PHARMACOLOGICAL ACTIVITY OF PF-904 IN GUINEA-PIG IN-VIVO, AND ON HUMAN BRONCHUS AND NEUTROPHILS IN-VITRO

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 exami ned in guinea-pig airways in vivo, in human isolated bronchus and huma n polymorphonuclear leukocytes. PF-904 (12.5-200 mg/kg, intraduodenal) reduced bronchoconstriction in response to histamine, arachidonic aci d, platelet-activating factor (PAF) and methacholine. PF-904 (50-200 m g/kg) prevented PAF-induced airways hyperreactivity and inhibited anti gen-induced bronchoconstriction, airway microvascular leakage and eosi nophil lung accumulation, but antigen-induced airways hyperresponsiven ess was not reduced. PF-904 (1 mu M-1 mM) produced complete inhibition of spontaneous (-logEC(50) = 3.57 +/- 0.04; n = 10) and histamine-sti mulated tone (-log EC50 = 3.66 +/- 0.07; n = 10) of human isolated bro nchus. Glibenclamide (10 mu M) or precontraction with KCl (80 mM) did not impede PF-904-induced bronchial relaxation. PF-904 inhibited cycli c AMP (-logIC(50) = 2.83 +/- 0.25; n=8) and cyclic GMP (-logIC(50) = 2 .90 +/- 0.21; n = 8) phosphodiesterase activity in human bronchus. The activity of type IV phosphodiesterase was inhibited by PF-904 (-logIC (50) = 3.43 +/- 0.11; n = 3). PF-904 also inhibited superoxide release by N-formylmethionyl-leucyl-phenylalanine stimulated human polymorpho nuclear leukocytes, but the maximal effect was approx. 50% of that pro duced by rolipram (10 mu M). This profile of activities of PF-904 sugg ests that this compound has potential therapeutic value as an anti-ast hma drug. (C) 1997 Elsevier Science B.V.