A NEW ISOSORBIDE DINITRATE EXTENDED-RELEASE FORMULATION - PHARMACOKINETIC AND CLINICAL-PARAMETERS IN PATIENTS WITH STABLE ANGINA-PECTORIS

In a double-blind, cross-over study the acute clinical efficacy and ph armacokinetic profile of a newly developed isosorbide dinitrate extend ed-release (ISDN-ER) formulation (10 mg immediate release and 60 mg sl ow release) were examined in eight angina patients. Exercise tests wer e done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; simil ar testing was repeated after 14 days of open-labelled treatment. At 1 , 6 and 10 h after administration, ISDN-ER significantly reduced the m ean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, a nd 0.6 mm, respectively. Total exercise duration increased significant ly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduc ed significantly at any time, while digital plethysmography demonstrat ed a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbi de mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high a t 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml(-1), respectively. Thu s, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.