In vitro and ex vivo assays have found that low concentrations of E5564 time dependently lose ability to inhibit LPS response. In light of these observations, it is perhaps not surprising that low doses of E5564 demonstrate a time-dependent loss of activity after administration into normal volunteers. This loss in activity is overcome when E5564 doses are increased (67) . Phase I clinical safety and tolerability assays indicate that E5564 is safe and except for the occurrence of phlebitis, well tolerated at doses up to 252 mg administered over 72 h. At this dose, in vivo antagonistic activity is retained for at least an additional 72 h after discontinuing infusion. This leads us to believe that sufficient therapeutic activity can readily be administered to patients (67) . The safety and efficacy of E5564 are currently been analyzed in a phase III randomized controlled study.