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Lack of Pharmacologic Tolerance and Rebound Angina Pectoris during Twice-Daily Therapy with Isosorbide-5-Mononitrate

Udho Thadani, MBBS; Claude R. Maranda, MD; Ezra Amsterdam, MD; Leo Spaccavento, MD; Richard G. Friedman, MD; Robert Chernoff, MD; Stephen Zellner, MD; Jeffrey Gorwit, MD; and Paul H. Hinderaker, MD
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University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Queen Elizabeth Hospital, McGill University, Montreal, Quebec. University of California, Sacramento, California. Wilford Hall, USAF Medical Center, Lackland Air Force Base, Texas. Center for Stress Studies of San Diego, San Diego, California. Taylor Hospital, Ridley Park, Pennsylvania. Clinical Physiology Associates, Fort Myers, Florida. Escondido Cardiology, Escondido, California. The Jackson Clinic, Madison, Wisconsin. Requests for Reprints: Udho Thadani, MBBS, Cardiology Section, University of Oklahoma Health Sciences Center, 920 Stanton Young Boulevard, 5SP-300, Oklahoma City, OK 73104. Acknowledgments: The authors thank Mr. Wes Pierson of A. H. Robins Company for organizing the study, supplying the study medication, which is manufactured by Boehringer Mannheim, and monitoring the study. These data were collected from individual centers by A. H. Robin's monitors, and statistical analysis of the data was done by Mr. Robert Herbertson of A. H. Robins. The data were also independently interpreted by the principal investigators of the study. The authors also thank Ms. Linda Turner for preparation of the manuscript. Grant Support: By a grant from A. H. Robins Company.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;120(5):353-359. doi:10.7326/0003-4819-120-5-199403010-00001
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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.

Design: Multicenter, placebo-controlled, parallel-group, double-blind, randomized study.

Setting: Four university teaching hospitals and five private cardiology outpatient clinics.

Patients: 116 patients with stable exertional angina who stopped treadmill exercise because of angina pectoris.

Intervention: After stopping all antianginal drugs with the exception of β-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.

Measurements: 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.

Conclusion: 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.


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Figure 1.
Change in exercise duration among patients receiving placebo and those receiving isosorbide-5-mononitrate therapy.PP

Mean changes in total exercise duration from respective pretherapy baseline values after 0800-hour and 1500-hour doses of isosorbide-5-mononitrate (IS-5-MN) and placebo. Total exercise duration increased significantly ( < 0.01) with IS-5-MN compared with placebo at 2, 5, and 7 hours after the 0800-hour dose and at 2 and 5 hours after the 1500-hour dose (hours 9 and 12 after the 0800-hour dose). Exercise time before the 0800-hour dose did not change significantly. Mean values ±SE are shown by the vertical bars. *  < 0.01.

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