A method for estimating the potency of angiotensin‐converting enzyme inhibitors in man.

Wellstein, Anton; Essig, J.; Belz, G. G.

doi:10.1111/j.1365-2125.1987.tb03188.x

Cited by 17 publications

(11 citation statements)

References 9 publications

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“…This may be related to the suppression of renin release (Table 2) following the administration of propranolol. Compared with cilazapril alone, the amount of angiotensin I available as a substrate for conversion and as a competitor at the enzyme site (Belz et al, 1987;Wellstein et al, 1987a) is thereby reduced. These biochemical changes may contribute to the more intense blood pressure effect observed after the coadministration of both drugs.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, an evaluation of the possible pharmacokinetic and dynamic interactions of compounds belonging to these groups seemed justified. For this investigation, we selected cilazapril, a potent new ACE inhibitor (Belz et al, 1987;Wellstein et al, 1987a), and propranolol, the prototype of a 3-adrenoceptor antagonist. The half-life of their effects is about 5 h, and nearly identical, as determined from agonist responses (Wellstein etal., 1988(Wellstein etal., , 1987b.…”

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confidence: 99%

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Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.

Belz¹,

Essig²,

Kleinbloesem³

et al. 1988

Brit J Clinical Pharma

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1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day‐1), cilazapril (2, 5 mg day‐1), and a combination of both in a double‐blind cross‐over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose‐effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose‐ effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin‐stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.

Belz¹,

Essig²,

Kleinbloesem³

et al. 1988

Brit J Clinical Pharma

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“…Investigation of the dose effect of an agonist in the presence of its antagonist is a useful way to evaluate the pharmacologic properties in vivo and to compare the selectivity, potency, and time kinetics among different antagonists of the same class 4 , 5 . A single oral dose of candesartan has been shown to cause a long‐lasting rightward shift of the angiotensin II dose‐effect curves in humans, with a strong effect still present at 24 hours 6 .…”

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confidence: 99%

Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay*1

Belz

Butzer

Kober

et al. 1999

Clinical Pharmacology & Therapeutics

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Angiotensin II antagonistic effects of irbesartan, valsartan, and losartan were compared. Irbesartan showed the slowest decay and longest duration of its antagonistic effects. With the recommended initial doses used in this study, the following rank order of antagonistic intensity was obtained: irbesartan > valsartan > losartan. The findings of this study, specifically the longer-lasting effects of irbesartan, may have clinical implications.

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“…Before dosing and at 3 h, 6 h, 9 h, 12 h and 24 h after administration of study drug exogenous angiotensin II diluted with physiological saline solution was continuously infused in increasing dose steps at 3 min intervals (0.17 up to 20 μg min −1 ) as described in detail previously [15, 17–19]. Three min after dose increase a steady state in blood pressure increase was achieved, as shown even for angiotensin I by Essig et al [19].…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man

Malerczyk¹,

Fuchs

Belz³

et al. 1998

Brit J Clinical Pharma

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AimsThe pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose-effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p. ]-angiotensin II). Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an E max model and dose ratios (DR) calculated from the antagonist induced rightward shifts. Results Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t 1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6-9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent K i -doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. Conclusions A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.

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A method for estimating the potency of angiotensin‐converting enzyme inhibitors in man.

Cited by 17 publications

References 9 publications

Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.

Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.

Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay*1

Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man

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