PMID- 11808823
OWN - NLM
STAT- MEDLINE
DCOM- 20020708
LR  - 20190826
IS  - 0091-2700 (Print)
IS  - 0091-2700 (Linking)
VI  - 42
IP  - 1
DP  - 2002 Jan
TI  - Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its 
      metabolites during an extended infusion in patients with severe heart failure.
PG  - 43-51
AB  - Levosimendan is a new calcium sensitizer developed for the short-term intravenous 
      treatment of congestive heart failure. The aims of the present open-label, 
      nonrandomized study were to determine the tolerability, hemodynamic effects, and 
      the basic pharmacokinetics of levosimendan and its metabolites during an extended 
      continuous infusion of levosimendan. Twenty-four patients with New York Heart 
      Association (NYHA) III-IV heart failure in two groups of 12 patients were exposed 
      to either 0.05 microg/kg/min or 0.1 microg/kg/min of levosimendan for 7 days. 
      Heart rate and blood pressure were measured, and blood samples for the 
      determination of plasma concentrations of the parent drug and its metabolites 
      were drawn daily during the infusion and the 10 to 15 days' follow-up. The 7-day 
      infusion was well tolerated and no premature discontinuations occurred. Both 
      systolic and diastolic blood pressure decreased maximally by 6 mmHg in the lower 
      and by 11 mmHg in the higher levosimendan dose groups during the infusion period 
      (p < 0.05 for both groups). The mean heart rate values increased maximally by 18 
      and 26 beats/min in the lower and higher levosimendan dose groups, respectively 
      (p < 0.001 for both groups). The hemodynamic effects peaked at the end of the 
      infusion period and thereafter slowly declined during the follow-up. After the 
      recommended infusion period of 24 hours, the mean heart rate increase was only 2 
      and 6 beats/min in the lower and higher levosimendan dose groups, respectively. 
      The elimination half-life of levosimendan was approximately 1 hour and of the 
      metabolites 70 to 80 hours. It can be concluded that levosimendan, even 
      administered considerably longer than the recommended 24 hours, was well 
      tolerated. The 7-day infusion induced a prolonged increase in heart rate and a 
      minor decrease in blood pressure. The long-lasting effects are probably explained 
      by the active metabolite.
FAU - Kivikko, Matti
AU  - Kivikko M
AD  - Orion Pharma, Clinical Research, Cardiovascular Projects, Espoo, Finland.
FAU - Antila, Saila
AU  - Antila S
FAU - Eha, Jaan
AU  - Eha J
FAU - Lehtonen, Lasse
AU  - Lehtonen L
FAU - Pentikainen, Pertti J
AU  - Pentikainen PJ
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Hydrazones)
RN  - 0 (Pyridazines)
RN  - 349552KRHK (Simendan)
SB  - IM
MH  - Aged
MH  - Analysis of Variance
MH  - Blood Pressure/drug effects
MH  - Body Weight/drug effects
MH  - Calcium Channel Blockers/*administration & dosage/*adverse 
      effects/pharmacokinetics
MH  - Cardiotonic Agents/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Chronic Disease
MH  - Electrocardiography/drug effects
MH  - Erythrocyte Indices/drug effects
MH  - Female
MH  - Heart Failure/*drug therapy/metabolism/physiopathology
MH  - Heart Rate/drug effects
MH  - Humans
MH  - Hydrazones/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Infusions, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Pyridazines/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Simendan
EDAT- 2002/01/26 10:00
MHDA- 2002/07/09 10:01
CRDT- 2002/01/26 10:00
PHST- 2002/01/26 10:00 [pubmed]
PHST- 2002/07/09 10:01 [medline]
PHST- 2002/01/26 10:00 [entrez]
AID - 10.1177/0091270002042001005 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2002 Jan;42(1):43-51. doi: 10.1177/0091270002042001005.