Disease relevance of CI 959

• We conclude that CI-959-associated cardiac hypertrophy in rats was not a direct drug effect but instead was probably mediated by endogenous catecholaminergic stimulation of cardiac beta 1-adrenoceptors [1].
• Reduction of canine myocardial infarct size by CI-959, an inhibitor of inflammatory cell activation [2].
• Nasal toxicity of CI-959, a novel anti-inflammatory drug, in Wistar rats and Beagle dogs [3].
• CI-959 generally did not suppress immunological responses in rats at doses lower than those which also altered body weight gain and reduced spleen and thymus weights [4].
• Suppression of polarity, locomotion and F-actin levels of Walker carcinosarcoma cells by the inhibitor CI-959 [5].

High impact information on CI 959

• In view of the emerging role of neutrophils in gastric erosive damage, the goals of this study were to assess the gastric cytoprotective effects of CI-959 and identify the mechanism responsible for this action [6].
• Cytoprotective effects of CI-959 in the rat gastric mucosa: modulation of leukocyte adhesion [6].
• BACKGROUND & AIMS: CI-959 is an anti-inflammatory agent that inhibits neutrophil adhesion, respiratory burst, and mast cell histamine release in vitro [6].
• At concentrations up to 100 microM, CI-959 had no effect on the respiratory burst or degranulation in response to L-alpha-1,2-dioctanoylglycerol (DiC8) or phorbol 12-myristate 13-acetate (PMA) [7].
• CI-959 inhibited spontaneous migration and chemotaxis toward N-formyl-methionyl-L-leucyl-L-phenylalanine (fMLP) with 50% inhibition (IC50) values of 3.6 and 3.1 microM, respectively [7].

Biological context of CI 959

• The ability of CI-959 to inhibit these immunologically induced contractions indicates that the release of all mediators responsible for bronchoconstriction was effectively inhibited [8].

Anatomical context of CI 959

• To assess the effects of CI-959 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity, and reticuloendothelial system clearance of sRBC [4].
• Natural killer cell cytotoxicity was unaffected by 100 mg/kg CI-959 [9].
• Decreased body weight and histopathological lesions were observed in the thymus and spleen of rats administered 100 mg/kg CI-959 [9].
• The number of T- and B-lymphocytes, proliferative response to mitogens, and macrophage activity of the reticuloendothelial system were not affected by CI-959 [4].
• Based on these ex vivo and in vivo assays, the rodent immune system does not appear to be a sensitive or toxicologically important target for CI-959 [4].

Associations of CI 959 with other chemical compounds

• The in vivo effects of CI-959 on gastric acid secretion, arachidonic acid metabolism, and intracellular sulfhydryl and leukocyte adhesion were also examined [6].
• The cell activation inhibitor CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[ b]thiophene-2- carboxamide, monosodium salt] was evaluated for its effects on human neutrophil functions [7].
• In comparison, CI-959 inhibited myeloperoxidase release in response to C5a, fMLP, SOZ, and Con A with IC50 values of 11.6, 16.1, 7.5, and < 1.0 microM, respectively, while inhibiting the response to A23187 by only 5.5% at 100 microM [7].

Gene context of CI 959

• Inhibition of IL-2 production required the presence of CI-959 in culture medium for the first 9 hr [10].
• In contrast, CI-959 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase with an IC50 of 7.5 microM, while inhibiting release of lysozyme from secondary granules by only 11.4% at 100 microM [11].
• At 100 microM, CI-959 inhibited the release of eosinophil peroxidase and macrophage N-acetyl-beta-D-glucosaminidase by only 19.5 and 25.6%, respectively [11].
• Natural Killer cell activity was significantly reduced at 50 and 75 mg/kg CI-959 [4].
• CI-959 was locally toxic to nasal cavity respiratory and olfactory epithelia in rats and respiratory epithelium in dogs [3].

Analytical, diagnostic and therapeutic context of CI 959

• Maximum plasma drug concentrations (Cmax) were significantly higher when CI-959 was given by bolus intravenous injection, suggesting that cardiac effects were dependent on high Cmax concentrations [1].
• Cardiac hypertrophy was not evident when CI-959 was given orally or by continuous intravenous infusion with ALZA osmotic pumps [1].
• CI-959 is an orally effective inhibitor of cellular activation in both in vitro and animal models [4].

References