SAFETY AND PHARMACOLOGICAL ACTIVITY OF A NEW NITRATE ESTER, ITF-296, AFTER INTRAVENOUS ADMINISTRATION IN HEALTHY-VOLUNTEERS

To evaluate the safety and pharmacologic activity of ITF 296 in humans , three groups of healthy male normotensive subjects were studied. The first two groups (six subjects each) received, in ascending order, th ree dose levels of ITF 296 by 30-min intravenous infusion (group I, 0. 1, 0.5, 1.0 mu/kg/min; group II, 2.0, 4.0, 6.0 mu g/kg/min). The third group of eight subjects received, in ascending order, four dose level s of ITF 296 (10, 20, 40, 80 mu g/kg) by 1-min i.v. injection. The stu dy was double-blind, and placebo-controlled according to a within-pati ent, incomplete, unbalanced block design, such that each subject recei ved the placebo once. Hemodynamics were assessed by means of Dynamap a nd BOMED, The following parameters were evaluated at different times b efore and after ITF 296 administration: systolic blood pressure (SEP), diastolic blood pressure (DBP), heart rate (HR), stroke volume index (SVI), cardiac index (CI), and systemic vascular resistance index (SVR I). Blood samples for kinetic assessment of ITF 296 were taken before and at different times after ITF 296 administration. The drug was well tolerated. Only a few mild (except for one, moderate) side effects (m ainly headache and dizziness) were reported, usually at the higher dos e levels. All safety clinical chemistry add hematologic parameters wer e unaffected, After i.v. infusion of ITF 296, blood pressure started t o fall at the dose of 2 mu g/kg/min, DBP being significantly reduced a t doses above 1 mu g/kg/min. The effect lasted for up to 60 min after the end of the infusion, The increase in heart rate was only modest, a lthough apparently dose-dependent. SVI was only slightly reduced, and the other hemodynamic parameters did not change. After bolus administr ation of ITF 296, SEP was significantly reduced starting at a dose of 20 mu g/kg with higher doses producing a more marked effect (up to -15 mm Hg). DBP was significantly reduced only at the higher dose level o f 80 mu g/kg. The effect lasted for up to 60 min after bolus administr ation, HR was slightly increased after doses of 40 and 80 mu g/kg. SVI was slightly reduced and a small transient decrease in CI was observe d, whereas SVRI did not change, Satisfactory, linear kinetic correlati on was found between total doses administered and AUCs measured. ITF 2 96 in healthy male normotensive volunteers was effective and well tole rated. The results of this study justify the planning of further studi es in patients in order to test the anti-ischemic activity of the comp ound.