in half of patients with hypertension and has been shown to be associated with increased cardiovascular morbidity and mortality, as well as the development of heart failure. With the high prevalence of hypertension and its associated complications, treatment of diastolic dysfunction in hypertension is an important and desirable goal. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have been shown to be effective in improvement of measures of diastolic function and are recommended as first-line agents in the control of hypertension in patients with diastolic heart failure. Beta-blockers, calcium channel blockers, and diuretics have also shown some efficacy in improved indices of diastolic filling. However, the independent impact of these pharmacologic interventions on prognosis and outcome in diastolic dysfunction has yet to be clarified. The Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) study, Candesartan in Heart Failure: Assessment in Reduction of Mortality and Morbidity (CHARM-Preserved) trial and the Losartan Intervention For End-point Reduction in Hypertension (LIFE) Study all failed to show improved morbidity and mortality with these drugs although, the LIFE study showed reduced heart failure hospitalization in hypertensive patients with normal in-treatment diastolic function. The Trial Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) is an on-going large, international study evaluating the effect of spironolactone on cardiovascular mortality, aborted cardiac arrest, or hospitalization for diastolic heart failure. This and other studies will provide further insight into the pathophysiology and management of patients with diastolic dysfunction.