title: Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion.
abstract: 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.
authors.affiliation: The Rogosin Institute, New York, NY 10021-9809, USA. gordobr@mail.rockefeller.edu
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Gordon
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Parker
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Levine
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Saal
authors.forename: Lisa Cooper
authors.initials: LC
authors.lastname: Hudgins
authors.forename: Betty-Jane
authors.initials: BJ
authors.lastname: Sloan
authors.forename: Cindy
authors.initials: C
authors.lastname: Chu
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Stenzel
authors.forename: Albert L
authors.initials: AL
authors.lastname: Rubin
mesh_terms: 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
chemical_list: D001053:Apolipoproteins; D001647:Bile Acids and Salts; D002793:Cholic Acids; D004731:Endotoxins; D005217:Fat Emulsions, Intravenous; D010743:Phospholipids; D014280:Triglycerides