Human pharmacokinetic and pharmacodynamic studies on Ro31‐1118, a new beta‐adrenoceptor antagonist.

O'Connor, PC; Arnold, Jennifer M.; Brown, A. N.; Francis, Robert J.; Finch, MB; Galloway, D. B.; Harron, D. W. G.; McDevitt, D. G.; Shanks, R. G.

doi:10.1111/j.1365-2125.1985.tb02650.x

Cited by 8 publications

(1 citation statement)

References 18 publications

(18 reference statements)

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“…The dose-response curve for the effect of H-I 42 on the exercise tachycardia appeared to be flatter than that for atenolol as there was little difference in the effects of 200 and 400 mg H-I 42 but an increase in effect from 50 to 100 mg atenolol with the response to both of these doses being greater than 400 mg H-I 42. A similar flattening of the dose-response curve for the effects of ,B-adrenoceptor blocking drugs on an exercise tachycardia has been described for those drugs that possess partial agonist activity O'Connor et al, 1985).…”

Section: Discussionsupporting

confidence: 61%

The assessment in man of the beta‐adrenoceptor blocking activity and cardioselectivity of H‐I 42 BS, a long acting beta‐adrenoceptor blocking drug.

Pringle

Deering

Scott

et al. 1987

Brit J Clinical Pharma

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Ireland1 The pharmacokinetic and pharmacodynamic effects of the ,3-adrenoceptor antagonist H-I 42 BS were examined in healthy subjects. 2 In an open dose ranging study, H-I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H-I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 ± 1.0% -mean ± s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 ± 7.2%). 3 Seven subjects received in double-blind, randomised order, single oral doses of H-I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H-I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H-I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P < 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H-I 42 BS 50 mg was 10.9 ± 7.1%, after 100 mg was 18.7 ± 5.8%, after 200 mg was 20.6 + 6.4% and after 400 mg was 21.9 ± 8.2%. H-I 42 BS 400 mg still caused 11.0 ± 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 ± 6.0% but did not reduce exercise heart rate after 24 h. 4 The mean peak plasma concentrations for all doses of H-I 42 BS occurred at 5.1 ± 1.5 h. The plasma elimination half-life was 47.6 ± 8.1 h. There was a linear correlation between the dose and AUCO-o (r = 0.97). 5 The cardioselectivity of H-I 42 BS and atenolol was compared. Six subjects received in double-blind random order H-I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min-1 . Dose-response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. 6 There was no difference in the dose-response curves for forearm blood flow or finger tremor after H-I 42 BS400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P < 0.01) of the diastolic blood pressure response. 7 These results indicate that H-I 42 BS is a cardioselective ,B-adrenoceptor antagonist with a long duration of action in man.

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Section: Discussionsupporting

confidence: 61%

The assessment in man of the beta‐adrenoceptor blocking activity and cardioselectivity of H‐I 42 BS, a long acting beta‐adrenoceptor blocking drug.

Pringle

Deering

Scott

et al. 1987

Brit J Clinical Pharma

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Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man

Wagner

Rogge

Natale

et al. 1987

Biopharm & Drug Disp

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An aqueous solution containing 1 mg of adinazolam mesylate per ml was administered orally as a single dose (40 mg) and with loading doses followed by hourly doses such that final dose rates of 1, 2, and 3 mg h-1 were administered to steady-state. Four subjects exhibited linear steady-state kinetics, while the other four exhibited Michaelis-Menten kinetics, based on measurement by HPLC of both unchanged drug and the major N-demethyl metabolite. The drug is very rapidly absorbed and has an intrinsic clearance of total (bound + free) drug which averaged 2.14 l min-1 based on the steady-state data and 1.17 l min-1 based on the single dose data, but these means do not differ significantly. The apparent metabolite clearance, CLmc/fm (where fm = fraction of adinazolam converted to the N-demethyl metabolite), averaged 0.170 l min-1 based on steady-state data and 0.179 l min-1 based on single dose data and these means do not differ significantly. Pharmacokinetic parameters, such as these clearances, had large intersubject variations. Three types of bioavailabilities were estimated from the data.

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Ro 31-1118, a new cardioselective ?-adrenoceptor antagonist

Jamieson

Petrie

Webster

et al. 1985

Eur J Clin Pharmacol

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Five patients with mild hypertension were given single oral doses of Ro 31-1118 (10,20,40, and 80 mg) and placebo in a randomized, double-blind, within-patient study. Plasma concentrations of Ro 31-1118 and supine, standing, exercise, and post-exercise heart rates and blood pressures were measured before and at regular intervals after drug administration. The pharmacokinetic data were consistent with a one-compartment model with first-order absorption and a variable time lag. Peak plasma concentrations and area under curve were linearly related to dose, whereas time to peak concentration, half-time, clearance and apparent volume of distribution were dose-independent. There was a reduction in exercise and post-exercise heart rate of approximately 10% after 10 mg and 20 mg Ro 31-1118, and of approximately 15% after 40 mg and 80 mg. At all doses standing systolic blood pressure was reduced by approximately 5%. A similar fall was seen in exercise and post-exercise systolic blood pressures. There was no substantial effect of Ro 31-1118 on supine or standing heart rates nor on diastolic blood pressure. No adverse effects were reported. It is concluded that Ro 31-1118 has linear pharmacokinetics over the dose range 10-80 mg, and has a weak antihypertensive effect when administered in single doses to patients with mild hypertension.

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Human pharmacokinetic and pharmacodynamic studies on Ro31‐1118, a new beta‐adrenoceptor antagonist.

Cited by 8 publications

References 18 publications

The assessment in man of the beta‐adrenoceptor blocking activity and cardioselectivity of H‐I 42 BS, a long acting beta‐adrenoceptor blocking drug.

The assessment in man of the beta‐adrenoceptor blocking activity and cardioselectivity of H‐I 42 BS, a long acting beta‐adrenoceptor blocking drug.

Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man

Ro 31-1118, a new cardioselective ?-adrenoceptor antagonist

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