While resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets. We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB(2). Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex, and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of low-dose aspirin.

Protein-protein interfaces (PPIs) are an important class of drug targets. We report on the first large-scale validation study on docking into PPIs. DrugScore-adapted AutoDock3 and Glide showed good success rates with a moderate drop-off compared to docking to "classical targets". An analysis of the binding energetics in a PPI allows identifying those interfaces that are amenable for docking. The results are important for deciding if structure-based design approaches can be applied to a particular PPI.

No abstract

This study demonstrates for the first time that dipyrone and other pyrazolinones have a high potential to attenuate or prevent the antiplatelet effect of aspirin. This should be considered if pyrazolinone analgesics are administered to patients with cardiovascular disease requiring antiplatelet aspirin therapy.

P o l y t e c h n i c , Sunderland. SR1 3SD, U.K.The a c t i o n of phenoxyethanol upon Pseudomonas a e r u g i n o s a NCTC 6749 was s t u d i e d u s i n g c u l t u r e s growing i n v a r i o u s media and washed s u s p e n s i o n s p r e p a r e d from s t a t i o n a r y phase ( 2 h o u r s ) c a r b o n -l i m i t e d ( s u c c i n a t e ) l i q u i d c u l t u r e s .Up t o t h e minimum growth i n h i b i t o r y c o n c e n t r a t i o n (MIC) ( c i r c a 0.25% w/v) phenoxyethanol d i d n o t induce g r o s s morphological changes i n growing c u l t u e s , and l i t t l e b a c t e r i c i d a l a c t i v i t y o c c u r r e d with washed s u s p e n s i o n s below 0.8% w/v (LT 90% = 240 min.) .A 1% w/v s o l u t i o n had modest b a c t e r i c i d a l a c t i v i t y (LT 90% = 10.3 min.)and a c o n c e n t r a t i o n exponent ( 7 ) of 11.8 w a s determined. o f d r u g were adsorbed and a C-type a d s o r p t i o n i s o t h e r m o b t a i n e d w i t h o u t a n i n f l e x i o n o r s a t u r a t i o n p l a t e a u .Treatment o f t h e c e l l s with phenoxyethanol, even a t markedly b a c t e r i c i d a l c o n c e n t r a t i o n s (LT 99% < 0.5 min.) , r e s u l t e d i n l e a k a g e i n t o t h e suspending menstruum of o n l y low l e v e l s of g e n e r a l i o n i c materials as e s t i m a t e d by c o n d u c t i v i t y measurements. A small p r o p o r t i o n of t h i s w a s shown t o be i n o r g a n i c phosphate i o n s , and o n l y very low l e v e l s o f p e n t o s e -c o n t a i n i n g and p u r i n e , o r pyrimidine-containing cytoplasmic m e t a b o l i t e s c o u l d be d e t e c t e d , T h i s i n d i c a t e s t h a t phenoxyethanol d i d n o t c a u s e g r o s s damage t o t h e osmo-regulatory p r o p e r t i e s o f t h e cytoplasmic membrane. The a b i l i t y of phenoxyethanol t o uncouple o x i d a t i v e p h o s p h o r y l a t i o n was i n d i c a t e d by its a b i l i t y t o t r a n s l o c a t e p r o t o n s a c r o s s t h e cytoplasmicmembrane even a t low d r u g l e v e l s (0.1% w/v) , i o n s from c e l l s s i m i l a r l y o c c u r r e d a t t h e s e low d r u g l e v e l s . o f e x t e r n a l l y added s u b s t r a t e s by c e l l s u s p e n s i o n s w a s markedly s e n s i t i v e t o phenoxyethanol, 0.5% w/v c a u s i n g almost complete i n h i b i t i o n . i n h i b i t i o n s v a r i e d s l i g h t l y i n t h e o r d e r g l u c o s e < s u c c i n a t e < l a c t a t e < o x a l o a c e t a t e < p y r u v a t e < malate. Complete, i r r e v e r s i b l e , o x i d a t i o n of t h e t e r m i n a l r e s p i r a t o r y cytochrome c h a i n w a s induced by b a c t e r i c i d a l d r u g l e v e l s (1% W/V and above).c o n c e n t r a t i o n s induced a s i m i l a r b u t i n c r e a s i n g l y t r a n s i e n t and l e s s e x t e n s i v e o x i d a t i o n with no o b s e r v a b l e e f f e c t a t t h e MIC. These f i n d i n g s s u g g e s t d i f f e r e n c e s i n t h e mode(s) of a c t i o n o f p...