Efficacy and duration of action of three doses of Zatebradine (ULFS 49 CL) in patients with chronic angina pectoris compared to placebo

Use‐dependent block of Ih in mouse dorsal root ganglion neurons by sinus node inhibitors

“…SA node inhibitors were developed as a drug for treatment of ischemic heart disease (Kobinger & Lillie, 1987) and might be beneficial in the treatment of ischemic heart disease (Baiker et al , 1991). The main side effect of these products are visual disturbances such as light flashes and flickering (Frishman et al , 1995).…”

“…These sinus node inhibitors, or specific bradycardic agents, form a class of cardiac drugs selectively reducing heart rate by slowing diastolic depolarization rate in the SA node (Kobinger, 1989). As these drugs can reduce myocardial oxygen consumption and increase oxygen supply, without compromising myocardial contractility or atrioventricular conduction characteristics, they might be beneficial in the treatment of ischemic heart disease (Baiker et al , 1991).…”

Class III Antiarrhythmic Effects of Zatebradine

“…However, these pharmacokinetic studies were performed in healthy volunteers after the administration of zatebradine at doses different from those recommended in patients with coronary heart disease (2.5 to 7.5 mg twice a day). 12 Furthermore, the terminal half-life after oral administration was 2 to 3 hours, whereas the anginal and bradycardic effects of zatebradine persisted for >10 hours. 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.…”

“…12 Furthermore, the terminal half-life after oral administration was 2 to 3 hours, whereas the anginal and bradycardic effects of zatebradine persisted for >10 hours. 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.…”