The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers.
We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 micrograms.kg-1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electrocardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing. All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 micrograms.kg-1). Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (< 20%) systemic clearances and larger values of Cmax and AUC. Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 micrograms.kg-1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 micrograms.kg-1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Wolf
D L
DL
Department of Clinical Research, Upjohn Company, Kalamazoo, Michigan.
Ferry
J J
JJ
Hearron
A E
AE
Froeschke
M O
MO
Luderer
J R
JR
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D020108:Nicorandil; D011187:Posture; D016037:Single-Blind Method; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil