INHIBITION OF THE SEROTONERGIC COMPONENT OF HUMAN PLATELET-AGGREGATION FOLLOWING INTRAVENOUS ADMINISTRATION OF LY215840, A 5-HT2A RECEPTOR ANTAGONIST

LY215840 is an ergoline with high affinity for the 5-HT2 family of ser otonergic receptors. The present study was designed to examine the saf ety Profile of intravenously administered LY215840 and its ability to exert ex vivo platelet aggregation responses to serotonin in healthy h uman subjects. LY215840 was relatively well tolerated demonstrating sa fety in this clinical study with regard to cardiovascular and haematol ogical parameters. LY215840 (at infusion rates of less than or equal t o 0.6 mg/kg over 15 min) had no effect on QT(c) interval, APPT, PT, bl ood pressure or heart rate. Infusion of LY215840 was associated with t he dose-dependent occurrence of minor side effects, including nausea, tiredness and dizziness. LY215840 inhibited the serotonin component of serotonin-amplified ADP-induced platelet aggregation at all doses stu died relative to placebo. The inhibition lasted at least 24 h after te rmination of the infusion. In fact, in the lowest administered dose (0 .1 mg/kg iv), LY215840 Produced a significant and long-lasting inhibit ion of ex vive aggregation responses to serotonin. This inhibition occ urred in the absence of any observed side effects. Based on these obse rvations, LY215840 was relatively well tolerated after iv administrati on to healthy human subjects and found to block serotonin amplified-pl atelet aggregation responses, an effect mediated by blockade of 5-HT2A receptors.