Lack of effect of asymmetrical dosage timing of isosorbide-5-mononitrate on nitrate tolerance during long-term administration
Isosorbide 5-mononitrate is an active metabolite of isosorbide dinitrate and possesses many theoretical advantages over its parent drug. However, the development of partial tolerance has been demonstrated when the drug is given 12 hourly or 8 hourly. We have therefore evaluated the acute and sustained (2 weeks) effects of isosorbide-5-mononitrate 40 mg given twice daily (08.00 h and 14.00 h, allowing an 18-h dose-free period) in 19 patients with stable chronic angina, using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were two phases of 2 weeks each in which patients received placebo or active isosorbide-5-mononitrate. Acute testing was performed 2 h after the first dose and chronic testing 2 h after the morning dose on Day 14. Acute testing showed an increase in exercise time from a mean (SD) of 6.7 (2.2) min to 10.1 (2.95) min (P<0.01) after a single dose of isosorbide-5-mononitrate 40 mg. The time to 1 mm of ST depression, and rest and peak exercise heart rates increased significantly during acute testing with isosorbide-5-mononitrate; resting and peak exercise systolic blood pressures fell significantly. Due to drop outs cross-over analysis was performed on 11 patients who completed both chronic phases and 13 patients were assessed for the comparison of acute isosorbide-5-mononitrate with chronic isosorbide-5-mononitrate. After 2 weeks of therapy exercise time did not show a sustained increase 8.01 (2.14) min chronic placebo to 8.58 (1.93) min chronic isosorbide-5-mononitrate. The improvement in ST segment variables seen acutely was not sustained. These data suggest that the attenuation of the effect of isosorbide-5-mononitrate due to partial tolerance is not mitigated by using an asymmetrical dose regimen.