INCREASING NITROGLYCERIN RELEASE FROM PATCHES ENABLES CIRCUMVENTION OF EARLY NITRATE TOLERANCE

Continuous treatment with transdermal nitroglycerin leads to tolerance development within the first day of application. Effective long-term therapy can be provided by interval treatment with nightly patch remov al, but even during the hours of intermittent patch application there Is rapid attenuation of initial effects. To assess whether an unattenu ated antiischemic and antianginal efficacy during the hours of intermi ttent dosing can be maintained, a modified drug-release profile with i ncreasing plasma concentrations was evaluated using a double-blind, pl acebo-controlled crossover protocol. Eleven patients with documented c oronary artery disease received, in a randomized order, a total of fou r low-dose nitroglycerin patches (5 mg/24 h each) or placebo, respecti vely, at intervals of 3 hours. After a treatment interval of 12 hours, all patches were removed for an equally long patch-free interval prio r to renewed application of one patch the next morning. At a comparabl e workload, reductions of ST-segment depression of 65%, 63%, and 56% w ere found at 2.5 hours, 8 hours, and 12 hours after application of the first patch on day 1, respectively (all significant vs, placebo; 2.5 hours vs. 12 hours, n.s.). On day 2, the comparable reduction of 63% a t 2.5 hours after renewed application indicates prevention of toleranc e development during subchronic treatment. Effects on exercise capacit y and angina pectoris paralleled those on exercise-induced ST-segment depression. Plasma concentrations of nitroglycerin increased from 223 pg/mL to 558 and 803 pg/mL on day 1 and amounted to 205 ng/mL at 2.5 h ours on day 2. Thus, interval therapy with increasing nitroglycerin co ncentrations provides unattenuated antiischemic and antianginal effica cy during the hours of treatment and circumvention of early tolerance during subchronic application. This modified pharmacokinetic profile c an be regarded as a model for an improved dosage regimen in nitrate in terval therapy.