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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Over the past 4 years, six angiotensin II receptor antagonists (ARBs) were approved for treating essential hypertension. They differ with respect to dosing, metabolism, elimination, clinical efficacy, and investigational applications. Candesartan cilexetil is the only prodrug among the agents. Losartan is distinguished from other ARBs by cytochrome P450 (CYP) 3A4- and CYP2C9-mediated biotransformation to its active metabolite EXP-3174. No ARB requires dosage adjustment for renal impairment, but the initial dose of losartan should be reduced 50% in hepatically impaired patients. None of the drugs is significantly cleared by hemodialysis. Completion of continuing trials will elucidate the drugs' role in treating heart failure, cerebral stroke, and myocardial infarction.
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PMID:Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. 1067 91

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
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PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

The nonpeptide angiotensin II (AII) subtype-1 (AT1) receptor antagonist candesartan cilexetil is completely converted to its active form, candesartan, during gastrointestinal absorption. In in vitro studies, candesartan has been found to act as an insurmountable antagonist at the AT1 receptor that dose-dependently reduces the maximal contractions induced by AII and, at high concentrations, virtually eliminates the AT1-receptor-mediated effects of AII. Receptor binding studies suggest that insurmountable antagonism may be due to tight binding to the AT1 receptor and slow dissociation from it. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension. Candesartan cilexetil exerts a long-lasting antihypertensive action in spontaneously hypertensive rats in the low dose range of 0.1-10 mg/kg. The long-lasting antihypertensive effect of candesartan cilexetil is confirmed by the trough/peak ratio in hypertensive patients. It has been demonstrated that administration of AII receptor antagonists is followed by a rise in AII levels, and the increased AII levels result in competition with the antagonist for binding to the receptor. Insurmountable antagonists would seem to be more advantageous since they would block more efficiently in the presence of increasing AII levels than surmountable antagonists. A growing number of studies indicate that candesartan cilexetil provides end-organ protection in addition to lowering blood pressure. The utility of AT1 antagonists may extend beyond treatment of hypertension, chronic heart failure and renal diseases, as suggested by the potential usefulness of ACE inhibitors in the treatment or prevention of many other cardiovascular diseases.
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PMID:[Candesartan cilexetil: pharmacological properties and protective effects against organ damage of a novel nonpeptide angiotensin II-receptor antagonist]. 1087

Patients with hypertension do not comprise a homogeneous group, and the majority present with a variety of concomitant and associated conditions. Antihypertensive therapies should therefore be effective and well tolerated in a wide range of patients and should, ideally, ameliorate the negative target-organ effects of hypertension, such as atherosclerosis, cardiovascular remodelling and renal impairment. Evidence is accumulating that the new angiotensin II type 1 receptor blocker, candesartan cilexetil, lowers blood pressure effectively and is well tolerated in a variety of patient groups, including women and the elderly. In patients with severe hypertension, a treatment schedule based on candesartan cilexetil, with the addition of diuretic and calcium antagonist therapy as needed, has been found to control blood pressure successfully. Candesartan cilexetil does not affect glucose tolerance or lipid profiles in patients with diabetes mellitus, and it is not associated with any of the side effects of other antihypertensive agents that would make it unsuitable for use in patients with pulmonary disease. Initial clinical studies have indicated that candesartan cilexetil is well tolerated and effective in patients with heart failure. Furthermore, the available evidence shows that treatment with candesartan cilexetil can reverse the negative effects of hypertension on left ventricular hypertrophy and microalbuminuria. It therefore appears that the pronounced efficacy and placebo-like tolerability of candesartan cilexetil, as demonstrated in large clinical trials of patients with mild to moderate hypertension, can be extended to a wide range of specific patient groups.
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PMID:Efficacy and tolerability of candesartan cilexetil in special patient groups. 1105 33

Prognosis can be improved in hypertensive patients not only by reducing blood pressure, but probably also by effective suppression of adverse neurohormonal influences. Inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors effectively reduces left ventricular hypertrophy and decreases morbidity and mortality due to heart failure, as well as slowing the progression of renal disease. Initial data from studies of angiotensin II type 1 (AT1) receptor blockers indicate that these agents should also be effective in reducing cardiac and renal damage. In this class, candesartan, by virtue of its tight and long-lasting binding to the AT1-receptor, provides pronounced 24-h blood pressure control with effective blockade of all the major negative cardiovascular effects of angiotensin II. Candesartan cilexetil has also been shown to be effective and well tolerated in combination with hydrochlorothiazide in those hypertensive patients who require more than one agent to reach their target blood pressure.
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PMID:Improving prognosis in hypertension: exploring the benefits of angiotensin II type 1 receptor blockade. 1105 34

Hypertension is a major cardiovascular risk factor, but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. Angiotensin receptor blockers have emerged as a major therapeutic class because they meet both of these requirements. Numerous studies indicate that all approved angiotensin receptor blockers are highly selective for angiotensin-1 receptors, lower blood pressure as monotherapies, and work well in combination with other drugs - particularly diuretics. The side-effect profile of angiotensin receptor blockers is similar to that of placebo and they have not been associated with known side effects of angiotensin-converting enzyme inhibitors such as cough and angioneurotic edema. Candesartan cilexetil is an angiotensin receptor blocker with insurmountable binding properties to the angiotensin-1 receptor, long duration of action and improved efficacy. In patients with hypertension, candesartan monotherapy has been shown to be safe and effective. Comparative data have shown similar or better results to other monotherapies in blood-pressure control, and in combination with hydrochlorothiazide it has been shown to have additive or synergistic effects. More recent data demonstrate that candesartan cilexetil is useful in the treatment of patients with heart failure and may protect against diabetic nephropathy. Studies have also shown protection from stroke, particularly in patients with isolated systolic hypertension.
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PMID:Candesartan cilexetil in cardiovascular disease. 1550 Apr 28

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. Clinical trials have demonstrated its efficacy at a dose range of 2 to 32 mg once daily in hypertension of all grades, heart failure, in reducing urinary albumin excretion in diabetes mellitus and in coexisting hypertension and renal failure. Pharmacokinetic properties of candesartan cilexetil in elderly patients are not significantly different from those in younger individuals. Hepatic impairment does not change pharmacokinetics of candesartan cilexetil at doses up to 12 mg/day. No dose adjustment is necessary in patients with mild or moderate renal impairment. Tolerability of candesartan cilexetil is not much different from that of placebo. All adverse events are usually of mild to moderate severity and not dose-related. The most common adverse events were headache, upper respiratory tract infection, back pain, and dizziness. The incidence of these adverse effects, as well as of cough, was similar in patients treated with candesartan cilexetil or placebo. The incidence of adverse events in long-term trials was not different from that in short-term trials. Tolerability of candesartan cilexetil does not differ with either age or gender.
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PMID:Candesartan. 1559 74

Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function. Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) < or =40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens.
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PMID:Candesartan cilexetil: a review of its use in the management of chronic heart failure. 1573 14

Candesartan cilexetil is a nonpeptide selective blocker of the angiotensin II receptor sub-type 1. It is a prodrug that is converted to its active metabolite during its variable absorption. It is highly protein bound with a small volume of distribution and a nine-hour half-life. Candesartan is one of two angiotensin receptor blockers approved for use in heart failure. MEDLINE was searched using OVID and PubMed to evaluate the evidence for using candesartan in patients with heart failure. Pharmacologic and pharmacokinetic evaluations, as well as clinical trials, were selected and are presented in this review. Clinical evidence supports the indication for use in systolic heart failure. Results for use in patients with diastolic heart failure were non-significant. Candesartan was well tolerated in the trials, with hyperkalemia, renal dysfunction, and hypotension being the most common adverse events. Use of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors needs further study; however, candesartan appears to provide added benefit in this setting. Candesartan is a safe and effective option for patients with systolic heart failure. Data regarding other angiotensin receptor blockers is underway.
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PMID:Candesartan in heart failure. 1804 13


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