All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ----------------------------------------------------------- Source: Yakugaku Zasshi 2000 Dec;120(12):1261-75 Title: Angiotensin II receptor antagonists: candesartan cilexetil. Authors: Naka T, Kubo K, Nishikawa K, Inada Y, Furukawa Y. INTRODUCTION: We recently discovered a new class of potent nonpeptide angiotensin 2 receptor antagonists, including candesartan. Candesartan is very potent at tying up angiotensin 2 receptors. FINDINGS: The presence of a carboxyl group at the 7-position was found to be the needed factor to make the drug completely block the angiotensin 2 receptors. To improve the body's use of candesartan, we made some changes to its chemistry and got candesartan cilexetil, a prodrug of candesartan. CONCLUSIONS: Candesartan cilexetil is a potent and long-acting blocker that - when given once a day - gives effective 24 hour blood pressure control. PMID: 11193378 ===================================== Source: Blood Press Suppl 2000;1:44-8 Title: Exploring new treatment strategies in heart failure. Author: Swedberg K. INTRODUCTION: One of heart failure's key causes is hormone activity through the sympathetic nervous system and the RAS (renin-angiotensin system). Blockers of this nervous system (beta-blockers) and blockers of the RAS (ACE inhibitors and ARBs) are critical in treating heart failure. DISCUSSION: Using ARBs such as candesartan gives more specific and possibly more complete blockade of heart-damaging effects of angiotensin 2 than is possible using just ACE inhibitors. A major international study - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been started to test candesartan cilexetil in heart failure patients. The 6500 CHARM patients will be divided into 3 integrated studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who do not tolerate ACE inhibitors. The third study group will examine the effects of the drug in people with heart failure symptoms but "normal" systolic function. PMID: 11059637 ===================================== Source: Blood Press Suppl 2000;1:27-30 Title: Efficacy and tolerability of candesartan cilexetil in special patient groups. Author: Trenkwalder P. INTRODUCTION: People of all types and with all kinds of health problems have high blood pressure. Treatment should therefore be effective and well tolerated in a wide range of patients. DISCUSSION: Recent evidence shows that the angiotensin II type 1 receptor blocker (ARB), candesartan cilexetil, lowers blood pressure well and is well tolerated in many patient groups, including women and the elderly. In those with severe high blood pressure, treatment with this drug, combines with a diuretic and calcium channel blocker if necessary, has controlled blood pressure successfully. Candesartan cilexetil does not affect glucose or cholesterol levels in diabetic patients. It is well tolerated in patients with lung disease. So far, studies show that it is well tolerated and effective in patients with heart failure. Available evidence also shows that treatment with this drug can reverse the negative effects of high blood pressure on heart enlargement. PMID: 11059633 ===================================== Source: Cardiology 2000;93(3):175-82 Title: Hemodynamic and hormonal effects of the angiotensin II antagonist, candesartan cilexetil, in patients with congestive heart failure. Authors: Yoshimura M, Yasue H. INTRODUCTION: Candesartan cilexetil is a new angiotensin II type 1 receptor antagonist (ARB). It is a prodrug and is converted to its active form - candesartan - by the enzyme 'esterase' when it is absorbed in the intestine. We did a single-dose study to measure the drug's effect on heart function and hormone response in 13 heart failure patients. FINDINGS: Average blood pressure did not change in patients taking either 2 or 8 mg. PCWP went down 35% in patients taking 8 mg. Cardiac index did not change. Peripheral vascular resistance went down after one hour in patients taking 2 or 8 mg and continued to go down slightly for 8 hours after taking the dose. Atrial natriuretic peptide (ANP) levels went down 16% two hours after taking 8 mg. Brain natriuretic peptide (BNP) levels went down slightly after taking the drug. CONCLUSIONS: Taking candesartan cilexetil reduces cardiac preload and afterload and should be useful for treating congestive heart failure. PMID: 10965089 ===================================== Source: Am Heart J 2000 Apr;139(4):609-17 Title: Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Authors: Granger CB, Ertl G, Kuch J, Maggioni AP, McMurray J, Rouleau JL, Stevenson LW, Swedberg K, Young J, Yusuf S, Califf RM, Bart BA, Held P, Michelson EL, Sellers MA, Ohlin G, Sparapani R, Pfeffer MA. INTRODUCTION: Many heart failure patients do not tolerate ACE inhibitors. We tested these patients' ability to tolerate an ARB - candesartan cilexetil. FINDINGS: Patients with CHF and an ejection fraction under 35%, who could not tolerate ACE inhibitor use were studied. In double-blind randomizationm they took either candesartan (179 patients) or placebo (91 patients). Starting dose was 4 mg per day. Dose was increased to 16 mg per day if the drug was tolerated. Previous reasons for not taking an ACE inhibitor were cough (67% of patients), low blood pressure (15%), or weak kidneys (11%). The drug was continued for 12 weeks by 83% of candesartan patients versus 87% of placebo patients. Sixty-nine percent of candesartan patients reached the target dose of 16 mg versus 84% of placebo patients. Death and complications were about the same in both groups: Candesartan group Placebo group Death 3.4% 3.3% Worsening CHF 8.4% 13.2% Heart attack 2.8% 5.5% All-cause hospitalization 12.8% 18.7% Death or hospitalization for heart failure 11.7% 14.3% CONCLUSIONS: Candesartan was well tolerated by patients who could not or would not take ACE inhibiotrs. Effect of the drug on clinical end points such as death remains to be seen. PMID: 10740141 ===================================== Source: J Am Coll Cardiol 2000 Mar 1;35(3):714-21 Title: Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure. Authors: Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, Matsumoto T, Kinoshita M. INTRODUCTION: Angiotensin 2 stimulates production of immune factors. We studied the effects of candesartan cilexetil (an ARB) on the immune system in CHF patients. FINDINGS: 23 patients with mild to moderate CHF were randomly divided into 2 groups. One group took candesartan cilexetil (14 patients and the other took placebo (9 patients). We measured blood levels of immune factors such as TNF (tumor necrosis factor alpha), IL-6 (interleukin-6), sICAM-1 (soluble intercellular adhesion molecule-1) and sVCAM-1 (soluble vascular cell adhesion molecule-1 (sVCAM-1). We also measured blood levels of ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide), and cGMP (cyclic guanosine monophosphate) - a marker of ANP and BNP. Levels of TNF, IL-6, sICAM-1 and sVCAM-1 went down in the 23 CHF patients after 14 weeks of candesartan cilexetil compared to placebo patients. Levels of BNP - a marker of heart injury - went down in patients taking the drug but not in placebo patients. CONCLUSIONS: Fourteen weeks of treatment with an ARB - candesartan cilexetil - lowered blood levels of immune markers such as TNF, IL-6, sICAM-1 and sVCAM-1, and improved levels of heart natriuretic peptides in patients with mild to moderate CHF. PMID: 10716475 ===================================== Source: Pharmacotherapy 2000 Feb;20(2):130-9 Title: Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. Authors: Song JC, White CM. INTRODUCTION: Over the past 4 years, 6 ARBs (angiotensin II receptor antagonists) were approved for treating high blood pressure. They are different in some ways - dosing, metabolism, elimination, and effectiveness in specific areas. DISCUSSION: Candesartan cilexetil is the only prodrug among them. Losartan is different from other ARBs by the way it is changed in the body to its active form. No ARB dose needs to be changed for patients with weak kidneys but starting dose of losartan should be reduced 50% in patients with weak liver function. None of the drugs is eliminated from the body by hemodialysis. Ongoing trials will help show the drugs' role in treating heart failure, cerebral stroke, and heart attack. PMID: 10678291 ===================================== Source: Am J Hypertens 2000 Jan;13(1 Pt 2):25S-30S Title: Update on the clinical pharmacology of candesartan cilexetil. Author: Gavras H. INTRODUCTION: The RAS (renin-angiotensin system) is one key to regulating blood pressure - through its primary active hormone angiotensin II. ACE inhibitors, and more recently, ARBs that selectively 'block' AT1-angiotensin receptors have proven effective in treating CHF by changing RAS activity. FINDINGS: The long-acting drug candesartan cilexetil is an effective ARB. It causes a dose-dependent lowering of of both diastolic and systolic blood pressure at doses of 4 to 16 mg once daily. Further blood pressure lowering is obtained with a 32 mg once daily dose. In trials, 8 mg of candesartan cilexetil and 10 to 20 mg of enalapril (Vasotec) gave similar blood pressure reduction. Candesartan cilexetil appears to be as safe and well tolerated as placebo. It does not cause "ACE cough." PMID: 10678285 ===================================== Source: Ann Pharmacother 1999 Dec;33(12):1287-98 Title: Candesartan cilexetil: an angiotensin II receptor blocker. Author: Stoukides CA, McVoy HJ, Kaul AF. INTRODUCTION: We studied all the medical literature on on candesartan cilexetil, an ARB. FINDINGS: ARBs are a new class of drugs useful for treating high blood pressure. Trials are studying their use for treating CHF. Candesartan cilexetil is one of the newest drugs in this class, which includes losartan, irbesartan, and valsartan. Candesartan cilexetil has 1000 times more affinity for the angiotensin II, type AT1 receptor ARBs. Its action is stronger than losartan. At doses of 4 to 16 mg, candesartan cilexetil is better at reducing blood pressure than 50 mg of losartan. Candesartan cilexetil causes reductions in blood pressure similar to the ACE inhibitor enalapril (Vasotec), with fewer side effects. Dose adjustments are not necessary for elderly patients or in patients with mild kidney or liver problems. Diabetic patients are not affected in blood glucose, hemoglobinA1c, or cholesterol levels by the drug. Side effects are actually about equal to placebo. CONCLUSIONS: Candesartan cilexetil is well tolerated and effective in reducing blood pressure. Due to its greater affinity for the angiotensin II receptor, this drug seems to have a longer effect than losartan. PMID: 10630830 ===================================== Source: Circulation 1999 Nov 30;100(22):2224-30 Comment in: Circulation. 1999 Nov 30;100(22):2208-9 Title: Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure (STRETCH) Investigators. Authors: Riegger GA, Bouzo H, Petr P, Munz J, Spacek R, Pethig H, von Behren V, George M, Arens H. INTRODUCTION: The RAS (renin-angiotensin system) plays a large role in congestive heart failure. We studied the effect of the angiotensin II type 1 receptor antagonist candesartan cilexetil on exercise ability and CHF symptoms. FINDINGS: Eight hundred and forty-four CHF patients took either placebo (211 patients) or 4 mg candesartan cilexetil (208 patients), 8 mg of the drug (212 patients), or 16 mg of the drug (213 patients) fro 12 weeks. Changes in exercise time, shortness of breath, fatigue, heart class, and heart size were measured. Candesartan cilexetil improved exercise time. The 16 mg drug patients had a much greater improvement than placebo patients. (47 versus 31 seconds). All doses of the drug improved shortness of breath and fatigue versus placebo. Heart class improved more often in the candesartan cilexetil groups but was not significant. Heart size went down slightly with 4 to 16 mg of the drug. In all drug groups, renin activity and blood angiotensin II levels went up. Aldosterone levels went down in the 8 mg and 16 mg drug groups. The drug was well tolerated at all doses. CONCLUSIONS: Treatment with candesartan cilexetil caused significant improvements in exercise tolerance, heart size, and CHF symptoms. The drug was well tolerated. PMID: 10577995 ===================================== Source: J Card Fail 1999 Sep;5(3):276-82 Title: Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. Authors: Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, Ohlin G, Olofsson B, Ostergren J, Yusuf S. INTRODUCTION: CHF treatment with ACE inhibitors and beta-blockers improves survival and reduces hospitalizations in patients with low ejection fractions. Despite these drugs, complications and mortality remain high. many CHF patients have a preserved ejection fraction. We don't know if standard treatments benefit this group. FINDINGS: CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) studies the usefulness of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil. A wide range of heart failure patients are included. CHARM consists of 3 independent, placebo-controlled studies in patients with: 1) EF less than or equal to 40%, ACE-inhibitor treated (2,300 patients) 2) EF less than or equal to 40%, ACE-inhibitor intolerant (1,700 patients) 3) EF greater than 40%, not treated with ACE inhibitors (2,500 patients) The 3 studies will be combined to decide the effect of the drug on all-cause mortality across a range of CHF patients. Primary endpoint in each trial is effect on mortality or CHF hospitalization. Secondary endpoints include effect on heart attack, all-cause hospitalization, and resource use. CHARM should include 6,500 CHF patients from 26 countries. Patients began enrolling in March of 1999. The follow-up period is at least 2 years. The study is expected to end in the third quarter of 2002. PMID: 10496201