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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Candesartan is a highly potent, long-acting and selective angiotensin II type 1 (AT1) receptor blocker. It is administered orally as the inactive prodrug candesartan cilexetil which is rapidly and completely converted to candesartan during gastrointestinal absorption. In vitro studies have shown that candesartan acts as an insurmountable angiotensin II receptor antagonist, binding tightly to and dissociating slowly from the AT1 receptor. The above characteristics are thought to contribute to the marked and long-lasting antihypertensive effects of candesartan cilexetil in several animal models of hypertension. These included rodent models of renal hypertension in which candesartan cilexetil also demonstrated efficacy equivalent to or greater than enalapril. In other animal models, candesartan cilexetil reduced the incidence of stroke, renal dysfunction and renal disease while reducing cardiac and vascular hypertrophy. Furthermore, candesartan cilexetil conferred some protection against cerebral and renal damage at a dose that had no blood pressure-lowering effect. In toxicity and general pharmacology studies, candesartan cilexetil was shown to possess a 'clean' profile with a large safety margin. Also it did not potentiate chemical- or autocoid-induced cough or anaphylactoid reactions.
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PMID:Candesartan cilexetil: a review of its preclinical pharmacology. 933 Sep 99

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

The effects of the selective angiotensin II type 1 receptor antagonist candesartan on cardiac, systemic, and regional hemodynamics and on cardiac, pulmonary, and hepatic histomorphometry were investigated in cardiomyopathic hamsters (CMHs), Bio TO-2 dilated strain, with advanced congestive heart failure (CHF). Two groups were treated orally with candesartan cilexetil at 22 or 50 mg/kg/d from 190 days of age and compared with a control group (38 animals/group). Investigations were performed at 225, 255, and 285 days of age. Left ventricle (LV) and systemic blood pressures and cardiac output and mesenteric and femoral blood flows were measured in anesthetized animals. LV cavity area, LV and right ventricle (RV) wall thickness and collagen density, and pulmonary and hepatic congestion were assessed. Compared with the control group, candesartan did not modify cardiac hemodynamics but significantly and dose-dependently decreased systemic vascular resistances (on average: -23 and -32% after 22 and 50 mg/kg, respectively) and increased stroke volume (+32 and +42%) and cardiac output (+27 and +34%). Candesartan did not modify mesenteric vascular resistances and blood flow but significantly and dose-dependently decreased femoral vascular resistances (-19 and -33%) and increased femoral blood flow (+33 and +43%). Candesartan significantly decreased LV cavity area (-14 and -8%) and LV (-15 and -31%) and RV (-16 and -24%) collagen density but did not modify LV and RV wall thickness. Candesartan decreased pulmonary congestion at 255 and 285 days of age but did not modify hepatic congestion. In CMHs with advanced CHF, candesartan cilexetil improves systemic and femoral hemodynamics, partly reverses cardiac remodeling, and decreases pulmonary congestion.
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PMID:Systemic and regional hemodynamic and cardiac remodeling effects of candesartan in dilated cardiomyopathic hamsters with advanced congestive heart failure. 1213 48

Hypertension is an established risk factor for stroke and other cerebrovascular disorders. Both stroke and small lacunar infarcts or white matter lesions can cause cognitive impairment and dementia, and there is evidence that vascular risk factors play a major role in the development of both Alzheimer's disease and vascular dementia. Several large epidemiological studies have shown that raised blood pressure in midlife is a strong risk factor for dementia later in life; however, blood pressure often decreases following the development of dementia. The cognitive function hypothesis proposes that elevated blood pressure increases the risk of decline of cognitive function, and that this can be reversed by active lowering of blood pressure. Evidence in support of this hypothesis comes from the Syst-Eur Dementia project, and from a number of smaller studies. SCOPE (Study on Cognition and Prognosis in the Elderly) is a large prospective study involving almost 5000 elderly patients (age 70-89 years), who are randomised to receive candesartan cilexetil, 8-16 mg, or placebo. Candesartan was chosen for this study because it is effective and well tolerated in elderly patients. SCOPE should provide important information on the long-term effects of AT(1)-receptor blocker treatment with candesartan on morbidity-including effects on cognitive function-and cardiovascular mortality in elderly hypertensive patients.
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PMID:Potential for antihypertensive treatment with an AT(1)-receptor blocker to reduce dementia in the elderly. 1214 Jul 32

Angiotensin II plays a pathophysiological role for the development of cardiovascular disease. Angiotensin receptor blocker(ARB) is an antihypertensive drug that blocks the angiotensin II receptor. Recently, according to the reports of basic research, ARB has various cerebrovascular-protective-effects such as improvement of cerebrovascular auto-regulation, stroke prevention, reduction of brain edema, improvement of neurological outcome in cerebral ischemia and so on. There is no report of ARB being used for the acute stage of stroke. In an ongoing ACCESS(Acute Candesartan Cilexetil Evaluation in Stroke Survivors) trial, the ARB candesartan is being used to treat the acute stage of stroke. This trial is expected to clarify whether early treatment with candesartan during the acute stage of stroke is beneficial for the neurological outcome or prognosis.
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PMID:[Beneficial effect of ARB for ischemic stroke]. 1239 96

Candesartan is a novel high-affinity type 1 AT(1)-receptor blocker characterized by prolonged binding to and slow dissociation from the receptor. Pharmacokinetic properties of candesartan explain its pronounced and lengthy (24-36 hours) antihypertensive action which does not depend on patients sex, age and body mass. Long term use of candesartan has been associated with regression of left ventricular hypertrophy, renoprotective effect and lowered risk of stroke. Candesartan is well tolerated. All these features make the drug suitable for wide application in the management of hypertension. Preliminary results suggest that candesartan can be useful in the treatment of diabetic nephropathy.
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PMID:[Candesartan - a novel AT(1)-angiotensin receptor blocker: peculiarities of pharmacology and experience of use in arterial hypertension]. 1502 49

Patients who survive a first stroke are often left with permanent disabilities, and have significant needs for rehabilitation and long-term care. Antihypertensive treatment reduces the risk of cardiovascular events such as stroke. The purpose of this study was to investigate the cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke. The cost-effectiveness analysis was based on data from Study on COgnition and Prognosis in the Elderly (SCOPE), where patients were randomly assigned to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive treatment added as needed. The analysis was carried out using a Markov model, which combined clinical and resource utilization data from SCOPE with Swedish retail prices for drugs and unit costs for in-patient stays, and outpatient visits. The cost per patient was 1949 EUR in the candesartan group and 1578 EUR in the control group. The largest share of the cost was attributed to antihypertensive treatment in the candesartan group and to the long-term cost of stroke in the control group. Candesartan-based antihypertensive treatment was associated with 0.0289 additional quality-adjusted life-years (QALYs) per patient and an incremental cost per QALY gained of approximately 13,000 EUR. Sensitivity analyses showed that these results were fairly stable. In conclusion, the cost per QALY gained with candesartan-based antihypertensive treatment lies within the range of society's willingness to pay for health gains. The results indicate that candesartan-based antihypertensive treatment is cost-effective for the prevention of nonfatal stroke.
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PMID:The cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke: results from the Study on COgnition and Prognosis in the Elderly. 1580 Jun 64

The Study on Cognition and Prognosis in the Elderly (SCOPE) assessed the effect of candesartan on cardiovascular and cognitive outcomes in elderly patients (aged 70-89 years) with mild to moderate hypertension. Patients were randomized to treatment with candesartan 8-16 mg daily (n = 2477) or placebo (n = 2460) and followed for 3.7 years on average. In agreement with the study protocol, other antihypertensive drugs were added if blood pressure remained 160 mHg systolic and/or 90 mmHg diastolic. Due to extensive add-on therapy, particularly in patients randomized to placebo, the between-treatment difference in blood pressure was only 3.2/1.6 mmHg. Nevertheless, the main analysis showed that non-fatal stroke was reduced by 28% (p = 0.04) in the candesartan group compared with the control group, and there was a non-significant 11% reduction in the primary endpoint, major cardiovascular events (p = 0.19). This review article presents different predefined and post hoc analyses made so far. Of particular interest are significant risk reductions with candesartan in major cardiovascular events (32%, p = 0.013), cardiovascular mortality (29%, p = 0.049) and total mortality (27%, p = 0.018) in patients who did not receive add-on therapy after randomization, and in whom the difference in blood pressure was 4.7/2.6 mmHg. Other analyses suggest positive effects of candesartan-based treatment on cognitive function, quality of life and new-onset diabetes. In conclusion, SCOPE strongly suggests that candesartan treatment reduces cardiovascular morbidity and mortality in old and very old patients with mild to moderate hypertension. Candesartan-based antihypertensive treatment may also have positive effects on cognitive function and quality of life.
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PMID:Findings and implications of the Study on COgnition and Prognosis in the Elderly (SCOPE) - a review. 1675 69

Hypertension is a major risk factor for stroke and dementia and is associated with white matter hyperintensities (WMH) and reduced brain volumes. We measured the increase in WMH volume, and rate of cerebral atrophy over two years, in hypertensive subjects participating in the Study on COgnition and Prognosis in the Elderly (SCOPE), receiving candesartan or placebo, and normotensive controls. We recruited 163 subjects who had MRI (FLAIR and volumetric T1) at 2 and 4 years after baseline assessment. From these two scans, volumetric change in WMH (n = 133) and brain atrophy rates (n = 95) were determined. Total WMH fraction increased in both normotensive and treated hypertensive groups (p < 0.01) median change: 0.05% of brain volume [range: -0.45% to 1.51%]. Deep WMH increased in hypertensive (p = 0.001) but not the normotensive group. The number of subjects with an increase of total WMH in the 5(th) quintile differed between the treatment groups (chi square p = 0.006), being greatest in the placebo group (32%), then candesartan (20%) then normotensive (5%). Regression analysis found significant predictors of change in WMH to be blood pressure and initial deep WMH, but not treatment group. Increased atrophy rate was predicted by baseline systolic blood pressure (p = 0.02) but was not associated with measures of WMH. Similar to WMH, there was a trend with treatment, with atrophy in normotensive < Candesartan < Placebo (Spearman's rho = 0.23, p = 0.026). Hypertension in older people is associated with increased rates of progressive whole brain atrophy and an increase in WMH. These changes are independent. Successful hypertension treatment was associated with reduced risk of WMH progression and possibly brain atrophy.
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PMID:Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure. Brain atrophy, WMH change and blood pressure. 1744 97

Cerebral ischemia results in enhanced expression of smooth muscle cell endothelin and angiotensin receptors in cerebral arteries. We hypothesise that this phenomenon may be detrimental and that acute treatment with a combined non-hypotensive dose of the angiotensin AT(1) receptor inhibitor candesartan and the endothelin ET(A) receptor antagonist ZD1611 reduces the infarct in experimental ischemic stroke. Transient middle cerebral artery occlusion was induced in male Wistar rats by the intraluminal filament technique for 2 h followed by recirculation. The animals received systemic candesartan (0.05 mg/kg/day), ZD1611 (0.15 mg/kg/day), both combined or vehicle with start immediately after the occlusion. After 48 h the rats were sacrificed, the brains sliced and stained with 1% 2, 3, 5-triphenyltetrazolium chloride (TTC) and the volume of ischemic damage determined. The middle cerebral arteries were harvested for immunocytochemical studies of angiotensin AT(1) and endothelin ET(A) receptor expression. Candesartan or ZD1611 did alone not significantly decrease the brain damage or improve neurological scores as compared to vehicle controls. The combined inhibition of angiotensin AT(1) and endothelin ET(A) receptors however decreased the brain damage and improved the neurological scores (both P<0.05). The treatment did not change resting mean arterial blood pressure. In addition, there was an upregulation of angiotensin AT(1) receptors in the ischemic middle cerebral artery smooth muscle cells, which was normalised by the combined treatment. In conclusion, the present study shows that combined inhibition of angiotensin AT(1) and endothelin ET(A) receptors reduces the brain damage and improves the neurological outcome after ischemic stroke in rat.
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PMID:Cooperative effect of angiotensin AT(1) and endothelin ET(A) receptor antagonism limits the brain damage after ischemic stroke in rat. 1759


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