Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure.

AIMS: To determine the duration of haemodynamic and neurohormonal action of a 24-h infusion of levosimendan in heart failure. METHODS AND RESULTS: This was a double-blind, parallel group study in patients with New York Heart Association class II to IV heart failure. Twenty-two patients, with left ventricular ejection fraction <35% and pulmonary capillary wedge pressure (PCWP) above 12 mmHg, were randomised to receive either levosimendan (12 microg/kg followed by a continuous infusion of 0.1-0.2 microg/min) or placebo. Invasively measured cardiac output (CO) increased from 4.3 l/min to 5.4 l/min in the levosimendan group at 6 h. PCWP decreased from 20 mmHg to 15 mmHg in response to levosimendan. Echocardiographically measured maximal effect on PCWP occurred after 6 h, whereas CO reached its highest value at 24 h. The estimated duration of the decrease in PCWP was 7-9 days, and in CO was 12-13 days. Plasma NT-proANP and NT-proBNP levels reached their lowest values at days 3 and 2, and the treatment effect was estimated to last 16 and 12 days, respectively. The long-acting haemodynamic responses reflect levels of the active metabolites OR-1896 and OR-1855, maximal metabolite levels occurred at day 3. CONCLUSIONS: Levosimendan infusion achieved a rapid improvement in haemodynamic parameters in patients with congestive heart failure with maximal effects occurring 1-3 days after starting the infusion, effects were sustained for up to at least a week.

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

AIMS: The aim of the study was to evaluate the effects on systemic and coronary haemodynamics and myocardial substrate utilization of a new calcium sensitizer, levosimendan, after coronary artery bypass grafting. METHODS AND RESULTS: Twenty-three low-risk patients were included in this randomized and double-blind study. They received placebo (n = 8), 8 (n = 8) or 24 (n = 7) micrograms.kg-1 of levosimendan after coronary artery bypass operation. Systemic and coronary sinus haemodynamics with thermodilution and myocardial substrate utilization were measured. The heart rate increased 11 beats.min-1 after the higher dose (P < 0.05). Cardiac output increased by 0.7 and 1.61.min-1 (P < 0.05 for both) after 8 and 24 micrograms.kg-1 of levosimendan, respectively. Systemic and pulmonary vascular resistance decreased significantly after both doses. Coronary sinus blood flow increased by 28 and 42 ml/(P = 0.054 for the combined effect) after the lower and higher dose, respectively. Myocardial oxygen consumption or substrate extractions did not change statistically significantly. CONCLUSION: Despite improved cardiac performance, levosimendan did not increase myocardial oxygen consumption or change myocardial substrate utilization. Thus levosimendan has the potential to treat low cardiac output states after cardiopulmonary bypass surgery.

Hemodynamic and neurohumoral effects of levosimendan, a new calcium sensitizer, at rest and during exercise in healthy men.

Levosimendan is a novel inodilator that increases the calcium sensitivity of troponin C in a calcium-dependent way. Cardiac function (impedance cardiography, systolic time intervals), neurohumoral responses at rest and during exercise at 2 workloads, and peripheral blood flow (plethysmography) were studied in 14 healthy young men. Vehicle and 2 doses of levosimendan (6.5 micrograms/kg, low dose [LD]; and 25 micrograms/kg, high dose [HD]) were given intravenously in a crossover study. Measurements taken 15 minutes after a supine rest showed HD levosimendan shortened electromechanical systole (QS2i) by 16 ms maximally (p < 0.001), and decreased systemic vascular resistance by 25% (p < 0.001), compared with baseline values. Diastolic blood pressure fell by 9 mm Hg (p < 0.01). When the changes after vehicle were compared with the changes after HD levosimendan, the difference was 2.1 L/min after 25 micrograms/kg (p < 0.001), caused by an increase in stroke volume, with the heart rate being unaffected. Leg blood flow increased by 35% (p < 0.001). During exercise at the lower workload, HD levosimendan increased cardiac output by 1.5 L/min (p < 0.05), compared with that caused by vehicle, by an increase in heart rate, with the stroke volume being unchanged. Electromechanical systole was shortened significantly (20 ms, p < 0.001 after HD; 12 ms, p < 0.01 after LD). At the higher workload, no effects on electromechanical systole or cardiac output compared with that associated with administration of vehicle were seen, but the mean heart rate increased (p < 0.001, LD and HD) and mean diastolic blood pressure decreased (p < 0.01, HD).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction.

Levosimendan, a new drug that sensitizes troponin-C to calcium and selectively inhibits phosphodiesterase III, was administered to 24 patients with ischemic heart disease and ejection fraction below 40%. In a placebo-controlled, crossover, double-blind study, each patient received two intravenous doses of levosimendan on 2 consecutive study days. The doses were 0.25 mg (n = 6), 0.5 mg (n = 11), 1 mg (n = 12), 2 mg (n = 12), and 4 mg (n = 5). After 0.25 mg and 0.5 mg, cardiac output increased by 0.49-0.67 L/min (p < 0.05) due to an increase in stroke volume of 6-11 ml. After 2 and 4 mg, cardiac output increased by 0.61-0.88 L/min due to an increase in heart rate of 6-12 beats/min. The baseline filling pressures, i.e., right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP), were within the normal range. RAP decreased significantly (p < 0.05) after 2 and 4 mg and PCWP after 0.5, 1, 2, and 4 mg. The most profound decreases were observed 10 min after infusion of 4 mg, from 5.0 to 3.2 mm Hg in RAP and from 9.8 to 6.0 mm Hg in PCWP. Total peripheral resistance decreased significantly only after 2 and 4 mg, by 13 and 21%, respectively. However, there were no statistically significant changes in pulmonary vascular resistance. It is concluded that levosimendan has a hemodynamically favorable action after 0.25 and 0.5 mg but that decreases in filling pressures probably prevented the increase in stroke volume and caused a reflex increase in heart rate after 2 and 4 mg.

Pharmacokinetics and pharmacodynamics of simendan, a novel calcium sensitizer, in healthy volunteers.

OBJECTIVE: To assess pharmacokinetics and correlation of pharmacokinetics and pharmacodynamics of simendan, a new calcium-sensitizing compound aimed at the treatment of congestive heart failure, in healthy volunteers. METHODS: Simendan was administered to eight healthy subjects in seven different doses, and its concentrations in plasma and proportions of enantiomers (levosimendan and dextrosimendan) were determined. Hemodynamic effects were measured by M-mode echocardiography. RESULTS: The area under the plasma concentration time-curve increased linearly and correlated with dose (p < 0.001). The volumes of distribution were small (mean VC, 8.5 to 14.1 L; VSS, 12.8 to 28.4 L) and elimination fairly fast (mean t1/2 beta, 0.83 to 1.77 hours). There were only minor differences between the pharmacokinetic profiles of the enantiomers of simendan. The increase in maximal ejection fraction (EF) correlated significantly with the plasma concentrations of simendan (p < 0.01; r2 = 0.33). However, the correlation coefficient was higher between estimated concentrations of simendan in peripheral compartment and ejection fraction; r2 was 0.79 (p < 0.01) and 0.94 (p < 0.001) after 2 and 5 mg doses, respectively. One subject after 5 mg simendan and one subject after 10 mg simendan had transient vasovagal reactions consisting of decreases in heart rate and blood pressure. CONCLUSIONS: Simendan has favorable and predictable hemodynamic actions. The pharmacokinetic profile facilitates rapid dose adjustments during intravenous administration.

Hemodynamic effects of the novel cardiotonic drug simendan: echocardiographic assessment in healthy volunteers.

Simendan is a novel cardiotonic drug with mixed properties, including calcium sensitization. Simendan was given intravenously to eight healthy volunteers in doses from 0.1 to 10.0 mg to define its safety and dose-response effects. Its effects on myocardial function were recorded by echocardiography with simultaneous measurement of heart rate (HR) and blood pressure (BP). A linear dose response was observed in all echocardiographic indices. Fractional shortening increased from a basal value of 29.5% to 32.4% (p < 0.05), 34.7% (p < 0.001), and 39.4% (p < 0.001) 10 minutes after doses of 1.0, 2.0, and 5.0 mg of simendan, respectively. The mean velocity of maximal circumferential fiber shortening increased from the baseline of 2.22 lengths/sec to 2.7 lengths/sec after the 2.0 mg dose (p < 0.05) and to 3.31 lengths/sec after the 5.0 mg dose (p < 0.001). Mean BP decreased slightly and mean HR increased only by 5.2 beats/min after the 5.0 mg dose. Because of the potent effect seen on hemodynamic indices and due to two vasovagal reactions, 10 mg was given to two subjects only. These results revealed that simendan has hemodynamic effects that can be explained by positive inotropy as well as vasodilatation, in agreement with preclinical findings. Further studies with patients disabled by heart failure are warranted.

Haemodynamic dose-efficacy of levosimendan in healthy volunteers.

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.