THE METABOLIC EFFECTS OF PLATELET-ACTIVATING-FACTOR ANTAGONISM IN ENDOTOXEMIC MAN

Objective: To determine if the inflammatory phospholipid platelet-acti vating factor (PAF) participated in the symptomatologic, metabolic, an d counterregulatory hormonal responses of human endotoxemia. Design: I n a double-blind, placebo-controlled study, five subjects received 10 mg of the PAF antagonist Ro 24-4736 orally, while five control subject s received a placebo. Eighteen hours later, all subjects were administ ered 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 w ere pretreated with the PAF antagonist experienced fewer symptoms, inc luding rigors at 1 hour (P<.05) and myalgias at 1 through 4 hours (P<. 05) after administration of lipopolysaccharide. This was in concert wi th 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 t he face of unaltered circulating cytokines tumor necrosis factor alpha , interleukin 1 beta, and interleukin 6, as well as the tumor necrosis factor receptor-Is, suggest that PAF may influence some endotoxin-ind uced, counterregulatory hormonal responses and symptoms through cytoki ne-independent mechanisms. This study further supports the role of PAF antagonists as an adjunct to cytokine blockade in the treatment of gr am-negative sepsis.