Haemodynamic dose-efficacy of levosimendan in healthy volunteers

Abstract

Levosimendan is a new calcium-sensitiser intended for the treatment of congestive heart failure. The results of preclinical studies indicate it has positive inotropic and vasodilator effects. In the open study reported here up to 5 mg levosimendan and vehicle were administered to 8 healthy male volunteers at one- to 2-week intervals. Efficacy was evaluated using M-mode echocardiography, and by measuring systolic time intervals, recording ECG and measuring blood pressure. For almost all haemodynamic parameters except heart rate (HR) the maximum effect was seen 10 or 20 min after drug infusion. Effects 10 min after infusion of drug and vehicle were compared. HR was significantly increased 10 min only after infusion of 5 mg: significant increases were seen 60 min after infusions of 2, 3 and 5 mg (4, 8 and 17 beats.min-1, respectively). Diastolic blood pressure was significantly lower after doses of 1 mg or more. The decrease after 5 mg was 17 mmHg. Systolic blood pressure tended to increase. Fractional shortening (FS) and ejection fraction (EF) increased significantly after doses of 1 mg and higher. EF 10 min after infusion of vehicle was 54%. It increased to 73% after 5 mg. Decreases in electromechanical systole (QS2i) 10 min after 2, 3 and 5 mg were significant. There were no clinically significant adverse events or changes in laboratory safety values. The changes in QS2i, FS, EF and blood pressure indicate that levosimendan has positive inotropic and vasodilator effects in healthy subjects.

Cardiovascular effects of the novel Ca2+‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

“…These ®ndings with levosimendan in awake dogs are very similar to our data with pimobendan in awake normal pigs (Duncker et al, 1987a). In healthy resting humans, levosimendan also increased cardiac output, which was due to an increase in stroke volume at a lower dose, while at a higher dose it resulted entirely from an increase in heart rate (Lilleberg et al, 1994;Sundberg et al, 1995). Although we failed to ®nd evidence to support a signi®cant contribution of phosphodiesterase inhibition to the actions by EMD 57033, direct evidence that the positive inotropic actions of EMD 57033 are mediated by an increase in responsiveness of the myo®laments to Ca 2+ has so far been obtained exclusively in in vitro studies.…”

Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting

“…The increase in cardiac output after 24 g . kg 1 of levosimendan was related to increases in heart rate and stroke volume, as demonstrated in previous studies with levosimendan [23] . This phenomenon is typical of almost all inotropic and vasodilating compounds in acute intravenous use.…”

“…Systemic haemodynamics changed, as expected from previous studies with levosimendan [11,12,23] . The increase in cardiac output after 24 g .…”

Levosimendan has a prolonged antispasmodic effect in isolated human radial artery bypass grafts and inhibits thrombin-induced aggregation of human platelets in vitro

“…In our study, contractions with heart [39,53]. Levosimendan has both inotropic and vasodilating effects in this concentration [54][55][56][57]. It has been demonstrated recently that a single loading dose of the inodilator would normalize the hemodynamic conditions including total peripheral resistance days after bypass graft surgery [35].…”

“…Administration of the inodilator, after the contraction of the RA had been completed, resulted in an EC 50 value of 0.3 µmol/L [31]. Based on the short half life of levosimendan (approximately 1 hour) [54], the relaxing effect was expected to decrease profoundly as late as after one and a half hour of the removal of the inodilator from the organ bath. In our study, 0.16 µmol/L levosimendan exerted 85% relaxation after 45 minutes and 88% after 90 minutes, an increasing rather than a decreasing vasorelaxing effect in time.…”