Sinitrodil

Clinical trials have shown the potential of benzoxazinones, a new class of organic nitrates, in cardiovascular therapy. In particular Sinitrodil possesses a coronary vascular selectivity greater than that of Nitroglycerin and isosorbide dinitrate. The objective of this study was a preliminary evaluation of the ability of these new organic nitrate derivatives to reach therapeutical steady-state plasma concentrations following a transdermal administration. In vitro permeation studies through human stratum corneum and epidermis have been conducted on two members of this class: Sinitrodil (ITF 296) and ITF 1129. Comparative studies have also been carried out with Nitroglycerin, Isosorbide dinitrate and Nicorandil. Two different fixed concentrations were tested: 0.08% w/v solution and saturated solution. Sinitrodil could be considered a good candidate for transdermal administration on the basis of the in vitro permeation results and of the known therapeutical plasma concentration.

ITF 296 is a new orally active nitrate acting selectively on large arterial vessels over a wide range of doses. In healthy volunteers it causes less reduction in vascular resistance and less venodilatation than classic nitrates. Its pharmacokinetic profile was evaluated after intravenous infusion and oral (solution and immediate-release tablet) administration in a randomised cross-over design on 11 healthy volunteers. The plasma levels of ITF 296 and its metabolite ITF 1124 were determined by a HPLC method. The drug is rapidly distributed (mean steady-state distribution volume 53+/-17 liters) and eliminated (half-life of about 25 minutes) both after intravenous and oral administration. The total clearance is 2. 31+/-0.46 l/min. The oral solution of ITF 296 is well absorbed (Cmax=0.057 microg/ml, tmax=30 min) but it undergoes a first-pass effect (F=25%). The tablet, developed only for Phase 1 clinical studies, is characterised by an immediate release (Cmax=0.057 microg/ml, tmax=30 min). The extent of its absolute and relative bioavailability is about 14% and 53% respectively.