title: Pharmacological activity of PF-904 in guinea pig in vivo, and on human bronchus and neutrophils in vitro.
abstract: The effects of PF-904 (4-amino-1-ethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide), a pyrazinothiadiazine derivative, were examined in guinea-pig airways in vivo, in human isolated bronchus and human polymorphonuclear leukocytes. PF-904 (12.5-200 mg/kg, intraduodenal) reduced bronchoconstriction in response to histamine, arachidonic acid, platelet-activating factor (PAF) and methacholine. PF-904 (50-200 mg/kg) prevented PAF-induced airways hyperreactivity and inhibited antigen-induced bronchoconstriction, airway microvascular leakage and eosinophil lung accumulation, but antigen-induced airways hyperresponsiveness was not reduced. PF-904 (1 microM-1 mM) produced complete inhibition of spontaneous (-logEC50 = 3.57+/-0.04; n = 10) and histamine-stimulated tone (-logEC50 = 3.66+/-0.07; n = 10) of human isolated bronchus. Glibenclamide (10 microM) or precontraction with KCl (80 mM) did not impede PF-904-induced bronchial relaxation. PF-904 inhibited cyclic AMP (-logIC50 = 2.83+/-0.25; n = 8) and cyclic GMP (-logIC50 = 2.90+/-0.21; n = 8) phosphodiesterase activity in human bronchus. The activity of type IV phosphodiesterase was inhibited by PF-904 (-logIC50 = 3.43+/-0.11; n= 3). PF-904 also inhibited superoxide release by N-formylmethionyl-leucyl-phenylalanine-stimulated human polymorphonuclear leukocytes, but the maximal effect was approx. 50% of that produced by rolipram (10 microM). This profile of activities of PF-904 suggests that this compound has potential therapeutic value as an anti-asthma drug.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortijo
authors.forename: M
authors.initials: M
authors.lastname: Martí-Cabrera
authors.forename: L
authors.initials: L
authors.lastname: Berto
authors.forename: F
authors.initials: F
authors.lastname: Antón
authors.forename: E
authors.initials: E
authors.lastname: Carrasco
authors.forename: M
authors.initials: M
authors.lastname: Grau
authors.forename: E J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000503:physiopathology / Q000517:prevention & control; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013829:Thiadiazines / Q000494:pharmacology*
chemical_list: D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; C108915:PF 904; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D011719:Pyrazines; D013829:Thiadiazines; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine