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Volume 1, Number 4, December 2000
The pharmacological potency of various AT1 antagonists assessed by Schild regression technique in man
Gustav G Belz, Kerstin Breithaupt-Grögler, Raunhild Butzer, Winfried Fuchs, Christian Hausdorf, Christian Mang 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 Ki-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. JRAAS 2000;1:336-341. View full PDF article (open in new window)
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