Hemodynamic, anti-ischemic, and neurohumoral effects of slow-release isosorbide-5-mononitrate in patients with coronary artery disease after short- and long-term therapy.
In 20 patients with established coronary artery disease, stable angina pectoris and reproducible ST-segment depression, the pharmacokinetics and pharmacodynamic effects of 60 mg slow-release isosorbide-5-mononitrate (IS-5-MN) (10 patients) after a 7-day therapy were compared with those of a placebo group (10 patients) using a randomized double-blind, placebo-controlled study design. Ten patients could be controlled after long-term therapy over a mean of 399 +/- 111 days. There was no significant change under IS-5-MN of either blood pressure, heart rate, rate-pressure product, or myocardial oxygen consumption. Treatment over one week significantly reduced ST-segment depression 4 and 8 h after drug intake (38-48% of the placebo value, p less than 0.01). Maximum reduction in ST-segment depression was found 4 and 8 h after IS-5-MN intake both after one-week and long-term therapy at the time of peak plasma drug concentration (341 +/- 95 and 405 +/- 125 ng/ml, respectively). At a residual plasma concentration below 100 ng/ml, ST depression was not significantly improved 24 h after drug intake compared with placebo. Technetium-99m ventriculography showed an insignificant increase in ejection fraction and a slight reduction of ventricular volumes after both short- and long-term therapy with IS-5-MN (p greater than 0.05). The drug's plasma levels were higher under chronic than under short-term therapy which may be due to enzyme saturation. Maximum IS-5-MN plasma concentrations at a mean of 445 +/- 116 ng/ml were reached after 5.8 +/- 2.9 h. Beta-phase half-life of elimination was 9 +/- 3 h. IS-5-MN administered as a single 60 mg dose of a slow-release preparation/day proved to have a favorable pharmacokinetic profile as well as an efficient antiischemic activity after both short- and long-term therapy. Problems of tolerance or activation of hormonal counter-regulation due to vasodilation were not observed.
Mitrovic
V
V
Kerckhoff-Klinik of the Max-Planck-Society, Bad Nauheim, Germany.
Gessner
C
C
Hain
P
P
Müller
K D
KD
Schlepper
M
M
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000097:blood*; D009638:Norepinephrine / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D010919:Placebos; D012083:Renin / Q000097:blood; D013997:Time Factors; D014667:Vasopressins / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
D003692:Delayed-Action Preparations; D018377:Neurotransmitter Agents; D010919:Placebos; D014667:Vasopressins; D000804:Angiotensin II; D012083:Renin; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; D009638:Norepinephrine; D004837:Epinephrine