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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Five clinical studies were conducted to investigate the pharmacokinetic profile and safety of candesartan cilexetil in patients with either normal or impaired renal or hepatic function. Participants in these open-label, single- or parallel-group prospective studies were administered candesartan cilexetil 8 or 12 mg as a single oral dose and then, in all but one study, as a repeated once-daily oral dose regimen. A total of 94 patients of either gender aged between 18 and 75 years with normal or mild to moderate hepatic dysfunction (Study 1) and normal or mild to moderate/severe renal dysfunction (Studies 2-5) were included. Subjects recruited to all studies evaluating the effect of renal impairment also had some degree of hypertension. Patients with mild to moderate hepatic impairment showed no significant differences in the key plasma pharmacokinetic parameters or plasma protein binding profile of candesartan compared with healthy volunteers. In patients with mild to moderate or severe renal impairment there were significant increases in the maximum plasma concentration, area under the plasma drug concentration-time curve and elimination half-life of candesartan and its inactive metabolite (CV-15959) when compared to volunteers with normal renal function following repeated administration of candesartan cilexetil 8 or 12 mg. However, there was no evidence of accumulation following treatment with the 8 mg dose apart from those with severe disease requiring dialysis. Nevertheless, dialysis itself did not appear to affect the pharmacokinetic profile of candesartan or that of CV-15959. Candesartan cilexetil was found to have a good safety profile and to be well tolerated by patients with hepatic or renal impairment. There were no clinically relevant changes detected in vital signs, laboratory safety parameters or in ECG readings. The most common adverse events were headache and dizziness. This series of studies show that candesartan cilexetil 8 mg once daily is suitable for administration to patients with mild to moderate renal or hepatic impairment with no need for additional dose adjustment. A lower starting dose may be appropriate in patients with severe renal impairment including those requiring dialysis.
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PMID:Pharmacokinetics of candesartan cilexetil in patients with renal or hepatic impairment. 933 Oct 4

Antihypertensive treatment achieves its greatest benefit in the primary prevention of stroke. Primary prevention studies show 38% fewer strokes when systolic/diastolic values are reduced by 10-12/5-6 mmHg. Secondary stroke prevention has been less investigated, but restrokes seems to be reduced with antihypertensive treatment. Secondary prevention achieves 25-30% less strokes, if diastolic BP can be reduced by 3-4 mmHg. Today's guidelines for antihypertensive therapy in acute ischemic stroke suggest reducing BP values over 220 mmHg systolic (AHA) or 200/110 (German Hypertension Society). No data are available about antihypertensive treatment in acute stroke patients. No intervention trials have so far evaluated an immediate BP reduction on the clinical outcome of the patients neurological status (morbidity) or mortality rates in the acute stroke situation. However, some studies show an increase in mortality after a quick and rapid BP reduction in a short time interval. The ACCESS study was designed to evaluate the possible benefits of a careful and moderate, but immediate blood pressure reduction in patients with an acute stroke compared to a restrictive antihypertensive therapy. Candesartan cilexetil was selected as the antihypertensive drug for its slow onset of action and moderate BP reduction, as well as its very good tolerability. Experimental studies point at possible advantages in acute stroke. The study was designed as a prospective, randomized, double-blind, placebo-controlled, multicenter trial (500 patients). Inclusion criteria were an acute ischemic stroke with a motor paresis and severe hypertension. Primary endpoints were the patients morbidity (functional status measured with Rankin and Barthel index, degree of motor deficity by NIH scale) and mortality rates after three months. First results are presented.
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PMID:Hypertension and stroke--rationale behind the ACCESS trial. Acute Candesartan Cilexetil Evaluation in Stroke Survivors. 983 67

Chronic administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces systemic hypertension and progressive development of preglomerular sudanophilic (SB+) lesions. This study investigates whether progression of SB+ lesion formation froin 4 to 6 wk of L-NAME treatment (20 mg/kg per d, orally) would be affected by 2 wk administration of either the angiotensin II type 1 receptor antagonist candesartan cilexetil (3 and 10 mg/kg per d) or the vasodilator hydralazine (15 mg/kg per d). Frequencies of arcuate arterial branches (ArcB), interlobular arteries (ILA), and afferent arterioles (AA) endowed with SB+ lesions were assessed on preglomerular vasculatures isolated after HCl maceration. Systolic BP (SBP, tail-cuff manometry) increased from a baseline of 125+/-2 to 185+/-4, and to 193+/-4 mmHg after 4 and 6 wk of L-NAME treatment, respectively. During the fourth- to sixth-week period, albumin excretion increased significantly from 3.7+/-1.1 to 52.5+/-22.4 mg/24 h. At that time, SB+ lesions affected 62+/-8, 61+/-8, and 13+/-4% of ArcB, ILA, and AA, respectively. Candesartan cilexetil dose dependently reduced SBP, albumin excretion, and lesion development. At the highest dose, SB+ lesions only affected 12+/-6, 15+/-7, and 1+/-1% of ArcB, ILA, and AA, respectively. Hydralazine similarly reduced SBP and albumin excretion, although frequencies of SB+ lesions appeared less affected along ArcB and ILA. In conclusion, progression of preglomerular SB+ lesion formation during L-NAME hypertension can be prevented by angiotensin II type 1 receptor blockade, partly through pressure-lowering effects.
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PMID:Candesartan and progression of preglomerular lesions in N(G)-nitro-L-arginine methyl ester hypertensive rats. 989 69

Clinical trials of candesartan cilexetil conducted in Japan are reviewed. Candesartan cilexetil inhibited the pressor response to intravenous angiotensin II in healthy volunteers, with peak effects observed at 4 or 8 h after oral dosing; suppressing effects persisted up to 24 h. In 14 multicentre studies with 928 hypertensive patients treated for 8 to 12 weeks, candesartan cilexetil had an efficacy rate (reduction of systolic/diastolic blood pressure > or = 20/10 mm Hg and/or mean blood pressure > or = 13 mm Hg) of 72% and 63%, and an adverse effect rate of 9.9% and 7.3%, in patients with mild-to-moderate essential hypertension and those with impaired renal function, respectively. When data for elderly patients were analysed, there was no difference in efficacy and tolerability compared to non-elderly patients. In a double-blind comparative study, candesartan cilexetil was superior to enalapril in hypertensive patients: efficacy rate, 74% vs 66% (NS); adverse symptom rate, 10.4% vs 27.3% (P < 0.01); incidence of cough, 1.5% vs 14.8% (P < 0.01). Treatment with 2-8 mg of candesartan cilexetil once daily for 8 to 12 weeks reduced the left ventricular mass index without deterioration of cardiac function. In conclusion, 4-12 mg of candesartan cilexetil once daily is effective and well tolerated in patients with essential hypertension, including elderly patients, those with severe hypertension, and hypertensive patients with renal insufficiency. Its improved tolerability profile over angiotensin-converting enzyme inhibitors, as well as its end-organ protective effects, suggest that candesartan cilexetil is useful as a first-line antihypertensive drug.
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PMID:Clinical efficacy and tolerability of candesartan cilexetil. Candesartan Study Groups in Japan. 1007 18

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.
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PMID:Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action. 1007 25

On the basis of results of long-term trials, to date, it is reasonable to conclude that blood pressure lowering, per se, rather than the identity of the antihypertensive regimen, is associated with reducing risk for stroke and coronary heart disease in patients with hypertension. Clinicians should identify drugs within each antihypertensive class that reduce blood pressure consistently over a 24-hour period and have a duration appropriate for once-daily administration. Candesartan cilexetil is an appropriate choice among angiotensin II receptor blockers (ARBs); it has a trough: peak ratio of 0.9-1.1, which fully justifies once-daily dosing. Once genuinely long-acting antihypertensive medications are used routinely, it will be possible to evaluate whether the different drug classes provide ancillary benefits beyond blood pressure lowering.
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PMID:Do pharmacologic differences among antihypertensive agents point to clinical benefits? 1058 91

Blood pressure remains poorly controlled in the hypertensive population due in large part to low or unsatisfactory patient compliance. Clinical studies that incorporate an intentionally missed dose have been designed to evaluate the impact of poor patient compliance on the effectiveness of antihypertensive medications. In these studies, ambulatory blood pressure monitoring is continued throughout the dosing interval and beyond in order to determine when systolic and diastolic blood pressure increase into the hypertensive range. In an 8-week, randomized, double-blind, placebo-controlled trial in patients with mild-to-moderate hypertension, the antihypertensive effects of candesartan cilexetil 16 mg were maintained after a missed dose, whereas systolic and diastolic blood pressure increased toward baseline levels after a missed dose of losartan 100 mg. Candesartan cilexetil provided a significantly greater reduction in sitting systolic (p = 0.004) and diastolic blood pressure (p = 0.008) than losartan when measured 48 hours after the last dose. Moreover, the homogeneity of antihypertensive effects was greater after candesartan cilexetil than losartan based on calculation of the smoothness index from ambulatory systolic and diastolic measurements during the first 24-hour period after dosing and during the 12-hour period after the missed dose. These results demonstrate that missing or delaying a dose of candesartan cilexetil has less impact on antihypertensive efficacy than missing or delaying a dose of losartan.
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PMID:Comparison of angiotensin II receptor blockers: impact of missed doses of candesartan cilexetil and losartan in systemic hypertension. 1058 92

This randomized, double-blind, placebo-controlled multicenter study was designed to evaluate the efficacy, tolerability, and safety of candesartan cilexetil in a diverse population of patients with severe systemic hypertension (diastolic blood pressure > or =110 mm Hg). After a placebo run-in period, patients were given hydrochlorothiazide (HCTZ) 12.5 mg once daily for 1 week. A total of 217 patients with sitting diastolic blood pressure >95 mm Hg while receiving HCTZ were then randomized in a 2:1 ratio to receive candesartan cilexetil or placebo once daily for 4 weeks. Candesartan cilexetil was started at 8 mg and titrated to 16 mg if needed for blood pressure control; background HCTZ was continued in both groups. Candesartan cilexetil was significantly more effective than placebo in lowering trough diastolic and systolic blood pressure. The mean change in trough sitting diastolic blood pressure from the end of the HCTZ run-in period to the week 4 endpoint (primary study endpoint) was -9.1 mm Hg with candesartan cilexetil and -3.1 mm Hg with placebo (p = 0.0001). A higher percentage of patients treated with candesartan cilexetil than placebo responded to treatment (53% vs 29%) and achieved diastolic blood pressure <90 mm Hg (32% vs 15%). Subgroup analyses indicated that candesartan cilexetil was especially effective in patients with higher trough diastolic blood pressure at randomization, and it was significantly more effective than placebo in both black and nonblack patients alike as well as in women and men. Candesartan cilexetil was safe and well tolerated, with an adverse-event profile comparable to placebo. These results demonstrate that candesartan cilexetil added to background HCTZ therapy is effective and well tolerated in lowering blood pressure in patients with severe systemic hypertension.
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PMID:Candesartan cilexetil in combination with low-dose hydrochlorothiazide is effective in severe hypertension. 1058 93

The renin-angiotensin system plays a central role in the regulation of blood pressure through its primary effector hormone angiotensin II. Studies conducted nearly 30 years ago with peptidic angiotensin II receptor blockers (ARB) suggested that disruption of the renin-angiotensin system offered considerable promise for the treatment of hypertension as well as heart failure. This promise was initially realized with the advent of angiotensin converting enzyme inhibitors, and more recently with nonpeptidic ARB that selectively antagonize the AT1-angiotensin receptor subtype. The potent and long-acting agent candesartan cilexetil illustrates how these new ARB fulfill the promises suggested by the early studies. Candesartan cilexetil provides a clinically relevant, dose-dependent reduction in diastolic and systolic blood pressure at doses of 4 to 16 mg once daily in patients with mild to moderate hypertension. Recent studies suggest that further blood pressure lowering is obtained with a 32-mg once daily dose. In comparative clinical trials, 8 mg of candesartan cilexetil and 10 to 20 mg of enalapril provided comparable antihypertensive effects. The safety and tolerability profile of candesartan cilexetil is comparable to placebo. Notably, this agent does not produce the dry, nonproductive cough that often limits use of angiotensin converting enzyme inhibitors, nor does it cause side effects that limit other antihypertensive drug classes. On the basis of the results of initial clinical studies, ARB also possess cardioprotective and renoprotective properties that promise to expand the role that these new agents will play in treating cardiovascular disorders.
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PMID:Update on the clinical pharmacology of candesartan cilexetil. 1067 85

The aim of this large, randomized, double-blind, parallel-group study in hypertensive women was to compare the antihypertensive efficacy and effects on subjective symptoms and quality of life of the new angiotensin II type 1 (AT1) receptor blocker candesartan cilexetil, the angiotensin-converting enzyme inhibitor enalapril, and the diuretic hydrochlorothiazide (HCTZ). Women, aged 40 to 69 years, with a seated diastolic blood pressure (DBP) of 95 to 115 mm Hg, were randomized to candesartan cilexetil, 8 to 16 mg (n = 140), enalapril, 10 to 20 mg (n = 146), or HCTZ, 12.5 to 25 mg (n = 143), for 12 weeks; the higher doses were used if DBP was greater than 90 mm Hg after 6 weeks. Candesartan cilexetil lowered seated blood pressure by 17/11 and 19/11 mm Hg after 6 and 12 weeks of treatment, respectively. This reduction was greater (P < .01) than with enalapril (12/8 and 13/9 mm Hg) or HCTZ (12/7 and 13/8 mm Hg). The proportions of patients with controlled DBP (< 90 mm Hg) after 12 weeks of treatment with candesartan cilexetil, enalapril, or HCTZ were 60%, 51%, and 43%, respectively. Patients experienced less dry cough (P < 0.001) with candesartan cilexetil or HCTZ than with enalapril. No treatment differences were found in the incidence of dizziness and quality of life was well maintained in all groups. Compared with candesartan cilexetil and enalapril, HCTZ increased uric acid and decreased serum potassium (P < .001). In conclusion, candesartan cilexetil reduced blood pressure more effectively and was better tolerated than enalapril or HCTZ in women with mild to moderate hypertension.
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PMID:Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide. 1082 1


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