Pharmacokinetics of Levosimendan in Healthy Volunteers and Patients with Congestive Heart Failure

Sandell, Esa-Pekka; Häyhä, Marja; Antila, Saila; Heikkinen, Paula; Ottoila, Pekka; Lehtonen, Lasse; Pentikäinen, Pertti J.

doi:10.1097/00005344-199500001-00008

Cited by 52 publications

(66 citation statements)

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“…Because only high concentrations of levosimendan (more than 90 ng/ml) are thought to inhibit phosphodiesterase-III,30 31 we believe that inhibition of phosphodiesterase activity by levosimendan can be ruled out in our study as plasma concentrations never exceeded 30 ng/ml. In addition, although tissue cAMP concentrations were raised in the ischaemic region of the levosimendan treated hearts, this increase was similar in both treatment and control groups.…”

Section: Discussionmentioning

confidence: 79%

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model

Toit

Hofmann

McCarthy

et al. 2001

Heart

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Objective-To determine whether levosimendan, a calcium sensitiser that facilitates the activation of the contractile apparatus by calcium, improves myocardial contractile function during severe ischaemia and reperfusion without exacerbating the incidence of arrhythmias. Design-Pigs were pretreated orally twice daily for 10 days with 0.08 mg/kg levosimendan or placebo. On day 11 the left main coronary artery was ligated for 30 minutes, followed by 30 minutes of reperfusion. A bolus dose of levosimendan, 11.2 µg/kg intravenously, or placebo was given 30 minutes before coronary ligation, followed by a continuous infusion of 0.2 µg/kg/min levosimendan or placebo for the remainder of the experiment. Results-During the ischaemic period, cardiac output was higher in the levosimendan group than in the placebo group (mean (SD): 2.6 (0.5) v 2.0 (0.2) l/min, p < 0.05) and systemic vascular resistance was lower (2024 (188) (130) mm Hg/s, p < 0.05) were increased by levosimendan. The incidence of ischaemic ventricular fibrillation and tachycardia was similar in the two groups but there were more arrhythmic events (ventricular tachycardia and ventricular fibrillation) in the levosimendan treated group (8/12 levosimendan v 1/9 control p = 0.05). Conclusions-Levosimendan improved cardiac output and myocardial contractility during coronary artery ligation and reperfusion. However, it increased the number of arrhythmic events during ischaemia in this model of in vivo regional ischaemia. (Heart 2001;86:81-87)

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Section: Discussionmentioning

confidence: 79%

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model

Toit

Hofmann

McCarthy

et al. 2001

Heart

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“…The long-term hemodynamic responses [10] following the administration of short-lasting levosimendan [13, 30] relate to the combination of differences in elimination half-life [11, 20], and plasma protein binding [12, 20] of levosimendan and OR-1896 [17, 24–27]. In fact, in addition to a calcium-sensitizing effect similar to that of levosimendan, OR-1896 exerts a potent vasodilatory effect on isolated coronary and skeletal muscle arteries in the rat [6].…”

Section: Discussionmentioning

confidence: 99%

Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo

Gődény

Pollesello

Édes

et al. 2013

Pharmacological Reports

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Background Levosimendan and its long-lived metabolite OR-1896 produce vasodilation in different types of vessels by activating ATP-sensitive (KATP) and other potassium channels. Methods In the present study we applied intravital videomicroscopy to investigate the in situ effects of levosimendan and OR-1896 on the diameters of real resistance arterioles (rat cremaster muscle arterioles with diameters of ~ 20 μm). Results Levosimendan and OR-1896 induced concentration-dependent (1 nM – 100 μM) dilations to similar extents in these arterioles (maximal dilation from 23 ± 2 to 33 ± 2 μm and from 22 ± 1 to 32 ± 1 μm, respectively). The arteriolar dilations induced by the selective KATP channel opener pinacidil (1 nM – 10 μM) (maximal dilation from 22 ± 4 μm to 35 ± 3 μm) were diminished in the presence of the selective KATP channel blocker – glibenclamide (5 μM) (maximal diameter attained: 22 ± 1 μm). Glibenclamide also counteracted the maximal dilations in response to levosimendan or OR-1896 (to 23 ± 3 μm or 22 ± 5 μm, respectively). Conclusions In conclusion, this is the first demonstration that levosimendan and OR-1896 elicit arteriolar dilation in vivo, via activation of KATP channels in real resistance vessels in the rat.

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“…Plasma levels below 100 ng m1-1 have little effect on heart rate, but at concentrations above that level there is a dose-dependent positive chronotropic effect, that is probably related to the PDE inhibitory action of the drug. Since levosimendan is highly protein bound, its haemodynamic effects in vivo are seen with a free fraction of the drug of 1-2ngml -] [10]. ACE-inhibiting drugs are one of the primary therapies given to heart failure patients.…”

Section: Introductionmentioning

confidence: 99%

“…It is important to see whether ACE-inhibitors given concomitantly with inodilator drug may induce potentially harmful excessive vasodilatation. In previous dose-ranging studies [6,10], levosimendan has been administered to some patients receiving ACEinhibiting drugs without problems. The present study was planned primarily to evaluate the safety of the concomitant administration of therapeutic IV doses of levosimendan with an ACE-inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril

Antila

Eha

Heinpalu

et al. 1996

Eur J Clin Pharmacol

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Pharmacokinetics of Levosimendan in Healthy Volunteers and Patients with Congestive Heart Failure

Cited by 52 publications

References 0 publications

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model

Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril

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