title: Application of lipid microspheres to prepare a thromboxane A2 receptor antagonist aerosol for inhalation.
abstract: The methyl ester of a new thromboxane A2 receptor antagonist, (+)S-145, i.e. (1R,2S,3S,4S)-(5Z)-7-(3-phenyl-sulfonyl-aminobicyclo[2,2,1]he pt-2-yl)heptenoic acid, was incorporated into lipid microspheres (lipo S-145-Me) and its pharmacological effect and tissue distribution were examined in guinea pigs following aerosol delivery. Bronchoconstrictive responses induced by intravenous injection of U46619 or the inhalation of ovalbumin were suppressed in a dose-dependent manner by aerosol inhalation of lipo S-145-Me, which was 3-10 times more potent that the unencapsulated calcium dihydrate of the original drug (S-1452). There was no significant difference in the airway tissue distribution of labelled lipo S-145-Me versus S-1452 after 2 or 5 min of inhalation, but the encapsulated drug showed marked accumulation in the lungs after 30 min of inhalation. The in vitro uptake of lipo [14C] S-145-Me by fresh human neutrophils and an eosinophil cell line was respectively 7 times and 3.5 times higher than that of [14C] S-1452. These results suggest that lipo S-145-Me has the potential to be used as an inhalational antiasthma agent, and that its effect may be partly attributable to a for inflammatory cells which are responsible for allergic airway inflammation.
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takenaga
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: R
authors.initials: R
authors.lastname: Igarashi
authors.forename: Y
authors.initials: Y
authors.lastname: Mizushima
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects; D000485:Allergens / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008055:Lipids / Q000737:chemistry; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000336:Aerosols; D000485:Allergens; D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D007202:Indicators and Reagents; D008055:Lipids; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C056566:S 145; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid