The metabolic effects of platelet-activating factor antagonism in endotoxemic man.
OBJECTIVE
To determine if the inflammatory phospholipid platelet-activating factor (PAF) participated in the symptomatologic, metabolic, and counterregulatory hormonal responses of human endotoxemia.


METHODS
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.


METHODS
The Clinical Research Center of The New York Hospital-Cornell Medical Center.


METHODS
Healthy male volunteers.


METHODS
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.
Thompson
W A
WA
Department of Surgery, New York Hospital-Cornell University Medical College, New York.
Coyle
S
S
Van Zee
K
K
Oldenburg
H
H
Trousdale
R
R
Rogy
M
M
Felsen
D
D
Moldawer
L
L
Lowry
S F
SF
D000328:Adult; D016207:Cytokines / Q000097:blood*; D004311:Double-Blind Method; D004731:Endotoxins / Q000097:blood*; D006728:Hormones / Q000097:blood; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D010617:Phenanthridines / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D014115:Toxemia / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
D016207:Cytokines; D004731:Endotoxins; D006728:Hormones; D008070:Lipopolysaccharides; D010617:Phenanthridines; D010972:Platelet Activating Factor; D014227:Triazines; C071318:Ro 24-4736