PMID- 12940594
OWN - NLM
STAT- MEDLINE
DCOM- 20040120
LR  - 20181130
IS  - 0946-1965 (Print)
IS  - 0946-1965 (Linking)
VI  - 41
IP  - 8
DP  - 2003 Aug
TI  - Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral 
      levosimendan in patients with severe congestive heart failure.
PG  - 365-73
AB  - OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations 
      after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in 
      patients with congestive heart failure (CHF). METHODS: This was an open-label, 
      non-randomized Phase II trial in 29 patients with New York Heart Association 
      (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were 
      given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 
      1-week washout, the patients received a 2 mg single oral dose of levosimendan. 
      Heart rate-corrected electromechanical systole QS2i was the primary variable. 
      Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood 
      pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 
      515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 
      mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline 
      to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 
      0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms 
      (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The 
      concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis 
      with both modes of administration. sBP and dBP decreased both during infusion and 
      after 2 mg oral dose. HR remained unchanged during both modes of administration. 
      CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed 
      that levosimendan possesses moderate inotropic and vasodilatory effects in 
      patients with severe congestive heart failure, which could be described as 
      counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared 
      earlier than the inotropic effect.
FAU - Poder, P
AU  - Poder P
AD  - Cardiovascular Projects, Research Centre, Orion Pharma, Espoo, Finland. 
      pentti.poder@orionpharma.com
FAU - Eha, J
AU  - Eha J
FAU - Sundberg, S
AU  - Sundberg S
FAU - Antila, S
AU  - Antila S
FAU - Heinpalu, M
AU  - Heinpalu M
FAU - Loogna, I
AU  - Loogna I
FAU - Planken, U
AU  - Planken U
FAU - Rantanen, S
AU  - Rantanen S
FAU - Lehtonen, L
AU  - Lehtonen L
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Int J Clin Pharmacol Ther
JT  - International journal of clinical pharmacology and therapeutics
JID - 9423309
RN  - 0 (Hydrazones)
RN  - 0 (Pyridazines)
RN  - 349552KRHK (Simendan)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Blood Pressure/*drug effects
MH  - Electric Stimulation/methods
MH  - Female
MH  - Heart Failure/*drug therapy
MH  - Heart Rate/*drug effects/physiology
MH  - Humans
MH  - Hydrazones/*administration & dosage/metabolism/*pharmacokinetics
MH  - Infusions, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Myocardial Contraction/*drug effects/physiology
MH  - Pyridazines/*administration & dosage/metabolism/*pharmacokinetics
MH  - Simendan
MH  - Time Factors
MH  - Vasodilation/drug effects
EDAT- 2003/08/28 05:00
MHDA- 2004/01/21 05:00
CRDT- 2003/08/28 05:00
PHST- 2003/08/28 05:00 [pubmed]
PHST- 2004/01/21 05:00 [medline]
PHST- 2003/08/28 05:00 [entrez]
PST - ppublish
SO  - Int J Clin Pharmacol Ther. 2003 Aug;41(8):365-73.