[Prevention of the development of tolerance to isosorbide dinitrate in interval therapy]

A number of carefully controlled studies in recent years have unequivocally documented evidence of tolerance development with respect to anti-ischemic effects during longterm treatment with nitrates [1, 3, 4, 5, 7, 8]. To determine to what extent tolerance development can be circumvented through an interval regimen, a study was performed in ten patients with stable angina pectoris and reproducible ST-segment depression according to a randomized, double-blind, cross-over, placebo-controlled protocol. Analysis of the anti-ischemic effect of 20 mg ISDN was carried out after acute administration and during chronic treatment on an interval regimen with the administration of 20 mg ISDN in the morning (at 8 a.m.) and at midday (1 p.m.) (Figure 1). On acute administration, 20 mg ISDN led to a reduction in ST-segment depression from 2.15 to 0.40 mm (p less than 0.01) and during longterm treatment from 2.25 to 0.40 mm (p less than 0.01) (Figure 2, Table 1). After acute administration the plasma concentration of ISDN was 9 ng/ml, 2-ISMN 34 ng/ml and 5-ISMN 149 ng/ml (Figure 5, Table 2). Of the control values during longterm treatment, a detectable level was found only for 5-ISMN with a concentration of 36 ng/ml while that of both 2-ISMN and ISDN was 0 ng/ml. On renewed administration, there was an increase of ISDN to 9 ng/ml, 2-ISMN to 37 ng/ml and 5-ISMN to 208 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)