A comparison of the anti-inflammatory activity of selective 5-lipoxygenase inhibitors with dexamethasone and colchicine in a model of zymosan induced inflammation in the rat knee joint and peritoneal cavity.
Intraperitoneal and intra-articular (knee joint) injection of zymosan in the rat caused two phases of increased vascular permeability, a rapid increase (0.25-0.5 h) and a secondary increase (2-3 h) which was temporally associated with the onset of leukocyte infiltration. Intraperitoneal injection of zymosan led to a single peak of eicosanoid production (LTB4, C4, D4, E4 and 6-oxo-PGF1 alpha) which was maximal at 0.125-0.25 h. Intra-articular injection led to an initial peak of LTB4 production (maximal at 0.25 h) and a secondary peak of LTB4 and PGE2 production (maximal at 3 h). Oral administration of the 5-lipoxygenase (5-LO) inhibitors phenidone, BW A4C (N-hydroxy-N-[3-(3-phenoxyphenyl)-2-propenyl] acetamide), A63162 (N-hydroxy-N-[1-(4-(phenylmethoxy) phenyl)ethyl] acetamide and ICI 207 968 (2-[3-pyridylmethyl]-indazolinone inhibited LTB4 production in A23187 stimulation blood ex vivo. The glucocorticosteroid dexamethasone had no effect in this model. The initial phase of increased vascular permeability in the peritoneal cavity and LTB4 production was dose dependently inhibited by the 5-LO inhibitors phenidone, BW A4C, A63162, and ICI 207 968 but not by dexamethasone or colchicine. The initial phase of increased permeability in the joint was unaffected by phenidone, BW A4C, dexamethasone or colchicine. However the latter two drugs inhibited the later phase of increased permeability and leukocyte infiltration in the joint and peritoneal cavity. These results demonstrate that zymosan induces eicosanoid production in vivo but the relative importance of these mediators varies depending on the inflammatory site.(ABSTRACT TRUNCATED AT 250 WORDS)
Griffiths
R J
RJ
Department of Pharmacology, Fisons plc, Research and Development Laboratories, Loughborough.
Li
S W
SW
Wood
B E
BE
Blackham
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D044482:Benzeneacetamides; D000001:Calcimycin / Q000494:pharmacology; D003078:Colchicine / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007700:Kinetics; D007719:Knee Joint; D007962:Leukocytes / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008297:Male; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D015054:Zymosan
D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D007975:Leukotriene B4; D000001:Calcimycin; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D015054:Zymosan; C015429:phenidone; D015232:Dinoprostone; D003078:Colchicine