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At least 19 recordsLinked to original sources
PubMed1994

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.

Adult↗
PubMed2001

Improved survival with simendan after experimental myocardial infarction in rats.

This study compared the effects of simendan, a calcium sensitizer, with those of milrinone and enalapril on survival of rats with healed myocardial infarction. Seven days after ligation-induced myocardial infarction, the rats were randomized to control, milrinone, enalapril, or simendan groups. All compounds were administered via the drinking water for 312 days, at which time there was 80% mortality in the control group--the study's primary endpoint. The infarct sizes were similar across all groups. At endpoint, the mortality rates were: 63% (milrinone), 56% (enalapril) and 53% (simendan); the risk reductions were 25% (P = 0.04 vs. control) and 28% (P = 0.02 vs. control) with enalapril and simendan, respectively. Milrinone had no statistically significant effect on the survival rate. These findings suggest that, like enalapril, simendan improved survival in rats with healed myocardial infarction.

Animals↗
PubMed1994

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.

Adult↗
PubMed1996

Enantiomeric bioanalysis of simendan and levosimendan by chiral high-performance liquid chromatography.

rac-Simendan, (+/-)-(R,S)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl ] hydrazono]propanedinitrile, and the levorotatory enantiomer levosimendan, are drug candidates intended for the treatment of congestive heart failure. An enantiospecific high-performance liquid chromatographic (HPLC) method suitable for determination of the ratio of the enantiomer concentrations in blood plasma samples was developed. Direct resolution of the enantiomers was achieved by using a chiral beta-cyclodextrin stationary phase in reversed phase mode. With an eluent containing 24-33% of methanol in a 0.5% (v/v) triethylammonium acetate buffer, pH 6.0, and a flow rate of 1 ml/min, a resolution (1.2-1.6) adequate for the determinations was achieved. By using UV detection, the relative concentration of the enantiomers in plasma was assessed down to 10 ng/ml. For the racemate, the results indicated a slightly enantioselective disposition and plasma protein binding in rat, dog, and man. The pure enantiomer, levosimendan, was found not to isomerize in vivo.

Animals↗
PubMed1994

Maltooligosaccharides as chiral selectors for the separation of pharmaceuticals by capillary electrophoresis.

Complexation between the linear maltodextrin oligosaccharides and certain enantiomeric compounds of pharmaceutical interest in buffered solutions can lead to an analytically desirable chiral recognition. Different maltodextrins were assessed in their capacity to cause enantiomeric separations under various conditions of capillary electrophoresis. The mechanism of chiral recognition has been probed through electrophoretic mobility and selectivity measurements for different buffer solutions and organic solvent additives. A differential interaction of chiral solutes with the maltodextrin helical entities emerges as the basis of such enantioselectivity. This notion is further supported by 1H- and 13C-NMR experiments. Optimized separations of simendan, ibuprofen, warfarin, and ketoprofen enantiomers are demonstrated together with a chiral determination of ibuprofen in a blood serum sample at the therapeutic level.

Blood Chemical Analysis↗
PubMedDate not supplied

Automated analysis of levosimendan in human plasma by on-line dialysis and liquid chromatography.

A fully automated method for quantitation of levosimendan, (R)-(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl]hydrazono]propanedinitrile, in human plasma is described. The method involves on-line dialysis of the samples, trace enrichment of the dialysates, and reversed-phase high-performance liquid chromatography with UV detection at 380 nm. An internal standard was used to compensate for variations in the dialysis rate caused by temperature fluctuations. The precision and accuracy of the method were good. The between-day variation (RSD) was 2.7% at a plasma concentration of 15 ng/mL and 1.7% at 450 ng/mL. The limit of quantitation was 5 ng/mL with an RSD of 4.0%. The completion time of the assay was 19 min.

Autoanalysis↗
PubMed1998

Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit.

Effects of levosimendan on myocardial contractility and Ca2+ transients were assessed in the ventricular myocardium of the rabbit. Levosimendan at and above 0.1 microM had a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aqeuorin. The maximum inotropic response to levosimendan at 3 microM was approximately 20% of the maximum response to isoproterenol (ISOmax), whereas the maximum increase in the amplitude of Ca2+ transients was approximately 11% of ISOmax. For a given PIE, levosimendan increased the amplitude of Ca2+ transients much less than an elevation of [Ca2+]o. Levosimendan did not prolong the relaxation time. Similar results were obtained in single ventricular cardiomyocytes that had been loaded with indo-1. In the presence of the muscarinic receptor agonist carbachol, both the PIE and the increase in the Ca2+ transient induced by levosimendan were markedly attenuated. During wash-out of both carbachol and levosimendan, the contractile force increased conspicuously with little change in the amplitude of Ca2+ transients, an indication that the increase in myofibrillar sensitivity to Ca2+ ions elicited by levosimendan was susceptible to carbachol. Levosimendan at and above 0.03 microM shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 microM and higher in the isolated right atrium of the rabbit. These findings indicate that, in addition to the increase by levosimendan of the sensitivity of contractile proteins to Ca2+ ions, the accumulation of cyclic AMP due to the phosphodiesterase-inhibitory action of levosimendan might contribute to the PIE of this drug.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan.

Levosimendan, an inodilatory drug discovered using troponin C as a target protein, has a cardiac effect deriving from the calcium sensitization of contractile proteins. The aim of this study was to give further evidence that levosimendan binds to cardiac troponin C and that the binding involves amino acid residues on helixepsilon of the N-terminal domain of this calcium-binding protein. Nine organic molecules, obtained by chemical modification of levosimendan, were tested both for their calcium-dependent binding to troponin C and troponin complex affinity HPLC columns, and for their ability to increase the calcium sensitivity of myofilaments in cardiac skinned fibers. A good correlation between the calcium sensitization and the calcium-dependent binding to troponin complex (r=0.90) and to cardiac troponin C (r=0.91) for the analogs of levosimendan was shown. In addition, the effect of levosimendan on the calcium-induced conformational changes in native and point-mutated cTnC was studied. Cys84-->Ser, Asp87-->Lys and Asp88-->Ala point-mutated cTnC were shown to maintain a high affinity to calcium, but their Ca(2+)titration curves were not influenced by levosimendan as for the native protein. Finally, it was demonstrated that the NMR chemical shifts of the terminal methyl groups of Met47, Met81, and Met85 on calcium-saturated cTnC were changed after addition of levosimendan in water solution at pH 7.4. This effect was not seen when adding an analog of levosimendan, which did not bind to the troponin C affinity HPLC column and did not increase the calcium-induced tension in cardiac skinned fibers.

Calcium↗
PubMed1996

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril.

OBJECTIVE: Levosimendan in a new inodilator drug that sensitizes troponin C in heart muscle cells to calcium, thus improving contractility. In previous studies, a single 2 mg intravenous dose of levosimendan increased cardiac output (CO) in healthy volunteers by about 40% and decreased pulmonary capillary wedge pressure in heart failure patients by 40-50%. The aim of the present, double-blind study was to evaluate the safety of concomitant use of levosimendan and an ACE-inhibiting drug. METHODS: The haemodynamic effects of levosimendan, given with or without captopril, were evaluated by using 2-dimensional echocardiography, repeated blood pressure measurements and by ambulatory ECG recordings. Twenty-four male patients with stable NYHA II-III heart failure (EF < 40%) after a previous myocardial infarct were given, in randomised order, a single i.v. infusion of levosimendan or placebo. The infusions were repeated after 2 weeks treatment with upto 50 mg b.i.d. of captopril. Twelve patients received levosimendan 1 mg and twelve received 2 mg. RESULTS: Mean CO was increased from 6.0 to 6.8 1 . min-1 in patients receiving 1 mg levosimendan compared to placebo, but only from 6.3 to 6.5 1 . min-1 in patients receiving 2 mg. The increase in CO was statistically significant when all levosimendan patients were compared to placebo. Heart rate did not change after either dose. Mean stroke volume increased significantly after 1 mg but not after 2 mg of levosimendan. The addition of captopril did not change the effects of levosimendan. No additional decrease in systolic or diastolic blood pressure was observed when levosimendan and captopril were given concomitantly. CONCLUSION: It seems that concomitant treatment with captopril does not change the haemodynamic effects of levosimendan. No adverse haemodynamic interactions were seen.

Adult↗
PubMedDate not supplied

Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency.

We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). Myocardial contractility was assessed with the end-systolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of differentially loaded LV pressure-volume diagrams. LV-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. Levosimendan (0.75, 1.5, and 3.0 micrograms.kg-1.min-1) significantly (p < 0.05) increased heart rate, +dP/dt, and ejection fraction (EF) and decreased mean arterial pressure (MAP), pressure-work index (PWI; an estimate of myocardial-oxygen consumption), and LV systolic and end-diastolic pressures (LVSP and LVEDP) and volumes (EDV and ESV). Levosimendan-induced augmentation of myocardial contractility (Ees, Msw and +dP/dt) and reductions in LV afterload (Ea) caused increases in the Ees/Ea ratio (0.61 +/- 0.10 during control to 3.3 +/- 0.7 during the high dose) consistent with enhancement of LV-arterial coupling. Levosimendan increased SW/PVA (0.48 +/- 0.05 during control to 0.84 +/- 0.04 during the high dose), indicating this drug improves the transfer of myocardial potential energy to external work. Levosimendan also increased the ratio of SW to PWI (109 +/- 18 during control to 255 +/- 50 mmHg.min.100g during the high dose), suggesting that myocardial metabolic efficiency was improved as well. Like levosimendan, pimobendan and milrinone (10, 20, and 40 and 1.0, 2.0, and 4.0 micrograms.kg-1.min-1, respectively) increased HR, +dP/dt, EF, Ees, and Msw and decreased MAP, LVSP, LVEDP, EDV, ESV, and Ea. In contrast to levosimendan, neither agent reduced PWI. Pimobendan and milrinone caused dose-related increases in Ees/Ea, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturate-anesthetized dogs.

Animals↗
PubMed1994

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.

Adult↗
PubMed2002

Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca2+ transients under acidotic condition in aequorin-loaded canine ventricular myocardium.

We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the influence of acidosis on the positive inotropic effect (PIE) of OR-1896 (R)- N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic in acidotic conditions (pH(o) 6.6) that was essentially the same as that in control conditions (pH(o) 7.4). The CRC for PIE of OR-1896 reached a plateau at 10(-6) M (first phase) and it became steeper again at 10(-3) M (second phase). Under acidotic conditions the efficacy of the first phase was 10% of the maximal response to isoproterenol (ISO(max)) and the PIE was associated with an increase in Ca(2+) transients of 2% of ISO(max) (P<0.05). The sensitivity of myofilaments to Ca(2+) ions was increased by OR-1896 in acidotic conditions, whereas the relationship of Ca(2+) transients and contractile force during an increase in elevation of the extracellular Ca(2+) concentration and during application of dihydroouabain was shifted prominently to the right in acidotic conditions. In conclusion, OR-1896 elicited a PIE due to an increase in the sensitivity of myofilaments to Ca(2+) ions even in acidotic conditions. The PIE of OR-1896 in acidotic conditions was much less than that in control conditions because the effect of the compound to induce an increase in intracellular Ca(2+) mobilization was markedly attenuated in acidotic conditions.

Acetamides↗
PubMed2002

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.

Administration, Oral↗
PubMed2000

Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin.

OBJECTIVE: To study the effects of possible interactions between levosimendan and warfarin on pharmacokinetics and pharmacodynamics. Furthermore, the effects of levosimendan on blood coagulation were investigated. METHODS: Open, randomised cross-over design with two treatment phases was used. During one phase, levosimendan (0.5 mg four times daily) was given orally to ten healthy subjects for 9 days. On the fourth treatment day with levosimendan, a single oral dose of warfarin (25 mg) was given. Pharmacokinetic parameters of levosimendan from the third and fourth treatment days were compared with each other. During the other treatment phase the subjects received only a single dose of warfarin. Pharmacokinetic parameters of warfarin alone were compared with those determined after concomitant administration of levosimendan. Changes in blood coagulation parameters were evaluated after levosimendan and warfarin alone and after concomitant administration. RESULTS: Warfarin did not change the pharmacokinetics of levosimendan. The distribution volume of warfarin was higher and elimination half-life shorter after concomitant levosimendan administration than after warfarin alone. However, concomitant levosimendan administration did not potentiate the effects of warfarin on blood coagulation assessed using activated partial thromboplastin time (APTT) and thromboplastin time (TT-SPA). Levosimendan alone for 3 days did not change APTT or TT-SPA values. There were no changes in the protein binding of levosimendan or warfarin upon concomitant administration. Continuous treatment with oral levosimendan caused headache, which was probably due to cerebral vasodilation. CONCLUSIONS: Concomitant levosimendan administration did not potentiate the effect of warfarin on blood coagulation after a single dose. Levosimendan itself had no effects on blood coagulation.

Adult↗
PubMedDate not supplied

Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5-mononitrate in healthy subjects.

OBJECTIVE: The new calcium sensitiser levosimendan also possesses vasodilatory effects due to potassium-channel opening. The aim of the present study was to assess the possible haemodynamic interactions between levosimendan and isosorbide-5-mononitrate in young healthy men. METHODS: The study was crossover, placebo controlled, double blind, randomised, and it comprised of four study days with one medication--levosimendan, isosorbide-5-mononitrate, levosimendan plus isosorbide-5-mononitrate or placebo--given on each. Levosimendan was administered i.v. as an initial bolus dose of 12 microg/kg over 10 min, followed by a continuous infusion of 0.2 microg/kg/min for a total time of 2 h. Isosorbide-5-mononitrate (20 mg) was given orally as a single dose. Leg blood flow and venous capacity (venous occlusion plethysmography), cardiac output (impedance cardiography), skin blood flow (laser-Doppler flowmetry), blood pressure and heart rate were recorded at baseline, and 20 min, 1 h, 2 h, 4 h and 6 h after the start of the infusion. An orthostatic test was performed at baseline and at 2 h 15 min. Twelve healthy, male subjects were included. Their mean age was 24 years (range 20-34 years). RESULTS: Levosimendan increased leg blood flow by 32%, and no additive effect of the combination of levosimendan and isosorbide-5-mononitrate was observed. The effects of levosimendan on heart rate and blood pressure were minimal and in close conformity with previous studies. In general, there were no additive effects of the combination compared with each drug alone at rest. The only additive effect was seen in the orthostatic response. Heart rate increased by 40 beats min(-1) with the combination (95% confidence interval compared with placebo 11-24 beats min(-1)), by 30 beats min(-1) with levosimendan (2-15 beats min(-1)), by 28 beats min(-1) with isosorbide-5-mononitrate (1-15 beats min(-1)), and by 22 beats min(-1) with placebo. Furthermore, three subjects were unable to stand upright for the stipulated time with the combination, and the orthostatic test had to be discontinued prematurely. There were no changes in the conduction intervals in the electrocardiogram on any of the treatments. The combination had no influence on the occurrence of headache compared with isosorbide-5-mononitrate alone. CONCLUSION: No major additive haemodynamic effects of the combination of levosimendan and isosorbide-5-mononitrate compared with each drug alone could be observed at rest. However, during an orthostatic test, the circulatory response was significantly potentiated with the combination, and three of the subjects were unable to stand upright for the stipulated time.

Adult↗
PubMed1999

The effects of levosimendan on the left ventricular function and protein phosphorylation in post-ischemic guinea pig hearts.

The widely accepted theories for the decreased function in the stunned myocardium relate to Ca2+ desensitization and free radical-mediated tissue damage of the myofilaments. The aim of the present study was to examine whether the depressed contractile function and Ca2+ responsiveness of the stunned myocardium may be restored by a new Ca2+ sensitizer (levosimendan), which has been shown to improve the Ca2+ response of the myofilaments. The effects of levosimendan on the left ventricular function and the in vivo protein phosphorylation were examined in both the non-ischemic and the stunned myocardium. Myocardial stunning was induced in Langendorff-perfused guinea pig hearts by suspending the circulation for 8 min, followed by a 20-min reperfusion period. Perfusion of post-ischemic guinea pig hearts with levosimendan (0.03-0.48 microM, 6 min) was associated with dose- and time-dependent increases in both dP/dtmax (contractility) and dP/dtmin (speed of relaxation). When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time point (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 microM) levosimendan concentration did not reveal any qualitative or quantitative difference in the phosphodiesterase inhibitory potential of the compound (elevation of tissue cyclic AMP levels and characteristics of protein phosphorylation) between the non-ischemic and the post-ischemic myocardium. However, when isoproterenol was administered to induce maximal in vivo phosphorylation of cardiac phosphoproteins, an attenuation of the 32P-incorporation into troponin I was noted in the post-ischemic hearts. The decrease in isoproterenol-induced 32P-incorporation into troponin I was associated with similar alterations in the tissue level of this protein. We conclude that the Ca2+ sensitizer levosimendan exerts dose- and time-dependent positive inotropic and lusitropic effects on the post-ischemic myocardium, lending support to the hypothesis tha Ca2+ desensitization of the myofibrils is involved in myocardial stunning.

Animals↗
PubMed2000

Levosimendan: A promising agent for the treatment of hospitalized patients with decompensated heart failure.

Levosimendan is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. The combination of positive inotropy with anti-ischemic effects of K-channel opening offers many potential benefits in comparison to currently available intravenous inotropes, that are more or less contraindicated in patients with ongoing myocardial ischemia. Levosimendan has been extensively studied in various animal models of heart failure, in which the drug has increased contractility without adverse effects on diastolic function. These results have been repeated in patients with heart failure, by whom levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. On higher doses, the drug can induce tachycardia and hypotension. In clinical trials, drug-induced ventricular arrhythmia have been rare. Recently, trials in patients with decompensated heart failure have suggested that short-term intravenous treatment with levosimendan might improve the survival of these critical patients. These results highlight the importance of adequate treatment of the acute heart failure patients for their long-term outcome.

Animals↗