UNLABELLED: The aim of this study was to evaluate two ways of long-term therapy with lower doses of oral isosorbide dinitrate (ISDN) in normal tablets and in sustained-release form (SR), in patients with stable angina.
METHODS: In double-blind, placebo (PL) controlled with cross-over design study 38 male patients with stable angina and angiographically proven coronary artery disease, received ISDN in normal tablets in two doses: 10 mg and 20 mg, and also two doses SR: 20 mg-SR and 40 mg-SR or PL in the first ingestion and in long-term therapy in two 7 day phases: 4-times-daily (4x) every 6 h and 3-times-daily (3x) with 12 h interval. In 3x patients received ISDN only in doses: 20 mg, 20 mg-SR and 40 mg-SR. After the first ingestion and on the last day of long-term phases, exercise stress tests on the treadmill were performed: preceding ingestion, 2 h and 6 h after. Evaluation of antianginal efficacy of ISDN was performed by analysis of walking times: total, to angina and to ischemia (WTI).
RESULTS: 6 h after first ingestion all doses of ISDN improved significantly WTI in comparison to PL: 10 mg by 34.6% (p < 0.01), 20 mg by 49.6% (p < 0.0001), 20 mg-SR by 42.9% (p < 0.001) and 40 mg-SR by 52.5% (p < 0.0001). None of the doses improved significantly WTI in the long-term 4x phase, in 3x--only 40 mg-SR by 12.1% (p < 0.05).
CONCLUSIONS: Tolerance to anti-anginal efficacy of ISDN in lower doses in long-term therapy 4-times-daily, every 6 h, was found. A 12-h interval is sufficient to prevent tolerance in long-term treatment of sustained-release ISDN in 40 mg dose. Intermitted dosing of nitrates, as a prevention of tolerance, and the practical results of works using other pharmacologic interventions in a clinical setting are discussed in the final section of this paper.