Comparison of the Initial Hemodynamic Effects of Immediate‐Release versus Sustained‐Release Isosorbide‐5‐Mononitrate following Single Oral Doses

Abstract

In this double-blind, randomized, placebo-controlled cross-over study, the authors investigated the initial time course of effects of isosorbide-5-mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate-release formulation (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b-ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate-release or the sustained-release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS-5-MN following both formulations. Thus, the administration of the sustained-release formulation of IS-5-MN 50 mg caused similar maximum effects when compared with an immediate-release formulation (20 mg). While the onset of effect of IS-5-MN on the a/b-ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate- or the sustained-release formulation, the onset of effect of the sustained-release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.

Organic Nitrate Maintains Bone Marrow Blood Perfusion in Ovariectomized Female Rats: A Dynamic, Contrast-Enhanced Magnetic Resonance Imaging (MRI) Study

“…However, the high dose of 100 μM is difficult to achieve in vivo as evidenced by pharmacokinetic studies. Trenk et al reported that single oral dose of 20 mg ISM increased the plasma concentration up to 406 ng/mL (2.12 μM) within one hour [ 35 ]. Similar result was also found in rat model after the administration of isosorbide dinitrate [ 36 ].…”

A Sustained Release Formulation of Isosorbide‐5‐mononitrate With a Rapid Onset of Action

“…The three studies described here give reassuring findings in this respect. Trenk et al 4 compared haemodynamic effects after a single dose of 20 mg ISMN immediate release or 50 mg ISMN‐SR in 16 healthy volunteers. Effects could be seen 10 minutes after administration of both formulations: significant effects on heart rate following orthostatic challenge and on a/b ratio of the finger pulse curve were seen after 30 minutes (Figure 2).…”

“…Measurement of the haemodynamic effects of two different doses of ISMN on the finger pulse curve expressed as the a/b ratio 4 …”