Candesartan Group Research Articles

An Angiotensin II Type 1 Receptor Blocker, Candesartan, Increases Myocardial Apoptosis in Rats with Acute Ischemia-Reperfusion.

Angiotensin II (Ang II) and apoptosis contribute significantly to myocardial ischemia-reperfusion (I-R) injury. Evidence indicates that Ang II may activate apoptosis in myocytes. The present study was undertaken to investigate the effects of angiotensin receptor blockers (ARBs), candesartan, on the apoptosis of cardiac myocytes in rats after I-R. Rats were divided into a control group, a candesartan group I (0.015 mg/kg), and a candesartan group II (0.03 mg/kg). Candesartan was intravenously administered 30 min before ischemia. All rats were subjected to 30 min of coronary occlusion followed by 3 h of reperfusion. The data showed that left ventricular (LV) systolic pressure and LV +dp/dt was decreased after administration of candesartan, but increased after reperfusion in the candesartan group II, compared with those in the candesartan group I and control group. LV -dp/dt was decreased after candesartan administration in candesartan group II. The number of apoptotic cells in the candesartan groups (497+/-204 and 543+/-254, respectively) was higher than that in the control group (287+/-166; p<0.05). There was no significant difference in infarct size among the three groups. However, plasma CPK was lower in the candesartan groups than in the control group. Northern blot analysis showed that p53 mRNA was upregulated in the candesartan groups, in association with increased expression of bax mRNA. Immunohistochemical analysis showed that p53 and bax immunoreactivity were increased in both of the candesartan groups. In conclusion, candesartan increased apoptosis in the rat hearts after acute I-R, and this increase was possibly mediated by upregulation of p53 and bax gene expressions. In addition, candesartan was shown to improve LV function, in association with reduction of CPK release.

Effects of Angiotensin-Converting Enzyme Inhibitor, Angiotensin II Receptor Antagonist and Calcium Antagonist on Urinary Podocytes in Patients with IgA Nephropathy

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.

Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation.

The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling. In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149+/-11 to 132+/-16 ms, P<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142+/-9 to 147+/-12 ms with candesartan, from 153+/-15 to 153+/-14 ms with captopril, P=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups. The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.

Ambulatory blood pressure assessment of once-daily candesartan cilexetil versus enalapril in patients with hypertension

Blood pressure reduction, effect duration and tolerability of the AT1-receptor blocker candesartan and the ACE inhibitor enalapril, once daily, was studied in a multicenter, double-blind, randomised, parallel group study. A total of 395 patients, aged 20–80 years, with mean sitting diastolic blood pressure 95–114 mmHg and mean awake diastolic ambulatory blood pressure (ABP) >85 mmHg after a 4-week placebo run-in period were randomised to 8 weeks treatment. The starting doses were candesartan cilexetil 8 mg or enalapril 10 mg. After 4 weeks the doses were doubled to 16 mg and 20 mg respectively, for all patients. At the end of the study, ABP was measured 0–36 hours after dose. Trough blood pressure was calculated as ABP 22–24 hours post dose. The mean adjusted reduction from baseline to after 8 weeks of trough diastolic ABP was 8.7 mmHg (95% CI 7.0–10.5) in the candesartan group vs 5.8 mmHg (95% CI 4.0–7.6) in the enalapril group (p = 0.008). For trough systolic ABP 22–24 hours post dose, the mean adjusted reduction in the candesartan group was 13.5 mmHg (95% CI 10.9–16.1) vs 9.9 mmHg (95% CI 7.3–12.6) in the enalapril group (p = 0.032). Mean adjusted reduction of diastolic ABP on the day of a missed dose (6 a.m.–6 p.m.) was 8.0 mmHg (95% CI 6.7–9.3) in the candesartan group vs 4.5 mmHg (95% CI 3.2–5.9) in the enalapril group (p < 0.001). The corresponding reductions in systolic ABP were 11.4 mmHg (95% CI 9.3–13.5) with candesartan and 7.2 mmHg (95% CI 5.1–9.4) with enalapril (p = 0.002). The proportion of patients who discontinued due to adverse events was 2.0% and 3.6% in the candesartan and enalapril groups, respectively. Once-daily candesartan cilexetil, 16 mg, was superior to enalapril, 20 mg, in reducing blood pressure at trough. At least 12 hours after a missed dose there was a persistent reduction of blood pressure during treatment with candesartan. Both treatments were well tolerated.

Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors

Background May patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme (ACE) inhibitors because of intolerance. We sought to determine the tolerability of an angiotensin II receptor blocker, candesartan cilexetil, among patients considered intolerant of ACE inhibitors. Methods Patients with CHF, left ventricular ejection fraction less than 35%, and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind randomization in a 2:1 ratio to receive candesartan (n = 179) or a placebo (n = 91). The initial dosage of candesartan was 4 mg/d; the dosage was increased to 16 mg/d if the drug was tolerated. A history of intolerance of ACE inhibitor was attributed to cough (67% of patients), hypotension (15%), or renal dysfunction (11%). Results The study drug was continued for 12 weeks by 82.7% of patients who received candesartan versus 86.8% of patients who received the placebo. This 4.1% greater discontinuation rate with active therapy was not significant; the 95% confidence interval ranged from 4.8% more discontinuation with placebo to 13% more with candesartan. Titration to the 16-mg target dose was possible for 69% of patients who received condesartan versus 84% of those who received the placebo. Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% and 3.3%, worsening heart failure 8.4% and 13.2%, myocardial infarction 2.8% and 5.5%, all-cause hospitalization 12.8% and 18.7%, and death or hospitalization for heart failure 11.7% and 14.3%). Conclusions Candesartan was well tolerated by this population. The effect of candesartan on major clinical end points, including death, remains to be determined.

Antihypertensive Effects and Tolerability of Candesartan Cilexetil in an Elderly Population

The pharmacokinetics and pharmacodynamics of antihypertensive drugs are often influenced by age, and may be different in elderly and younger patients. The choice of drug and dosage in the elderly therefore merits special consideration. The aim of this placebo-controlled study was to determine the efficacy and tolerability of the angiotensin II type 1 (AT 1 ) receptor blocker candesartan cilexetil with placebo in elderly patients with primary hypertension. Men and women, aged 65 years or older and with supine diastolic blood pressure (DBP) of 95-114 mmHg, were randomized to double-blind, once-daily treatment with candesartan cilexetil, 8 mg ( n = 96), or placebo ( n = 97) for 12 weeks. The dose was increased to 16 mg once daily if DBP was greater than 90 mmHg after 6 weeks of treatment. Forty-nine per cent of the patients remained on the 8 mg dose. At each visit, systolic blood pressure (SBP) and DBP were measured 24 h after dosing. After the first dose following randomization, blood pressure was also measured at 2 and 4 h. Placebo-corrected changes in supine blood pressure with candesartan cilexetil are shown in the Table. At the end of the study, the mean reductions in placebo-corrected supine DBP and SBP in patients receiving candesartan cilexetil were 7.5 mmHg and 13.6 mmHg, respectively ( p < 0.001 vs placebo). The incidence of adverse events in this treatment group was similar to that in the placebo group. Only four patients in the candesartan cilexetil group withdrew due to adverse events, compared with ten in the placebo group. There was no evidence of an orthostatic effect. In conclusion, in elderly hypertensive patients, candesartan cilexetil, 8-16 mg once daily, is an effective and well-tolerated antihypertensive treatment, which has a smooth onset of action and no exaggerated response after the first dose.

Candesartan Cilexetil is not Associated with Cough in Patients with Enalapril-induced Cough

Treatment with angiotensin-converting enzyme (ACE) inhibitors is frequently associated with persistent dry cough. This side effect is thought to be due to the non-specific action of ACE inhibitors, which, in addition to suppressing the renin-angiotensin system (RAS), leads to the accumulation of kinins, encephalins and other biologically active peptides. Candesartan cilexetil is a new, long-acting angiotensin II type 1 (AT 1 ) receptor blocker, which offers a more specific means of suppressing the RAS than can be achieved with ACE inhibitors. In this study, we compared the incidence and severity of cough during treatment with candesartan cilexetil, enalapril and placebo in patients with hypertension and enalapril-induced cough. Men and women, aged 20-80 years, with a history of medically treated primary hypertension and ACE-inhibitor-related cough were enrolled. The presence of cough was confirmed during a 4-week challenge period with enalapril, 10 mg, which abated during a subsequent 4-week washout period with placebo. Patients with confirmed ACE-inhibitor-related cough were then randomized to double-blind treatment with candesartan cilexetil, 8 mg once daily ( n = 62), enalapril, 10 mg once daily ( n = 66), or placebo ( n = 26). Baseline blood pressure was similar in all groups. Although blood pressure was recorded during the study, this was for safety monitoring, and the measurements were not standardized in relation to study drug intake or time of day. The frequency of dry cough was recorded on a visual analogue scale (VAS). For each assessment, patients marked a cross on a straight horizontal 100 mm line, rating cough frequency from 'none of the time( at one end of the line to 'all of the time( at the other end. The impact of treatment on quality of life was also studied, using the Symptom Assessment (SA) questionnaire and the Minor Symptom Evaluation (MSE) profile. The SA questionnaire assessed the severity of nine symptoms, including dry cough, by means of a five-graded Likert scale (not at all, a little, moderately, quite a bit, extremely). Changes in the three dimensions of the MSE profile - contentment, vitality and sleep - were recorded using a VAS. Candesartan cilexetil was superior to enalapril regarding the change in frequency ( p = 0.001) and severity ( p < 0.001) of dry cough. After 8 weeks of treatment, the proportions of patients with cough were 26.9% for placebo, 35.5% for candesartan cilexetil and 68.2% for enalapril ( p < 0.001, candesartan cilexetil versus enalapril; p > 0.20, candesartan cilexetil versus placebo). Treatment with candesartan cilexetil did not compromise patients' well-being. Compared with placebo, candesartan cilexetil was superior in terms of its effect on contentment; similar trends were noted for vitality and sleep, although the differences were not significant. When all adverse events were considered, candesartan cilexetil was very well tolerated. No serious adverse events occurred in the candesartan cilexetil or placebo groups, while three patients in the enalapril group reported serious adverse events (chest pain, agranulocytosis, accidental fracture). No treatment-related changes of clinical relevance could be found with regard to laboratory variables, ECG or vital signs/physical findings, except the anticipated blood pressure reduction in the active treatment groups. In conclusion, candesartan cilexetil is not associated with cough in hypertensive patients with previous ACE-inhibitor-induced cough. The incidence of dry cough in patients treated with candesartan cilexetil was similar to that of placebo and lower than that of enalapril.

Effects of the insurmountable angiotensin AT 1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts

Two angiotensin AT 1 receptor antagonists with different receptor binding characteristics, candesartan (insurmountable antagonism) and losartan (surmountable antagonism), were compared as regards their effects on angiotensin II-induced vasoconstriction and on myocardial ischemia/reperfusion injury. In isolated rat hearts perfused under constant flow, it was found that at equipotent concentrations candesartan (10 nM) and losartan (3 μM) almost completely inhibited the angiotensin II-induced increase in coronary perfusion pressure. However, if a washout period was introduced before the angiotensin II challenge, the effect of losartan quickly vanished, while that of candesartan remained. In hearts subjected to 25 min of global ischemia and 45 min of reperfusion, pre-treatment with candesartan (10 nM) or losartan (3 μM) immediately prior to ischemia improved the recovery of left ventricular developed pressure as compared to the effect of vehicle (69±3.2 and 64±2.3 vs. 44±6.2%, respectively; mean±S.E.M, P<0.05). When ischemia was initiated following 30 min of washout after drug administration, the recovery of left ventricular developed pressure was higher in the candesartan group (73±3.2%, P<0.05), but not in the losartan group (63±2.8%), than in the vehicle group (58±4.8%). The cumulative creatine kinase release during the first 30 min of reperfusion in the washout experiments was lower in the candesartan group (28.5±2.30 U, P<0.05), but not in the losartan (40.8±6.73 U) group, than in the vehicle group (48.1±4.35 U). No significant difference between groups in left ventricular end-diastolic pressure and coronary perfusion pressure was found. The present results demonstrate that angiotensin AT 1 receptor antagonists at equipotent concentrations could differ in their cardioprotective effects in hearts subjected to ischemia/reperfusion. It is suggested that the insurmountable AT 1 receptor characteristics of candesartan could provide more persistent cardioprotection than the surmountable receptor characteristics of losartan.

Effects of candesartan cilexetil in patients with severe systemic hypertension

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) ≥110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP ≥90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24 ± 3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, −11.3/−9.1 mm Hg versus −4.1/−3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or ≥10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.

Candesartan Cilexetil: Comparison of once-daily versus twice-daily administration for systemic hypertension

This randomized, double-masked, placebocontrolled, forced-titration, parallel-arm study was designed to compare the blood pressure (BP)-lowering effect of candesartan cilexetil, a potent antagonist of the angiotensin II receptor subtype AT 1, administered once daily with that of the same agent administered twice daily at the same total daily dose of 16 mg. After a 4- to 5-week placebo run-in period, 277 patients with a sitting diastolic BP of 95 to 109 mm Hg were randomly allocated to receive placebo (n = 92) or candesartan cilexetil 8 mg once daily for 4 weeks, followed by forced titration to either 16 mg once daily (n = 91) or 8 mg twice daily (n = 94) for 4 weeks. At 8 weeks, mean reductions in trough sitting diastolic BP were similar for the once- and twice-daily treatment groups (9.4 and 10.3 mm Hg, respectively). After 8 weeks of treatment, no statistically significant differences were observed in diastolic or systolic BP, peak or trough BP, or sitting or standing BP between the 2 active-treatment groups. The rates of positive responses (defined as a trough sitting diastolic BP of <90 mm Hg or a decrease in BP of ≥10 mm Hg) were also similar (approximately 60%) in the once- and twice-daily candesartan cilexetil groups. Furthermore, placebocorrected trough-to-peak ratios for sitting diastolic BP exceeded 75% for both candesartan cilexetil regimens, indicating a persistent 24-hour duration of drug effect. Ambulatory BP monitoring performed in a subset of patients (n = 44) confirmed the consistent 24-hour BP-lowering effect and preservation of diurnal variation with once-daily dosing. No significant betweengroup differences were observed in the incidence or severity of clinical or laboratory adverse events. The results of this study suggest that identical daily doses of candesartan cilexetil administered once or twice daily have comparable efficacy and tolerability and that no additional clinical benefit is derived from twice-daily administration.

The angiotensin II AT1 receptor antagonist candesartan at antihypertensive plasma concentrations reduces damage induced by ischemia-reperfusion.

The aim of this study was to investigate if the angiotensin II AT1 receptor antagonist candesartan in antihypertensive plasma concentrations improves myocardial function and limits infarct size in anesthetized pigs. Animals were subjected to 45 min of regional ischemia and 240 min of reperfusion. Starting 60 min before ischemia, two groups of pigs (n = 6 in each) received either candesartan (25 micrograms/kg bolus followed by a continuous infusion at a rate of 14 micrograms/kg/h) or the corresponding volume of vehicle throughout the study period. Left ventricular systolic segment shortening (%SS) was measured by sonomicrometry, and infarct size was determined by triphenyl tetrazolium chloride staining. The plasma concentration of candesartan during the experiment was between 100 and 150 nmol/L, which was considered to be within the therapeutic range. Neither candesartan nor vehicle affected hemodynamics or coronary blood flow prior to ischemia. Compared to vehicle, candesartan improved recovery of %SS in the ischemic area. At 240 min of reperfusion, the %SS was significantly higher in pigs given candesartan than in pigs given vehicle (7.1 +/- 0.87% vs-1 +/- 1.79%; p < 0.01). In both groups the area at risk was approximately 20% of the left ventricle. Infarct size as a percentage of the area at risk was significantly smaller in the candesartan group than in the vehicle group (46 +/- 3.0 vs 73 +/- 3.6%; p < 0.01). The results suggest that angiotensin II AT1 receptor blockade, obtained in antihypertensive plasma concentrations, supports myocardial functional recovery and limits infarct size.