Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion.
BACKGROUND
Lipids and lipoproteins have been shown to bind and neutralize endotoxin and to improve outcomes in animal models of sepsis.


OBJECTIVE
To provide safety and pharmacokinetic data for a protein-free, phospholipid-rich emulsion developed as an agent to neutralize endotoxin, and to study the changes in lipids and lipoproteins following emulsion administration.


METHODS
Thirty healthy male volunteers (aged 18-45 y) were given an emulsion containing 92.5% soy phospholipid, 7.5% soy triglyceride, and 18 mM sodium cholate using a double-blind, placebo-controlled crossover protocol. Emulsion at 3 escalating doses (75, 150, 300 mg/kg) based on phospholipid content was administered by intravenous infusion over 2 hours in the low- and mid-dose groups and 6 hours in the high-dose group.


RESULTS
All subjects completed the protocol without significant toxicities. A slight dose-dependent increase in indirect bilirubin at the 24-hour time point was observed in the emulsion treatment period, with a maximum difference between placebo and emulsion of 0.9 mg/dL. Mean +/- SD peak phospholipid levels were 316 +/- 30, 533 +/- 53, and 709 +/- 86 mg/dL, and phospholipid half-lives were 5.4 +/- 0.6, 5.4 +/- 0.5, and 8.0 +/- 0.8 hours for the low, mid, and high doses, respectively. Increases in total cholesterol, low-density lipoprotein cholesterol and apolipoprotein A-I and B levels were observed. High-density lipoprotein cholesterol decreased immediately following emulsion infusion, but rebounded to above placebo levels by 24 hours.


CONCLUSIONS
A unique phospholipid-rich emulsion was shown to have a favorable safety profile and to expand the blood lipid and lipoprotein pool without the use of human-derived blood products. Lipid levels expected to protect against the physiologic effects of bacterial endotoxin were achieved.
Gordon
Bruce R
BR
The Rogosin Institute, New York, NY 10021-9809, USA. gordobr@mail.rockefeller.edu
Parker
Thomas S
TS
Levine
Daniel M
DM
Saal
Stuart D
SD
Hudgins
Lisa Cooper
LC
Sloan
Betty-Jane
BJ
Chu
Cindy
C
Stenzel
Kurt H
KH
Rubin
Albert L
AL
D000293:Adolescent; D000328:Adult; D001053:Apolipoproteins / Q000032:analysis; D001647:Bile Acids and Salts / Q000032:analysis; D002793:Cholic Acids / Q000032:analysis; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004731:Endotoxins / Q000378:metabolism*; D005217:Fat Emulsions, Intravenous / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010743:Phospholipids / Q000009:adverse effects / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
D001053:Apolipoproteins; D001647:Bile Acids and Salts; D002793:Cholic Acids; D004731:Endotoxins; D005217:Fat Emulsions, Intravenous; D010743:Phospholipids; D014280:Triglycerides