Lexipafant (BB-882), a platelet activating factor receptor antagonist, ameliorates mucosal inflammation in an animal model of colitis.
OBJECTIVE
To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis.


METHODS
An animal intervention study.


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). Rectal dialysis was performed before induction of colitis and sacrifice. Dialysate leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined. Tissue was saved for histology and measurement of myeloperoxidase content.


RESULTS
There was a dose-dependent improvement in macroscopic scores (2.4 and 3.2 mg/kg: P < 0.02, P < 0.001) and myeloperoxidase levels (3.2 mg/kg: P < 0.04). Dialysate LTB4 levels fell (2.4 and 3.2 mg/kg: P < 0.03, P < 0.02) as did PGE2 levels. TXB2 concentrations remained unaffected.


CONCLUSIONS
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.
Meenan
J
J
Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, The Netherlands.
Grool
T A
TA
Hommes
D W
DW
Dijkhuizen
S
S
ten Kate
F J
FJ
Wood
M
M
Whittaker
M
M
Tytgat
G N
GN
van Deventer
S J
SJ
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D015232:Dinoprostone / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005557:Formaldehyde; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000032:analysis; D008297:Male; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013929:Thromboxane B2 / Q000032:analysis
C094498:BB 882; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D005557:Formaldehyde; D007975:Leukotriene B4; D013929:Thromboxane B2; D007930:Leucine; D015232:Dinoprostone