Gustav Georg Belz

Interaction between digoxin and calcium antagonists and antiarrhythmic drugs

The influence of several calcium antagonists and antiarrhythmic drugs on digoxin kinetics and actions were investigated in 36 healthy men during digoxin steady state (0.375 mg/day). The subjects were randomly assigned to three subgroups and each group received placebo (control) and two of the following regimens (doses three times a day) in a randomized sequence for 2 wk each: verapamil (80 mg) and nifedipine (10 mg), verapamil (120 mg) and gallopamil (50 mg), or propafenone (150 mg) and quinidine (250 mg). Plasma digoxin concentration (PDC) rose during the cotreatments in the sequence: gallopamil (+16%) < propafenone (+37%) < nifedipine (+45%) < verapamil (almost independent of dose, +69%) < quinidine (+118%). These increases in PDC correlated closely to decreases in renal digoxin clearances. Renal creatinine clearance was virtually unaffected. The rise of PDC resulted in increased glycoside effects, as measured by the shortening of systolic time intervals and flattening of T wave. There was a linear correlation between PDC and changes in mean corrected electromechanical systole and T wave flattening. We conclude that, in addition to quinidine, other antiarrhythmic drugs and various calcium antagonists interact kinetically with digoxin and that the increasing PDCs are cardioactive.

Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40‐5967 were investigated in 64 patients with hypertension. In a double‐blind, placebo‐controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40‐5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose‐dependently reduced over the full 24‐hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, −34/−25 mm Hg, p < 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose‐dependently increased and concentration‐effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40‐5967 has a long‐lasting antihypertensive effect after once‐daily administration.

Dose-proportionality of oral thioctic acid : coincidence of assessments via pooled plasma and individual data

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.

Influence of dihydralazine induced afterload reduction on systolic time intervals and echocardiography in healthy subjects.

The influence of a pure afterload reduction on systolic time intervals and various echocardiographic indices was assessed in six healthy volunteers, who underwent a single blind placebo controlled trial of three regimens of intravenous dihydralazine (6.25, 12.5, and 25.0 mg). Subsequently autonomic blockade (propranolol and atropine) was used to eliminate the influence of the autonomic reflex action during dosage with dihydralazine 6.25 mg. Dihydralazine increased heart rate to an extent depending on dose, decreased diastolic blood pressure, end systolic diameter, and end systolic wall stress, and enhanced fractional shortening and cardiac output. Heart rate corrected pre-ejection period was shortened and left ventricular ejection time was prolonged, whereas electromechanical systole remained virtually unchanged. Autonomic blockade eliminated dihydralazines effect on heart rate and cardiac output; blood pressure and systolic wall stress fell appreciably, whereas dihydralazine-induced changes in the systolic time intervals were virtually unaffected. Thus the present study indicates that regardless of the autonomic reflexes heart rate corrected pre-ejection period and left ventricular ejection time, but not electromechanical systole, are highly dependent on afterload, and this effect should be considered when systolic time intervals are evaluated.

Comparative Pharmacodynamics and Pharmacokinetics of Candesartan and Losartan in Man

The angiotensin II antagonistic effects of candesartan and losartan were compared in‐vivo after single and repeated doses. Effects were related to antagonistic activity in plasma.

Dynamic responses to intravenous urapidil and dihydralazine in normal subjects

Hemodynamic responses after urapidil were compared with those after dihydralazine in placebocontrolled, double‐blind studies after cumulative intravenous doses. We recorded heart rate, blood pressure, systolic time intervals corrected for heart rate (electromechanical systole and preejection period), electrical impedance cardiography [(dZ/dt)/RZ index and mean electrical thorax impedance], and M‐mode echocardiogram (end‐systolic and ‐diastolic diameters, end‐systolic wall stress, fractional shortening, and cardiac output). Both drugs induced dose‐dependent reductions in total peripheral resistance, which resulted in reduction in left ventricular end‐systolic wall stress and increases in heart rate (limited at +10 bpm with urapidil), fractional shortening, cardiac output, and the (dZ/dt)/RZ index. With each drug, diastolic blood pressure fell by 5 mm Hg, the corrected preejection period shortened (dihydralazine > urapidil), the corrected electromechanical systole did not change, and mean electrical thorax impedance rose with urapidil. The spectrum of effects indicates that both drugs reduce left ventricular afterload, thereby increasing left ventricular pump performance. Urapidil also exerts some preload reduction.

Dose-response following single administrations of a new cardiac performance enhancer RO 13-6438 in normal volunteers

We assessed the changes in cardiovascular function in humans caused by RO 13–6438. a new drug that enhances cardiac performance, by means of noninvasive methods which included measurement of systolic time intervals and electrical impedance cardiography. Twelve healthy male volunteers received RO 13–6438 doses of 10 and 20 mg intravenously and 20, 40, and 60 mg orally according to a double blind, randomized, crossover, placebo-controlled design. A dose-dependent distinct enhancement in cardiac performance was seen. This was attributed to positive inotropism (shortening of heart rate-corrected electromechanical systole) and to a vaso-dilating action (decline of diastolic blood pressure and total peripheral resistance). In addition, the drug increased heart rate slightly. The cardiac effects were detectable for 6 h. To reach the average equivalent inotropic response over 6 h. the oral dose was 1.8-fold of the i.v.: this indicated a high bioavailability of RO 13.6438. Transient color vision disturbances were reported mainly following the intravenous administration. The properties of RO 13–6438 suggest that it may be useful for treatment of heart failure.

Kinetics of fenoximone, a new cardiotonic, in healthy subjects

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (±SD) elimination t½ (t½β) of 60 ± 14 min after intravenous injection and 78 ± 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 ± 846 ml/min, renal clearance (ClR) was 5.3 ± 2.4 ml/min, and extrapolated volume of distribution was 0.37 ± 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t½βs were calculated as 132 ± 15 min after intravenous injection and 140 ± 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 ± 106 ml/min after intravenous injection; 24‐hr urinary recovery of the sulfoxide was 75.7% ± 5.7% after intravenous injection and 64.3% ± 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).

QTU-ABNORMALITIES, SINUS BRADYCARDIA AND ADAMS-STOKES ATTACKS DUE TO VENTRICULAR TACHYARRHYTHMIA

Tachyarrhythmic Adams‐Stokes attacks, provoked by physical and emotional stress, are reported in a 10‐year‐old girl with sinus brady‐cardia at rest, prominent U waves, a normal resting QT‐interval but QT‐prolongation on exercise. Two brothers, the father and the paternal grandmother have a slight QT‐prolongation but no attacks. In the proband, physical exercise and small doses of a beta‐adrenergic stimulator reliably cause ventricular bigemini and/or runs of multifocal ventricular extra‐systoles while increase in heart rate by Atropine and atrial pacing does not. The ventricular arrhythmia is improved by beta‐receptor blocking agents. It is proposed that in this and other patients with abnormal repolarization the ventricular myocardium is unduely sensitive to sympathetic stimuli, resulting in ventricular tachyarrhythmia.

The pharmacological potency of various AT1 antagonists assessed by Schild regression technique in man

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.