Disease relevance of BB 882

• PATIENTS: A total of 290 patients with predicted severe acute pancreatitis previously studied in a trial of lexipafant, recruited from 78 hospitals through 18 centres in the UK [1].
• Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023) [2].
• To examine the effects of BB-882, a novel potent PAF receptor antagonist, on general hemodynamics and regional flow distribution in a canine endotoxic shock model, 14 anesthetized and ventilated dogs received 2 mg/kg of Escherichia coli endotoxin intravenously (i.v.) followed by generous fluid resuscitation [3].
• 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 [4].
• CONCLUSION: The PAF receptor antagonist BB-882 shows efficacy in treating inflammation in an animal model of acute colitis as evidenced by a dose-dependent fall in macroscopic mucosal damage, neutrophil infiltration and reduced generation of inflammatory mediators [5].

Psychiatry related information on BB 882

• The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance [6].

High impact information on BB 882

• Hope or hype for lexipafant [7]?
• METHODS: Data from the international phase III trial of the platelet-activating factor receptor-antagonist Lexipafant were used to develop a 4-variable prognostic model [8].
• Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups [2].
• Treatment with lexipafant 30 min and 6h after pancreatitis reduced severity of pancreatitis-associated intestinal dysfunction, associated with a diminish in systemic concentrations of IL-1 and local leukocyte recruitment [9].
• CONCLUSION: Treatment with lexipafant and monoclonal antibodies against ICAM-1 or PECAM-1 reduced the severity of pancreatitis-associated gut endothelial dysfunction, and decreased systemic concentrations of IL-1 and local leucocyte recruitment [10].

Chemical compound and disease context of BB 882

• The aim of the present study was to investigate the potential effect of treatment with a platelet-activating factor (PAF) antagonist, lexipafant (BB-882), on gut endothelial and epithelial barrier dysfunction and leukocyte recruitment in rats with acute pancreatitis [9].
• Published clinical trials of lexipafant (BB-882) in acute pancreatitis were retrieved by MEDLINE, EM Base, and Science Citation Index [11].

Biological context of BB 882

• The administration of BB-882 resulted in a dose-dependent reduction in cardiac output and an increase in systemic and pulmonary vascular resistance [3].
• 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 [4].
• Effect of platelet-activating factor antagonists (BN-52021, WEB-2170, and BB-882) on bacterial translocation in acute pancreatitis [12].
• This study investigates the effects of a platelet activating factor antagonist, lexipafant, on peritoneal adhesion formation and wound healing [13].
• Histology scores did not differ between Lexipafant-treated and control rats in either GDOC or enterokinase rats [14].

Anatomical context of BB 882

• One hundred fifty patients undergoing coronary artery bypass grafting were randomized by minimization into three groups to receive placebo infusion, 10 or 100 mg of lexipafant for over 24 hours [15].
• Neither PAF nor Lexipafant influenced the mRNA levels and the secretion of apoA-I, apoB and apoE in HepG2 cells, indicating that the effects of PAF or Lexipafant on the apoM production on hepatic cells are selective for apoM [16].
• Only lexipafant inhibited the increase in vascular permeability in the thymus (36%) [17].
• METHODS: Myeloperoxidase (MPO) content in the small intestinal mucosa, serum levels of interleukin-1beta and -6, and plasma protease inhibitors, and intestinal endothelial and epithelial permeability were assessed, with or without treatment with the PAF antagonist lexipafant [18].
• In the BDL/BB-882 group was observed less fibrosis and neutrophil infiltration CONCLUSIONS: These results suggest that BB-882 (lexipafant) may reduce the severity of the inflammatory response to liver injury produced by bile duct ligation in rats [19].

Associations of BB 882 with other chemical compounds

• METHODS: Following the rectal instillation of formalin 0.75% into male New Zealand White (NZW) rabbits, 0.85 ml of aggregated immunoglobulin was administered i.v. Treatment groups (0.8 mg/kg, n = 6; 2.4 mg/kg, n = 13; 3.2 mg/kg, n = 10) were given bolus doses of BB-882 two-hourly i.v. (control group, n = 25) [5].
• CONCLUSION: Treatment with NAC, lexipafant, and/or monoclonal antibodies against PECAM-1, inserted at a later stage of I/R, reduced the severity of I/R-associated intestinal dysfunction and decreased the systemic concentrations of IL-1 beta, local leukocyte recruitment (MPO), and partly restored plasma protease inhibitor levels [20].
• METHODS: Fifty male Sprague-Dawley rats (200-225 g) were divided into five groups each containing 10 rats; group SO: Sham operation group; group I: hepatic ischaemia group; group IR: ischaemia-reperfusion (IR); group M: IR plus pretreatment with molsidomine; group L: IR plus pretreatment with lexipafant [21].
• A number of PAF antagonists (apafant, lexipafant, BN-52021, SCH-37370, SR-27417, UR-12670) inhibited [3H]apafant binding with slopes near unity and with a rank order of potency in good agreement with their ability to inhibit PAF-induced rabbit platelet aggregation, suggesting that the sites labelled are functional PAF receptors [22].

Gene context of BB 882

• Lexipafant treatment significantly reduced serum IL-8 (P = 0.038), and IL-6 declined on day 1 [23].
• Plasma PMNE-alpha 1-AT complexes peaked on day 1; the gradual fall to baseline over 5 days observed in controls did not occur in patients given Lexipafant [23].
• Furthermore, Lexipafant, a PAF-receptor (PAF-R) antagonist significantly suppressed the mRNA level and the secretion of apoM in HepG2 cells in a dose-dependent manner [16].
• RESULTS: Pretreatment with lexipafant, a potent PAF receptor antagonist, significantly reduced the pancreatitis-induced increase in pancreatic endothelial barrier dysfunction, pancreatic leukocyte recruitment and serum levels of IL-1 beta, although a difference persisted between animals with sham operation and pancreatitis [24].
• 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 [4].

Analytical, diagnostic and therapeutic context of BB 882

• METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6 [2].
• This study provides a rationale for further clinical trials with the potent PAF antagonist Lexipafant in human acute pancreatitis [23].
• INTERVENTIONS: 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 [25].
• At entry, patients receiving Lexipafant (n = 42) or placebo (n = 41) were matched for age and sex, aetiology, APACHE II score and OFS [23].
• Pretreatment with BB-882 at the dose used only enhanced mesenteric perfusion [3].

References