Clinical pharmacology of two specific bradycardic agents

Abstract

The effect of two i.v.-infusion regimens of falipamil on atropine-induced changes of heart rate and the effect of ULFS 49 Cl in 3 different oral doses during a 7-day medication period were studied in volunteers. Both studies were double-blind, randomized and placebo controlled. Under placebo, low doses of atropine caused a 16% reduction in heart rate, a 1 mg cumulative dose increased heart rate by 23%. 100 mg falipamil was followed by a 9% reduction in heart rate. Low doses of atropine enhanced this decrease to 14%, whereas a 1 mg cumulative dose of atropine increased heart rate by only 3%. Similar results were obtained after administration of 200 mg falipamil. ULFS 49 Cl induced a constant reduction of heart rate at rest and during ergometry without changing systolic and diastolic blood pressure. Because no interrelation was found between efficacy and corresponding plasma levels of the drug, it can be concluded that the concentration of the drug in the tissue is responsible for efficacy and duration of action. The minimal effective and the therapeutic doses were 3 X 2.5 mg p.o. and 3 X 5 mg p.o. respectively. In contrast to falipamil, which increased the QT-interval by approximately 20%, ULFS 49 Cl did not change QT-time. Side-effects typical for 'specific bradycardic agents', such as coruscation were seen. Peak occurrence was between day 1 and day 4, thereafter a decreasing frequency was observed. In general, both drugs were effective and well tolerated.

Intrinsic autoregulation of cardiac output in rainbow trout(Oncorhynchus mykiss) at different heart rates

“…As shown in Fig.·2, a dose of zatebradine of 2.79±0.47·mg·l -1 decreased heart rate by half the maximum change, which compares well with similar experiments in mammals (Franke et al, 1987;Kalman et al, 1995;Ryu et al, 1996;Schipke et al, 1991). Thus, zatebradine is also a bradycardic agent in trout, indicating that the hyperpolarization current (If) is also a component of the pacemaker currents in nodal cells in this species.…”

Class III Antiarrhythmic Effects of Zatebradine

“…12 Because of the discrepancy between pharmacokinetic data and clinical efficacy, it was suggested that the tissular concentration rather than the plasma level of zatebradine is relevant. 13 Under this assumption, the zatebradine-induced, use-dependent block of hKv1.5 channels could become of clinical relevance, since even at heart rates slower than the normal sinus rhythm (0.5 Hz), zatebradine is able to inhibit the hKv1.5-like current and thus prolong the action potential duration, probably with a K D value similar to that necessary to inhibit the I f in a use-dependent manner.…”

Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors.

“…"2 Heart rate reduction by (3-blockers is partially caused by a block of the stimulating effect of catecholamines on the hyperpolarization activated current If (or Ih) in the sinoatrial (SA) node.3-7 Since (3-blockers also have negative inotropic and dromotropic effects that can reduce their usefulness and applicability in ischemic heart disease, drugs targeted at the pacemaker current If can possibly be superior in certain aspects.8 '9 Zatebradine (UL-FS 49) is a drug with a specific bradycardiac effect.10-13 It reduces heart rate in a frequency-dependent manner with little or no effect on inotropism, both in animal models'0-22 and in humans. [23][24][25][26][27][28] The substance reduces the increase in heart rate caused by (3-stimulation in a noncompetitive manner, without influencing the positive inotropic effect. '3'29 Heart rate reduction is caused by a direct effect on diastolic depolarization rate (DDR) (phase IV) of the SA node action potential.…”