(Hypertension. 2000;36:454.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Efficacy of Candesartan Cilexetil Alone or in Combination With Amlodipine and Hydrochlorothiazide in Moderate-to-Severe Hypertension
From the Blood Pressure Unit, Department of Medicine, St. George’s Hospital Medical School, London, UK, and Barzilai Medical Center (J.R.V.), Faculty of Health Sciences, Ben-Gurion University, Ashkelon, Israel.
Correspondence to Prof Graham MacGregor, Blood Pressure Unit, Department of Medicine, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Abstract—This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period.
Key Words: candesartan cilexetil • amlodipine • hydrochlorothiazide • hypertension, essential • angiotensin II receptors antagonists
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The treatment of severe hypertension is often difficult, and multiple antihypertensive agents are often required.1 2 Studies suggest that antihypertensive monotherapy generally controls blood pressure (BP) in only 50% to 60% of patients.3
Angiotensin II type 1 receptor antagonists are a relatively new class of antihypertensive agents. In patients with mild-to-moderate hypertension, angiotensin II antagonists have been shown to lower BP as effectively as angiotensin-converting enzyme inhibitors.4 However, their role and efficacy in more severe hypertension has not been properly assessed. Although several studies have shown promising results with angiotensin II antagonists in this setting,5 6 these were not placebo-controlled studies; therefore, it is impossible to be certain that the fall in BP that occurs is related to the activity of the drug itself and not related to other drugs that were subsequently added.
Candesartan is a selective long-acting angiotensin II type 1 receptor antagonists. The drug is administered orally as candesartan cilexetil, an ester prodrug that is rapidly and completely converted to the active moiety during gastrointestinal absorption.7 Double-blind placebo-controlled studies have shown candesartan cilexetil to be efficacious and well tolerated in patients with mild-to-moderate essential hypertension.8 9 The drug has shown additive antihypertensive effects when combined with the thiazide diuretic, hydrochlorothiazide.10
The present multiphase study investigated the efficacy of candesartan in patients with moderate-to-severe essential hypertension who either had not received previous treatment or had previous treatment that was not controlling their blood pressure. Candesartan was initially used alone; then, if necessary, amlodipine was added, followed by the addition of a diuretic. When BP was controlled, the contribution of candesartan to BP control was assessed by double-blind withdrawal of candesartan.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Male and female patients with well-documented moderate-to-severe essential hypertension (sitting diastolic BP [DBP] >100 mm Hg) who were either untreated or unsatisfactorily treated were included in the present study. Females of child-bearing potential and patients with malignant hypertension, secondary hypertension, significant cardiac, hepatic, renal, or cerebrovascular disease, insulin-dependent diabetes mellitus, or other serious illness were excluded from the study. The protocol was approved by the local medical ethics committees at each center. Informed written consent was obtained from each patient.
Study Design
The present trial was a prospective multicenter study
conducted in 14 centers in the United Kingdom and 4 centers in Israel.
The study consisted of 3 periods (Figure 1). First, eligible patients entered a
single-blind placebo run-in period of up to 2 weeks. Patients meeting
the definition of moderate-to-severe hypertension during and at the end
of this period entered an open-label, response-dependent,
dose-titration period of up to 12 weeks. If the DBP reached 
110
mm Hg at any time during the run-in period, the investigator could
begin the dose-titration period, providing that the patient had
received at least 3 days of placebo treatment. It was mandatory to
begin active treatment if the DBP exceeded 115 mm Hg. The
candesartan dose was titrated according to individual responses. There
were 5 titration steps at 2-week intervals (Figure 1), with the
aim being to control sitting DBP to <95 mm Hg. All patients
initially received candesartan (8 mg once daily). This was increased to
16 mg once daily if BP control was not achieved. If necessary,
amlodipine (5 mg once daily) was then added, followed by
hydrochlorothiazide (25 mg once daily). If the DBP was
110 mm Hg at any time during the titration period, patients
proceeded to the next titration step (provided that they received at
least 3 days of treatment at a specified dosing regimen). Once the DBP
was controlled (ie, <95 mm Hg), patients remained on the same
maintenance dose for the remainder of the dose-titration
period. Patients whose DBP could not be controlled by dose titration to
<95 mm Hg or whose DBP subsequently became unstable (100
mm Hg) during maintenance treatment were, at the
investigator’s discretion, either withdrawn from the study or given
additional antihypertensive medication. In the latter circumstance, all
other study procedures were uninterrupted, and candesartan cilexetil
was administered continuously. These patients were termed the special
(or S) group, and their results are presented separately.
|
Patients who completed the dose-titration period and whose DBP was
controlled to <95 mm Hg and had not exceeded 99 mm Hg
during the maintenance treatment period entered a 4-week,
randomized, double-blind, placebo-controlled withdrawal period. S group
patients entered the withdrawal period if their DBP was 
99
mm Hg at the end of maintenance period. Patients were
randomized, with the use of a computer-generated code, to receive
either their maintenance candesartan dose or a matching
placebo. Concomitant amlodipine and hydrochlorothiazide
were continued unchanged. Compliance with study medication was checked
by counting returned tablets.
BP Measurements
Patients were assessed at 2 weekly clinic visits throughout the
study. BP measurements were performed after patients had at least 10
minutes of rest and immediately before administration of the study
medication; the validated semiautomatic oscillometric device OMRON
HEM705CP (Hutchings Health Care Ltd) was used for the
measurements.11 All measurements for an individual were
taken throughout the study from the arm in which the highest sitting
DBP was found at screening. Three sitting and 2 standing BP
measurements were obtained at 2-minute intervals. The arithmetic mean
of the last 2 sitting measurements was used as the reference value.
Pulse rate was measured with patients in sitting and standing
positions. Continuous 24-hour ambulatory BP monitoring (ABPM) was
performed at the beginning and at the end of the double-blind
withdrawal period by use of the validated AccuTracker II device
(Sun Tech Medical Instruments, North Carolina).12
Laboratory Tests
Blood and urine samples were obtained at selected times
throughout the study. Variables measured were serum electrolytes,
urea, creatinine, uric acid, glucose, total
cholesterol, triglycerides, and full blood
count. Plasma renin activity (PRA) and aldosterone were
measured by radioimmunoassay. All adverse experiences that were
reported by patients or observed by the investigator were recorded
irrespective of their causal relation to the study drug.
Statistical Analysis
Data from the dose-titration period were analyzed on an
intent-to-treat basis. Data from the withdrawal period were
analyzed on an intent-to-treat basis and a per protocol basis
(which included completion of this period by the patients with no major
protocol violations). Data from S group were presented
separately. All results are given as mean±SEM.
The overall response rate at the end of dose-titration period was
calculated as the proportion of patients with DBP<95 mm Hg. DBP
and systolic BP (SBP) changes from baseline were also
presented. Both of these analyses were stratified
according to the treatment taken at the end of this period. During the
double-blind withdrawal period, continuous data were analyzed
by 2-tailed unpaired or paired t test where appropriate.
Adjusted mean changes in DBP and SBP from baseline (end of
dose-titration period) to end point (last available assessment) were
compared between the candesartan cilexetil and placebo groups by 2-way
ANCOVA. Treatment, center, and baseline BP were used as covariates.
ANCOVA was also used to analyze differences between these
groups in the change in ambulatory DBP and SBP. The
2 test was used to compare categorical
demographic and adverse events data. Multiple regression was used to
examine the association of changes in BP and PRA. All statistical
analysis was performed using the Northwestern Universities
Statistical Package for the Social Sciences (SPSS Inc).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
A total of 216 patients entered the run-in period. Thirty-one were withdrawn at the end of this period, in most cases because their DBP was <100 mm Hg. Therefore, 185 patients entered the dose-titration period, and 162 completed it. Twenty-six patients were withdrawn during or at the end of this period because of adverse events (n=7), lack of efficacy (n=6, all in the S group), withdrawal of consent (n=6), death (n=1), and other reasons (n=3) or because they were lost to follow-up (n=3). The remaining 159 patients (of whom 28 were S group patients) were randomized to continue treatment with candesartan cilexetil (n=77) or to receive placebo (n=82). Five patients subsequently withdrew during this period: 3 from the candesartan cilexetil group (all because of adverse events) and 2 from the placebo group (because of lack of efficacy or other reasons). Thus, 154 patients (74 candesartan cilexetil, 80 placebo) completed the study. Table 1 shows baseline characteristics of all study patients. The demographic characteristics of the patients remained similar at each stage of the study and did not differ importantly between the randomized withdrawal treatment groups. The 185 patients (130 males, 55 females) who began the dose-titration period had a mean age of 54.7 years. The mean duration of hypertension was 9.7 years.
|
Analysis of Efficacy
Dose-Titration Period
At the end of the dose-titration period, 31 patients (19.1% of
the 162 patients completing this period) were treated with candesartan
cilexetil (8 mg); 25 (15.4%), with candesartan (16 mg); 47 (29.0%),
with candesartan cilexetil (16 mg) plus amlodipine (5 mg); and 29
(17.9%), with candesartan cilexetil (16 mg) plus amlodipine (5 mg) and
hydrochlorothiazide (25 mg). The remaining 30 (18.5%)
were given additional therapy and were classified as S group
patients.
The overall mean sitting DBP was reduced in this open part of the study by 19.8 mm Hg, from 107.8±0.4 mm Hg at baseline to 88.0±0.6 mm Hg at the end of the dose-titration period (Figure 2). Overall mean sitting SBP was reduced by 32.9 mm Hg, from 174.4±1.3 mm Hg at baseline to 141.5±1.2 mm Hg. A comparable pattern was observed across the subgroups. For both DBP and SBP, changes in standing measurements showed a pattern similar to that of the sitting measurements, with slightly higher absolute values.
|
Withdrawal Period
With the exclusion of the S group, 131 patients were randomized to
either continue candesartan cilexetil treatment (n=64) or receive
placebo (n=67). At the end of double-blind withdrawal period, the mean
sitting DBP increased significantly (by 7.1±1.0 mm Hg,
P<0.0001) in the placebo group (Table 2, Figure 2). In contrast, there
was no significant change in the candesartan cilexetil group
(+0.6±1.0 mm Hg, P=0.2735). ANCOVA showed the
difference between the treatment groups to be statistically significant
(P<0.0001). Differences between candesartan cilexetil and
placebo were also statistically significant in the subgroups of
patients treated with 8 mg candesartan cilexetil and those who received
16 mg candesartan cilexetil plus 5 mg amlodipine (Table 2). Patients in whom placebo was substituted for candesartan
cilexetil monotherapy (8 mg or 16 mg) showed a mean increase of
9.5±1.8 mm Hg in DBP, whereas those who continued active
monotherapy showed an increase of only 1.3±1.6 mm Hg. Mean
changes in sitting SBP showed a pattern comparable to the mean changes
in DBP. There was a mean increase of 12.5±2.8 mm Hg in SBP in
the placebo group (least squares method, P<0.0001) and a
decrease of 1.1±2.2 mm Hg in the candesartan cilexetil group
(P=0.7104); the difference between the groups was
statistically significant (ANCOVA, P<0.0001).
Analysis of the per protocol population, or inclusion of the S
group patients, showed no important differences to the
intention-to-treat analysis with regard to the changes in
DBP and SBP.
|
Ambulatory Blood Pressure Monitoring
ABPM was performed at the beginning and end of the withdrawal
period for 106 patients, of whom 86 had responded to dose titration and
20 belonged to the S group. Excluding the S group, mean baseline
24-hour DBP was 78.8±1.1 mm Hg in the placebo group (n=48) and
81.7±1.2 mm Hg in the candesartan cilexetil group (n=38). Four
weeks later, there was no change in mean DBP in the candesartan
cilexetil group compared with an increase of 6.4±0.92 mm Hg in
the placebo group (Figure 3). The
difference between the groups was statistically significant
(P=0.0001) and remained so if the S group was included in
the analysis. The difference between candesartan cilexetil and
placebo treatment in the withdrawal period was also statistically
significant in the groups treated with 8 mg candesartan cilexetil
(+10 mm Hg, P=0.0065), 16 mg candesartan cilexetil
(+7.6 mm Hg, P=0.0063), or triple therapy (+7.2
mm Hg, P=0.0205) during dose titration. A similar pattern
of results was observed in the changes in SBP, with significantly
greater increases occurring in placebo recipients than in those
continuing treatment with 8 mg candesartan cilexetil or triple therapy
(P<0.05).
|
PRA and Aldosterone
After 4 weeks of withdrawal of candesartan cilexetil, there was a
decrease of 1.94 ng/mL per hour in mean PRA in placebo recipients
compared with no change in patients who continued treatment with
candesartan cilexetil (P=0.017 between the groups, Figure 2). Mean plasma aldosterone levels increased in the
placebo group (by 68 pmol/L) and in the active treatment group (by 31
pmol/L), but the difference was not statistically significant between
groups. In the placebo group, there was a significant correlation
between the level of PRA at the end of withdrawal of candesartan
cilexetil and the rise in DBP (r=0.21, P=0.06)
and SBP (r=0.29, P<0.05; Figure 4) that occurred on stopping candesartan.
By multivariate analysis, the PRA level at the
end of withdrawal was still a significant predictor of the rise in SBP
in the placebo group after adjusting for age, gender, race, and body
mass index. No similar correlation was found for the change in plasma
aldosterone levels.
|
Tolerability
A total of 87 (47.0%) of 185 patients experienced a total of 219
adverse events during the dose-titration period. The most frequently
observed adverse event during this period was headache, followed by
upper respiratory tract infection, tiredness, increase in plasma
creatinine kinase levels, dizziness, lethargy, and cough.
Only 13 adverse events (5.9%) were classified as probably or
definitely related to study treatment. During the double-blind
withdrawal period, 41 (25.8%) of 159 patients experienced a total of
71 adverse events. There was no statistically significant difference in
the proportion of patients who experienced adverse events during
treatment with candesartan cilexetil (24 of 77, 31.2%) or placebo (17
of 82, 20.7%; P=0.1327). Again, headache was the most
frequent adverse event. Only 4 (5.6%) of the 71 adverse events were
classified as probably or definitely related to study treatment.
Adverse events were the primary cause of withdrawal of 10 patients from
the study and a secondary cause of the withdrawal of 5 others.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The present study demonstrates that candesartan cilexetil is an effective antihypertensive monotherapy in many patients with moderate-to-severe essential hypertension. Moreover, the drug is also effective in combination with either amlodipine and hydrochlorothiazide in patients who do not respond to monotherapy.
The use of a double-blind withdrawal study, once BP has been controlled in these more resistant patients, has been used infrequently in the past but has several advantages in that it allows the efficacy of a single treatment to be assessed by itself and in conjunction with other therapy. Most previous dose-titration studies of other angiotensin II type 1 receptor antagonists in moderate-to-severe hypertension have used an uncontrolled open-label design.5 6 Such studies cannot exclude the possibility that reductions in BP could be due to repeated measurements or to other drugs added within combination regimens. In contrast, the present study concluded with a randomized, double-blind, placebo-controlled withdrawal period to allow an unbiased assessment of the effect of candesartan cilexetil in controlling BP. The antihypertensive contribution of candesartan cilexetil is clearly shown by data from the withdrawal period, in which the drug effectively maintained the BP control achieved after dose titration, whereas the placebo did not. Overall, substitution of a placebo for candesartan cilexetil monotherapy or combination therapy resulted in statistically significant increases in mean DBP and SBP after 4 weeks, whereas no significant changes occurred in patients who continued candesartan cilexetil treatment. Substitution of placebo for candesartan cilexetil monotherapy resulted in a rise in DBP of 9.5 mm Hg compared with a rise of just 1.3 mm Hg in patients who remained on active treatment. However, the substitution of placebo for candesartan cilexetil within the combination regimens resulted in smaller increases. This may be explained by the fact that patients in the combination regimen groups did not respond adequately enough to candesartan monotherapy in the first place.
The ABPM data obtained in the present study support other evidence indicating that candesartan cilexetil has a 24-hour duration of action.13
The fall in PRA in the group in whom candesartan was withdrawn is the reverse of the rise in PRA seen on starting an angiotensin II type 1 receptor antagonist. This results from the inhibition of the negative feedback of angiotensin II on renin release. The significant relationship between the level of PRA after the withdrawal of candesartan and the BP increase that occurred with stopping candesartan supports the concept that the activity of the renin-angiotensin system is predictive of the antihypertensive response of candesartan. Indeed the PRA level at the end of withdrawal was still a significant predictor of the rise in systolic BP in the group in whom candesartan was withdrawn after adjusting for age, gender, race, and body mass index. This is the first observation of such a relationship in a relatively large number of hypertensive subjects. The lack of a significant change in plasma aldosterone levels on withdrawal of candesartan concurs with other observations that angiotensin II type 1 receptor antagonists do not appear to affect aldosterone levels.14 In contrast, angiotensin-converting enzyme inhibitors usually lower aldosterone levels.15 The explanation for this difference is unclear, because the adrenal angiotensin II type 1 receptor is bound by its antagonists16 and is thought to be important in regulating aldosterone secretion.
In conclusion, candesartan cilexetil is efficacious in the treatment of moderate-to-severe essential hypertension. The drug can be effectively combined with calcium channel blockers and/or diuretics in patients whose hypertension is resistant to monotherapy.
|
Acknowledgments |
|---|
This study was supported by a grant from Takeda Euro R&D.
|
Appendix 1 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
In addition to the authors, the UK and Israel Candesartan Investigator Group includes the following individuals and institutions. From Israel: Prof Shmuel Oren, University of Tel-Aviv, Institute of Preventive Cardiology; Prof Joseph B. Rosenfeld and Dr G Bott-Kanner, University of Tel-Aviv, Institute of Clinical Epidemiology; and Prof Reuven Zimlichman and Dr Bernard I. Chazan, Edith Wolfson Medical Center, Department of Medicine. From the United Kingdom: Dr Henry L. Elliott, University of Glasgow, Department of Medicine and Therapeutics; Prof G. Dennis Johnston, Queens University of Belfast, Department of Therapeutics and Pharmacology; Prof Michael Joy, St. Peter’s Hospital, Department of Cardiology; Dr Philip S. Lewis, Stepping Hill Hospital, Blood Pressure and Heart Research Center; Dr Andrew Moriarty, Craigavon Area Hospital Group Trust, Cardiology Department; Dr Jorg E.F. Pohl, Leicester General Hospital, Department of Medicine; Prof Peter C. Rubin, University of Nottingham, Therapeutics Department; Dr Peter R. Jackson and Dr Erica J. Wallis, Royal Hallamshire Hospital, Clinical Pharmacology and Therapeutics; Prof Peter S. Sever, Imperial College of Medicine, St. Mary’s Hospital; Prof David J. Webb, University of Edinburgh, Department of Medical Sciences; Dr John Webster, University of Aberdeen, Department of Medicine and Therapeutics; and Prof Robert Wilkinson, Freeman Hospital, Department of Pharmacology.
Received December 14, 1999; first decision January 17, 2000; accepted March 16, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. Cappuccio FP, Markandu ND, Singer DRJ, MacGregor GA. Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and predictors of response. J Hypertens. 1993;11:839–847.[Medline] [Order article via Infotrieve]
2.
Antonios TFT, Cappuccio FP, Markandu ND,
Sagnella GA, MacGregor GA. A diuretic is more effective than
a ß-blocker in hypertensive patients not controlled on
amlodipine and lisinopril. Hypertension. 1996;27:1325–1328.
3.
Materson BJ, Reda DJ, Cushman WC, Massie BM,
Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, et
al. Single-drug therapy for hypertension in men: a comparison of six
antihypertensive agents with placebo: the Department of Veterans
Affairs Cooperative Study Group on Antihypertensive Agents.
N Engl J Med. 1993;328:914–921.
4. Zanchetti A, Omboni S, Di Biagio C. Candesartan cilexetil and enalapril are of equivalent efficacy in patients with mild to moderate hypertension. J Hum Hypertens. 1997;11(suppl 2):S57–S59.
5. Dunlay MC, Fitzpatrick V, Chrysant S, Francischetti EA, Goldberg AI, Sweet CS. Losartan potassium as initial therapy in patients with severe hypertension. J Hum Hypertens. 1995;9:861–867.[Medline] [Order article via Infotrieve]
6. Larochelle P, Flack JM, Marbury TC, Sareli P, Krieger EM, Reeves RA. Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension: Irbesartan Multicenter Investigators. Am J Cardiol. 1997;80:1613–1615.[Medline] [Order article via Infotrieve]
7. Hübner R, Högemann AM, Sunzel M, Riddell JG. Pharmokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers. J Hum Hypertens. 1997;11(suppl 2):S19–S25.
8. Sever P, Holzgreve H. Long-term efficacy and tolerability of candesartan cilexetil in patients with mild to moderate hypertension. J Hum Hypertens. 1997;11(suppl 2):S69–S73.
9. Elmfeldt D, George M, Hubner R, Olofsson B. Candesartan cilexetil, a new generation angiotensin II antagonist, provides dose dependent antihypertensive effect. J Hum Hypertens. 1997;11(suppl 2):S49–S53.
10. Plouin PF. Combination therapy with candesartan cilexetil plus hydrochlorothiazide in patients unresponsive to low-dose hydrochlorothiazide. J Hum Hypertens. 1997;11(suppl 2):S65–S66.
11. O’Brien E, Mee F, Atkins N, Thomas M. Evaluation of three devices for self-measurement of blood pressure according to the revised British Hypertension Society Protocol: the Omron HEM-705CP, Philips HP5332, and Nissei DS-175. Blood Press Monit. 1996;1:55–61.[Medline] [Order article via Infotrieve]
12. White WB, Lund-Johansen P, McCabe EJ, Omvik P. Clinical evaluation of the Accutracker II ambulatory blood pressure monitor: assessment of performance in two countries and comparison with sphygmomanometry and intra-arterial blood pressure at rest and during exercise. J Hypertens. 1989;7:967–975.[Medline] [Order article via Infotrieve]
13. Heuer HJ, Schondorfer G, Hogemann AM. Twenty-four hour blood pressure profile of different doses of candesartan cilexetil in patients with mild to moderate hypertension. J Hum Hypertens. 1997;11(suppl 2):S55–S56.
14. Hubner R, Hogemann AM, Sunzel M, Riddell JG. Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers. J Hum Hypertens. 1997;11(suppl 2):S19–S25.
15. Burnier M, Brunner HR. Renal effects of angiotensin II receptor blockade and angiotensin-converting enzyme inhibition in healthy subjects. Exp Nephrol. 1996;4(suppl 1):41–46.
16. Noda M, Shibouta Y, Inada Y, Ojima M, Wada T, Sanada T, Kubo K, Kohara Y, Naka T, Nishikawa K. Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new nonpeptide AII antagonist. Biochem Pharmacol. 1993;46:311–318.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  P. A Swift and G. A MacGregor Review: The frequent need for three or more drugs to treat essential hypertension. What evidence for optimal combinations? Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 103 - 108. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||