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 −1, intraduodenal) reduced bronchoconstriction in response to histamine, arachidonic acid, platelet-activating factor (PAF) and methacholine. PF-904 (50–200 mg kg −1) 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 μM–1 mM) produced complete inhibition of spontaneous (−log EC 50=3.57±0.04; n=10) and histamine-stimulated tone (−log EC 50=3.66±0.07; n=10) of human isolated bronchus. Glibenclamide (10 μM) or precontraction with KCl (80 mM) did not impede PF-904-induced bronchial relaxation. PF-904 inhibited cyclic AMP (−log IC 50=2.83±0.25; n=8) and cyclic GMP (−log IC 50=2.90±0.21; n=8) phosphodiesterase activity in human bronchus. The activity of type IV phosphodiesterase was inhibited by PF-904 (−log IC 50=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 ~50% of that produced by rolipram (10 μM). This profile of activities of PF-904 suggests that this compound has potential therapeutic value as an anti-asthma drug.