lexipafant and Sepsis

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.

Topics: Bacterial Infections; Cytokines; Double-Blind Method; Humans; Imidazoles; Lactates; Leucine; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Sepsis

To evaluate the safety and efficacy of the platelet-activating factor receptor antagonist BB-882 in the treatment of patients with sepsis.. Double-blind, placebo-controlled, randomized, multi-centered study.. Thirty-four European intensive care units.. One hundred fifty-two patients with clinical suspicion of infection and a mean APACHE II score between 15 and 35 in the 24 hrs before entry into the trial.. Patients received either a loading dose of 4 mg of BB-882 on the first day, followed by an intravenous infusion of 96 mg/24 hrs for up to 120 hrs, or placebo.. Hemodynamic, respiratory and oxygen transport variables, blood lactate concentrations, interleukin-6, interleukin-8, tumor necrosis factor (TNF)-alpha, soluble TNF receptor concentrations, organ failure score, 28-day mortality rate, Acute Physiology And Chronic Health Evaluation (APACHE) II score within 24 hrs of entry.. Sixty-nine patients (42 male, 27 female) received placebo and 83 (59 male, 24 female) received BB-882. Patients ranged in age from 16 to 89 yrs (mean, 60 yrs). No important differences existed between the two groups in terms of gender distribution, age, or initial APACHE II score. Sepsis was identified as Gram-positive in 49 patients, Gram-negative in 40, mixed in 37, and unknown in 26. No important differences were shown in hemodynamic, respiratory, or oxygen transport variables between groups during the study. Organ failure scores were similar in the two groups throughout the study. Cytokine concentrations were not significantly different in the two groups. Within 28 days of entering the study, 75 patients died, including 31 (45%) in the placebo group and 44 (53%) in the treatment group, p = .32. The median time to death in the placebo group was 6.0 days, and in the treatment group, it was 4.5 days (p = .30).. Treatment of sepsis with the platelet-activating factor antagonist BB-882 offers no advantage over placebo on survival, hemodynamic status, respiratory function, or organ failure scores.

Topics: Adult; Aged; Aged, 80 and over; APACHE; Cytokines; Double-Blind Method; Europe; Female; Hemodynamics; Humans; Immunotherapy; Infusions, Intravenous; Lactic Acid; Leucine; Male; Middle Aged; Multiple Organ Failure; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Respiratory Function Tests; Sepsis; Survival Analysis

To study the effects of platelet activating factor (PAF) antagonism on cardiovascular function in Escherichia coli endotoxaemia in non-hypotensive anaesthetised pigs.. Experimental study.. Trauma research unit, Sweden.. 24 Domestic juvenile pigs.. 18 Pigs received a continuous infusion of E coli endotoxin in a dose of 36 micrograms/kg/hour for 5 hours. They were allocated to two groups of 9 each. The first group (BB-882 group) received a continuous infusion of BB-882 (a novel potent PAF antagonist) 33 mg/kg/hour 30 minutes before the endotoxin while the second group (placebo group) received vehicle alone. Another 6 pigs (control group) received only BB-882.. Blood temperature, rigors, heart rate, intravascular pressure, cardiac and stroke volume indices and systemic vascular resistance.. Animals in the BB-882 group had significantly fewer rigors (p < 0.001) and episodes of tachycardia (p < 0.001) than the placebo group. BB-882 significantly reduced the endotoxin-induced systemic hypertension (p < 0.001) and the rise in systemic vascular resistance (p < 0.001). BB-882 group had significantly higher central venous pressure (p < 0.05), pulmonary capillary wedge pressure (p < 0.001), cardiac index (p < 0.02), and stroke volume index (p < 0.001).. Pretreatment with a potent PAF receptor antagonist improved the cardiovascular function during non-hypotensive E coli endotoxaemia in pigs.

Topics: Animals; Blood Pressure; Cardiac Output; Endotoxemia; Escherichia coli Infections; Heart Rate; Hemodynamics; Leucine; Platelet Activating Factor; Sepsis; Stroke Volume; Swine