title: Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate.
abstract: OBJECTIVE
  To determine whether isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, when given twice daily (in the morning and 7 hours later), prevents development of tolerance and reduction in exercise performance or is associated with a rebound increase in anginal attacks in patients with stable angina pectoris.
  
  
  METHODS
  Multicenter, placebo-controlled, parallel-group, double-blind, randomized study.
  
  
  METHODS
  Four university teaching hospitals and five private cardiology outpatient clinics.
  
  
  METHODS
  116 patients with stable exertional angina who stopped treadmill exercise because of angina pectoris.
  
  
  METHODS
  After stopping all antianginal drugs with the exception of beta-blockers, patients received single-blind placebo for 1 week followed by either 20 mg of IS-5-MN (n = 60 patients) or placebo (n = 62 patients) twice daily at 0800 hours and 1500 hours for 2 weeks.
  
  
  METHODS
  Serial symptom-limited exercise tests and patients' diaries recording activity and date, time, and severity of anginal attacks.
  
  
  RESULTS
  Compared with placebo recipients, patients receiving IS-5-MN walked significantly longer at 2, 5, and 7 hours after the 0800-hour dose (P < 0.01) and at 2 and 5 hours after the 1500-hour dose (P < 0.01). Before the morning (0800-hour) dose, exercise duration increased by 0.53 minutes in placebo recipients and by 0.85 minutes in those receiving IS-5-MN therapy (P = 0.10). Neither nocturnal nor early-morning anginal attacks increased during IS-5-MN therapy compared with placebo. Headaches occurred in 19 (32%) patients in the IS-5-MN group and in 9 (15%) patients in the placebo group but necessitated discontinuation of treatment in only 2 (3%) patients in the IS-5-MN group.
  
  
  CONCLUSIONS
  Isosorbide-5-mononitrate, 20 mg twice daily given 7 hours apart, was well tolerated and improved exercise performance for 7 hours after the morning dose and for 5 hours after the afternoon dose without evidence of development of pharmacologic tolerance. No rebound increase in anginal attacks was found.
authors.affiliation: Cardiology Section, University of Oklahoma Health Sciences Center, Oklahoma City 73104.
authors.forename: U
authors.initials: U
authors.lastname: Thadani
authors.forename: C R
authors.initials: CR
authors.lastname: Maranda
authors.forename: E
authors.initials: E
authors.lastname: Amsterdam
authors.forename: L
authors.initials: L
authors.lastname: Spaccavento
authors.forename: R G
authors.initials: RG
authors.lastname: Friedman
authors.forename: R
authors.initials: R
authors.lastname: Chernoff
authors.forename: S
authors.initials: S
authors.lastname: Zellner
authors.forename: J
authors.initials: J
authors.lastname: Gorwit
authors.forename: P H
authors.initials: PH
authors.lastname: Hinderaker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008297:Male; D008875:Middle Aged; D005082:Physical Exertion; D016037:Single-Blind Method; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D014665:Vasodilator Agents; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate