ANTIISCHEMIC EFFECTS OF FIRST AND 2ND DOSE OF 20 MG ISOSORBIDE DINITRATE ADMINISTERED 5 HOURS APART - ATTENUATION OF EFFECTS DESPITE RISINGPLASMA-CONCENTRATION

Based on evidence that there may be early tolerance development even w ithin the first daily cycle of treatment, this study was undertaken to evaluate the duration and extent of the antiischemic effects of two 2 0 mg doses of isosorbide dinitrate as used in a well-established regim en documented;to maintain effectiveness during long-term treatment. Is chemia parameters were analyzed at 2 and 41/2 hours after the first do se as well as at 2 and 7 hours after the second dose given 5 hours lat er. The studies were performed in 10 male patients with documented cor onary artery disease using bicycle ergometry and a double-blind, rando mized, placebo-controlled, crossover protocol. ST-segment depression w as reduced by 59% (p < 0.0005) at 2 hours and by 42% (p < 0.01) at 41/ 2 hours after the first tablet and by 38% (p < 0.005) at 2 hours and b y 15% (p < 0.05) at 7 hours after the second tablet. Increments in isc hemia-free workload capacity amounted to 112% (p < 0.005) and to 41% ( p < 0.05) after the first tablet and 68% (p < 0.05) and 38% (p < 0.05) at 2 and 7 hours after the second tablet. At 2 and 41/2 hours after t he first tablet, plasma concentrations of isosorbide dinitrate were 8. 4 and 5.9 ng/ml, and those of isosorbide-5-mononitrate were 166.6 and 130.3 ng/ml. At 2 and 7 hours after the second tablet, the concentrati ons of isosorbide dinitrate were 9.1 and 5.9 ng/ml, and those of isoso rbide-5-mononitrate were 224.5 and 148.1 ng/ml. Even during the first 12 hours after the initial administration, there is continuous attenua tion of the antiischemic effects in spite of increasing plasma concent rations consistently in the therapeutic range. Accordingly, with this eccentric nitrate dosing regimen, there are comparable effects at the same time of day when compared on a day-to-day basis. Nevertheless, ef fective therapy is only enabled for a period of less than 12 hours of the 24-hour treatment cycle. An enhanced action of longer duration cou ld possibly be achieved by increasing the dose of the second tablet.