title: Usefulness of twice-daily isosorbide-5-mononitrate in preventing development of tolerance in angina pectoris.
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.
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005080:Exercise Test; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D005082:Physical Exertion; D011897:Random Allocation; D013997:Time Factors
chemical_list: D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate