G. G. Belz

Dose‐effect and pharmacokinetic‐pharmacodynamic relationships of the β1adrenergic receptor blocking properties of various doses of carvedilol in healthy humans

To evaluate the pharmacodynamic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol.

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

To compare the angiotensin II antagonistic properties of the usual recommended oral starting doses of various angiotensin II receptor antagonists—150 mg irbesartan, 80 mg valsartan, and 50 mg losartan—in humans.

Affinity and selectivity of beta-adrenoceptor antagonists in vitro

&NA; The potency order of the catecholamines (‐)isoprenaline (Iso), ( ‐ )‐noradrenaline (NA), and ( ‐ )‐adrenaline (Adr) in competition for radiolabelled sites is used for their pharmacological classification. It is shown that the radioligand 3H‐CGP 12177 exclusively labels &bgr;1‐adrenoceptors in rat salivary gland membranes (Iso > NA > Adr), and &bgr;2‐adrenoceptors in rat reticulocytes (Iso > Adr ≥ NA). These models are then used to derive the subtype‐selectivity of the classical &bgr;‐adrenoceptor antagonists (±)‐propranolol (prop; twofold &bgr;2‐selective) and (±)‐atenolol (aten; 35‐fold &bgr;1‐selective), as well as of the newer antagonists (±)betaxolol and (±)‐bisoprolol (betax and biso; 35‐fold and 75‐fold &bgr;1‐selective, respectively). The ligand with the highest selectivity is ICI 118,551 (ICI), with a 300‐fold &bgr;2‐subtype selectivity. For comparison with antagonistic effects in humans at given plasma concentrations, the equilibrium dissociation constants of the ligands are measured in the presence of native human plasma and yield values for the relative selectively labelled subtype in the mean (Ki‐values in nmol/l): prop: 20, aten: 250, biso: 24, betax: 23, and ICI: 2.5.

Inhibition of angiotensin‐I response by cilazapril and its time course in normal volunteers*

Cilazapril is a new angiotensin‐converting enzyme (ACE) inhibitor. In a double‐blind crossover study six normal male volunteers received single oral doses of cilazapril, 4 mg, captopril, 25 mg, enalapril, 10 mg, and placebo. The response of diastolic blood pressure to an intravenous infusion with increasing doses of angiotensin I (AT‐I) (0.1 to 18 μg/min) was determined at control and up to 36 hours after oral drug intake. Additionally the response to AT‐I was established before, during, and after cessation of a 15‐day 2.5 mg/day cilazapril administration. The ACE inhibitors antagonized the AT‐I effects and shifted the AT‐I dose‐effect curves rightward, whereas placebo was not effective. After single doses the effects of cilazapril and enalapril declined with a similar elimination half‐life of ~4 hours; with captopril ~2 hours was observed. After multiple administration of cilazapril there was no evidence of cumulative effects. Cilazapril is an orally active ACE inhibitor that does not show pharmacodynamically relevant accumulation.

Influence of the angiotensin converting enzyme inhibitor cilazapril, the β-blocker propranolol and their combination on haemodynamics in hypertension

This study compared the antihypertensive effects and the haemodynamic mechanisms of action of an angiotensin converting enzyme (ACE) inhibitor, a beta-blocker and the combination of both in patients with mild to severe hypertension. After a placebo run-in period of 2 weeks, patients were treated for 3 weeks with each of the following: cilazapril (2.5 mg daily) and propranolol (120 mg daily), in a randomized sequence, and thereafter a combination of the two drugs. Blood pressure, cardiac output (measured by Doppler ultrasound) and total peripheral resistance (TPR) in a sitting position at rest were determined. One patient out of 18 was withdrawn in the cilazapril phase. Both monotherapies yielded significant and similar reductions of diastolic blood pressure (average -10 mmHg). Cardiac output and TPR showed opposite effects. Cardiac output was lower with the beta-blocker than with the ACE inhibitor (3.4 versus 4.5 l.min-1), while TPR behaved conversely (2646 versus 2005 dyne.s.cm-5). The combination of both drugs lowered diastolic blood pressure significantly more than the monotherapies (average -20 mmHg); the haemodynamic effects of the monotherapies were attenuated by the combination (cardiac output = 3.7 l.min-1; TPR = 2170 dyne.s.cm-5). A sitting diastolic blood pressure of less than or equal to 90 mmHg could be achieved in six out of 17 patients with propranolol alone, in eight out of 18 with cilazapril alone, and in 14 out of 17 with the coadministration of both drugs. The combination was better tolerated subjectively than the beta-blocker alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic responses to angiotensin I in normal volunteers and the antagonism by the angiotensin-converting enzyme inhibitor cilazapril

According to classic pharmacologic theory, agonist/antagonist competition can be used to quantify an antagonists potency by measurement of agonist dose- response curves in the presence of varying doses of the antagonist. We used this principle to characterize the interaction between angiotensin I (AI) and the angiotensinconverting enzyme (ACE) inhibitor cilazapril in humans. In addition, by comparing the effects of AI and angiotensin II before and after administration of a 30-mg dose of cilazapril, we could show the specific AI antagonism of the ACE inhibitor in humans. To obtain the antagonists dose-response curves, six healthy male volunteers received five single oral doses of cilazapril, 0.5–8.0 mg. Enalapril, 10 mg, and captopril, 12.5 mg, served as positive controls and placebo as the negative control. Dose-response curves following intravenous infusions of AI were established 4 h after oral ingestion of the ACE inhibitors. Noninvasively measured systolic and diastolic blood pressures and total peripheral resistance assessed AI effects. Cilazapril dose dependently shifted the AI dose-response curve rightward, with 1.0 mg inducing a twofold shift. Enalapril and captopril appear less potent, on a milligram basis, in antagonizing AI effects 4 h after drug intake. The methodology could be a useful tool for a rational testing and comparison of ACE inhibitors in clinical pharmacology.

Effect of pretreatment with the selective β1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and β-adrenoceptor subtype specific occupancy of celiprolol in healthy man

SummaryThe cardiovascular effects at rest and during exercise and β1- and β2-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p. o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p. o., using a place-bo-controlled, 2-way cross-over design.The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median β1-RRA and β2-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to β1-adrenoceptors, moderately to β2-adrenoceptors, acts as β1-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect β1-adrenergic agonism, but which might reflect β2-adrenergic agonism.

Review of studies on the clinical pharmacodynamics of cilazapril

Several studies were performed to evaluate the degree of inhibition of angiotensin-converting enzyme (ACE) by an ACE inhibitor by assessing the blood pressure response to a continuous i.v. infusion of increasing doses of angiotensin I in healthy volunteers. We assessed pharmacokinetic and pharmacodynamic interactions of the ACE inhibitor cilazapril and the p-blocker propranolol in healthy volunteers and patients with essential hypertension. We also evaluated the effect of cilazapril on aortic compliance in hypertension by pulse-wave velocity along the aorta. We showed that single oral doses of cilazapril 4 mg, captopril 25 mg, or enalapril 10 mg shifted the angiotensin I dose-effect curve to the right and determined a pharmacologic half-life of about 4 h for cilazapril. Increasing single oral doses (1.25, 3.75, 10, and 30 mg) of cilazapril reduced diastolic blood pressure dose-dependently and shifted the angiotensin I dose-response curves to the right. The dose representing 50% inhibition of ACE activity (apparent Ki dose) was about 0.6 mg 3 h after cilazapril administration. Cilazapril and propranolol did not exhibit significant pharmacokinetic interaction in healthy volunteers; each drug reduced diastolic and systolic blood pressure by about 7 mm Hg, and this was doubled by the combination. Monotherapy with each drug reduced blood pressure, and combined administration enhanced the antihypertensive effect. The reduction in cardiac output and the increase in total peripheral resistance induced by propranolol were attenuated by the cilazapril-propranolol combination. In comparison with hydrochlorothiazide, the ACE inhibitor at the same degree of blood pressure reduction seems to have a more intense effect on aortic compliance. Therefore, ACE inhibition by cilazapril, in addition to its effects on blood pressure, could provide further benefit in hypertensive patients.

Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and (3) clinical perception upon application.Pharmacokinetically, the time courses of the plasma concentrations of GTN and its dinitrate metabolites, 1,2- and 1,3-GDN, subsequent to the sublingual administration of 0.8 mg GTN showed somewhat lower bioavailability of GTN and its metabolites than to the reference. Pharmacodynamically, the changes in the DPG signals after the application of 0.8 mg GTN with TL were biostatistically euivalent with R (estimated ratio TL/R for the maximum decrease of the ratio between the systolic a wave and c incisure: 0.98; 90% CI: 0.84–1.14; and for the average decrease of the c: a ratio: 0.97; 90% CI: 0.80–1.16). The time of occurrence of the maximum effect of TL was not significantly different from that of R (estimated difference TL-R: -2.25 min; 95% CI:-9.5 min to 2 min).In contrast, after the administration of an FCH-free GTN spray with a higher ethanol content (TH, active control), the effect had a slightly earlier onset (TH-R:-6 min, 95% CI: -9.5 to -2 min) and there was a higher average response (TH/R: 1.12: 90% CI: 0.95 to 1.34). However, TH was consistently judged to cause an extremely unpleasant burning sensation in the mouth and thus was perceived as distinctly different from R. In contrast, TL was well tolerated and could not be distinguished from R.Therefore only TL met the criteria of overall therapeutic equivalence to R.

Captopril does not interact with the pharmacodynamics and pharmacokinetics of digitoxin in healthy man.

SummaryThe chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: −7.9 to −1.6 beats · min−1), in mean diastolic blood pressure (95 % CI: −8.3 to −0.4 mm Hg), shortening of the QTc-interval (95 % CI: −42 to −19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: −16 to −1 ms) and electromechanical systole QS2c (95 % CI: −25 to −1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation.The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state.Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.