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.Despite significant advances in antimicrobial treatment and intensive care support, sepsis remains a difficult medical management problem with mortality rates between 30 and 50% (5, 11). Proinflammatory cytokines and platelet-activating factor (PAF) are generated in large amounts during the septic response (1). PAF, an ether-linked phospholipid, is one of the most hypotensive and inflammatory agents yet discovered (1, 2, 3, 7). The effects of PAF are mediated through specific PAF receptors. PAF is produced by a broad range of cell types, including monocytes, macrophages, eosinophils, and platelets as well as vascular, kidney glomerular, and gastrointestinal endothelial cells. A wide variety of mediators stimulate these cells to produce PAF; many of these mediators are secreted during the cytokine cascade associated with septic shock. These include tumor necrosis factor (TNF), thrombin, leukotrienes, and bradykinin. PAF has several biological actions characteristic of a proinflammatory agent. When administered systemically to animals, it produces many of the features of septic shock. In experimental septic shock, blocking either the proinflammatory cytokines TNF and interleukin 1 (IL-1) or lipid mediators such as PAF decreases the severity of the disease (12, 13). In one study, the PAF antagonist BN 52021 was shown to be a safe and promising treatment of patients with severe gram-negative sepsis (6).Lexipafant (BB-882; British Biotechnology Ltd., Watlington, Oxford, United Kingdom) is another newly developed PAF antagonist. Lexipafant was shown to be a potent antagonist of PAF in in vitro studies involving the inhibition of [ 3 H]PAF receptor binding and in a PAF receptor binding assay conducted on human platelet membranes. In the latter system, lexipafant bound to the receptor seven times more avidly than native PAF (unpublished data). We report here results of a randomized placebo-controlled study to evaluate the clinical safety and efficacy of lexipafant as an adjunct to the treatment of severe sepsis. Lexipafant has been shown to be well tolerated when given intravenously to volunteers, to patients with pancreatitis, and to patients with sepsis (unpublished data). MATERIALS AND METHODSStudy design and patient ...

Signaling via Platelet-Activating Factor Receptors Accounts for the Impairment of Neutrophil Migration in Polymicrobial Sepsis

“…This tenet is further reinforced by the studies showing that serum levels of PAF acetylhydrolase, which inactivates PAF, are decreased in severe sepsis (61,62) and that PAFR antagonists improve resistance against the lethal effects of experimental endotoxemia (16 -20). However, clinical trials with recombinant human PAF acetylhydrolase or PAFR antagonists have not been shown to reduce the mortality of patients with severe sepsis (21)(22)(23). Similarly, we observed that the protective effect of PAFR antagonist reduced when it was used as posttreatment protocol (Fig.…”

“…Moreover, the overexpression of the PAFR increases lethality in response to LPS administration in mice (14), and the administration of PAFR antagonists to animals and humans protect them from the deleterious effects of LPS (15)(16)(17)(18)(19)(20). However, clinical trials using recombinant human PAF acetylhydrolase or PAFR antagonists failed to reduce the mortality of severe septic patients, although a substantial reduction in organ dysfunction was achieved (21)(22)(23).…”

Melioidosis: Epidemiology, Pathophysiology, and Management

“…In a randomized placebo-controlled trial in Thailand involving 131 patients, no significant difference in mortality was observed in patients with severe sepsis, including 36 patients with melioidosis (418). Although exogenous administration of G-CSF has not been associated with improved outcomes in patients with pneumonia and/or severe sepsis in large clinical trials (310,311,361), melioidosis may differ from infections due to other organisms because of the key role of neutrophils in patients with recognized risk factors for neutrophil defects.…”

Regulating inflammation through the anti-inflammatory enzyme platelet-activating factor-acetylhydrolase

“…In subsequent studies, increased PAF bioactivity was also reported in plasma samples from patients with bacteremia compared with blood from control subjects (Heuer 1991). Despite encouraging results with PAF receptor antagonists in animal models of endotoxemia and sepsis (Chang et al 1987, Rabinovici et al 1990), most of the clinical trials conducted with these drugs have not confirmed the benefits of these drugs in humans (Dhainaut et al 1998, Suputtamongkol et al 2000. Importantly, Graham et al (1994) reported decreased PAF-AH plasma activity in blood samples from septic patients and that the half-life of PAF was prolonged in the plasma of septic patients who died compared to survivors or normal volunteers.…”