Easthope SE, Jarvis B
Candesartan cilexetil - An update of its use in essential hypertension
Drugs 2002;62 (8);1253-87
The use of candesartan cilexetil in the treatment of essential hypertension is discussed with
reference to pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, dosage,
administration and hypertension management. It is mentioned that candesartan cilexetil is an
orally administered non-peptide angiotensin II type 1 (AT1) receptor antagonist. Candesartan
has been shown to be more powerful than EXP-3174 (the active metabolite of losartan),
eprosartan, irbesartan and valsartan at blocking angiotensin II binding to human AT1
receptors in vitro. Candesartan was found to cross the blood brain barrier and induced a
decrease in the maximal contractile response to angiotensin II in animal studies. Receptor
inhibition in vascular preparations by candesartan was reversed by losartan. Dissociation of
candesartan from the AT1 receptor was found to take a prolonged period in vitro.
Pretreatment with candesartan suppressed accumulation of inositol triphosphate in the cells by
94% in vitro. The response to angiotensin II was reduced by candesartan cilexetil to a similar
level as irbesartan and to a similar or greater extent than by losartan. The apparent dose
needed for a 2-fold shift in the angiotensin II dose-response curve was found to be 1.94 mg 24
h after administration in 1 trial and 6 mg in another trial. The greatest response to single oral
doses of candesartan cilexetil 4-16 mg occurred approximately 6-9 h after administration and
effects lasted for over 24 h, while multiple doses improved the response by 33% more.
Candesartan decreased plasminogen activator inhibitor-1 (PAI-1) levels in animal and in vitro
studies but increased levels in postmenopausal women. Left ventricular (LV) mass, LV mass
index and blood pressure (BP) are decreased by candesartan, which may induce regression of
LV hypertrophy. Renal vascular resistance, glomerular filtration rate, renal plasma flow,
filtration fraction and renal blood flow are all improved by candesartan cilexetil. Candesartan
improved urinary albumin levels and urinary protein excretion but no effect on potassium,
sodium and uric acid excretion has been found. A beneficial effect on the vasoconstrictive
response to N(G)-monomethyl-L-arginine (L-NMMA) and a reduction in vasodilatory
response to the endothelin A/B receptor antagonist TAK 044 and in circulating endothelin-1
concentrations occurred with candesartan cilexetil treatment. Oral candesartan cilexetil is
absorbed through the gastrointestinal wall and hydrolysed by carboxylesterase to candesartan.
The absolute oral bioavailability of candesartan (approximately 15%) and AUC are not
altered by the presence of food while Cmax and Tmax values are. Peak Cmax values ranged
between 27.6 mcg/l in young healthy volunteers and 244 mcg/l in renally impaired patients on
dialysis and were dose-related. Tmax values for oral candesartan cilexetil 4-16 mg were
approximately 3-5 h after administration. AUC was dose-dependent and ranged between
approximately 250 and 1100 mcg/h/l. It is noted that candesartan is over 99% bound to
plasma proteins, with a low volume of distribution after iv administration. Candesartan is
eliminated in the urine (33%) and feces (68%) with approximately 75% eliminated as
candesartan and 25% as an inactive metabolite. The elimination half-life was approximately
9-13 h and was dose-independent. Clearance rates of 0.022 l/h/kg have been recorded in
healthy volunteers after iv administration. Renal clearance of 0.642 l/h occurred with a single
oral dose of candesartan cilexetil 8 mg in healthy subjects and clearance of 14.07 l/h occurred
in hypertensive patients given 2-16 mg/day. Hypertensive, renally impaired patients had
greater AUC, Cmax and elimination half-life values with candesartan than healthy patients.
Hemodialysis did not affect elimination of candesartan. The pharmacokinetics of candesartan
were not affected by the occurrence of mild-to-moderate hepatic impairment but AUC and
Cmax were significantly increased in patients with moderate to severe hepatic impairment.
The coadministration of candesartan and hydrochlorothiazide, sustained-release nifedipine,
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glibenclamide, digoxin, ethinylestradiol, levonorgestrel or warfarin did not affect the
pharmacokinetics of the drugs, however, coadministration of lithium and candesartan
increased lithium concentrations. Candesartan cilexetil (8-32 mg/day) was found to be more
effective than losartan in treating hypertension and controlling SBP and DBP and pulse
pressure, with a longer duration of action. Losartan or candesartan with hydrochlorothiazide
were found to induce greater decreases in trough seated DBP than candesartan or losartan
alone. Candesartan was more effective in reducing BP at higher doses. Treatment with
candesartan 8-16 mg/day was found to induce similar reductions in SBP and DBP as achieved
with irbesartan, losartan or valsartan but induced greater reductions than
enalapril. Patients who received candesartan and enalapril had similar mean ambulatory BP
24 h. Less patients receiving candesartan required a dose increase. Candesartan was
associated with greater reductions in DBP and SBP, but with similar health-related quality of
life, than ACE inhibitors and hydrochlorothiazide while the response rate with candesartan
was greater than with ACE inhibitors but similar to that of hydrochlorothiazide. BP reductions
were similar with candesartan cilexetil and amlodipine in patients with mild or mild-tomoderate hypertension but a greater decrease in SBP occurred with candesartan cilexetil plus
amlodipine. Comparable decreases in SBP and DBP were seen with candesartan, felodipine
and lisinopril, while an additive effect was seen when candesartan and felodipine or lisinopril
were used together. The urinary albumin to creatinine ratio was decreased similarly by
candesartan and lisinopril. Candesartan was found to be efficacious as an add-on therapy and
as a long-term therapy. In various trials, candesartan was found to be effective in patients with
moderate to severe hypertension, elderly patients, patients with NIDDM, renal failure, stroke
and in hypertensive patients of ethnic groups. Candesartan has been found to be well-tolerated
in clinical trials, with adverse events including back pain, headache, cough, increases in liver
enzyme concentrations and hypotension. The recommended doses of candesartan range
between 16-32 mg/day,in the USA and 4-16 mg/day in Europe. A fixed dose product
comprising candesartan cilexetil/hydrochlorothiazide is also available. Candesartan should not
be given to pregnant or lactating women and should be given with caution to patients with
renal artery stenosis or volume- and/or salt-depleted
patients. The authors conclude that candesartan cilexetil is an effective antihypertensive
therapy with renoprotective effects.
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Melian EB, Jarvis B
Candesartan cilexetil plus hydrochlorothiazide combination - A review of its use in
hypertension
Drugs 2002; 62(5):787-816
This review discusses the pharmacodynamic properties, pharmacokinetic properties, the
therapeutic use, the tolerability, the dosage and administration of candesartan cilexetil and
hydrochlorothiazide as well as the role of both agents combined in the treatment of patients
with hypertension. In the introduction, it is mentioned that the renin-angiotensin system
(RAS) is inhibited by candesartan. Candesartan cilexetil is a nonpeptide angiotensin II
receptor blocker that binds with high specificity to angiotensin subtype 1 (AT1) but not to
angiotensin subtype 2 (AT2) receptors. It is rapidly and completely converted to candesartan,
the active compound, during absorption from the upper gastrointestinal tract. Regarding the
pharmacodynamic properties, it was shown that plasma renin activity and plasma angiotensin
II concentration were dose-dependently increased by oral candesartan cilexetil 1-8 mg (single
dose). The increase was accentuated with repeated dose, and was significant and long-lasting
(present 24 h after drug administration). In healthy volunteers, it was shown that 24 h after
administration candesartan had an angiotensin II inhibiting activity per mg stronger than that
of losartan, irbesartan, telmisartan and valsartan. The inhibitory effect of candesartan cilexetil
also appears to be of longer duration than that of losartan. Studies comparing irbesartan 150
mg with candesartan cilexetil 8 mg showed, in vivo, a similar angiotensin II inhibiting activity
after administration of single (1 day) or multiple (87 days) doses. Ex vivo, irbesartan 150 mg
appeared to induce a greater AT1 blockade than candesartan cilexetil 8 mg. In AT1 receptortransfected Chinese Hamster Ovary Cells (CHO-hAT1), the half-life of candesartan was 120
min. The authors state that "candesartans slow dissociation from and rebinding to AT1
receptors may explain its long-lasting effect in clinical setting". Other studies have shown that
among patients receiving candesartan cilexetil 16 mg/day, 48 h after administration,
significant reductions of systolic blood pressure (SBP) and diastolic blood pressure (DBP)
were observed despite undetectable plasma concentrations of candesartan. It has been
demonstrated that in 15 patients with hypertension, candesartan cilexetil improved tonic nitric
oxide (NO) release and reduced the vasoconstrictive effect of endogenous endothelin-1 (ET1). Candesartan cilexetil 8 or 16 mg/day reduced plasma ET-1 concentration from baseline
after 2 and 12 months (2.49, 1.61 and 0.72 ng/l respectively). Furthermore, after 2 and 12
months of treatment, candesartan cilexetil enhanced vasoconstriction to intra-arterial Ngmonomethyl-L-arginine. Several studies conducted with hypertensive patients treated with
candesartan cilexetil showed a reduction of the left ventricular (LV) mass, beneficial effects
on diastolic function, a reduction of LV hypertrophy as well as forearm vascular resistance at
rest and after ischemia, an improvement in mean diastolic time and peak velocity filling. A
reduction of LV mass index, and a deceleration time and isovolumetric relaxation time were
observed with long term (52 weeks) candesartan cilexetil 16 mg once daily. In hypertensive
patients with concomitant NIDDM and/or renal impairment, candesartan cilexetil
improves/preserves renal function and reduces proteinuria without affecting urinary sodium,
potassium, or uric acid excretion. Studies showed that candesartan 4-8 mg/day for 2 weeks or
16 mg (single dose) given to hypertensive patients induced a significant reduction of the the
renal vascular resistance and filtration fraction as well as a significant increase of renal
plasma flow and blood flow. Some studies found that the glomerular filtration rate was
affected by candesartan cilexetil but others did not. The Candesartan And Lisinopril
Microalbuminuria (CALM) study showed that candesartan reduced the urinary albumin to
creatinine ratio in hypertensive patients with NIDDM. Another study also showed an increase
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in creatinine clearance. The effect of candesartan cilexetil on plasminogen activator inhibitor
1 (PAI-1) is unclear. In vitro experiments on animal and human models showed that
candesartan induced a reduction of PAI-1 concentrations but these results were not confirmed
by other studies. A reduction of aortic and cardiac PAI-1 expression was observed following
an infusion of candesartan cilexetil in spontaneously hypertensive rats receiving angiotensin II
infusion. Studies have shown that in adipocytes not challenged with angiotensin II,
candesartan cilexetil reduced PAI-1 release and in postmenopausal women treated with
candesartan cilexetil, a significant increase in the plasma concentration of PAI-1 was noted.
The section discussing the pharmacodynamic properties of hydrochlorothiazide reports
studies which showed that, regarding LV mass reduction, hydrochlorothiazide treatment was
similar to captopril and atenolol treatment while, regarding reduction in left atrial size,
hydrochlorothiazide was superior to diltiazem, clonidine, prazosin, captopril and atenolol
treatment. Regarding the pharmacokinetics of the combination of candesartan cilexetil and
hydrochlorothiazide, it was found that the peak plasma concentration (Cmax), Tmax or
elimination half-life (t1/2) of hydrochlorothiazide were not affected by the coadministration
of candesartan. However, candesartan did significantly decrease the AUC of the serum
concentration-time values of hydrochlorothiazide. On the other hand, coadministration of
hydrochlorothiazide increased the bioavailability of candesartan by 20% and Cmax by 23%,
but tmax, t1/2 and mean residence time were not affected. In the section discussing the
pharmacokinetics of candesartan cilexetil, it is mentioned that in healthy volunteers and
various patient groups, candesartan cilexetil is rapidly and completely hydrolyzed to the
active compound candesartan during absorption from the gastrointestinal tract. Cmax
occurred 3-5 h after oral administration and increased in a dose-related manner. Accumulation
of candesartan was not observed after repeated administration of candesartan cilexetil and its
bioavailability was 42% of that seen in iv administration. In hypertensive patients, total
plasma clearance of candesartan was 14.07 l/h and in healthy volunteers it was 0.25 and 0.20
l/h/kg depending on the dosage. The t1/2 ranged from 9-13 h and was dose-independent. In an
elderly population (aged > = 65 years), candesartan cilexetil Cmax and AUC values were
higher by 50% and 80%, respectively and the t1/2 was slightly longer. In comparison with
hypertensive patients with normal kidney function, substantial increases in Cmax and AUC
after repeated doses of candesartan cilexetil were reported in those patients with renal
impairment. For patients with severe hepatic impairment, it is recommended to reduce the
initial dosage of candesartan cilexetil. Indeed, in patients with severe hepatic impairment an
increase in AUC and Cmax by 78% and 64%, respectively have been reported. Concerning
potential drug interactions, the authors mention that "since candesartan is poorly metabolized
by CYP system enzymes, inhibitors and inducers of these enzymes are not likely to interact
with candesartan". In the studies assessing the therapeutic efficacy of the combination
hydrochlorothiazide-candesartan cilexetil, the combination therapy was given once daily, as a
fixed combination tablet or as separate tablets of the drugs. It appears from several studies
that in the treatment of patients with mild to moderate hypertension, the combination therapy
candesartan cilexetil (4, 8, or 16 mg) plus hydrochlorothiazide (12.5 or 25 mg) was effective
and induced greater reductions of blood pressure than equivalent monotherapy with either
drug. Several experiments conducted with patients who previously failed to respond to
hydrochlorothiazide monotherapy showed that these patients responded to add-on candesartan
cilexetil. Several clinical trials showed that the fixed combination candesartan cilexetil (16
mg)/hydrochlorothiazide (12.5 mg) was more efficacious than the combination of losartan (50
mg) and hydrochlorothiazide (12.5 mg) in the treatment of mild to severe hypertension; and it
was as efficacious as the combination of lisinopril (10 mg) and hydrochlorothiazide (12.5 mg)
in patients with mild to moderate hypertension. Regarding the tolerability of the combination,
the most common adverse events reported are headache, back pain, dizziness, respiratory tract
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infection, influenza-like symptoms and in rare cases hypokalemia. The combination therapy
of hydrochlorothiazide with either candesartan cilexetil, lisinopril or losartan are all well
tolerated. However, comparing lisinopril and candesartan cilexetil, it appears that the
incidence of at least 1 adverse event and cough was higher among the patients treated with
lisinopril/hydrochlorothiazide. Regarding the dosage and administration of the combination of
candesartan cilexetil and hydrochlorothiazide, the authors mention that this combination is
recommended for the treatment of patients with hypertension who do not achieve blood
pressure (BP) control after receiving monotherapy with either drug. Usually, it is advised to
start with a low dose and to increase it slowly depending on the clinical effect. As
monotherapy, candesartan cilexetil recommended daily doses are 8-32 mg in United States,
but the maximum is only 16 mg in Europe. For hydrochlorothiazide, the daily doses are 12-50
mg. In patients whose BP is not controlled with candesartan cilexetil 32 mg, the combination
of candesartan cilexetil 32 mg and hydrochlorothiazide can be administered, and those
patients who do not respond to candesartan cilexetil 16 mg can receive the combination of
candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg. For patients with renal
impairment, the combination of candesartan cilexetil of hydrochlorothiazide can be
administered only if the patient's creatinine clearance is > = 30 l/h. For patients with hepatic
deficiency, this combination should be administered carefully and it is even recommended to
reduce the initial dose of candesartan cilexetil. This combination can be prescribed with other
hypertensive agents and administered with or without food but it should not be administered
to pregnant women. The authors conclude that the candesartan cilexetil/hydrochlorothiazide
combination is an effective treatment for patients with hypertension, is significantly more
efficacious than either agent alone and has an excellent adverse event profile.
5/19
Gleiter CH, Morike KE
Clinical pharmacokinetics of candesartan
Clinical Pharmacokinetics 2002 ;41(1):7-17
In this review recently published data on the clinical pharmacokinetics of candesartan are
presented. Candesartan cilexetil is the esterified prodrug of candesartan. The following
characteristic kinetic data were observed after investigations in healthy volunteers.
Candesartan cilexetil is rapidly and totally hydrolysed enzymatically to candesartan during
absorption in the gastrointestinal tract following oral administration. The oral bioavailability
in humans is about 40%. Plasma concentrations of candesartan cilexetil are not detected after
oral administration of the drug. The active metabolite appears after a mean lag-time of 1 h
after a single dose as well as after 8 consecutive days of treatment. Cmax was reached
between 3.5 and 6 h. AUC and Cmax values increased in proportion to the dose after the 3
lowest doses (1, 2 and 4 mg once daily). In general the plasma protein binding of candesartan
in humans is more than 99%. It also appears that candesartan is unable to penetrate blood
cells. A mass balance study showed that when C-14 candesartan was administered to healthy
volunteers as a single dose, 33% of the radioactivity was discovered in the urine and 68% in
the faeces. Following both iv and oral administration, it was found that more than 90% of
total radioactivity was excreted within 72 h of administration. Therefore a great deal of
candesartan cilexetil is not absorbed and any candesartan that reaches the systemic circulation
is mainly excreted by the kidneys. In vitro studies have shown that candesartan failed to
illustrate any affinity for any of the clinically relevant cytochrome enzymes. In healthy
volunteers a 1-compartment model was used to show a mono-exponential decline of
candesartan plasma concentrations with a half-life of 3.5 h (day 1) and 4 h (day 8). Other
studies are also examined and the authors believe that the terminal elimination half-life of
candesartan may have been underestimated. When candesartan was administered iv to healthy
volunteers the total clearance was 0.0222 l/h/kg. In volunteers (aged 18-50 years) after a
single oral dose of candesartan cilexetil 8 mg, the renal clearance was 0.64 l/h. No clinically
significant effects of food on therapy with candesartan cilexetil are documented. Tmax was
decreased and Cmax increased in healthy volunteers after taking candesartan 8 mg in the fed
state, whilst AUC remained unaffected. Candesartan cilexetil can be administered irrespective
of meals. Candesartan cilexetil had no pharmacodynamic or pharmacokinetic interactions
with nifedipine, glibenclamide, digoxin, ethinylestradiol/levonorgestrel, warfarin or
hydrochlorothiazide in a series of drug-drug interaction studies. The inhibitory effect of
candesartan on systolic blood pressure response to angiotensin II was long lasting and doserelated. The study by Azizi et al., where candesartan 8 and 12 mg/day was compared with
losartan showed that a dose-response relationship existed for both doses of candesartan. The
clinically effective dosage range of between 8 and 32 mg/day was established following
several dose-finding studies. The maximum antihypertensive effect is reached after an intake
of the drug for about 1 week. AUC/dose corrected for body mass was not different between
males and females. Pharmacokinetic parameters are similar in Black and in non-Black
populations. When candesartan was administered to healthy young and elderly volunteers at
dosages of 2 to 16 mg/day it resulted in higher Cmax and AUC in the elderly population but
drug accumulations did not occur. In a double-blind study oral doses of candesartan 2, 4, 8, 12
and 16 mg/day in 232 patients with hypertension aged between 28 and 69 years it was shown
that age of the hypertensive patient population did have an influence on the distribution and
elimination of the drug. Evaluation of the studies to date leads scientists to believe that
candesartan has an elimination half-life longer than 8 hours. Part of this review examines
disease and the pharmacokinetics candesartan in patients with hypertension and with normal
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to severely impaired renal function. Pharmacokinetics and pharmacodynamics of candesartan
8 mg/day were studied. Serum concentrations at trough were significantly higher in patients
with severely impaired renal function compared with those with normal kidney function.
Subsequent analysis revealed the absence of clinically relevant accumulation of candesartan at
the 8 mg dose. It was also noticed that a considerable negative correlation between AUC and
glomerular filtration rate (GFR) occurred. An accumulation of candesartan was found with
multiple doses of candesartan 12 mg/day where the drug was administered to patients with
renal impairment and hypertension. In patients with renal impairment the mean Cmax, AUC
and elimination half-life values increased. The accumulation factor was 1.71 in this study and
a similar sub-study found the accumulation factor to be 1.44 for candesartan 8 mg/day.
Analysis by Pfister et al. illustrated that no significant elimination of candesartan occurs with
hemodialysis. Dosages of up to 12 mg/day do not require precautions in patients with mild to
moderate liver disease. Candesartan is mainly excreted unchanged through renal and biliary
routes. Evidence thus far suggests that any state of hypertension by itself is unable to change
the pharmacokinetics of candesartan. The authors conclude that candesartan cilexetil appears
to be a reasonably easy to handle drug for patients with hypertension who do not tolerate ACE
inhibitors.
7/19
Rossing K, Jensen BR, Christensen PK, Parving HH
Dual blockade of the renin-angiotensin system in diabetic nephropathy - A randomized
double-blind crossover study
Diabetes Care 2002;25(1):95-100
The aim of this study was to determine the short-term effect of a dual blockade of the reninangiotensin system (RAS) by adding candesartan cilexetil to the treatment of patients with
diabetic nephropathy (DN) responding insufficiently to previous antihypertensive treatment.
17 out of 18 patients (13 male, 4 female, mean age 58 years) with IDDM and DN completed
this randomized, double-blind, crossover study. All the patients had antihypertensive therapy
including enalapril 20 mg once daily (n = 9), lisinopril 20 mg (n = 5) once daily or captopril
100 mg/day (n = 4). Moreover, 15 patients received diuretics, 11 had calcium channel
antagonist and 3 had a beta-blocker. Candesartan cilexetil 8 mg once daily for 8 weeks or
placebo tablet daily for 8 weeks were added to the antihypertensive treatment. Albuminuria,
arterial blood pressure as well as serum potassium and creatinine were measured. The results
showed that the values for 24-h systolic blood pressure, albuminuria, the fractional clearance
of albumin and IgG were significantly lower when candesartan cilexetil was added to
conventional ACE inhibitor treatment than the ACE inhibitor treatment given alone. The
decrease in the 24-h systolic blood pressure was sustained day and night. It also induced a
reduction of the glomerular filtration rate (GFR), the albuminuria (25%), the fractional
clearance of albumin (35%) and IgG (32%). However, diastolic blood pressure and mean
heart rate were not affected by candesartan. The authors also found that the level of
angiotensin II during placebo treatment and the absolute decrease in arterial blood pressure
during addition of candesartan were significantly and positively correlated. A significant
correlation was observed between changes in systolic blood pressure and albuminuria.
Furthermore, during candesartan administration, the relative decline in GFR was positively
correlated with the decline in systolic blood pressure. Serum potassium, sodium, creatinine,
HbA1c, angiotensin II and urinary sodium excretion did not change with the addition of
candesartan. Finally, only 1 patient withdrew after 2 weeks because of side effects (nausea
and stomach upset). The authors conclude that "dual blockade of the RAS is well tolerated
and reduces albuminuria and blood pressure in patients with IDDM and DN responding
insufficiently to antihypertensive combination therapy".
8/19
Noh G, Ackad T, Hsueh WA, Law RE, Collins NR
Effects on atherosclerosis by Omapatrilat and Candesartan in ApoE-/- mice
Arteriosclerosis, Thrombosis and Vascular Biology 2002;22(5):A21, Abs P122.
In this study the role of omapatrilat and candesartan on the formation and progression of
atherosclerosis in male apoE-/- mice was examined in the presence or absence of angiotensin
II infusion. In the study mice were assigned to 3 different groups; in group (a) mice were
administered chow, group b received chow with omapatrilat and mice in group c received
chow with candesartan for a 12 week period. Results showed that omapatrilat and candesartan
substantially reduced systolic blood pressure. The formation of fatty streaks was also blocked
by both drugs. Investigators then assessed the role of candesartan and omapatrilat on
atherosclerosis during Angil-induced hypertension. For this experiment mice were placed on
the same dietary regimen as the previous experiment only this time all mice were infused with
Angil 2.5 mcg/kg/min for 4 weeks. In both the chow and omapatrilat groups Angil increased
systolic blood pressure however candesartan decreased blood pressure when compared to
non-infused controls. Angil infusion led to marked increases in the rate and progression of
atherosclerosis in the chow and omapatrilat groups. This phenomenon did not occur in the
candesartan group. In their last experiment investigators determined whether candesartan
could cause regression on pre-existing lesions. For this purpose 6- month-old apoE mice were
assigned to 1 of 3 groups; group (a) controls, (b) 3 months continued chow or (c) 3 months on
chow/candesartan. Results showed that that the inclusion of candesartan in the diet of the
mice reduced the further development in the percentage of the aortic surface covered by
lesions. The authors conclude that both omapatrilat and candesartan demonstrated significant
atherosclerotic protective effects in this study.
9/19
Ito M, Hachiya A, Fujii M, Katagiri M, Nakano S, Kurita T, Matsuzaki H, Iida K, Miki K
Effect of the angiotensin II receptor antagonist (AT-IIRA) candesartan cilexetil on
portal blood flow in liver cirrhosis
Gastroenterology 2002;122(4)(Suppl 1):A656, Abs M1262.
The purpose of this study was to establish whether candesartan cilexetil affects portal venous
flow plus hepatic function and reduces portal hypertension. In the study cirrhotic patients (n =
30) were recruited. Portal blood flow, systemic arterial pressure, hepatic function and hepatic
venous pressure gradient (HVPG) were measured before and 2 weeks after the daily oral
administration of candesartan 4 mg. Other parameters to be measured included congestion
index (CI) of the portal vein. Results showed candesartan considerably reduced HVPG from
17.2 to 14.6 mm Hg. Maximum velocity significantly increased and CI substantially
decreased. The 15-min indocyanine green retention rate and the plasma ammonium level rate
both decreased considerably. The authors conclude that sinusoidal resistance was reduced by
candesartan which led to a reduction in portal venous congestion and reduced portal
hypertension moderately.
10/19
Collins AR, Noh G
Effects of candesartan and omapatrllat on atherosclerosis in ApoE-/- mice
Circulation 2002;105(14):E106, Abs 114.
The aim of this animal study was to investigate the role of omapatrilat and candesartan on the
formation and progression of atherosclerosis in male ApoE-/- mice in the presence and
absence of angiotensin II infusion. In the first part of the study 3-month-old male mice were
used to investigate the effects of omapatrilat and candesartan on the progression of early
xanthoma formation. The animals were fed either chow, chow with omapatrilat or chow with
candesartan for 12 weeks. Both agents reduced systolic blood pressure significantly and
inhibited the formation of fatty streaks by approximately 70%. To investigate the role of
omapatrilat and candesartan on atherosclerosis during angiotensin II-induced hypertension 3month-old mice were placed on the same dietary supplementation as the previous experiment
but were also infused with angiotensin II 2.5 mcg/kg for 4 weeks. Systolic blood pressure
increased with angiotensin II infusion in both the chow and omapatrilat groups but decreased
in the candesartan group below the level of non-infused controls. Angiotensin II also
accelerated the rate and progression of atherosclerosis in the chow and omapatrilat groups but
this effect of angiotensin II was abrogated in the candesartan group. Heart weights increased
in the chow group but there was no change in the omapatrilat or candesartan groups. The
ability of candesartan to cause regression of pre-existing lesions was investigated in 6-monthold ApoE mice. In this experiment the animals were used as baseline controls, were fed chow
only, or were given chow and candesartan for 3 months. At the start of this experiment the
animals had 4.1% of the aortic surface covered by lesions. With candesartan administration
any increases in the percentage of the aortic surface covered by lesions was prevented
compared to chow-fed 9-month-old animals.
11/19
Dorffel Y, Bresan V, Stuhlmuller B, Dorffel WV, Pruss A, Scholze J
Candesartan - an inhibitor of monocyte activation in hypertensive patients?
Perfusion 2002;15(3):96-8, 100-1.
The purpose of this study was to investigate the possible role of the angiotensin II receptor
antagonist candestartan in the prevention of pre-activation of monocytes from hypertensive
patients. The study included 18 patients (12 male, 6 female; aged 28-67 years), suffering from
essential hypertension. Blood samples were obtained from patients before and after 6 weeks
of antihypertensive therapy with candesartan 8-16 mg/day. The activation of peripheral blood
monocytes from hypertensive patients after candesartan therapy in vivo was monitored by
measuring the release of tumor necrosis factor-alpha, interieukin-l-beta and interleukin-6 into
culture supernatants. The results of this part of the study showed that, after antihypertensive
therapy, the secretion of interieukin-l-beta and tumor necrosis factor-alpha was significantly
decreased in peripheral blood monocytes derived from patients. The interleukin-6 secretion
was diminished non significantly after therapy. The angiotensin II stimulated cytokine
secretion of monocytes was substantially decreased after candesartan therapy. The cytokine
levels after angiotensin II stimulation did not differ statistically between patients and control
monocytes after therapy. Another part of the study involved the preincubation of monocytes
with candesartan for 30 min. The results of this cytokine assay-response to angiotensin II
stimulation, showed that in monocytes preincubated with candesartan the tumor necrosis
factor-alpha secretion was diminished in both groups to comparable levels. The authors
conclude that the prevention of angiotensin II-mediated cell activation by candesartan may be
a novel therapeutic approach to prevent vascular alterations in hypertension.
12/19
Kincaid Smith P, Fairley K, Packham D
Randomized controlled crossover study of the effect on proteinuria and blood pressure
of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme
inhibitor in normotensive patients
Nephrology Dialysis Transplantation 2002;17(4):597-601.
In this article the authors investigated whether or not the addition of candesartan to the
regimens of patients already receiving an ACE inhibitor who had chronic renal disease and
were normotensive. The study population (n = 60; aged 23 - 75 years) were taking a number
of ACE inhibitors, with 1 patient receiving lisinopril 20 mg/day. Patients were randomly
allocated to a candesartan 8 mg/day group for 12 weeks, after which time candesartan
treatment was ended, while the other group had candesartan added in the second 12 week
period, after which time treatment again ceased. While the patients received candesartan they
remained on their normal regimens. The study found that there was a statistically significant
reduction in 24 h proteinuria as well as systolic and diastolic blood pressure. The candesartan
arm of the study also experienced a rise in serum urea and there was no change observed in
potassium and creatinine levels. 80% of the non diabetic patients in the study showed reduced
urine protein on the ACE inhibitor and candesartan. In contrast, only 1 of the 7 patients with
diabetic glomerulosclerosis showed a reduction in proteinuria, and diabetic patients had
higher blood pressure in comparison with the non diabetic patients receiving the combination
regimen. ACE inhibitor therapy alone was not satisfactory for controlling blood pressure in
diabetic patients. 6 patients did not complete their treatment courses for the 12 week periods,
as 3 of them developed postural hypotension, 1 developed hyperkalaemia when candesartan
treatment was started and another patient developed cholecystosis. 1 patient withdrew for
personal reasons. In their discussion, the authors mention a study which found that the
addition of losartan to a lisinopril regimen for patients with proteinuria and moderately
advanced chronic renal failure did not cause blood pressure or urine protein level to fall
(Agarwal et al 2001). The authors conclude that their results demonstrate the safety of adding
an angiotensin receptor antagonist (candesartan) to a regimen which includes an ACE
inhibitor.
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Berger ED, Bader BD, Ebert C, Risler T, Erley CM
Reduction of proteinuria; combined effects of receptor blockade and low dose
angiotensin-converting enzyme inhibition
Journal of Hypertension 2002;20(4):739-43.
The aim of this study was to determine the antiproteinuric and hemodynamic effects of
candesartan, compared with placebo, in addition to preexisting medication with ACE
inhibitors in patients with proteinuria > = 1 g/24 h due to chronic glomerulonephritis. 12
patients (6 male, 6 female; aged 30-66 years) were included in this randomized, double-blind
and placebo-controlled study. The ACE inhibitor therapy included 5 patients receiving
enalapril 10 mg/day, 2 patients treated with ramipril 10 mg/day, 3 patients with ramipril 5
mg/day, 1 patient had quinalapril 10 mg/day and another 1 captopril 50 mg/day. ACE
inhibitor therapy was given since at least 3 months. Patients received either oral candesartan
(8 mg/day) or placebo for 2 treatment periods of 8 weeks separated by a wash-out period of 4
weeks. Candesartan or placebo were given in addition to the preexisting medication. The
results showed that no side effects were reported by the addition of candesartan to treatment
with ACE inhibitors. A significant decrease in systolic and diastolic blood pressure were
observed after 8 weeks treatment with candesartan and the difference between the treatment
period was significant. Heart rate was not modified significantly during both treatment
periods. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF)
were not affected significantly by candesartan and the hormones of the renin-angiotensin
system did not vary significantly during the 2 treatment periods. Finally, compared with
placebo, candesartan induced a significant decrease of the proteinuria and the albuminuria.
The authors conclude that "candesartan promotes a complementary antiproteinuric and a
small antihypertensive effect after a treatment period of 8 weeks in patients with chronic
glomerulonephritis when given in conjunction with an ACE inhibitor".
14/19
Bagatell SJ, Miller CS, Mullins JJ, Mitchell KD
AT(1) receptor activation mediates reduced renal function in hypertensive transgenic
rats with inducible expression of the Ren2 renin gene
FASEB Journal 2002;16(P4 Pt 1):A419, Abs 37115.
The aim of this study was to determine the effects of chronic angiotensin II type 1 (AT1)
receptor blockade on the changes in renal function that occur in hypertensive Cypla1-Ren2
transgenic rats with inducible expression of the REN2 renin gene. Animals were fed with or
without indole-3-carbinol (I3C) for 11-12 days. Transgenic rats fed with I3C had higher mean
arterial pressure and lower plasma flow than transgenic rats not fed with I3C. There were no
difference between transgenic hypertensive rats and normotensive rats in terms of urine flow
and Na excretion. Transgenic hypertensive rats fed with I3C and treated with candesartan (25
mg/l in drinking water) for 8 days had lower mean arterial pressure and higher renal plasma
flow, urine flow and Na excretion than I3C-induced transgenic rats not treated with
candesartan. The authors conclude that "activation of AT1 receptors by angiotensin II
generated as a consequence of induction of the Cypla1-Ren2 transgene mediates the reduced
renal function in hypertensive Cypla1-Ren2 transgenic rats".
15/19
Matsuo T, Ishikawa E, Ohta M, Shibouta Y, Ishimura Y, Imura Y, Sugiyama Y
Renal protective effect of candesartan cilexetil in spontaneously hypercholesterolemic
rats
Japanese Journal of Pharmacology 2002;88(3):300-6.
The aim of this study was to investigate the renoprotective effect of candesartan cilexetil in
spontaneously hypercholesterolemic (SHC) rats compared to enalapril. In the first experiment
physiological differences were examined and compared in male Sprague Dawley and SHC
rats. In the second experiment SHC rats were divided into 4 groups, vehicle-treated,
candesartan cilexetil 0.1 mg/kg-treated, candesartan cilexetil 1 mg/kg-treated and enalapril 10
mg/kg-treated, for 6 weeks. Neither agent was found to influence the body weight of SHC
rats. Systolic blood pressure (SBP) changed from 146 to 155 mmHg for vehicle-treated SHC
rats after 5 weeks of administration, it changed from 148 to 145 mmHg for candesartan
cilexetil 0.1 mg/kg, from 153 to 131 mmHg for candesartan cilexetil 1 mg/kg and from 157 to
126 mmHg for enalapril-treated SHC rats. Candesartan cilexetil 1 mg/kg and enalapril
decreased SBP significantly and had comparable effects. Both candesartan cilexetil 1 mg/kg
and enalapril inhibited proteinuria in SHC rats, with similar effects. Candesartan cilexetil 1
mg/kg was found to significantly inhibit the increase of total cholesterol, so too did enalapril.
Neither candesartan cilexetil nor enalapril had any effect on glutamate pyruvate transaminase
activity, which is a liver injury marker. Candesartan cilexetil 1 mg/kg and enalapril tended to
increase creatinine clearance and significantly inhibited the enlargement of the kidney which
usually occurs in the SHC rats. Both candesartan cilexetil 1 mg/kg and enalapril significantly
inhibited glomerular injury comparably. However candesartan cilexetil 0.1 mg/kg had no
effect. Candesartan cilexetil 1 mg/kg prevented the increase in basophilic changes, cast
formation and mononuclear cell infiltration that usually occur in SHC rats. Enalapril
prevented the increase in cast formation and tended to prevent the basophilic changes and
mononuclear cell infiltration. Candesartan cilexetil 0.1 mg/kg exerted no significant effects.
The authors conclude that candesartan cilexetil and enalapril demonstrated beneficial
renoprotective effects in SHC rats, which represents a model of focal glomerulosclerosis with
hypercholesterolemia.
16/19
Nishiyama A, Yoshizumi M, Rahman M, Tamaki T, Kimura S, Abe Y
Contribution of AT1 receptor-mediated MAPK activation to renal injury in Dahl saltsensitive (DS) rats
Japanese Journal of Pharmacology 2002;88(Suppl 1):206P, Abs P-577.
The aim of this study was to establish the role of angiotensin II type 1 (AT1) receptormediated mitogen-activated protein kinase (MAPK) activation in renal injury in Dahl saltsensitive rats. Animals were given high salt diet (8.0% NaCl), low salt diet (0.3% NaCl) or
high salt diet + candesartan 15-20 mg/kg/day for 4 weeks. Mean blood pressure in rats given
high salt diet was higher than in those given low salt diet (179 vs 104 mmHg, respectively).
Urinary excretion of protein and renal cortical collagen content were higher in rats given high
salt diet. Candesartan did not affect the mean blood pressure but did significantly reduce
urinary excretion of protein and cortical collagen content in rats given high salt diet. In
addition, candesartan histologically improved the progressive sclerotic and proliferative
glomerular changes in rats given high salt diet. Finally, a significant decrease in kidney
angiotensine II content and in extracellular signal-regulated kinases 1/2 and c-Jun NH2terminal kinase activities was observed following administration of candesartan to rats given
high salt diet. The authors conclude that "renal injury is accompanied with AT1 receptormediated MAPK activation in rats given high salt diet".
17/19
Zhuo JL, Imig JD, Hammond TG, Orengo S, Benes E, Navar LG
Ang II accumulation in rat renal endosomes during Ang II-induced hypertension - Role
of AT(1) receptor
Hypertension 2002;39(1):116-21.
The aim of this study was to determine whether angiotensin II (Ang II) movement into renal
cortical endosomes is increased during Ang II hypertension, and if so, to examine whether the
Ang II type 1 (AT1) receptor antagonist, candesartan, impedes this accumulation. Included in
this assessment were Sprague-Dawley rats, which were divided into 3 groups; Group 1 were
controls, Group 2 received Ang II infusions for 13 days and Group 3 received concurrent Ang
II infusions plus candesartan 2 mg/kg/day for 13 days. The rats infused with Ang II developed
hypertension by day 6. The candesartan treatment in Group 3 prevented the development of
hypertension. Plasma renin activity (PRA) was considerably suppressed in Ang IIhypertensive rats, while it was elevated more than 6-fold in Group 3. Plasma Ang II
concentrations were found to increase by approximately 3-fold in Ang II-infused rats
compared with controls. Simultaneous treatment of Ang II with candesartan caused a
substantial elevation in PRA and an increase in plasma Ang II levels, more so than observed
in rats administered Ang II alone. Kidney Ang II levels in Group 3 did not increase
significantly from the levels found in control rats. Candesartan prevented the Ang II-induced
increases in both endosomal and intermicrovillar Ang II levels. A shift to the right of the 3dimensional frequency histogram in renal endosomes of Ang II-infused rats was prevented by
concurrent candesartan treatment. The authors conclude that there is a substantial intracellular
accumulation of angiotensin peptides in renal cortical endosomes during Ang II-dependent
hypertension via an AT1 receptor-mediated process.
18/19
Wakatsuki T, Hiura N, Yamamoto T, Saito A, Tabata T, Oki T.
Effects of candesartan to prevent fatal arrhythmias following acute myocardial ischemia
and reperfusion: An electrophysiological study using canine hearts. Journal of the
American College of Cardiology 2002;39(5)(Suppl A):93A.
The aim of this study was to determine the preventive role of candesartan against acute
arrhythmias through its electrophysiological effects following acute myocardial ischemia and
reperfusion in dogs. 40 dogs (Candesartan group, n = 20 and control group, n = 20) were
included in the experiment. 10 min before the left anterior descending coronary artery ligation
(LAD), the candesartan group received iv infusion of candesartan 1 mg/kg. The results
showed no difference between the 2 groups regarding the hemodynamics before, during and
after LAD. However, a significant suppression of the shortening of the effective refractory
period due to ischemia as well as the prolongation of intramyocardial conduction time during
ischemia and reperfusion was observed in the candesartan group compared with the control
group. Finally, candesartan induced a significantly lower frequency of ventricular fibrillation.
The authors conclude that "candesartan prevents critical electrophysiological changes during
acute ischemia and reperfusion, resulting in decreases in fatal arrhythmias".
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