|
Sign In to gain access to subscriptions and/or personal tools.
|
The pharmacological potency of various AT1 antagonists assessed by Schild regression technique in man
Gustav G Belz
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany
Kerstin Breithaupt-Grögler
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany
Raunhild Butzer
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany
Winfried Fuchs
Takeda Pharma GmbH, Aachen, Germany
Christian Hausdorf
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany
Christian Mang
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany
Rationale A quantitative technique was used to compare the pharmacological potency in healthy volunteers of angiotensin II receptor antagonists (AIIA): candesartan cilexetil, losartan, irbesartan, valsartan, and telmisartan.
Methods In a randomised, double-blind, parallel-group (4x12 subjects) study, single oral doses of candesartan cilexetil 4, 8 and 16 mg, losartan potassium 25, 50 and 100 mg, valsartan 40, 80 and 160 mg, and irbesartan 75, 150 and 300 mg were administered on three consecutive days. Telmisartan 20, 40 and 80 mg was similarly evaluated in 12 volunteers in an open amendment. Angiotensin II (Ang II) antagonistic effects were determined in vivo from rightward shifts in Ang II dose-response curves for diastolic blood pressure (BP) and dose ratios were calculated. Apparent Ki-doses, i.e. doses (in mg) required to induce a two-fold shift in Ang II dose-response curves (equivalent to approx. 50% blockade of receptors) were determined, using Schild regression analysis.
Results All treatments dose-dependently attenuated increases in diastolic BP induced by infusion of exogenous Ang II. Candesartan cilexetil appeared to have a more pronounced increase in effect following cumulative dosing. At 24 hours, apparent K i-doses were: candesartan cilexetil 6 mg, irbesartan 123 mg, valsartan 93.5 mg, and telmisartan 54 mg. It was not possible to determine an apparent Ki-dose for losartan at 24 hours.
Conclusion Consistent with results from experimental pharmacology, candesartan cilexetil displayed the highest pharmacological potency (i.e. antagonistic activity per mg substance) of the AIIAs tested. Apparent Ki-doses at 24 hours were within the dose range recommended for clinical use in patients with hypertension.
Key Words: angiotensin II antagonists • dose ratio • Schild regression technique • candesartan • irbesartan • losartan • telmisartan • valsartan
References
- Stroth U., Unger T. The renin-angiotensin system and its receptors. J Cardiovasc Pharmacol 1999;33(suppl 1):S21- S28; discussion S41-S43.[CrossRef][Web of Science]
- Messerli FH,Weber MA, Brunner HR Angiotensin II receptor inhibition. A new therapeutic principle. Arch Intern Med 1996;156(17):1957-65.[Abstract/Free Full Text]
- Kirch W. Angiotensin II Rezeptorantagonisten im Vergleich. Arzneimitteltherapie 1998;16:177-81.
- Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol 1995;75(12): 793-5.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Goa KL, Wagstaff AJ Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension [published erratum appears in Drugs 1996;52(4):540]. Drugs 1996;51(5):820-45.[Web of Science][Medline]
[Order article via Infotrieve]
- Belcher G., Hubner R., George M., Elmfeldt D., Lunde H. Candesartan cilexetil: safety and tolerability in healthy volunteers and patients with hypertension. J Hum Hypertens 1997;11(suppl 2):S85-S89.[Web of Science][Medline]
[Order article via Infotrieve]
- McClellan KJ, Goa KL Candesartan cilexetil.A review of its use in essential hypertension. Drugs 1998;56(5):847-69.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Markham A., Goa KL Valsartan. A review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54(2):299-311.[Web of Science][Medline]
[Order article via Infotrieve]
- Gillis JC, Markham A. Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension. Drugs 1997;54(6):885-902.[Web of Science][Medline]
[Order article via Infotrieve]
- Csajka C., Buclin T., Brunner HR, Biollaz J. Pharmacokinetic-pharmacodynamic profile of angiotensin II receptor antagonists. Clin Pharmacokinet 1997;32(1):1-29.[Web of Science][Medline]
[Order article via Infotrieve]
- 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.[Web of Science][Medline]
[Order article via Infotrieve]
- Sever PS Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists. J Hum Hypertens 1999;13(suppl 1):S3-S10; discussion S33-S34.[CrossRef][Web of Science]
- Andersson OK, Neldam S. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Press 1998;7(1):53-9.[CrossRef][Medline]
[Order article via Infotrieve]
- HednerT., Oparil S., Rasmussen K. et al. A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension. Am J Hypertens 1999;12(4 Pt 1):414-7.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kassler-Taub K., Littlejohn T., Elliott W., Ruddy T., Adler E. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators [published erratum appears in Am J Hypertens 1998;11(6 Pt 1):736] [see comments]. Am J Hypertens 1998;11(4 Pt 1):445-53.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Belz GG, Butzer R., Kober S., Mang C., Mutschler E. 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. Clin Pharmacol Ther 1999;66(4):367-73.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Azizi M., Chatellier G., Guyene TT, Menard J. Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan. J Hypertens 1999;17(4):561-8.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Lacourciere Y.,Asmar R.A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebo- controlled, forced titration study. Candesartan/Losartan study investigators.AmJHypertens 1999;12(12 Pt 1-2):1181-7.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Morimoto S., Ogihara T.TCV-116: a new angiotensin II type-1 receptor antagonist. Cardiovasc Drug Rev 1994;12:153-64.[CrossRef][Web of Science]
- Malerczyk C., Fuchs B., Belz GG et al. Angiotensin II antagonism and plasma radioreceptor-kinetics of candesartan in man. Br J Clin Pharmacol 1998;45(6):567-73.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Arunlakshana O., Schild HO Some quantitative uses of drug antagonists. 1958 [classical article]. Br J Pharmacol 1997;120(4 suppl):S151-S161; discussion S48-S50.
- Gaddum JH Theories of drug antagonism. Pharmacol Rev 1957;9:211-8.[Free Full Text]
- Van den Brink FG General theory of drug-receptor interactions. Drug-receptor interaction models. Calculation of parameters. In: van Rossum JM, editor. Kinetics of drug action. Handbook of Experimental Pharmacology, vol. 47. Berlin-Heidelberg, New York: Springer, 1977: 169-254.
- Wellstein A., Essig J., Belz GG Inhibition of angiotensin-I response by cilazapril and its time course in normal volunteers. Clin Pharmacol Ther 1987;41(6):639-44.[Web of Science][Medline]
[Order article via Infotrieve]
- Wellstein A., Essig J., Belz GGA method for estimating the potency of angiotensin-converting enzyme inhibitors in man. Br J Clin Pharmacol 1987;24(3):397-9.[Web of Science][Medline]
[Order article via Infotrieve]
- Belz GG, Essig J., Wellstein A. Hemodynamic responses to angiotensin I in normal volunteers and the antagonism by the angiotensin-converting enzyme inhibitor cilazapril. J Cardiovasc Pharmacol 1987;9(2):219-24.[Web of Science][Medline]
[Order article via Infotrieve]
- Wellstein A., Belz GG, Palm D. Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-plots. J Pharmacol Exp Ther 1988;246(1):328-37.[Abstract/Free Full Text]
- Breithaupt-Groegler K., Malerczyk C., Belz GG et al. Pharmacodynamic and pharmacokinetic properties of an angiotensin II receptor antagonist - characterization by use of Schild regression technique in man. Int J Clin Pharmacol Ther 1997;35(10):434-41.[Web of Science][Medline]
[Order article via Infotrieve]
- Hill AV The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 1910;40:iv-vii.
- WellsteinA, Palm D., Pitschner HF, Belz GG Receptor binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man. Eur J Clin Pharmacol 1985;29(2):131-47.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Essig J., Belz GG, Wellstein A. The assessment of ACE activity in man following angiotensin I challenges: a comparison of cilazapril, captopril and enalapril. Br J Clin Pharmacol 1989;27(suppl 2):S217-S223.[Web of Science]
Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 4,
336-341 (2000)
DOI: 10.3317/jraas.2000.063
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
|
|
