The effects of a novel sulphidopeptide leukotriene antagonist, BAY x7195, against elicited bronchoconstriction in the anaesthetized guinea-pig.
1. The novel leukotriene antagonist Bay x7195, has been evaluated against bronchoconstriction induced by leukotriene D4 (LTD4), the thromboxane A2 (TXA2) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modified Konzett-Rössler preparation. 2. LTD4, given intravenously (i.v.) at 1 or 3 microg kg(-1) in the presence of indomethacin and sotalol, caused a 50-70% maximal bronchoconstriction in most animals. 3. BAY x7195, given i.v., orally (p.o.), by aerosol or dry powder insufflation, in lactose, reduced LTD4-induced bronchoconstriction dose-dependently. The approximate ID50 values were 83 microg kg(-1), 3 mg kg(-1), 0.0003% w/v for 20 breaths and 20 microg respectively. 4. The action of BAY x7195 (10 mg kg(-1), p.o.) was long lasting, causing significant inhibition of the LTD4-induced response (88% reduction) 8 h after dosing. 5. When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID50 of 2 mg kg(-1). 6. At 3 mg kg(-1), i.v., a dose which abolished the response to LTD4, BAY x7195 had no effect on U46619- or histamine-induced bronchoconstriction. 7. BAY x7195 is a potent, selective and long acting antagonist of LTD4-induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma.
Francis
H P
HP
Research Department, Stoke Poges, Slough.
Patel
U P
UP
Thompson
A M
AM
Carpenter
T G
TG
Gardiner
P J
PJ
Abram
T S
TS
D000284:Administration, Oral; D000336:Aerosols; D000768:Anesthesia, General; D000818:Animals; D000941:Antigens / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006880:Hydroxy Acids / Q000494:pharmacology*; D007275:Injections, Intravenous; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000008:administration & dosage / Q000494:pharmacology; D008176:Lung Volume Measurements; D008297:Male; D011208:Powders; D013928:Thromboxane A2 / Q000008:administration & dosage / Q000494:pharmacology
D000336:Aerosols; D000941:Antigens; D001993:Bronchodilator Agents; D006880:Hydroxy Acids; D020024:Leukotriene Antagonists; D011208:Powders; D013928:Thromboxane A2; D017998:Leukotriene D4; C092294:BAY x 7195