Optimal nitrate therapy with a once-daily sustained-release formulation of isosorbide mononitrate

Abstract

During long-term prophylaxis of angina with oral nitrates, sustained high plasma nitrate concentrations produce partial or complete tolerance to both the haemodynamic and the clinical effects of the drug. There is substantial evidence that this can be prevented by an adequate nitrate-free or nitrate-low period during each 24 h dosing interval. However, a nitrate-free interval carries the risk of a rebound increase in myocardial ischaemia. Once-daily formulations of isosorbide mononitrate deliver high plasma nitrate concentrations that improve exercise tolerance in patients with angina for at least 12 h after dosing. During the remainder of the dosage interval, plasma nitrate concentrations fall but are sufficient to protect against coronary artery spasm overnight. Myocardial ischaemia has a marked circadian rhythm. All ischaemic events (total ischaemic burden, myocardial infarction and sudden cardiac death) are most frequent in the hours immediately after waking. Oral anti-ischaemic prophylaxis should ideally provide protection during this critical period, in order to minimize symptoms, maximize exercise capacity and perhaps also to reduce the risk of clinical events. The ideal long-acting nitrate formulation should therefore provide a rapid rise in plasma nitrate concentration as well as maintaining prolonged efficacy throughout the dosing interval. Elantan LA is a sustained-release capsule formulation of isosorbide mononitrate for once-daily dosing. This capsule contains pellets which release 30% of the dose immediately, while 70% is released slowly to maintain the therapeutic response. The pharmacokinetic profile of this formulation prevents the development of tolerance, while also conferring long-term anti-anginal efficacy. Patients reported an improvement in both severity of angina and quality of life indices when their therapy was changed from multiple daily dosing with isosorbide dinitrate to once-daily dosing with Elantan LA (50 mg). The anti-anginal effect of Elantan LA is attained rapidly after dosing. Within 30 min of ingestion, there are clinically significant improvements in exercise tolerance, comparable with the speed of onset after an immediate-release formulation of isosorbide mononitrate. Elantan LA is an effective once-daily prophylaxis for angina which also produces a rapid onset of therapeutic effect. The release profile of this formulation maximizes protection against the morning surge in myocardial ischaemia.