Absence of pre-dose rebound phenomena with once daily 5-ISMN in a controlled-release formulation

To avoid the development of nitrate tolerance secondary to relatively constant elevated plasma nitrate concentrations, intermittent nitrate dosing has been advocated. However, a nitrate-free interval may induce a rebound increase in myocardial ischaemia, and thus increase anginal symptoms during the latter portion of the dosing interval. This was suggested by the results of recent studies in which nitroglycerin patches were administered intermittently with a 12 h nitrate-free interval. The present investigation was carried out to determine whether a controlled-release formulation of 60 mg isosorbide-5-mononitrate (5-ISMN) would produce such a rebound phenomenon. Seventy-nine patients, who had participated in four crossover, placebo-controlled studies in which the treatment arms lasted for between 1 and 2 weeks, were reviewed. These studies had assessed the efficacy of this nitrate preparation by exercise testing and each had included exercise testing at the end of each treatment phase, 24 h after the last medication had been administered. There were no differences noted in the time to onset of angina, the time to onset of 1 mm ST segment depression or the total exercise duration between the two treatment phases, indicating an absence of rebound phenomena at the end of the dosing interval. The reason for the absence of a detectable pre-dose rebound is unclear, but the plasma concentration profile of 5-ISMN produced by the presently used preparation, resulting in a nitrate-low instead of nitrate-free interval, may have contributed.