958-94 Neurohormonal and Hemodynamic Effects of SDZ WAG 994 a Novel Selective A1Adenosine-receptor Agonist in Patients with Heart Failure

Abstract

Effects of stable, selective A 1 adenosine receptor agonist (N 6 -cyclohexyl-2’-0-methyladenosine) SDZ WAG 994 were investigated in a randomized, double-blind, placebo-controlled, parallel group, multicenter study. After baseline hemodynamic and neurohormone data were obtained in 50 patients (mean age 56 years) with left ventricular dysfunction (mean EF 30%), who were NYHA Class I (32%) or II (68%), they received either 1, 2 or 5 mg of SDZWAG 994 or placebo orally. Hemodynamic data were collected every 30 minutes for 4 hours and then every 2 hours for 20 hours. Neurohormones and plasma drug concentration were measured 2 hours after dosing. The active drug was clinically well tolerated as there were no significant differences comparing adverse events reported with placebo and the 3 active drug doses. No important effects were seen on systolic, right atrial, pulmonary artery or pulmonary artery wedge pressures, cardiac index, or heart rate. The PR interval increased slightly with the 5 mg dose (176 to 193 msec at 2 hrs). Atrial natriuretic peptide (ANP) levels increased significantly (216 ± 137 to 407 ± 146 pg/mL, p < 0.01) with the 5 mg dose and increases of lesser magnitude occurred with 1 and 2 mg doses. Interestingly, plasma norepinephrine also increased with the 5 mg dose (477 ± 243 to 618 ± 237 pg/mL, p < 0.01). No significant changes occurred in plasma renin activity or epinephrine levels. In summary, selective A 1 adenosine receptor agonism, evidenced by an increase in PR interval and plasma ANP. was safely achieved for several hours in patients with LV dysfunction. Significant neurohormonal effects were observed with no important hemodynamic changes. Both A 1 adenosine agonism and ANP have been shown to attenuate hypoxic cell damage and vasoconstriction and this agent could have clinical utility in ischemic heart disease