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INFECTIOUS DISEASES

Safety and Pharmacokinetics of an Endotoxin-Binding Phospholipid Emulsion

The Rogosin Institute; Professor of Clinical Medicine and Surgery, Weill Medical College of Cornell University, New York, NY

Thomas S Parker, PhD

The Rogosin Institute; Associate Professor of Biochemistry, Weill Medical College of Cornell University

Daniel M Levine, PhD

The Rogosin Institute; Associate Professor of Biochemistry, Weill Medical College of Cornell University

Stuart D Saal, MD

The Rogosin Institute; Professor of Clinical Medicine and Surgery, Weill Medical College of Cornell University

Lisa Cooper Hudgins, MD

The Rogosin Institute; Associate Professor of Pediatrics in Medicine, Weill Medical College of Cornell University

Betty-Jane Sloan, MA

Research Manager, The Rogosin Institute

Cindy Chu, BA FNP

Nurse Practitioner, The Rogosin Institute

Kurt H Stenzel, MD

The Rogosin Institute; Professor of Medicine and Surgery, Weill Medical College of Cornell University

Albert L Rubin, MD

The Rogosin Institute; Professor of Medicine and Surgery, Weill Medical College of Cornell University

Reprints: Bruce R Gordon MD, The Rogosin Institute, 505 E. 70th St., New York, NY 10021-9809, FAX 212/288-8370, E-mail gordobr{at}mail.rockefeller.edu

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.

Key Words: emulsion, endotoxin, lipid, phospholipid

Published Online, May 23, 2003. www.theannals.com, DOI 10.1345/aph.1C390

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