Once-daily isosorbide mononitrate improves exercise duration With minimal development of tolerance in patients with angina

Development of tolerance is a limitation of the antianginal efficacy of isosorbide dtnitrate and is believed to result from maintenance of plasma levels within the therapeutic range over a 24-hour period. lsosorbide mononitrate. an active metabolite of isosorbide dinitrate. provides therapeutic levels for a 10- to 12-hour period, providing antianginal coverage during the most active parts of the day and allowing a washout period of plasma nitrate levels during non-active periods which may be adequate enough to decrease the tendency toward tolerance.

Therefore, to evaluate effectiveness of and development of tolerance to these agents, 18 patients with chronic stable angina pectoris received oral isosorbide dinitrate 30mg qid, isosorbide mononitrate 60mg once-daily and placebo for 11-14 days each in a double-blind randomised crossover study; each treatment phase was separated by a 1 week placebo washout period.

During short term therapy, both active drugs significantly improved treadmill walking times ( vs placebo); plasma nitrate levels paralleled the improvements in exercise performance. After 11-14 days of continuous therapy, only isosorbide mononitrate maintained any significant improvements in treadmill exercise tests; both drugs exhibited slightly higher plasma nitrate levels than during short term therapy. The decreased effectiveness of isosorbide dinitrate with continuous therapy may be indicative of the development of tolerance.

Thus ' ... a sustained-release preparation of ISMN [lsosorbide mononltrate] may be an effective once­daily prophylactic ant/anginal agent to be used only by the patient who experiences angina predominantly during finite periods of time. . .. In such a person, the loss of effectiveness during Inactive periods produces no symptomatic manifestations and minimizes the development of tolerance during the active periods, when ant/anginal prophylaxis Is most needed'. Wosenberg G. Roks C, Nochol P. Goddard MD Sustaoned eHect of and lack of development of tolerance to controlled-release ososorbode·s· monomtrate on chronoc stable angona pectons Amerocan Journal of Cardoology 64 569-576. Sep 1989 1333

6 INPHARMA• 28 Oct 1989 0156-2703/89/1028-0006!0$01.00/0 © ADIS Press