Effect of YM934, a novel potassium-channel opener, in various experimental asthma models in guinea-pigs.
YM934 is a novel synthetic potassium-channel opener. We have investigated its anti-asthma effect after intravenous (i.v.) and oral (p.o.) administration in various experimental asthma models in the guinea-pig, and compared the results with those for lemakalim, theophylline and salbutamol. In an ovalbumin-active sensitization anaphylaxis asthma model, YM934, lemakalim, theophylline and salbutamol dose-dependently prolonged the time before the occurrence of asthma attacks and reduced the mortality rate. The respective ED50 values (dose required to prolong by 50% the time before the occurrence of attacks) of the anti-asthma effects of YM934, lemakalim, theophylline and salbutamol were 6, 340, 30000, and 45 micrograms kg-1 (i.v.); the efficacy ratios were YM934 (1) > salbutamol (1/9) > lemakalim (1/57) > > theophylline (1/5000). YM934 also prolonged the period before the occurrence of attacks in the anti-BSA (bovine serum albumin) serum-passive sensitization anaphylaxis, histamine-induced and methacho-line-induced asthma models, with respective ED50 values for these models of 15, 22 and 20 micrograms kg-1 (i.v.). Among these models a reduction in mortality rate was seen in the histamine- and methacholine-induced asthma models. After oral administration, YM934 showed an anti-asthma effect in the ovalbumin-active sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values of 38, 44 and 193 micrograms kg-1. YM934 was 5-6 times more potent than salbutamol. These results indicate that YM934 has potent anti-asthma activity, and that this activity is mainly attributable to bronchodilation, most likely mediated through its potassium-channel opening activity.
Ishikawa
J
J
Infectious Disease & Immunology Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Saitoh
C
C
Masaki
K
K
Asano
M
M
D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D010078:Oxazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects*
D018927:Anti-Asthmatic Agents; D048588:Benzoxazines; D003497:Cyclic N-Oxides; D010078:Oxazines; D015221:Potassium Channels; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide