A Double-Blind Placebo-Controlled Study of an Infusion of Lexipafant (Platelet-Activating Factor Receptor Antagonist) in Patients with Severe Sepsis

ABSTRACT Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.

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Effects of L-652,731, a platelet activating factor (PAF) receptor antagonist, in splanchnic artery occlusion (SAO) shock in rats

Pharmacological Research ◽

10.1016/1043-6618(90)90804-m ◽

1990 ◽

Vol 22 ◽

pp. 53-54

Author(s):

F SQUADRITO

Keyword(s):

Receptor Antagonist ◽

Platelet Activating Factor ◽

Artery Occlusion ◽

Splanchnic Artery ◽

Paf Receptor ◽

Paf Receptor Antagonist

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Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Clinical Science ◽

10.1042/cs1000601 ◽

2001 ◽

Vol 100 (6) ◽

pp. 601-607 ◽

Cited By ~ 1

Author(s):

Roger TAYLOR ◽

Daniel FATOVICH ◽

Thomas HITCHCOCK ◽

Catherine MORRISON ◽

Lloyd CURTIS

Keyword(s):

Myocardial Infarction ◽

Blood Pressure ◽

Acute Myocardial Infarction ◽

Receptor Antagonist ◽

Platelet Activating Factor ◽

Systolic Pressure ◽

Induced Hypotension ◽

Paf Receptor ◽

Double Blinded ◽

Paf Receptor Antagonist

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n = 35), or matching placebo (n = 36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5×106 units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43±28 mmHg (mean±S.D.) and 40±26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to < 90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3±17.5 and 40.2±13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

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Receptor mechanisms of PAF mediated lymphatic constriction in the canine forelimb

Mediators of Inflammation ◽

10.1155/s0962935192000590 ◽

1992 ◽

Vol 1 (6) ◽

pp. 391-395 ◽

Cited By ~ 3

Author(s):

D. E. Dobbins

Keyword(s):

Smooth Muscle ◽

Receptor Antagonist ◽

Lymphatic Vessel ◽

Perfusion Pressure ◽

Muscle Tone ◽

Platelet Activating Factor ◽

Arterial Infusion ◽

Paf Receptor ◽

Transport Fluid ◽

Paf Receptor Antagonist

Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 × 10−6, 7.47 × 10−5and 7.47 × 10−4M) increased lymphatic perfusion pressure at the two highest infusion rates. PAF mediated lymphatic constriction was not altered by the intra-arterial infusion of phentolamine but was blocked by the intra-arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF's effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by α-receptors but rather through PAF receptor mediated mechanism.

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