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CARDIOVASCULAR ANESTHESIA

Randomized Safety Studies of Intravenous Perflubron Emulsion. II. Effects on Immune Function in Healthy Volunteers

Robert J. Noveck, MD, PhD^*, E. J. Shannon, PhD, Phillip T. Leese, MD, Jolene S. Shorr, MA^§, Kathryn E. Flaim, PhD^§, Peter E. Keipert, PhD^§, and Catherine M. Woods, PhD^§

*Clinical Research Center, New Orleans, Louisiana; Louisiana State University, Baton Rouge, Louisiana; Innovex Inc., Lenexa, Kansas; and §Alliance Pharmaceutical Corp., San Diego, California

Address correspondence and reprint requests to Peter E. Keipert, PhD, Alliance Pharmaceutical Corp., 3040 Science Park Rd., San Diego, CA 92121.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent^TM [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study). The study described herein focuses on safety concerning immune function. The primary endpoint was defined prospectively as delayed hypersensitivity skin test responses with lymphocyte proliferative responses to mitogenic stimulation providing a secondary measure for changes in cell-mediated immunity. Subjects received either perflubron emulsion IV (1.2 g PFC/kg or 1.8 g PFC/kg) or saline (3 mL/kg) control. Perflubron emulsion had no effect on delayed hypersensitivity skin reactions, lymphocyte proliferative potential, circulating immunoglobulins, complement activation, or plasma levels of the inflammatory cytokines, tumor necrosis factor-, interleukin-1 , and interleukin-1 ß. Perflubron emulsion was generally well tolerated, although there was a dose-dependent increase in minor flu-like symptoms in the perflubron treatment groups at 24 h after dosing. Increased serum levels of interleukin-6 were observed in those subjects exhibiting febrile responses. The clinical safety profile of perflubron emulsion supports its continued investigation as a temporary oxygen carrier in surgical patients to reduce exposure to allogeneic blood transfusion.

Implications: In major surgical procedures, perfluorocarbon-based temporary oxygen carriers are potentially important alternatives to blood transfusion. Early perfluorocarbon-based oxygen carriers were limited by side effects that have been overcome with the newer, second-generation oxygen carriers. This report summarizes Phase I clinical safety findings of an improved second-generation oxygen carrier, perflubron emulsion.

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