Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

BACKGROUND: Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models. OBJECTIVE: We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined. RESULTS: Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ≥0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95-10.07). CONCLUSIONS: Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763.

Acetylation status does not affect levosimendan's hemodynamic effects in heart failure patients.

OBJECTIVE: Levosimendan is indicated for acute heart failure. The formation of levosimendan's active metabolite OR-1896 is dependent on the acetylator status. We evaluated whether acetylator status affects the hemodynamic responses after levosimendan infusion. METHODS: Forty-one NYHA III to IV heart failure patients were divided into rapid and slow acetylators by population kinetic modeling. Invasive hemodynamics and plasma concentrations of levosimendan and its metabolites were followed serially. RESULTS: Fifty-six percent of the patients were rapid and 44% slow acetylators. Levosimendan induced increases in heart rate and cardiac output, and decreases in pulmonary capillary wedge pressure (PCWP) and blood pressure, which were sustained at 24 hours after stopping the infusion. At this time, levosimendan levels were undetectable, and OR-1896 levels were about two-fold higher in rapid acetylators. However, hemodynamic effects were similar; mean(SEM) change from baseline in cardiac output was +2.0(0.3) vs. +1.6(0.3) l/min (p = 0.309), and in PCWP -8(2) vs. -7(1) mmHg (p = 0.536), in rapid and slow acetylators, respectively. CONCLUSION: The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.

Clinical pharmacology of levosimendan.

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.

Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study.

The objective of this study was to explore the pharmacodynamics and pharmacokinetics of oral levosimendan in patients with severe congestive heart failure. This was a randomized, parallel-group, double-blind, placebo-controlled trial. Oral levosimendan 2 to 8 mg daily or placebo was administered to 25 patients with New York Heart Association class III-IV congestive heart failure for 4 weeks. Pharmacodynamic variables consisted of heart rate-corrected electromechanical systole, heart rate, and systolic and diastolic blood pressure. The pharmacokinetics of levosimendan and its metabolites, OR-1855 and OR-1896, was assessed. The 4- to 8-mg daily doses of oral levosimendan showed moderate inotropic effects. Blood pressure remained unchanged with all doses. A moderate increase in heart rate was observed except with the 2-mg dose. Pharmacokinetic parameters of the metabolites increased linearly with the dose (P < or = .002 for Cmax and AUC0-8h for both treatment groups). It was concluded that oral levosimendan has inotropic and chronotropic effects in patients with severe congestive heart failure. Plasma concentrations of its metabolites increase dose dependently.

The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia.

OBJECTIVES: We assessed the effects of levosimendan on left ventricular (LV) function in patients with acute myocardial ischemia and after coronary angioplasty. BACKGROUND: The calcium sensitizer levosimendan improves the function of myocardium in experimental stunning. METHODS: Twenty-four patients with an acute coronary syndrome underwent angioplasty followed by double-blinded, randomized treatment with 24 microg/kg of levosimendan (n = 16) or placebo (n = 8). Left ventricular pressures and volumes were recorded by cineventriculography and micromanometer-tipped catheters 10 min after angioplasty before drug administration (baseline) and 20 min after drug administration. Left ventricular function was assessed by the pressure-volume loop, and regional function analysis by the Slager method. RESULTS: The number of hypokinetic segments decreased with levosimendan, from 8.9 +/- 0.9 to 6.5 +/- 1.1 (mean +/- SEM), as compared with an increase from 7.8 +/- 1.0 to 8.5 +/- 1.1 with placebo (p = 0.016). A leftward and/or upward shift of the systolic part of the pressure-volume loop, indicating improved systolic function, was observed in eight of 16 of the levosimendan-treated and one of eight of the placebo patients (p = 0.178). In addition, the single-beat elastance was increased by levosimendan (p = 0.045). The pressure-volume area (p = 0.001), end-systolic pressure (p = 0.002), and volume index (p < 0.001) were decreased by levosimendan, but there was no change in the end-systolic pressure-volume ratio. End-diastolic pressure remained unchanged, whereas the end-diastolic volume index was decreased by levosimendan (p = 0.002). The time constant of isovolumic LV pressure fall decreased with levosimendan (p = 0.001). CONCLUSIONS: Levosimendan improved the function of stunned myocardium without obvious impairment of diastolic function.

The contractility enhancing effect of the calcium sensitiser levosimendan is not attenuated by carvedilol in healthy subjects.

OBJECTIVE: It was assessed whether the contractility enhancing effect of the calcium sensitiser levosimendan is altered by carvedilol. METHODS: Twelve healthy subjects received 2 mg levosimendan i.v. both alone and in addition to a 7-9-day treatment with 25 mg carvedilol orally, twice daily, in a cross-over, placebo-controlled, double-blind, randomised study. Systolic time intervals, heart rate, and blood pressure were measured at baseline and up to 2 h after drug administration. RESULTS: When levosimendan was administered in addition to carvedilol, the shortening of electromechanical systole QS2i (indicating increased contractility) was similar to that found with levosimendan alone ( P=0.475). Also, the maximum heart rate change was similar, although a statistically significant difference in heart rate was detected due to minor differences at two time points during the 2-h follow-up ( P=0.018). There were no differences in diastolic blood pressure response ( P=0.962), but the systolic blood pressure response was attenuated by about 4 mmHg with the combination ( P=0.013). CONCLUSIONS: The contractility enhancing effect of levosimendan was not altered in healthy subjects who had received carvedilol for at least 1 week. Heart rate and diastolic blood pressure responses were not altered either, while the systolic blood pressure response was blunted.