The metabolic effects of platelet-activating factor antagonism in endotoxemic man
W. A. Thompson, S. Coyle, K. Van Zee, H. Oldenburg, R. Trousdale, M. Rogy, D. Felsen, L. Moldawer and S. F. Lowry
Department of Surgery, New York Hospital-Cornell University Medical College, New York.
OBJECTIVE: To determine if the inflammatory phospholipid
platelet-activating factor (PAF) participated in the symptomatologic,
metabolic, and counterregulatory hormonal responses of human endotoxemia.
DESIGN: In a double-blind, placebo-controlled study, five subjects received
10 mg of the PAF antagonist Ro 24-4736 orally, while five control subjects
received a placebo. Eighteen hours later, all subjects were administered 4
ng/kg of endotoxin (lipopolysaccharide) intravenously. SETTING: The
Clinical Research Center of The New York Hospital-Cornell Medical Center.
PARTICIPANTS: Healthy male volunteers. MAIN OUTCOME MEASURES: Repeated
measurements of vital signs, symptoms, cytokine and hormone levels, resting
energy expenditure, platelet aggregation, and bleeding times were performed
during a 24-hour period. RESULTS: Subjects who were pretreated with the PAF
antagonist experienced fewer symptoms, including rigors at 1 hour (P <
.05) and myalgias at 1 through 4 hours (P < .05) after administration of
lipopolysaccharide. This was in concert with a diminished peak cortisol
level (668 +/- 107 vs 959 +/- 159 nmol/L in controls; P < .05),
epinephrine secretion (1057 +/- 165 vs 2029 +/- 431 nmol/L in controls; P
< .05), and almost complete inhibition of PAF-induced platelet
aggregation ex vivo. CONCLUSIONS: These findings in the face of unaltered
circulating cytokines tumor necrosis factor alpha, interleukin 1 beta, and
interleukin 6, as well as the tumor necrosis factor receptor-I s, suggest
that PAF may influence some endotoxin-induced, counterregulatory hormonal
responses and symptoms through cytokine-independent mechanisms. This study
further supports the role of PAF antagonists as an adjunct to cytokine
blockade in the treatment of gram-negative sepsis.
