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Yoshinobu Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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Candesartan Cilexetil a review of its preclinical pharmacology
Journal of Human Hypertension, 1997Co-Authors: K Nishikawa, Takehiko Naka, F Chatani, Yoshinobu YoshimuraAbstract:: Candesartan is a highly potent, long-acting and selective angiotensin II type 1 (AT1) receptor blocker. It is administered orally as the inactive prodrug Candesartan Cilexetil which is rapidly and completely converted to Candesartan during gastrointestinal absorption. In vitro studies have shown that Candesartan acts as an insurmountable angiotensin II receptor antagonist, binding tightly to and dissociating slowly from the AT1 receptor. The above characteristics are thought to contribute to the marked and long-lasting antihypertensive effects of Candesartan Cilexetil in several animal models of hypertension. These included rodent models of renal hypertension in which Candesartan Cilexetil also demonstrated efficacy equivalent to or greater than enalapril. In other animal models, Candesartan Cilexetil reduced the incidence of stroke, renal dysfunction and renal disease while reducing cardiac and vascular hypertrophy. Furthermore, Candesartan Cilexetil conferred some protection against cerebral and renal damage at a dose that had no blood pressure-lowering effect. In toxicity and general pharmacology studies, Candesartan Cilexetil was shown to possess a 'clean' profile with a large safety margin. Also it did not potentiate chemical- or autocoid-induced cough or anaphylactoid reactions.
E L Michelson - One of the best experts on this subject based on the ideXlab platform.
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a forced titration study of antihypertensive efficacy of Candesartan Cilexetil in comparison to losartan claim study ii
Journal of Human Hypertension, 2001Co-Authors: Donald G Vidt, W B White, E L Michelson, Susan Harris, E Ridley, M Rahman, Jennifer Vendetti, Rebecca WangAbstract:An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of Candesartan Cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to Candesartan Cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of randomised treatment, the doses of Candesartan Cilexetil and losartan were doubled to 32 mg and 100 mg once daily and continued respectively for 6 weeks. At week 8, Candesartan Cilexetil lowered the blood pressure (BP) at 24 h (trough), 6 h (peak) and 48 h post dose to a significantly greater extent (P < 0.05) than losartan: Candesartan Cilexetil lowered trough BP by 13.4/10.5 mm Hg, peak BP by 15.5/12.9 mm Hg and 48-h BP by 10.5/9.9 mm Hg compared to a reduction of trough BP by 10.1/9.1 mm Hg, peak BP by 12.0/9.5 mm Hg, and 48-h BP by 5.9/7.0 mm Hg by losartan. The responder and control rates were numerically higher in the Candesartan Cilexetil group, but the differences did not reach statistical significance; the responder rates were 58.8% for the Candesartan Cilexetil group and 52.1% for the losartan group and control rates were 49.0% for the Candesartan Cilexetil group and 44.6% for the losartan group. Overall, both treatment regimens were well tolerated. A total of 15 of the 611 (2.5%) patients withdrew from the study due to an adverse event, including nine (2.9%) in the Candesartan Cilexetil group and six (2.0%) in the losartan group. In conclusion, this forced titration study confirms that Candesartan Cilexetil is more effective in lowering BP than losartan when compared at once daily maximum doses.
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comparative effects of Candesartan Cilexetil and amlodipine in patients with mild systemic hypertension
American Journal of Cardiology, 2001Co-Authors: Robert A Kloner, Myron Weinberger, James L Pool, Steven G Chrysant, Rajesh Prasad, Susan M Harris, Teresa Zyczynski, Nancy Kline Leidy, E L MichelsonAbstract:The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker Candesartan Cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received Candesartan Cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to Candesartan Cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the Candesartan Cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on Candesartan Cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on Candesartan Cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on Candesartan Cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan Cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan Cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.
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Comparative Effects of Candesartan Cilexetil and Amlodipine in Patients With Mild Systemic Hypertension
American Journal of Cardiology, 2001Co-Authors: Robert A Kloner, Myron Weinberger, James L Pool, Steven G Chrysant, Rajesh Prasad, Susan M Harris, Teresa Zyczynski, Nancy Kline Leidy, E L MichelsonAbstract:The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker Candesartan Cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received Candesartan Cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to Candesartan Cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the Candesartan Cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on Candesartan Cilexetil and 87% of those on amlodipine were controlled (diastolic BP
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The Effects of Candesartan Cilexetil in Isolated Systolic Hypertension: A Clinical Experience Trial.
Journal of Clinical Hypertension, 2000Co-Authors: Joel M. Neutel, E L Michelson, Matthew R. Weir, Marvin Moser, Susan Harris, Dianne T. Edwards, Rebecca Wang, Action Study InvestigatorsAbstract:: An 8-week, multicenter, open-label, clinical experience trial evaluated the efficacy of Candesartan Cilexetil either alone (34%) or as add-on therapy (66%) in 1014 patients with untreated or uncontrolled isolated systolic hypertension defined as systolic blood pressure 140-179 mm Hg/diastolic less than 90 mm Hg. Candesartan Cilexetil 16 mg once daily was given initially and was up-titrated to 32 mg once daily at week 2 or week 4 if systolic blood pressure remained at or above 140 mm Hg. Overall, Candesartan Cilexetil reduced both blood pressures by 16.5Â+/-0.6/4.5Â+/-0.2 mm Hg from 158Â+/-0.4/81Â+/-0.2 to 142Â+/-0.6/76Â+/-9.6 mm Hg with a control rate (systolic blood pressure less than 140 mm Hg) of 49%. Of the 492 (51%) patients remaining on the lower dose of Candesartan Cilexetil (40% as monotherapy; 60% as add-on), Candesartan Cilexetil 16 mg reduced blood pressure by 19.7Â+/-1.0/5.5Â+/-0.3 mm Hg and 62% of patients were controlled. For the 475 (49%) patients uncontrolled on Candesartan Cilexetil 16 mg and titrated to 32 mg (30% as monotherapy, 70% as add-on), the dose increase further reduced blood pressure by 8.9Â+/-0.4/3.8Â+/-0.1 mm Hg at week 8, and 36% of patients not responsive to the lower dose achieved blood pressure control on the higher dose. This dose response from Candesartan Cilexetil 16 mg to 32 mg was seen across age, sex, and race. Overall, tolerability was well maintained. Most adverse events were relatively infrequent, and only 8% withdrew due to adverse events; the most frequent adverse effects were dizziness (7%), headache (6%), and upper respiratory tract infection (5%). In conclusion, in this clinical experience trial for patients with isolated systolic hypertension, Candesartan Cilexetil 16 mg to 32 mg once daily produced a dose-related decrease in systolic blood pressure with a lesser decrease in diastolic blood pressure, resulting in a substantial decrease in pulse pressure. The dose response without dose dependent adverse effects was consistent across age, sex, and race, demonstrating that Candesartan Cilexetil is a therapeutic option for patients with isolated systolic hypertension. (c)2000 by Le Jacq Communications, Inc.
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efficacy of Candesartan Cilexetil as add on therapy in hypertensive patients uncontrolled on background therapy a clinical experience trial
American Journal of Hypertension, 2000Co-Authors: Matthew R. Weir, E L Michelson, Joel M. Neutel, Jennifer Vendetti, Michael A Weber, Rebecca WangAbstract:Abstract A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT 1 subtype) blocker Candesartan Cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5446 patients who had essential hypertension (HBP) and 1014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and α- or β-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan Cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, Candesartan Cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), β-blockers (16.5/10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), α-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan Cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, Candesartan Cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), β-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and α-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of Candesartan Cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with Candesartan Cilexetil alone, and 0.8% with Candesartan Cilexetil as add-on therapy. Thus, Candesartan Cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.
Blair Jarvis - One of the best experts on this subject based on the ideXlab platform.
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Candesartan Cilexetil an update of its use in essential hypertension
Drugs, 2002Co-Authors: Stephanie E Easthope, Blair JarvisAbstract:Candesartan Cilexetil is converted to the angiotensin II receptor antagonist Candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of Candesartan to the angiotensin II type 1 (ATi) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic blood pressure (BP) and diastolic BP are achieved with a once-daily dosage of Candesartan Cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, Candesartan Cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day Candesartan Cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, Candesartan Cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of Candesartan Cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with Candesartan Cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with Candesartan Cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with Candesartan Cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan Cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of Candesartan Cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity. Conclusions: Candesartan Cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that Candesartan Cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, Candesartan Cilexetil is a useful therapeutic option in the management of patients with hypertension.
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Candesartan Cilexetil plus hydrochlorothiazide combination a review of its use in hypertension
Drugs, 2002Co-Authors: Ezequiel Balmori Melian, Blair JarvisAbstract:Abstract The combination of Candesartan Cilexetil [an angiotensin II type 1 (AT1) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of Candesartan Cilexetil 4 to 16mg with hydrochlorothiazide 12.5 or 25mg induced significant reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension. Data from clinical trials indicated that reductions in BP induced by Candesartan Cilexetil 4 to 32mg/hydrochlorothiazide 12.5mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with Candesartan Cilexetil 16mg/hydrochlorothiazide 12.5mg or Candesartan Cilexetil 16mg induced SBP/DBP reductions of 12.0/7.5mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by Candesartan Cilexetil 16mg/hydrochlorothiazide 12.5mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given Candesartan Cilexetil 4 or 8mg/hydrochlorothiazide 12.5mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of Candesartan Cilexetil 16mg/hydrochlorothiazide 12.5mg demonstrated a greater antihypertensive effect than losartan 50mg/hydrochlorothiazide 12.5mg in two clinical trials. Candesartan Cilexetil 8mg/hydrochlorothiazide 12.5mg showed a similar antihypertensive effect compared with that of combined lisinopril 10mg/hydrochlorothiazide 12.5mg. Candesartan Cilexetil/hydrochlorothiazide combination therapy was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for Candesartan Cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving Candesartan Cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events. Conclusion: The combination of Candesartan Cilexetil and hydrochlorothiazide (AT1 receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of Candesartan Cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.
R Hubner - One of the best experts on this subject based on the ideXlab platform.
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Candesartan Cilexetil safety and tolerability in healthy volunteers and patients with hypertension
Journal of Human Hypertension, 1997Co-Authors: G Belcher, M George, R Hubner, D Elmfeldt, H LundeAbstract:: The tolerability and safety of Candesartan Cilexetil has been evaluated in over 5000 subjects enrolled into double-blind or open-label clinical studies. In double-blind clinical trials in patients with primary hypertension, Candesartan Cilexetil 2-16 mg once-daily was associated with a low incidence of adverse events and drug-related withdrawals, similar to placebo. The drug showed no evidence of dose-dependent adverse events and it was equally well tolerated by men and women and by elderly (> or =65 years) and younger (<65 years) patients alike. Candesartan Cilexetil had no effect on blood glucose control or serum lipid profile in patients with type II diabetes. It was very well tolerated also when given in combination with hydrochlorothiazide or amlodipine and during long-term open-label therapy (up to 1 year). Candesartan Cilexetil therefore possesses an excellent tolerability profile that extends to a wide variety of patients including the elderly and it does not aggravate co-existing risk factors such as hyperlipidaemia or glucose intolerance. It therefore appears to offer a better tolerated alternative to other commonly used antihypertensive agents.
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pharmacokinetics of Candesartan after single and repeated doses of Candesartan Cilexetil in young and elderly healthy volunteers
Journal of Human Hypertension, 1997Co-Authors: R Hubner, A M Hogemann, M Sunzel, J G RiddellAbstract:Abstract Candesartan Cilexetil is rapidly and completely hydrolysed to the active compound Candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, long-acting, selective angiotensin II AT1 receptor blocker. The pharmacokinetics of Candesartan were investigated after single and repeated once-daily doses of Candesartan Cilexetil in the dose range 2-16 mg in both younger (19-40 years) and elderly (65-78 years) healthy volunteers in five studies. Blood pressure, heart rate, and hormones associated with the renin-angiotensin system, and safety of Candesartan Cilexetil administration were also assessed. Placebo comparisons were made in four studies. Frequent blood samples were collected after the first single dose of Candesartan Cilexetil, and during the last dosing interval after 1 week repeated once-daily administration. Serum and plasma were analysed for Candesartan Cilexetil, Candesartan and its inactive metabolite, CV-15959, as well as angiotensin I and II, aldosterone, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity. The AUC and Cmax of Candesartan showed dose-proportional increases in the dose range of 2-16 mg Candesartan Cilexetil after both single and repeated once-daily tablet intake, indicating linear pharmacokinetics in both younger and elderly healthy subjects. The pharmacokinetics did not change on repeated dosing and, as expected from the half-life of Candesartan of approximately 9 h in younger subjects, there was almost no accumulation after repeated once-daily dosing. The time to peak Candesartan concentrations after tablet intake was consistently approximately 4 h at all dose levels. Both Cmax and AUC of Candesartan were increased after single and repeated once-daily dosing in the elderly compared to younger subjects by approximately 50%. However, no accumulation after repeated once-daily dosing were seen in the elderly. The half-life of Candesartan in the elderly (9-12 h) was somewhat longer than in the younger healthy adult volunteers (approximately 9 h) and no gender-related differences in the disposition of Candesartan were observed. Serum concentrations of CV-15959 were much lower than Candesartan, and reached peak serum concentrations later, about 4-9 h after dose intake. The elimination of CV-15959 was somewhat slower than that of Candesartan. Candesartan Cilexetil, the prodrug to Candesartan, was not measurable in serum. No differences in ACE activity or serum aldosterone concentrations were observed between subjects receiving Candesartan Cilexetil and placebo tablets. Plasma angiotensin I and II concentrations and PRA were augmented after single doses and further increased after 1 week repeated Candesartan Cilexetil dosing. Single and repeated doses of Candesartan Cilexetil were well tolerated in the younger and elderly volunteers. Only mild adverse events were recorded, with 'headache' as the most commonly reported event, and no increase in the number of reported adverse events was observed with higher doses of Candesartan Cilexetil. No clinically significant changes in respect to vital signs, physical examination, ECG, and clinical laboratory tests were observed.
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Candesartan Cilexetil a new generation angiotensin ii antagonist provides dose dependent antihypertensive effect
Journal of Human Hypertension, 1997Co-Authors: D Elmfeldt, R Hubner, M. George, B OlofssonAbstract:Candesartan Cilexetil, a new generation angiotensin II antagonist, provides dose dependent antihypertensive effect
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Candesartan Cilexetil: safety and tolerability in healthy volunteers and patients with hypertension.
Journal of human hypertension, 1997Co-Authors: G Belcher, R Hubner, D Elmfeldt, M. George, H LundeAbstract:The tolerability and safety of Candesartan Cilexetil has been evaluated in over 5000 subjects enrolled into double-blind or open-label clinical studies. In double-blind clinical trials in patients with primary hypertension, Candesartan Cilexetil 2-16 mg once-daily was associated with a low incidence of adverse events and drug-related withdrawals, similar to placebo. The drug showed no evidence of dose-dependent adverse events and it was equally well tolerated by men and women and by elderly (> or =65 years) and younger (
K Nishikawa - One of the best experts on this subject based on the ideXlab platform.
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Pharmacologic properties of Candesartan Cilexetil--possible mechanisms of long-acting antihypertensive action.
Journal of Human Hypertension, 1999Co-Authors: Y Inada, K Nishikawa, Mami Ojima, Ray Kanagawa, Y Misumi, Takehiko NakaAbstract:Candesartan Cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of Candesartan Cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of Candesartan Cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of Candesartan Cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, Candesartan, active form of Candesartan Cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin Il-receptor antagonists, and showed a shift to the right in the angiotensin Il-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated Candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated Candesartan binding (t 1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t 1/2 = 12 min). The insurmountable inhibition of Candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT, receptors. These characteristics are related to the potency and long duration of action in Candesartan Cilexetil.
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Candesartan Cilexetil a review of its preclinical pharmacology
Journal of Human Hypertension, 1997Co-Authors: K Nishikawa, Takehiko Naka, F Chatani, Yoshinobu YoshimuraAbstract:: Candesartan is a highly potent, long-acting and selective angiotensin II type 1 (AT1) receptor blocker. It is administered orally as the inactive prodrug Candesartan Cilexetil which is rapidly and completely converted to Candesartan during gastrointestinal absorption. In vitro studies have shown that Candesartan acts as an insurmountable angiotensin II receptor antagonist, binding tightly to and dissociating slowly from the AT1 receptor. The above characteristics are thought to contribute to the marked and long-lasting antihypertensive effects of Candesartan Cilexetil in several animal models of hypertension. These included rodent models of renal hypertension in which Candesartan Cilexetil also demonstrated efficacy equivalent to or greater than enalapril. In other animal models, Candesartan Cilexetil reduced the incidence of stroke, renal dysfunction and renal disease while reducing cardiac and vascular hypertrophy. Furthermore, Candesartan Cilexetil conferred some protection against cerebral and renal damage at a dose that had no blood pressure-lowering effect. In toxicity and general pharmacology studies, Candesartan Cilexetil was shown to possess a 'clean' profile with a large safety margin. Also it did not potentiate chemical- or autocoid-induced cough or anaphylactoid reactions.
