UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
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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

Candesartan cilexetil is highly effective at lowering blood pressure, whilst maintaining placebo-like tolerability, in a wide range of patient groups. Although the benefit of lowering blood pressure in elderly patients with moderate hypertension has been demonstrated in several large-scale clinical trials, elderly patients with mild hypertension have rarely been studied. The high incidence of cardiovascular and cerebrovascular mortality and morbidity, including dementia, in the elderly means that control of blood pressure is particularly important in this patient group. A major new international clinical trial - SCOPE (Study on COgnition and Prognosis in the Elderly) - has therefore been initiated. This is a prospective, randomized, double-blind, parallel comparison of the effects of candesartan cilexetil, 8 or 16 mg once daily, and placebo in about 5000 patients who will be followed for a mean of 2.5 years. SCOPE is the first study designed to assess the effect of antihypertensive therapy in elderly patients (70-89 years of age) with mild hypertension (sitting systolic blood pressure of 160-179 mmHg and/or sitting diastolic blood pressure of 90-99 mmHg). The primary objective of the study is to determine the effect of candesartan cilexetil on major cardiovascular events (cardiovascular death, non-fatal stroke and myocardial infarction, and silent myocardial infarction), while an important secondary objective is to determine the effect of such treatment on the prevention of cognitive impairment. SCOPE should provide definitive evidence of the cardiovascular and cerebrovascular benefits of treating mildly hypertensive elderly patients with angiotensin II type 1 receptor blockers, which not only reduce blood pressure, but may also provide significant protection from the negative effects of angiotensin II on target organs.
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PMID:Reducing cardiovascular morbidity and mortality in the elderly. 1105 36

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.
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PMID:Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. 1124 91

A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT1 subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5,446 patients who had essential hypertension (HBP) and 1,014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha- or beta-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/ 13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), beta-blockers (16.5/ 10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), alpha-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), beta-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and alpha-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.
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PMID:Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial. ACTION Study Investigators. 1141 37

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan. Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours. Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan. Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min x 1.73m(2), 30 to 60 ml/min x 1.73m(2) and 15 to 30 ml/min x 1.73m(2), the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.
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PMID:Clinical pharmacokinetics of candesartan. 1182 94

The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.
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PMID:Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. 1286 5

The nonpeptide AT(1) receptor antagonist candesartan is generated from the prodrug candesartan cilexetil during gastrointestinal absorption. In vitro studies have shown that candesartan acts as an insurmountable, tightly bound antagonist at the AT(1) receptor, producing a dose-dependent reduction in the maximal responses to angiotensin II (AII) and virtually an elimination of the AT(1) receptor-mediated effects of AII at high concentrations. The binding of candesartan to the AT(1) receptor is highly selective, and the drug dissociates slowly from the receptor. Candesartan cilexetil produces the expected changes in the parameters of the renin-angiotensin system. Plasma renin activity and plasma AII concentrations were increased and aldosterone levels decreased following drug application. As a consequence, stimulation of AT(2) receptor-mediated actions of AII, such as growth inhibition and vasodilation, may contribute to the overall effects of the AT(1) antagonist, since the AT(2) receptors are left unopposed by candesartan. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension including 2 kidney-1 clip and 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats (SHR). Candesartan cilexetil produced a slow onset, long-lasting antihypertensive action at a dose range of 0.1-10 mg/kg with no rebound effect upon drug withdrawal. A growing number of studies indicate that candesartan cilexetil can produce end organ protection in addition to lowering blood pressure. In preclinical studies, candesartan cilexetil caused prevention and regression of left ventricular hypertrophy and cardiac fibrosis, protected the heart against ischemia-reperfusion injury and reduced myocardial damage during myocarditis. In different animal models of renal dysfunction, candesartan cilexetil reduced proteinuria and albuminuria, inhibited histopathological renal changes and controlled the renal expression of TGF-beta1 and collagen types I and III. Finally, in stroke prone SHR, candesartan cilexetil markedly attenuated the incidence of stroke even at low doses, with minimal blood pressure lowering effects, and fully protected against stroke at higher doses.
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PMID:Candesartan cilexetil: development and preclinical studies. 1297 13

Hypertension is a major risk factor for cardiovascular events and the goal of treating hypertension is to prevent complications due to these events. However, some other properties, including few side-effects and improvement of the quality of life (QOL), are desirable in a drug as well as its antihypertensive effect. Dehydropydine calcium-channel blockers (DCCBs) are the most frequently used antihypertensive agents in Japan. The antihypertensive effect of DCCBs is satisfactory, but side-effects, e.g. nocturia, flushing and palpitations, are a problem. The aim was to evaluate the effects of a change of treatment from DCCBs on the QOL of hypertensive patients. An open study was performed to evaluate the effects of switching treatment from DCCBs to angiotensin II receptor blocker (ARB) therapy on the QOL of hypertensive patients. The ARBs have been reported to be effective and well-tolerated antihypertensive drugs. Candesartan cilexetil was selected because it is the most frequently used ARB in Japan. One hundred patients with mild to moderate hypertension, being treated with DCCBs, were randomly selected to receive candesartan cilexetil (8-12 mg once a day). The patients were followed for 3 months, while blood pressure (BP), side-effects and QOL were monitored. BP was equally well controlled before and after the change of antihypertensive therapy. The candesartan cilexetil-treated patients exhibited improvement of several aspects of QOL, including general symptoms, physical symptoms and well-being, work and satisfaction and sleep scale. Emotional state and cognitive function also improved. Patients aged 65 years or younger achieved significant improvement of sexual function. Changing treatment from DCCBs to ARB therapy achieved equal BP control with a lower drug dose. Moreover, the change to cadesartan cilexetil had a positive impact on the QOL.
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PMID:The effects of replacing dihydropyridine calcium-channel blockers with angiotensin II receptor blocker on the quality of life of hypertensive patients. 1476 Oct 73

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