Key Features of Candesartan Cilexetil and a Comparison with Other Angiotensin II Receptor Antagonists

Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists

PS Sever Imperial College of Science, Technology & Medicine at St Mary’s Hospital, London, UK

Current research on angiotensin II AT1-receptor antag- in patients with essential hypertension. Candesartan onists (AIIRAs) and selected studies presented at the cilexetil has a rapid onset of action (approximately 80% recent symposium held in Amsterdam, The Netherlands, of total blood pressure reduction within the first 2 on 6 June 1998, titled ‘Angiotensin II Receptor Antagon- weeks) and dose-dependent effects on blood pressure, ists are NOT all the Same’ are reviewed. AIIRAs offer a is comparable in efficacy to a number of classes of anti- number of potential advantages over alternative antihy- hypertensives, and is effective in combination therapy pertensive agents acting via the renin-angiotensin-aldo- (eg, with hydrochlorothiazide and amlodipine). This sterone system. They combine blood pressure-lowering favourable profile may be due in part to the highly selec- effects at least equivalent to those of angiotensin-con- tive, tight binding to and slow dissociation of candesar- verting enzyme (ACE) inhibitors, coupled with placebo- tan from the AT1 receptor. Preliminary studies suggest like tolerability. Candesartan cilexetil is a novel AIIRA that candesartan cilexetil also protects end organs that has demonstrated clinical efficacy superior to losar- (kidney, heart, vasculature, and brain) beyond blood tan, has a sustained duration of action over 24 hours pressure control. (trough:peak ratio close to 100%) and is well tolerated

Keywords: candesartan cilexetil; angiotensin II AT1-receptor antagonist; organ protection; review

Antihypertensive therapy associated adverse consequences.3 There is growing evidence from a wide variety of clinical trials that Non-peptide angiotensin II AT1-receptor antagonists the AIIRAs are able to combine or even to exceed (AIIRAs) are a new class of drugs that represent a the considerable benefits of ACE inhibition with the major advance in therapeutics for the treatment of added bonus of improved tolerability. With parti- cardiovascular disease. Members of this new class cular attention to candesartan cilexetil, this article have been proved effective in the treatment of gives an overview of the antihypertensive potential hypertension and have recently also shown promise of AIIRAs reviewed in this supplement which sum- for the treatment of heart failure. AIIRAs attenuate marises the recent symposium held in Amsterdam, the effects of angiotensin II by blocking its action, The Netherlands, on 6 June 1998, titled ‘Angiotensin competitively or non-competitively, at the AT1 II Receptor Antagonists are NOT all the Same’. receptor. This receptor subtype mediates the cardiovascular and metabolic activities of angiotensin II.1 This mode of action contrasts with that of angio- Criteria for selecting an antihypertensive agent tensin-converting enzyme (ACE) inhibitors, which partially inhibit the conversion of angiotensin I to The main criteria that need to be considered in mak- angiotensin II. One of the disadvantages of ACE ing choices between different antihypertensive inhibitors is that angiotensin II is also produced by agents, particularly in the context of the AIIRAs, are non-ACE-dependent pathways, notably those the following: (1) efficacy in lowering blood press- involving chymase in the heart and other tissues.2 ure; (2) onset and duration of action; (3) organ-pro- The more specific mechanism of action of AIIRAs tective effects; and (4) the side effects profile. The means that the actions of angiotensin II are com- sustained efficacy of any new antihypertensive agent pletely blocked at the effector site, independently of in lowering blood pressure over the full 24-h period the route of its production. Moreover, because ACE is particularly important, since existing therapies is identical to the enzyme kininase II, which inhibits have only achieved relatively small reductions, bradykinin formation, AIIRAs avoid the bradykinin averaging approximately 7%,4 which equate to only potentiation induced by ACE inhibitors and the a small reduction in risk. This outcome for hypertension management compares unfavourably with the situation for cardiovascular disease in general, where the 40% reduction in plasma cholesterol Correspondence: Professor Peter S Sever, Department of Clinical 5 Pharmacology and Therapeutics, Imperial College School of levels now attainable with some statins represents Science, Technology & Medicine at St Mary’s Hospital, London a very considerable reduction of risk for ischaemic W2 1NY, UK heart disease. The organ-protective effects of antihy- Angiotensin II AT1-receptor antagonists PS Sever S4 pertensive agents, as demonstrated with ACE inhibi- antagonist. The active losartan metabolite EXP 3174 tors, are of special interest, since they offer opport- in this model acts as a mixed antagonist. The obser- unities for preventing the long-term progression of vations are not easily reproduced in in vivo studies hypertension. A major problem with many contem- and to what extent they relate to differences in porary treatments is poor compliance that mainly apparent clinical efficacy and duration of action of results from intolerance and efficacy deficiencies of these drugs remain at present conjectural. many currently available agents. Duration of action Candesartan cilexetil—a novel A key efficacy criterion of choice of any given antihypertensive agent is the degree to which these angiotensin II AT1-receptor antagonist blood pressure-lowering effects are maintained Pharmacology throughout the 24-h period. Although sophisticated Candesartan cilexetil is a new, once-daily oral anti- measures of the 24-h profiles of antihypertensive hypertensive, which is completely hydrolysed drugs are being developed (Mancia G et al, unpub- during gastrointestinal absorption to the only active lished data), a widely recognised parameter is the compound, candesartan, a potent, long-acting AIIRA simple trough:peak blood pressure ratio. On this selective for the type 1 receptor subtype.6,7 The basis, candesartan cilexetil demonstrates an excellent 24-h blood pressure profile, with a trough:peak pharmacokinetics of candesartan cilexetil are not 13 affected by administration in the presence of food,8 ratio close to unity. This compares favourably with which simplifies treatment, and no clinically sig- lower trough:peak values for losartan and other nificant drug–drug interactions have been reported.9 AIIRAs. The prolonged antihypertensive activity of The pharmacology of angiotensin II receptors and candesartan cilexetil is likely related to its specific binding characteristics to the AT1 receptor at the AT1-receptor blockers, including candesartan cilexe- 14 til, is reviewed in this supplement by Dr Oliver tissue level. Chung and colleagues from the Institute of Pharma- Dr Inada’s group, of Pharmaceutical Research, cology, Christian-Albrechts-University, Kiel, Ger- Takeda Chemical Industries Ltd, Osaka, Japan, many. It is now known that drugs like ACE inhibi- report in this supplement on potent and long-lasting antihypertensive effects of candesartan cilexetil in tors or angiotensin AT1-receptor antagonists can exert further beneficial actions independent of a clinical trials and in several animal models of hyper- reduction in blood pressure. Dr Chung et al’s study tension. They confirm that the insurmountable reviews the literature, and reports on a reduction antagonism of candesartan cilexetil in vascular con- in vascular- and post-myocardial-infarction re- traction is likely the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. modelling, and a preservation of kidney function in 15 the presence of diabetic nephropathy, in hyperten- In a 12-month study, mean sitting diastolic sive patients taking candesartan cilexetil. blood pressure was progressively reduced from Preclinical and early clinical studies of the lead- approximately 100 mm Hg at baseline to approxi- ing group of AIIRAs that are currently available or mately 85 mm Hg with candesartan cilexetil, and a at advanced stages of development have been perfor- response rate of more than 80% was achieved med to explore the impact of the distinct differences (Figure 1). These data indicate that candesartan in mode of action from ACE inhibitors, particularly cilexetil is effective in a large proportion of hyper- with regard to their clinical benefits in terms of ACE- tensive patients and that blood pressure response is inhibitor-associated cough10 and angioneurotic oed- maintained long-term. ema.11 As predicted, the lack of bradykinin potentiation with AIIRA does indeed translate into placebo- Time-to-effect relationship like levels of these troublesome adverse effects. In a report by the author and colleagues, which was However, as our experience of using AIIRAs in the summarised in a poster session at the proceedings, clinic grows it is also increasingly apparent that a total of 1187 patients received 8 or 16 mg of cande- individual compounds display significant differ- sartan cilexetil or placebo once daily for 4 to 12 ences in their pharmacology and clinical behaviour weeks. The results of a meta-analysis showed that within the AIIRA class, which should be taken into approximately two-thirds of the total reduction in account by physicians when selecting the most blood pressure seen at 8 weeks with candesartan appropriate treatment. In particular, AIIRAs have cilexetil is achieved within 1 week of starting ther- marked differences in their binding characteristics apy, with 80% of the effect evident after 2 weeks at AT1 receptors. To what extent these differences and about 90% after 4 weeks (Sever et al, unpub- may be reflected in vivo remain uncertain. Candesar- lished data) (Figure 2). There was no evidence of tan has a much greater affinity for AT1 receptors orthostatic hypotension. These results equally relate than does losartan, the first non-peptide AIIRA to diastolic blood pressure and to systolic blood introduced. In in vitro studies, candesartan cilexetil pressure and to all dose levels. is highly selective for the AT1 receptor subtype and exhibits tight binding, as well as slow dissociation Antihypertensive efficacy of candesartan from the receptor.12 In similar in vitro studies, losartan is a competitive or surmountable antagonist with in clinical trials angiotensin II at the AT1 receptor, whereas candesar- A number of randomised, placebo-controlled clini- tan cilexetil distinctly acts as an insurmountable cal trials have demonstrated that, over the full dose Angiotensin II AT1-receptor antagonists PS Sever S5

Figure 1 Long-term reduction of sitting diastolic blood pressure (mean ± s.e.) in open-label treatment of hypertension with candesartan cilexetil (n = 244).19

Figure 2 Reduction in mean sitting systolic (A) and diastolic (B) blood pressure (trough effect) with candesartan cilexetil (n = 615) and placebo (n = 342) in hypertensive patients treated in controlled clinical trials for at least 8 weeks. range of 4 to 16 mg once daily, candesartan cilexetil tension was investigated in a multicentre, double- produces an impressive and distinctive dose-depen- blind study.25 Patients received candesartan cilexe- dent reduction in both systolic and diastolic blood til titrated according to response from 8 to 16 mg pressure.16 once daily, with sequential addition of amlodipine This body of clinical evidence compares favour- 5 mg and hydrochlorothiazide 25 mg once daily at ably with clinical experience gained with some set intervals. An overall response rate of 82% was other AIIRAs. Losartan and valsartan, for example, achieved after 12 weeks’ treatment with candesartan display a flat dose-response relationship in their cilexetil monotherapy or add-on therapy. blood pressure-lowering effects,17,18 while for irbes- Also included in this supplement is a review by artan there appears to be a dose-response relation- Dr Ogihara’s group at the Department of Geriatric ship in patients with mild to moderate hyperten- Medicine, Osaka University, and the Department of 19 sion. A meta-analysis of six large, placebo- Medicine, School of Medicine, Fukuoka University, controlled, randomised studies (Figure 3) clearly Japan, of results of Japanese clinical trials of candes- illustrates the dose-response relationship of candesartan cilexetil. They found that, in 14 multicentre artan cilexetil given in doses from 4–16 mg once 16 studies, low dose candesartan cilexetil (2–8 mg once daily. Clinical trials have also shown that the mag- daily) had an efficacy rate of 72% and 63%, and a nitude of blood pressure lowering with candesartan reported overall low adverse event rate of 9.9% and cilexetil is at least equivalent to that of several 7.3%, in patients with mild-to-moderate essential widely used antihypertensive agents, including the hypertension and those with impaired renal func- ACE inhibitor enalapril, the calcium antagonist tion, respectively. Elderly patients enjoyed the same amlodipine, and the diuretic hydrochlorothiazide.20–24 The additional lowering of blood pressure efficacy and tolerability as younger patients. In a that is possible with combined regimens of candes- double-blind comparative study, candesartan cilexe- artan cilexetil with hydrochlorothiazide23–25 and til was superior to enalapril in hypertensive amlodipine22 has also been confirmed by several patients. Daily treatment of candesartan cilexetil for studies. 8 to 12 weeks reduced the left ventricular mass The antihypertensive efficacy of candesartan index without deterioration of cardiac function in cilexetil in patients with moderate to severe hyper- patients with hypertension. Angiotensin II AT1-receptor antagonists PS Sever S6

Figure 3 A meta-analysis of six double blind placebo controlled clinical trials showing dose-dependent efﬁcacy of candesartan cilexetil in the treatment of hypertension.16

Comparative antihypertensive efficacy of jects with candesartan cilexetil, compared with an candesartan and other AIIRAs equivalent dose of losartan.31 Another factor to consider is that losartan achieves most of its antihyper- The intrinsic blood pressure-lowering efficacy of tensive activity from an active carboxylic acid new antihypertensive agents is an important factor metabolite, EXP 3174, via the action of hepatic to consider when selecting the most suitable treat- microsomal enzymes.26 On average, only 14% of los- ment for a particular patient group. A direct com- artan is converted in this way to EXP 3174. Candes- parison of the efficacy of standard once-daily doses artan cilexetil is completely hydrolysed to the active of candesartan cilexetil (8 mg and 16 mg/day) and moiety, candesartan, during gastrointestinal absorp- losartan (50 mg/day) by Andersson et al13 found a tion. Moreover, peak plasma concentrations of EXP significant (P = 0.013) difference in blood pressure 3174 exhibit wide intersubject variations, suggesting reduction with the two agents (Figure 4). The widespread differences in hepatic metabolism of reduction in mean diastolic blood pressure with losartan in a given patient population.31 candesartan cilexetil (16 mg) was more than 50% greater than that achieved with losartan (50 mg) although there was no comparison in this study with higher doses of losartan. Safety profile

As a class, AIIRAs have demonstrated a favourable Mechanism of action safety and tolerability profile compared with other The mechanism underlying the greater antihyper- classes of antihypertensives, including ACE inhibi- tensive efficacy of candesartan cilexetil over losartan tors and calcium antagonists. Candesartan follows and other AIIRAs is as yet unknown. It is perhaps this trend and displays a similar tolerability profile related to more complete AT1-receptor blockade as to placebo over its full dose range. Candesartan is suggested by the greater reactive rise in plasma renin equally well tolerated by men and women, and by activity observed in salt-replete, normotensive sub- elderly and younger patients.27

Figure 4 Changes in mean diastolic blood pressure with candesartan cilexetil 8 mg and 16 mg once-daily, compared with losartan 50 mg once-daily and placebo, showing the superior clinical efﬁcacy of candesartan cilexetil.13 Angiotensin II AT1-receptor antagonists PS Sever S7

Figure 5 Frequency of the ﬁve most common adverse effects reported with candesartan cilexetil and placebo, demonstrating the placebo-like safety proﬁle of the drug.27

Tolerability did patients treated with candesartan cilexetil (3.7% vs 0%). The typically asymptomatic nature of hypertension, Moreover, there is no indication that doses of can- coupled with its long-term course and link to cardio- desartan cilexetil higher than the clinically relevant vascular morbidity and mortality, means that the tol- dose range has any marked effect on tolerability. The erability profile of antihypertensive therapy is parti- absence of a dose-response relationship for adverse cularly important. Poor tolerability leads to non- events with candesartan cilexetil may be relevant for compliance and treatment failure. One of the most end-organ protection. Candesartan appears to be remarkable features of the AIIRA class generally, devoid of either orthostatic hypotension or first-dose and candesartan cilexetil in particular, is the toler- hypotension, and there have been no reports of ability profile virtually indistinguishable from that rebound hypertension after cessation of treatment.28 of placebo. This is illustrated by Figure 5, which shows the incidence of the six most common adverse events reported by healthy volunteers and Effect of candesartan on insulin sensitivity hypertensive patients treated with candesartan cilexetil or placebo.27 There were no significant dif- There is no evidence of adverse effects on serum ferences in the occurrence of these adverse events lipid profile or glucose homeostasis in a 12-week between the two groups, regardless of age, gender trial of once-daily treatment with candesartan cilex- or dose. etil in patients with hypertension and type II dia- Candesartan cilexetil is virtually devoid of the betes.29 Indeed, candesartan cilexetil is reported to troublesome cough typically associated with ACE- improve insulin sensitivity in patients with essen- inhibitor therapy. In a placebo-controlled compara- tial hypertension. Dr Higashiura and colleagues tive study, the incidence of adverse events with can- from the Second Department of Internal Medicine, desartan cilexetil (11.3%) was considerably lower Sapporo Medical University School of Medicine, than that with enalapril (23.5%), and lower than Sapporo, Japan, report in this supplement on the that found in the placebo group (15.9%).21 Enalapril- effect of candesartan cilexetil on sodium-retaining treated patients also experienced a higher incidence action and the activation of pressor systems by hy- of cough and withdrawal due to adverse events than perinsulinaemia, which might be related to pressor

Figure 6 Thickening of the carotid artery intima in vitro induced by endothelial damage (balloon catheter) with and without candesartan cilexetil, 10 mg/kg per day for 2 weeks, demonstrating its vasoprotective properties. Angiotensin II AT1-receptor antagonists PS Sever S8 mechanisms in essential hypertension. Candesartan gated by Dr Miyazaki and coworkers at the Depart- cilexetil restored insulin sensitivity in patients with ment of Pharmacology, Osaka Medical College, essential hypertension to the level of that in normo- Takatsuki, Japan, and the Pharmaceutical Research tensive subjects. In addition, the sodium-retaining Division, Takeda Chemical Industries, Ltd, Osaka, action of hyperinsulinaemia was attenuated by treat- Japan. In their study published in this supplement, ment with candesartan cilexetil. they administered oral candesartan cilexetil or enalapril to dogs twice daily for 5 weeks. After 1 week of active drug therapy, the common carotid and fem- End-organ protection oral arteries were unilaterally injured by balloon AIIRAs may confer advantages over ACE inhibitors catheterization. The authors found that candesartan with regard to end-organ protection (heart, vasculat- cilexetil significantly suppressed the formation of ure, brain, and kidneys). These effects may be partly intima hyperplasia in both the carotid and femoral related to or wholly independent of blood pressure- arteries, while enalapril significantly suppressed lowering effects. Not surprisingly, most available intima hyperplasia in the femoral, but not in the evidence at present is derived from experimental carotid, arteries. These results indicate that local animal models; clinical data are very limited, to angiotensin II production by ACE and chymase is date. involved in the hyperplasia seen in injured intima, and the difference in the inhibitory action of candes- Cardiac and vascular system: In an excellent artan cilexetil and enalapril reflects the extent of review of the effect of antihypertensive agents on contribution of each enzyme. That is, the effect of cardiac and vascular remodelling published in this enalapril depended on the activity of ACE, whereas supplement, Dr Mallion and colleagues of the Mede- that of candesartan cilexetil was independent of cine Interne et Cardiologie, Grenoble Cedex, France, ACE activity. Similar studies in which thickening of discuss the clinical implications of cardiac changes, the carotid artery intima was induced by endothelial the cause of structural changes, the distinction injury have demonstrated that administration of between left ventricular mass and vascular hypertro- candesartan cilexetil has a protective action on vas- phy, and the role of reference values and vascular culature (Figure 6). vs cardiac indices in the clinical management of hypertension. Brain: Perhaps one of the most exciting areas of Regression of vascular hypertrophy with AIIRA future development for AIIRAs such as candesartan and ACE inhibitor therapy has been demonstrated cilexetil is in protection against stroke, as already in an animal model. In an in vivo study reported studied in spontaneously hypertensive stroke-prone in this supplement, Tsutomu Yamazaki and Yoshio rats. In this model, higher doses of candesartan Yazaki, of the Department of Cardiovascular Medi- cilexetil reduced blood pressure, as well as the inci- cine, Faculty of Medicine, and the Health Service dence of stroke, compared with untreated controls.30 Centre, the University of Tokyo, treated spon- Interestingly, doses of candesartan cilexetil that taneously hypertensive rats with candesartan cilexe- have little or no effect on blood pressure also sig- til or hydralazine.39 Untreated rats progressively nificantly reduced the incidence of stroke. Extrapol- developed severe hypertension, and treatment with ating these findings to the clinical setting raises the candesartan cilexetil or hydralazine decreased blood prospect of developing interventional therapies with pressure. Candesartan cilexetil reduced left ven- the capacity to protect normotensive individuals tricular weight and wall thickness, transverse myo- from vascular disease and stroke. cyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treat- Kidney: The selective blockade of AT1-receptors ment with hydralazine slightly prevented an leaves the AT2 receptors exposed to elevated levels increase in left ventricular wall thickness, but proof endogenous angiotensin II. According to a report duced no significant reduction in the other para- in this supplement by Professor Kiyoshi Kurokawa, meters. In an in vitro study by the same authors, pre- Dean of the First Department of Internal Medicine, treatment with candesartan cilexetil diminished an School of Medicine, Tokai University, Japan, this increase in phenylalanine incorporation, MAP kin- may be an advantage of AT1-receptor blockade over ase activity, and c-fos gene expression induced by ACE inhibition in the management of a variety of the stretching of neonatal rat cardiomyocytes. They chronic vascular diseases, including chronic glo- also found that angiotensin II-evoked signal trans- merulonephritis and other glomerular diseases. In a duction pathways differed between cell types. In clinical trial, candesartan cilexetil effectively low- cardiac fibroblasts, angiotensin II activated MAP ered urinary protein excretion in patients with kinase through a pathway including the G␤␥ subunit chronic glomerulonephritis. This beneficial effect on of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein excretion was independent of the effect on protein kinase C were important in cardiac myo- systemic blood pressure, which was normal in the cytes. In another study, candesartan cilexetil and majority of patients studied. enalapril both exhibited protective effects in an Dr Maarten W Taal and Dr Barry M Brenner of the ischaemic model with myocardial fibrosis as the Renal Division, Department of Medicine, Brigham end-point, but no effects were seen with a non-selec- and Women’s Hospital, Harvard Medical School, tive vasodilator. Boston, Massachusetts, review, in this supplement, The roles of angiotensin II as produced by two dif- studies that have compared the effects of standard ferent enzymes, ACE and chymase, were investi- doses of ACE-I and AIIRAs in several rat models of Angiotensin II AT1-receptor antagonists PS Sever S9 chronic renal disease. Most studies found similar 4 Collins R, MacMahon S. Blood pressure, antihyperten- beneficial effects, including amelioration of pro- sive drug treatment and the risks of stroke and of cor- teinuria and glomerulosclerosis for renal diseases onary heart disease. Br Med Bull 1994; 50: 272–298. such as passive Heymann nephritis, hypertensive 5 Jones P, Kafonek S, Laurora I, Hunninghake D. Com- nephrosclerosis, diabetic nephropathy, and pro- parative dose efficacy study of atorvastatin versus sim- gressive glomerulosclerosis secondary to reduced vastatin, pravastatin, lovastatin and fluvastatin in patients with hypercholesterolemia (The CURVES renal mass. Study). Am J Cardiol 1998; 81: 582–587. Dr Sugimoto and coworkers at the Department of 6Hu¨ bner R, Ho¨gemann AM, Sunzel M, Riddell JG. Phar- Clinical Pharmacology, Jichi Medical School, macokinetics of candesartan after single and repeated Tochigi, Japan, investigated the influence of candes- doses of candesartan cilexetil in young and elderly artan cilexetil and enalapril on the oxidative state of healthy volunteers. J Hum Hypertens 1997; 11 (Suppl renal tissue and renal function in 5/6 nephrectom- 2): S19–S25. ized rats. In their report, published in this sup- 7 van Lier JJ, van Heiningen PNM, Sunzel M. Absorp- plement, they found that while both drugs signifi- tion, metabolism and excretion of 14C-candesartan cantly blunted the rise in urinary protein, neither and 14C-candesartan cilexetil in healthy volunteers. candesartan cilexetil nor enalapril affected antioxi- J Hum Hypertens 1997; 11 (Suppl 2): S27–S28. dant defences in renal tissue in nephrectomized 8 Riddell JG. A study of the food interaction potential rats, indicating that mechanisms other than alter- of candesartan cilexetil in healthy volunteers. J Hum ation in oxidative stress are involved in the renopro- Hypertens 1997; 11 (Suppl 2): S29–S30. 9 Jonkman JJ et al. Pharmacokinetic drug interaction tective effects of candesartan cilexetil and enalapril. studies with candesartan cilexetil. J Hum Hypertens One long-term study has shown greater inhibition 1997; 11 (Suppl 2): S31–S35. of glomerulosclerosis, interstitial fibrosis, and TGF- 10 Lacourcie`re Y, Lefebvre J. Modulation of the renin- ␤ synthesis in rats treated with candesartan cilexetil angiotensin-aldosterone system and cough. Can J than in those treated with enalapril after renal mass Cadiol 1995; 11 (Suppl F): 33F–39F. reduction. However, conclusions regarding the rela- 11 Vleeming W et al. ACE inhibitor-induced angioedema. tive efficacy of these two groups of agents in ame- Incidence, prevention and management. Drug Safety liorating the progression of chronic renal disease 1998; 18: 171–188. await the results of further long-term studies. 12 Nishikawa K, Naka T, Chatani F, Yoshimura Y. Cande- sartan cilexetil: a review of its preclinical pharmacology. J Hum Hypertens 1997; 11 (Suppl 2): S9–S17. Summary 13 Andersson OK, Neldam S. The antihypertensive effect This supplement reflects the current status of and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with research into AIIRAs in general, and candesartan losartan. Blood Press 1998; 7: 53–59. cilexetil, in particular. According to the selection 14 Belz GG et al. Inhibition of angiotensin II pressor criteria presented herein, candesartan cilexetil response and ex vivo angiotensin II radioligand bind- would appear to possess many of the features of an ing by candesartan cilexetil and losartan in healthy ideal antihypertensive agent. Dose-dependent and human volunteers. J Hum Hypertens 1997; 11 (Suppl effective blood pressure reduction is accompanied 2): S45–S47. by a 24-h profile of sustained activity that is ideally 15 Sever P, Holzgreve H. Long-term efficacy and toler- suited to once-daily administration. Candesartan ability of candesartan cilexetil in patients with mild cilexetil has a tolerability profile at all dose levels to moderate hypertension. J Hum Hypertens 1997; 11 that is indistinguishable from placebo and displays (Suppl 2): S69–S73. protective effects for key target organs. This recent 16 Elmfeldt D, George M, Hu¨ bner R, Olofsson B. Candes- addition to the arsenal of cardiovascular thera- artan cilexetil, a new generation angiotensin II antag- peutics is clearly eminently qualified as first-line onist, provides dose-dependent antihypertensive effect. J Hum Hypertens 1997; 11 (Suppl 2): S49–S53. therapy for hypertension in a wide variety of 17 Gradman AH et al. A randomized, placebo-controlled, patients, both as monotherapy and in combination. double-blind, parallel study of various doses of losar- As clinical experience with candesartan cilexetil tan potassium compared with enalapril maleate in and other AIIRAs grows, so do the future prospects patients with essential hypertension. Hypertension for greater and more diverse improvements in mor- 1995; 25: 1345–1350. bidity and mortality for patients with hypertension 18 Oparil S et al. The efficacy and safety of valsartan com- and other cardiovascular disease. In addition, we pared with placebo in the treatment of patients with will likely learn more about the differences between essential hypertension. Clin Ther 1996; 18: 797–810. the various AIIRAs currently in clinical use. 19 Guthrie R et al. for the Multicenter Investigators. Effi- cacy and tolerability of irbesartan, an angiotensin II receptor antagonist, in primary hypertension. 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