Disease relevance of Skf 86002

• Pigs were randomly assigned to one of four groups: LPS (n = 5), given .5 microgram/kg/h 055:B5 Escherichia coli lipopolysaccharide (LPS) intravenously (i.v.) for 6 h; saline (n = 5); SK&F 86002 (n = 3), given 50 mg/kg SK&F 86002 orally 30 min prior to anesthesia; and SK&F 86002 + LPS (n = 5) [1].
• Inhibition of corneal neovascularization in the rat by SK&F 86002, a dual inhibitor of arachidonic acid metabolism [2].
• Pretreatment with SK&F 86002 attenuated LPS induced hypotension, hypoxemia and bronchoconstriction and blocked the pulmonary hypertension [1].
• SK&F 86002 blocked the LPS-induced increase in myeloperoxidase activity, indicating a reduction in pulmonary neutrophil infiltration, but had no effect on systemic leukopenia [1].
• IL6 is another cytokine important in the mechanisms of bone resorption and could be a target for the actions of SK&F 86002 [3].

High impact information on Skf 86002

• A specific p38 MAPk inhibitor (SK&F 86002) blocked superoxide anion production in response to FMLP and reduced adhesion and chemotaxis in response to PAF or FMLP [4].
• These data show that in addition to the known cytokine inhibitory actions of SK&F 86002 and SB 203580, they also confer an additional potential anti-inflammatory activity through modulation of CD23 expression [5].
• However, suppression of PGHS-2 expression is not the result of suppressed cytokine production, because SK&F 86002 suppressed PGHS-2 expression initiated by IL-1beta and TNF-alpha, in addition to other stimuli [6].
• Using freshly elutriated human monocytes, we examined the effect on PGHS-2 expression of certain cytokine-suppressive anti-inflammatory drugs such as SK&F 86002 [6].
• The data suggest that L-709,049 and SK&F 86002 interfere with steps involved in IL-1 beta secretion, as opposed to synthesis [7].

Biological context of Skf 86002

• In addition, SK&F 86002 inhibited the generation of dihydroxyeicosatetraenoic acid (diHETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) by a high speed supernatant fraction of RBL-1 cells (IC50 10 microM) [8].
• Pharmacokinetics and metabolism of SK&F 86002 in male and female Sprague-Dawley rats [9].
• Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count [10].

Anatomical context of Skf 86002

• The effect of dual inhibitor, SK&F 86002, on helper T cell functions [11].
• Histological evaluation of the lesion in drug-treated animals revealed that SK&F 86002 impaired edema formation and caused a significant reduction in numbers of infiltrating neutrophils [12].
• SK&F 86002 significantly reduced thrombocytopenia at 30 min and 1 h (p less than 0.05), but not at 3 and 6 h, and had no effect on changes in white blood cell (WBC) count.(ABSTRACT TRUNCATED AT 250 WORDS)[13]
• Effects of SK&F 86002 on cytokine-stimulated IL6 production in cultured neonatal mouse calvaria and SaOS2 osteoblastic cells: the role of prostaglandins and other mechanisms of action [3].
• In vitro, SK&F 86002 inhibited LPS stimulated TNF-alpha production by the RAW 264.7 cell line and by oil elicited peritoneal macrophages with an IC50 of 5 microM [14].

Associations of Skf 86002 with other chemical compounds

• Further, evaluation of surface intact CD23 (iCD23) by flow cytometry demonstrated that SK&F 86002 and SB 203580 reduced the surface expression of iCD23 in a concentration-dependent fashion, while batimastat increased the surface expression of iCD23 [5].
• The effects of SK&F 86002 [5-(4-pyridyl)-6 (4-fluorophenyl)-2,3-dihydroimidazo (2,1-b) thiazole] on the generation of eicosanoids in vitro and on inflammatory responses in vivo are described and compared to other non-steroidal anti-inflammatory drugs [8].
• Several pharmacokinetic parameters for SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo(2,1-b)-thia zole] and its metabolites (sulfoxide, sulfone) were measured in male and female Sprague-Dawley rats after iv (5 mg/kg) and a wide range (10-80 mg/kg) of oral doses of SK&F 86002 [9].
• Therefore, these studies were designed to 1) identify the enzymes (flavin vs. cytochrome P-450-dependent monooxygenases) which were responsible for SK&F 86002 metabolism in vitro in hepatic microsomal suspensions from Sprague-Dawley rats, 2) characterize sex-dependent differences, and 3) quantitate the effect of pretreatment with SK&F 86002 [15].
• Taken together, these data illustrate the potent antiinflammatory effects of SK&F 86002 and support the suggestion that 5-lipoxygenase products play a significant role in both the edematous and cellular phases of arachidonic acid-induced inflammation [12].

Gene context of Skf 86002

• The IC50 of SK&F 86002 for the TNF production was 5-8 microM, and greater than 20 microM for the other three cytokines [16].
• Taken together these data indicate that the inhibitory effect of SK&F 86002 on IL-1 production is selective and the production of cytokines in drug treated monocytes can be differentially affected [16].
• The cytokine-suppressant anti-inflammatory drug (CSAID) SK&F 86002 inhibits bone resorption in vitro and this effect cannot be totally explained by its inhibition of IL 1 beta and TNF alpha release [3].
• Analysis of SK&F 86002 analogs also showed no clear correlation between 5LO and IL-1 synthesis inhibitory activity [17].
• Inhibition of IL-1 and TNF production was found to depend on the time of addition of SK&F 86002, with diminishing effect when added more than 2 h after LPS stimulation [18].

Analytical, diagnostic and therapeutic context of Skf 86002

• In addition, SK&F 86002 produced dose-related analgesia in mice, which was not reversed by the narcotic antagonist, naltexone [19].
• Following oral administration, SK&F 86002 and its analogs reduced serum TNF-alpha levels by > 80% and afforded 100% protection from lethality [14].

References