Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction.
Levosimendan, a new drug that sensitizes troponin-C to calcium and selectively inhibits phosphodiesterase III, was administered to 24 patients with ischemic heart disease and ejection fraction below 40%. In a placebo-controlled, crossover, double-blind study, each patient received two intravenous doses of levosimendan on 2 consecutive study days. The doses were 0.25 mg (n = 6), 0.5 mg (n = 11), 1 mg (n = 12), 2 mg (n = 12), and 4 mg (n = 5). After 0.25 mg and 0.5 mg, cardiac output increased by 0.49-0.67 L/min (p < 0.05) due to an increase in stroke volume of 6-11 ml. After 2 and 4 mg, cardiac output increased by 0.61-0.88 L/min due to an increase in heart rate of 6-12 beats/min. The baseline filling pressures, i.e., right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP), were within the normal range. RAP decreased significantly (p < 0.05) after 2 and 4 mg and PCWP after 0.5, 1, 2, and 4 mg. The most profound decreases were observed 10 min after infusion of 4 mg, from 5.0 to 3.2 mm Hg in RAP and from 9.8 to 6.0 mm Hg in PCWP. Total peripheral resistance decreased significantly only after 2 and 4 mg, by 13 and 21%, respectively. However, there were no statistically significant changes in pulmonary vascular resistance. It is concluded that levosimendan has a hemodynamically favorable action after 0.25 and 0.5 mg but that decreases in filling pressures probably prevented the increase in stroke volume and caused a reflex increase in heart rate after 2 and 4 mg.
First Department of Medicine, Helsinki University Hospital, Finland.
J
J
Lilleberg
S
S
Sundberg
M S
MS
Nieminen
D000368:Aged; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000009:adverse effects / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology*; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D010919:Placebos; D011652:Pulmonary Circulation / Q000187:drug effects; D011724:Pyridazines / Q000009:adverse effects / Q000494:pharmacology*; D000077464:Simendan; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology*
D002316:Cardiotonic Agents; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D010919:Placebos; D011724:Pyridazines; D000077464:Simendan