Pharmacokinetics and excretion balance of OR-1896, a pharmacologically active metabolite of levosimendan, in healthy men

Puttonen, Jaakko; Laine, Tarmo; Ramela, Meri; Häkkinen, Sari; Zhang, Wenhui; Pradhan, Rajendra; Pentikäinen, Pertti J.; Koskinen, Mikko

doi:10.1016/j.ejps.2007.08.003

Cited by 17 publications

(20 citation statements)

References 18 publications

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“…This notion is supported by the fact that MR plasma concentrations were at or above the target range (8) while the infusion drug persisted but had a rapid elimination phase once the infusion stopped (Figure 4b). As previously shown in healthy adult volunteers and patients with heart failure (14,15), the parent drug disappeared rapidly once the LEVO infusion was halted at 48 h (Figure 4a). The plasma concentration of the active metabolite OR1896 peaked at 36 h. As with adults (14), the active metabolite is detectable in plasma ~10 h after the initiation of the LEVO infusion, with the median OR1896 plasma concentration above 2 ng/ml.…”

Section: Articles Pellicer Et Alsupporting

confidence: 49%

“…This fact may indicate an early biotransformation of the parent drug in the intestinal tract by reduction to OR1855 and a fast acetylation process causing higher concentrations of OR1896 than OR1855. The delayed deacetylation of OR1896 may explain the progressive accumulation of OR1855 (14,15). The acetylation capacity of an individual has a marked effect on the plasma levels and exposure to both metabolites.…”

Section: Articles Pellicer Et Almentioning

confidence: 99%

“…The duration of treatment differed according to the IND based on a priori pharmacokinetic data (14)(15)(16). Per protocol, the infusion of LEVO was stopped 48 h after it was started.…”

Section: Interventionmentioning

confidence: 99%

“…LEVO binds to troponin C, which, in turn, enhances the sensitivity of contractile proteins to calcium. LEVO has a positive lusitropic effect (12,13) and induces vascular relaxation in the smooth muscle of the peripheral and coronary vascular bed (14)(15)(16)(17). The direct antiinflammatory and antiapoptotic cardioprotective actions of LEVO have also been reported (12).…”

mentioning

confidence: 99%

“…Levosimendan (LEVO) is a novel class IND developed for the treatment of heart failure (12)(13)(14)(15)(16)(17). LEVO binds to troponin C, which, in turn, enhances the sensitivity of contractile proteins to calcium.…”

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confidence: 99%

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Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

et al. 2012

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Background: Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (cPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LeVO), in newborns is anecdotal; no pharmacokinetic data in this population are available. Methods: This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5-1 μg/kg/min, n = 9) or LeVO (0.1-0.2 μg/kg/min, n = 11) as an i.v. continuous infusion, starting before cPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRs) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. serial biochemistry and pharmacokinetic studies were performed. results: During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. early postsurgery, MR-treated infants showed lower ph, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRs-derived variables from 24 to 96 h. study drug withdrawal at 96 h was more frequent with LeVO. LeVO intermediate metabolites were detected in plasma at day 14 after surgery. conclusion: LeVO is well tolerated in critically ill neonates. LeVO may have advantages over MR in terms of the dosing regimen.

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Section: Articles Pellicer Et Alsupporting

confidence: 49%

Section: Articles Pellicer Et Almentioning

confidence: 99%

“…The duration of treatment differed according to the IND based on a priori pharmacokinetic data (14)(15)(16). Per protocol, the infusion of LEVO was stopped 48 h after it was started.…”

Section: Interventionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

et al. 2012

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Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the European Society of Cardiology

Gustafsson

Damman

Nalbantgil

et al. 2023

European J of Heart Fail

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This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline‐directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end‐of‐life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

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Kreislauftherapie

Möllhoff¹,

Berendes²

2011

Pharmakotherapie in Der Anästhesie Und Intensivmedizin

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Pharmacokinetics and excretion balance of OR-1896, a pharmacologically active metabolite of levosimendan, in healthy men

Cited by 17 publications

References 18 publications

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the European Society of Cardiology

Kreislauftherapie

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