Tibenelast, 5,6-diethoxybenzo(B)thiophene-2-carboxylic acid, sodium salt (LY186655), is an orally active anti-asthma compound in the guinea pig.
Anaphylactic shock was induced in actively sensitized guinea pigs by free inhalation of a high dose of ovalbumin (10 mg/ml) aerosol. Tibenelast (LY186655), 5,6-diethoxybenzo(b)-thiophene-2-carboxylic acid, sodium salt, proved to be a potent orally active compound against anaphylactic shock induced by high dose antigen aerosol. When a lower aerosol challenge (0.05 mg/ml) was employed, bronchoconstriction was observed with a concomitant increase in lung resistance (RL) and a fall in dynamic compliance (Cdyn). Tibenelast at 25 mg/kg p.o. prevented these changes. Tibenelast was 10 times more potent than aminophylline by i.v. administration; normalization of pulmonary function was achieved at 1 mg/kg i.v. Tibenelast was synergistic with epinephrine. Combination of no-effect doses of epinephrine (0.025 mg/kg s.c.) and tibenelast (0.1 mg/kg i.v.) normalized pulmonary function. The oral dose response curve of tibenelast was enhanced with the co-administration of epinephrine. These data suggest that tibenelast may act at a site different from that of epinephrine, although the mechanism of action of tibenelast is unclear at present. Tibenelast may be of significant value in the treatment of asthma and other respiratory diseases.
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Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Bertsch
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B
Esterman
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Panetta
J A
JA
D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects; D000628:Aminophylline / Q000494:pharmacology / Q000627:therapeutic use; D000707:Anaphylaxis / Q000517:prevention & control*; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004837:Epinephrine / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D001993:Bronchodilator Agents; D013876:Thiophenes; D000628:Aminophylline; C063779:tibenelast; D004837:Epinephrine