In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma.
To test the hypothesis that leukotriene (LT) B4 antagonists may be clinically useful in the treatment of asthma, CP-105,696 was evaluated in vitro, using chemotaxis and flow cytometry assays, and in vivo, using a primate asthma model. CP-105,696 inhibited LTB4-mediated monkey neutrophil chemotaxis (isolated cells, LTB4 = 5 nM) and CD11b upregulation (whole blood, LTB4 = 100 nM) with IC50 values of 20 nM and 16.5 microM, respectively. Using a modification of a previously described in vivo protocol (Turner et al. Am. J. Respir. Crit. Care Med. 1994. 149: 1153-1159), we observed that treatment with CP-105,696 inhibited the acute increase in bronchoalveolar lavage (BAL) levels of IL-6 and IL-8 by 56.9 +/- 13.2% and 46.9 +/- 14.5%, respectively, 4 h after challenge with Ascaris suum antigen (Ag). CP-105,696 tended to reduce the increase in BAL protein levels 0.5 h after Ag challenge by 47.5 +/- 18.3%, but this was not statistically significant. In addition, CP-105,696 prevented the significant 11-fold increase in airway responsiveness to methacholine after multiple Ag challenge. These results suggest that LTB4 partially mediates acute and chronic responses to antigen in an experimental primate asthma model and support the clinical evaluation of LTB4 antagonists in human asthma.
Turner
C R
CR
Department of Immunology and Infectious Diseases, Pfizer Central Research, Groton, Connecticut 06340, USA.
Breslow
R
R
Conklyn
M J
MJ
Andresen
C J
CJ
Patterson
D K
DK
Lopez-Anaya
A
A
Owens
B
B
Lee
P
P
Watson
J W
JW
Showell
H J
HJ
D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001578:Benzopyrans / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002264:Carboxylic Acids / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D015854:Up-Regulation
D001578:Benzopyrans; D002264:Carboxylic Acids; D016177:Macrophage-1 Antigen; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C089698:CP 105696