ABSTRACT
Development of tolerance to nitrates during long-term therapy is a major concern. It has been suggested that isosorbide-5-mononitrate (IS-5MN), an active metabolite of isosorbide dinitrate, administered twice daily 12 hours apart does not lead to development of tolerance. The duration of effects of IS-5MN at a dose of 20 and 40 mg and of placebo was studied in patients with angina pectoris who responded to nitrates after the first dose (n = 12) and after 1 week of twice-daily therapy (n = 9). The study was double-blind, randomized and crossover in design. Compared with placebo values, after the first dose of 20 and 40 mg IS-5MN, exercise duration was higher at 2 hours (p less than 0.001) and 6 hours (p less than 0.02). After 1 week of twice-daily therapy at these doses, exercise duration increased at 2 hours (p less than 0.05) but not at 6 or 10 hours after the dose. After the first dose of 20 and 40 mg IS-5MN, standing systolic blood pressure decreased at 2 hours (p less than 0.02). Blood pressure did not change significantly after chronic therapy. Tolerance to antianginal effects during twice-daily therapy with 20 and 40 mg of IS-5MN developed despite higher plasma IS-5MN concentrations at 2 and 6 hours during twice-daily therapy than after the first dose. The tolerance during twice-daily therapy with IS-5MN was characterized by a reduced peak effect at 2 hours and shortened duration of action compared with first-dose effects.
Subject(s)
Angina Pectoris/drug therapy , Isosorbide Dinitrate/analogs & derivatives , Aged , Double-Blind Method , Drug Administration Schedule , Drug Tolerance , Exercise Test , Humans , Isosorbide Dinitrate/administration & dosage , Isosorbide Dinitrate/therapeutic use , Male , Middle Aged , Physical Exertion , Random Allocation , Time FactorsABSTRACT
In a double-blind, randomized, crossover study, the duration of effects of single oral doses of 20 and 40 mg isosorbide-5-mononitrate (IS-5MN) and matching placebo were studied in 12 male patients with angina pectoris. Plasma IS-5MN concentrations (mean +/- SD) 2 and 6 hours after administration were 300 +/- 60 and 144 +/- 43 ng/ml after 20 mg IS-5MN and 551 +/- 191 and 376 +/- 129 ng/ml after 40 mg IS-5MN. Exercise time to the onset of angina 2 and 6 hours after administration increased after 20 mg IS-5MN (5.88 +/- 1.85; P less than 0.001 and 5.08 +/- 1.97 minutes; P less than 0.002) and 40 mg IS-5MN (6.17 +/- 1.88; P less than 0.001 and 5.78 +/- 1.72 minutes; P less than 0.001) in comparison to placebo (4.57 +/- 1.22 and 4.15 +/- 1.22 minutes). Similarly, total exercise duration increased at 2 (P less than 0.001) and 6 hours (P less than 0.002) after both doses of IS-5MN. Compared with placebo, ECG ST segment depression during exercise was less (P less than 0.05) 2 hours after both doses of IS-5MN. Thus single oral doses of 20 and 40 mg IS-5MN exert antianginal and anti-ischemic effects for at least up to 6 hours.
