An evaluation of recombinant human platelet activating factor acetylhydrolase (rPAF-AH) in patients at risk for developing acute respiratory distress syndrome (ARDS)

Michael Metzler, Robert Balk, Daniel Schuster, Gus Slotman, John Michael, Janice Zimmerman, Eileen Coyne, John Pribble

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Introduction: Platelet activating factor (PAF) is a pro-inflammatory mediator that activates neutrophils, increases vascular permeability, and has been implicated in the pathogenesis of ARDS. PAF-AH is a naturally occurring human enzyme that binds to lipoproteins and degrades PAF to lyso-PAF, an inactive metabolite. A recombinant form of human plasma PAF-AH has been developed as a potential therapeutic agent. Methods: This 28 day study was a randomized, single-blind, placebo-controlled, multicenter trial undertaken to evaluate the safety, pharmacokinetics, and clinical pharmacology of rPAF-AH in severe sepsis or multiple trauma patients at risk for developing ARDS. Cohorts of six patients (4 rPAF-AH/2 placebo) were randomized to three dose levels of rPAF-AH (1.0, 2.5, or 5.0 mg/kg) and each patient received two doses of rPAF-AH or placebo, administered 72 hours apart, by 10 minute IV infusion. Results: Eighteen patients (7 sepsis/11 trauma) were enrolled. Age, APACHE II score, injury severity score (ISS), PaO2/FiO2, and multiple organ dysfunction score (MODS) were similar within and among cohorts at baseline. Sixteen serious adverse events were reported by six patients. There was no evidence of antigenicity or dose-related changes in clinical laboratory results among rPAF-AH treated patients. Pharmacokinetic parameters were similar after the first and second doses, and there was no evidence of accumulation in serum. The clearance of PAF-AH was approximately twice that previously observed in healthy subjects and was inversely related to lipoprotein concentrations. PaO2/FiO2 and MODS score improved in patients receiving rPAF-AH versus baseline, while patients receiving placebo had no change. Despite these improvements, there was no suggestion of a dose-response relationship with rPAF-AH treatment. Conclusions: Repeat doses of rPAF-AH were well tolerated and were not antigenic. The clearance of PAF-AH was increased relative to what was previously observed in healthy subjects. There was evidence of improvement in PaO2/FiO2 and MODS score with rPAF-AH treatment relative to placebo, although there was no evidence of a dose-response relationship. Further studies are warranted.

Original languageEnglish (US)
Pages (from-to)A85
JournalCritical Care Medicine
Volume27
Issue number1 SUPPL.
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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