Lack of tolerance after chronic administration of controlled-release isosorbide-5-mononitrate

Abstract

The effect of a controlled-release formulation of isosorbide-5-mononitrate (IS-5-MN) was studied in patients with coronary heart disease (CHD), with the aim of comparing the acute effect with that after chronic administration on parameters of ischemia. To determine whether any tolerance developed, several aspects of ischemia were observed: ECG signs, clinical parameters, and left ventricular function. Fifteen patients with angiographically proven CHD were examined with 12-lead exercise ECG before, 2 h and 4 h after the first dose and after 10 days of therapy with 60 mg IS-5-MN (Coleb-Duriles) once daily. After 7 days, three radionuclide ventriculographies were performed: control, 2 h after nitrate and 2 h after 75 mg gallopamil. Plasma concentrations of IS-5-MN were measured before every exercise test. The results showed a reduction of total ST-segment depression from 0.59 mV to 0.29 mV after 2 h (NS) and 4 h (P less than 0.05) on the 1st day and from 0.48 mV to 0.32 mV (P less than 0.05) and 0.31 mV (NS) after 10 days. The severity of angina pectoris was diminished by about 50%. The effect on exercise duration and time to ST-segment depression by more than 0.1 mV remained unchanged after 10 days, whereas the effect on blood pressure, heart rate and time to onset of angina was attenuated. The mean decrease in ejection fraction (EF) from rest to exercise was reduced from--5.9% to -1.9% (P less than 0.05) after nitrate, while an increase of +1.4% was seen after gallopamil (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled release profiles of dipyridamole from biodegradable microspheres on the base of poly(3-hydroxybutyrate).

“…Among those shortcomings hypertoxicity, instability, pulsative character of rate delivery, ineffective expenditure of drugs should be pointed out. Alternatively, applications of therapeutical polymer systems provide orderly and purposefully the deliverance for an optimal dose of agent that is very important at therapy of acute or chronic diseases [4]. At treatment of cardiovascular and other diseases one of the perspective classes of drugs is the class of inhibitors of cell proliferation (ICP).…”

Efficacy of Controlled-Release (Durules) lsosorbide-5-Mononitrate in Association with Calcium Antagonists or Beta-Blockers in Stable Effort Angina pectoris

“…Previous investigations on the effect on angina and ergometrie parameters of CR 60 mg IS5MN in patients with chronic stable angina pectoris showed a favorable effect, starting 2 h postdosing and lasting about 8-9 h [21,24,25,[29][30][31]; after 12 and 24 h on the other hand, no improvement of the ergometrie parameters was detect able anymore [21,25,29]. These results were observed not only after a single dose, but also over long-term administration, confirming the lack of development of tolerance, possibly due to the favorable kinetic profile of this preparation.…”

“…While the short-and long-term efficacy of once daily administration of controlled-release 'Durules' (CR) 60 mg IS5MN as a monotherapy has been shown in previous investigations [21][22][23][24][25][26][27][28][29][30][31], less information is available about its association with other antianginal drugs. The aim of the present study was to document the efficacy, the dura tion of action and the ability in preventing tolerance of once daily CR 60 mg IS5MN in patients with stable effort angina pectoris already on calcium antagonists or ß-block-…”

Nitric Oxide-Releasing Molecules for Cancer Therapy and Chemoprevention

“…To some extent, clinical nitrate tolerance is a red herring, because it is readily controlled by dosing, and is easily avoided for mononitrates, such as ISMN. However, the importance of formulations and dosing must be considered early in any nitrate drug development program (Manabe et al 2001;Stauch et al 1990;Thadani et al 1994). The question of cross-tolerance with other NO-release warheads is unclear.…”