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January 1994

The Metabolic Effects of Platelet-Activating Factor Antagonism in Endotoxemic Man

Arch Surg. 1994;129(1):72-79. doi:10.1001/archsurg.1994.01420250084011

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 α, interleukin 1β, 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.(Arch Surg. 1994;129:72-79)