In Wong, et al., determined the safety and tolerability of E5564 following a 30-min intravenous infusion in healthy male volunteers (74) . This was a single-center, randomized, double-blind, placebo-controlled, sequential-group, singledose study of E5564. The drug dose levels used were 350, 1,000, 2,000 or 3,500 μg. All doses of E5564 presented a long pharmacokinetic half-life and short in vivo pharmacodynamic half life which generally less than several hours when it is coadministered with LPS in healthy volunteers (74) . The C max and AUC (area under the curve) of E5564 increased in a dose-dependent manner. E5564 pharmacokinetics was characterized by a slow clearance (0.67-0.95 ml h −1 kg −1 ), a small volume of distribution (41-54 ml/kg), and a relatively long elimination half life (42-51 h) in healthy male volunteers. Thus, to overcome this low PD, the doses of E5564 given to the volunteers needed to be adjusted. In summary, all doses were demonstrated to be safe and well tolerated. Safety and tolerability assessments included monitoring and questioning of the subjects about adverse events, physical examinations, clinical laboratory tests (including hematology, blood chemistry, and urinalysis), and vital sign measurements (including supine and standing pulse rate and blood pressure), and 12-lead electrocardiograms (ECGs) and cytokine concentration testing. In this study, E5564 inhibited LPS-induced tumor necrosis factor-α in a dose-dependent manner, and at the higher doses (2 and 3.5 mg), antagonistic activity was measurable up to 8 h post-infusion. E5564 lacked LPS-like agonist activity at doses up to 3.5 mg (74).