In another study of healthy volunteers with experimental endotoxemia, Lynn et al. (66) found phlebitis was only associated with 72 h continuous intravenous infusion of E5564 but not with four hour infusion of E5564 into a peripheral vein. In this study the authors explored the possibility of extended pharmacokinetic activity of E5564. The infusion period was changed from bulk dosing to a 4-and 72-h infusions of E5564 into normal volunteers. They observed that at 4 h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h post-dosing. Additionally, they observed that administration of 3.4 mg of E5564/hX72 h completely blocked the effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h post dosing. A lower dose of E5564 of 2 mg was also studied, and they found that 0.5 mg/h×4 h, ameliorated but did not block most effects of endotoxin 8 h post-dosing. This work also studied the effect of varying plasma lipoprotein content on E5564 activity in subjects who have high or low cholesterol levels (>180 or <140 mg/dl) after a 72 h infusion of 252 mg of E5564. The distribution of E5564 into the lipoprotein fractions was not significantly different between the low-and highcholesterol groups (66) .