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PubMedDate not supplied

Pharmacodynamic interactions of levosimendan and felodipine in patients with coronary heart disease.

OBJECTIVE: The aim was to study the pharmacodynamic interactions and safety of the co-administration of the calcium sensitizer levosimendan and the calcium antagonist felodipine in patients with coronary heart disease (CHD) and with normal ejection fraction (EF). METHODS: The study was a randomized, double blind, placebo-controlled, crossover study in 24 male patients with Canadian Cardiovascular Society (CCS) class II CHD, consisting of four treatment periods, each period lasting for 7-10 days. In the first period the patients received either oral levosimendan (LS) (0.5 mg) or placebo (PL) four times daily and were then crossed over to the other therapy for the second and third period. After the third period the patients were changed back to the therapy administered in the first period. Open label felodipine (FD), 5 mg once daily, was co-administered on the third and fourth treatment period. Differences between the four treatments (LS, PL, FD and LS + FD) in systolic time intervals, exercise capacity, heart rate, blood pressure and 24-hour continuous electrocardiography (Holter) were assessed. RESULTS: The differences between treatments regarding heart rate corrected electromechanical systole (QS2i), pre-ejection period (PEP) and heart rate corrected left ventricular ejection time (LVETi) were significant (p < 0.001, p < 0.001 and p = 0.004, respectively). Levosimendan shortened QS2i by 10 ms (95% CI [-15, -4]), PEP by 6 ms (95% CI [-10, -3]) and LVETi by 7 ms (95% CI [-13, -2]) compared with placebo, indicating a moderate positive inotropic effect. The results were similar, when levosimendan was administered concomitantly with felodipine. Levosimendan did not significantly change systolic blood pressure and no potentiation of response was seen with concomitant administration with felodipine. The increase in heart rate after levosimendan and its combination with felodipine was equal (6-7 bpm). There was no difference in mean cumulative exercise time between the treatments. The combination of levosimendan and felodipine was well tolerated. CONCLUSION: No clinically significant pharmacodynamic interactions between levosimendan and felodipine were seen. Levosimendan did not aggravate myocardial ischemia. Levosimendan can safely be administered to patients with CHD together with a dihydropyridine calcium antagonist.

Blood Pressure↗
PubMed2004

The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin c.

Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increases. Effective treatments are being sought and recently a new class of drugs, the calcium sensitisers, was developed. These drugs cause a positive inotropic effect on cardio-myocytes by interacting directly with the contractile apparatus. Their mechanism of action is not accompanied by an increase in intracellular calcium concentration at therapeutic doses, as seen for the older generation of positive inotropic drugs, and thus does not induce calcium-related deleterious effects such as arrhythmias or apoptosis. Levosimendan is a novel calcium sensitiser which has been discovered by using cardiac troponin C (cTnC) as target protein. This drug has been proved to be a well-tolerated and effective treatment for patients with severe decompensated heart failure. This review describes the basic principles of muscle contraction, the main components of the contractile apparatus and their roles in the heart contraction. The regulatory proteins troponin C (cTnC), troponin I (cTnI), troponin T (cTnT), and tropomyosin (Tm) and their interactions are discussed in details. The concept of calcium sensitisation is thereafter explained and a few examples of calcium sensitisers and their putative mechanisms are discussed. Finally, the binding of levosimendan to cTnC and its mechanism of action are described and the results discussed under the light of the action of this drug in vitro and in vivo.

Animals↗
PubMed2005

Dual regulation of myofilament Ca2+ sensitivity by levosimendan in normal and acidotic conditions in aequorin-loaded canine ventricular myocardium.

Experiments were carried out in canine ventricular trabeculae loaded with aequorin to investigate the effects of levosimendan {(R)-([4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono)-propanedinitrile} on contractile force and Ca(2+) transients in normal and acidotic conditions. The concentration-response curve for the positive inotropic effect (PIE) of levosimendan was bell-shaped, that is, it declined markedly at 10(-4) M after achieving the maximum at 10(-5) M in normal (pH(o)=7.4) and acidotic conditions (pH(o)=6.6). The positive inotropic effect (PIE) of levosimendan up to 10(-5) M was associated with an increase in Ca(2+) transients and a shift of the relationship of Ca(2+) transients and force to the left of that of elevation of [Ca(2+)](o). Levosimendan at 10(-4) M elicited a negative inotropic effect (NIE) in association with a further increase in Ca(2+) transients, and during washout Ca(2+) transients increased further, while the force was abolished before both signals recovered to the control. In acidotic conditions, the relationship of Ca(2+) transients and force during the application of levosimendan in normal conditions was essentially unaltered, whereas the PIE was suppressed due to attenuation of the increase in Ca(2+) transients. In summary, in intact canine ventricular myocardium, levosimendan elicits a dual inotropic effect: at lower concentrations, it induces a PIE by a combination of increases in Ca(2+) transients and Ca(2+) sensitivity, while at higher concentrations it elicits an NIE due to a decrease in Ca(2+) sensitivity. Acidosis inhibits the PIE of levosimendan due to suppression of the increase in Ca(2+) transients in response to the compound.

Acidosis↗
PubMed2006

The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles.

1. We characterized the vasoactive effects of OR-1896, the long-lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. 2. The effect of OR-1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (approximately 150 microm) diameters was investigated by videomicroscopy. 3. OR-1896 elicited concentration-dependent (1 nM-10 microM) dilations in coronary (maximal dilation: 66+/-6%, relative to that in Ca2+-free solutions; pD2: 7.16+/-0.42) and gracilis muscle arterioles (maximal dilation: 73+/-4%; pD2: 6.71+/-0.42), these dilations proving comparable to those induced by levosimendan (1 nM-10 microM) in coronary (maximal dilation: 83+/-6%; pD2: 7.06+/-0.14) and gracilis muscle arterioles (maximal dilation: 73+/-12%; pD2: 7.05+/-0.1). 4. The maximal dilations in response to OR-1896 were significantly (P<0.05) attenuated by the nonselective K+ channel inhibitor tetraethylammonium (1 mM) in coronary (to 34+/-9%) and gracilis muscle arterioles (to 28+/-6%). 5. Glibenclamide (5 or 10 microM), a selective ATP-sensitive K+ channel (KATP) blocker, elicited a greater reduction of OR-1896-induced dilations in skeletal muscle arterioles than in coronary microvessels. 6. Conversely, the selective inhibition of the large conductance Ca2+-activated K+ channels (BK(Ca)) with iberiotoxin (100 nM) significantly reduced the OR-1896-induced maximal dilation in coronary arterioles (to 21+/-6%), but was ineffective in skeletal muscle arterioles (72+/-8%). 7. Accordingly, OR-1896 elicits a substantial vasodilation in coronary and skeletal muscle arterioles, by activating primarily BK(Ca) and K(ATP) channels, respectively, and it is suggested that OR-1896 contributes to the long-term hemodynamic effects of levosimendan.

Acetamides↗
PubMed2003

Population pharmacokinetics of levosimendan in patients with congestive heart failure.

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.

Adrenergic beta-Antagonists↗
PubMed2003

Hemodynamic effects of a continuous infusion of levosimendan in critically ill patients with cardiogenic shock requiring catecholamines.

BACKGROUND: Levosimendan, a novel inodilator, has been shown to improve hemodynamic function in patients with decompensated heart failure with preserved arterial blood pressure. Data on its use in patients with cardiogenic shock are rare. The present series describes the 24-h hemodynamic effects of levosimendan as add-on therapy in desperately ill patients with cardiogenic shock requiring catecholamines. METHODS: Ten patients with cardiogenic shock received levosimendan as continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. The patients were otherwise unselected. Hemodynamic measurements were routinely performed at baseline (time 0) and at 1, 8, 16 and 24 h after start of levosimendan (LS) using a Swan-Ganz thermodilution catheter. RESULTS: During the levosimendan infusion there was a significant increase in cardiac index from 1.8 +/- 0.4 to 2.4 +/- 0.6 L*min-1*m-2 (P = 0.023) and a significant decrease in systemic vascular resistance from 1559 +/- 430 to 1109 +/- 202 dyn*s*cm-5 (P = 0.001), respectively. Changes in catecholamine dose, and in systolic and diastolic blood pressure were not significant. Given the individual response to LS, 8/10 patients showed an increase in left ventricular stroke work index under reduced or roughly unchanged preload conditions after 8 h. CONCLUSION: This series shows that a LS infusion is feasible and able to improve hemodynamics in severely compromized, critically ill patients with cardiogenic shock requiring catecholamine therapy. Its potential advantages when compared with other inotropes are unclear. To clarify the potential role of LS in this clinical setting randomized controlled trials on hemodynamic and mortality endpoints are needed.

Aged↗
PubMed2003

New and emerging drug therapies for the management of acute heart failure.

In recent times, there have been many developments in therapies for acute heart failure, in contrast to the preceding 20 years. These have been mainly fueled by new and expanding knowledge about the pathophysiology of heart failure, which has allowed for insight into potential therapeutic strategies. This review will examine the key emerging therapies for acute heart failure, in light of available pathophysiological and clinical evidence.

Antidiuretic Hormone Receptor Antagonists↗
PubMed1998

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.

Adult↗
PubMed2002

Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN).

AIMS: To evaluate the safety and efficacy of levosimendan in patients with left ventricular failure complicating acute myocardial infarction. METHODS AND RESULTS: Levosimendan at different doses (0.1-0.4 microg x kg(-1) x min(-1)) or placebo were administered intravenously for 6h to 504 patients in a randomised, placebo-controlled, double-blind study. The primary end-point was hypotension or myocardial ischaemia of clinical significance adjudicated by an independent Safety Committee. Secondary end-points included risk of death and worsening heart failure, symptoms of heart failure and all-cause mortality. The incidence of ischaemia and/or hypotension was similar in all treatment groups (P=0.319). A higher frequency of ischaemia and/or hypotension was only seen in the highest levosimendan dose group. Levosimendan-treated patients experienced lower risk of death and worsening heart failure than patients receiving placebo, during both the 6h infusion (2.0% vs 5.9%; P=0.033) and over 24h (4.0% vs 8.8%; P=0.044). Mortality was lower with levosimendan compared with placebo at 14 days (11.7% vs 19.6%; hazard ratio 0.56 [95% CI 0.33-0.95];P =0.031) and the reduction was maintained at the 180-day retrospective follow-up (22.6% vs 31.4%; 0.67 [0.45-1.00],P =0.053). CONCLUSION: s Levosimendan at doses 0.1-0.2 microg x kg(-1) x min(-1) did not induce hypotension or ischaemia and reduced the risk of worsening heart failure and death in patients with left ventricular failure complicating acute myocardial infarction.

Acute Disease↗
PubMed2005

Levosimendan in cardiac surgery.

OBJECTIVE: Levosimendan is a new calcium sensitizer with inodilatory properties. There is growing clinical experience with levosimendan given to cardiac surgical patients. The aim of this report was to evaluate the effects of perioperative use of levosimendan in surgical patients with high perioperative risk, compromised left ventricular (LV) function, or difficulties in weaning from cardiopulmonary bypass (CPB). DESIGN: Case series. SETTING: Single-institution, university hospital. PARTICIPANTS: Patients undergoing cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Sixteen cardiac surgical patients received levosimendan infusion with a maximum duration of 29 hours. Eight were initiated preoperatively and 8 postoperatively. Coronary artery disease was the main operative indication in 10 of 16 cases, and 75% of the patients were high-risk patients. RESULTS: Continuous levosimendan infusion increased cardiac index significantly in both groups compared with preoperative baseline. Pulmonary capillary wedge pressure and systolic blood pressure did not change significantly. Norepinephrine and epinephrine were the most common concomitant vasoactive medications. Most importantly, weaning from CPB was successful in all patients even after failure to wean the patient with catecholamines. One high-risk patient in the preoperative group and 2 patients in the postoperative group died in the hospital. Another patient died during the 1-year follow-up. CONCLUSION: Levosimendan can be used for postoperative rescue therapy for patients difficult to wean from CPB. Also, elective preoperative initiation of levosimendan seems applicable to patients with high perioperative risk or compromised LV function.

Aged↗
PubMed2006

Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery.

OBJECTIVES: The purpose of this study was to compare the hemodynamic profiles and the postoperative insulin requirements in 2 groups of type 2 diabetic patients with depressed myocardial function who underwent elective surgery for coronary artery disease and who received levosimendan or milrinone for postcardiopulmonary bypass low-output syndrome. DESIGN: Randomized controlled trial. SETTING: The Chest Diseases Hospital, Safat, Kuwait. PARTICIPANTS: Type 2 diabetic patients undergoing elective surgery for coronary artery disease. INTERVENTIONS: Fourteen patients and 16 patients received levosimendan and milrinone infusions, respectively, for treatment of the low-output syndrome. MEASUREMENTS AND MAIN RESULTS: The hemodynamic, mixed venous oxygen saturation, oxygen extraction ratios, arterial lactate concentrations, and postoperative insulin infusion rates were serially documented for the first 48 hours after the diagnosis. The cardiac index and mixed venous oxygen saturation were significantly higher in the levosimendan group. The pulmonary capillary wedge pressure, systemic vascular resistance, and oxygen extraction ratios were significantly higher in the milrinone treatment group. The insulin requirements were similar for both of the treatment groups. CONCLUSIONS: Levosimendan was more efficient than milrinone for treating the hemodynamic manifestations of the postcardiopulmonary bypass low-output syndrome. However, all the values in the milrinone treatment group were normalized. In this small population, both treatment groups had similar postoperative insulin requirements.

Adult↗
PubMed2003

[Is levosimendan an inoprotective drug in patients with acute coronary syndrome undergoing surgical revascularization?].

Levosimendan, is a new calcium sensitiser with 2 major effects. First, levosimendan acts as a positive inotropic agent by binding calcium dependently to cardiac troponin C. Second, levosimendan activates adenosine triphosphate-regulated potassium (K (ATP)) channels. Thus it has vasodilatory properties and cardioprotective effects at a dose enhancing myocardial contractility. These unique properties of levosimendan might be of great advantage in patients with myocardial ischemia simultaneously requiring inotropic support. The concept of perioperative inoprotection is presented in 6 patients with acute ischemia undergoing emergent cardiac surgery.

ATP-Binding Cassette Transporters↗
PubMed2005

[Levosimendan].

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

Myocardial efficiency during levosimendan infusion in congestive heart failure.

AIMS: Levosimendan, a novel calcium-dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure. METHODS AND RESULTS: Eight hospitalized patients with New York Heart Association functional class III or IV heart failure received levosimendan or placebo intravenously in a randomized double-blind cross-over study. During steady-state, dynamic positron emission tomography with [11C]acetate was used to assess myocardial oxygen consumption and [15O]H2O to measure myocardial blood flow. Cardiac performance and dimensions were assessed by pulmonary artery catheterization and echocardiography. Compared with healthy volunteers, myocardial oxygen consumption during placebo was elevated in the right ventricle but comparable in the left ventricle. During administration of levosimendan, cardiac output increased by 32% (P = .002) mainly because of higher stroke volume. Coronary, pulmonary, and systemic vascular resistance values were significantly reduced. Mean myocardial blood flow increased from 0.76 to 1.02 mL/min/g (P = .033). Levosimendan was neutral on myocardial oxygen consumption and left ventricular efficiency, but it improved right ventricular mechanical efficiency by 24% (P = .012). CONCLUSIONS: Levosimendan has an energetically favorable short-term profile in the treatment of congestive heart failure. It enhances cardiac output without oxygen wasting, particularly by improving efficiency in the right ventricle.

Cardiotonic Agents↗