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Objective: This study was designed to evaluate therapeutic effects of bindarit, an indazolic derivative able to inhibit monocyte chemoattractant protein-1 (MCP-1) production, in adjuvant induced arthritis in rats., Materials and Methods: Arthritis was induced by Freund's complete adjuvant injection. Bindarit was given as a 0.5% medicated diet starting on day 11 after adjuvant injection. The course of arthritis was monitored by sequential paw volume measurement and by radiologic and histologic evaluations. Human osteoblast cell line Saos-2 stimulated with Interleukin-1 (IL-1) was used to assess in vitro bindarit effect on MCP-1 release. In addition, in vivo effects of bindarit on cytokine production were studied in mice injected with lipopolysaccharide (LPS). Immune function studies were performed in mice by evaluating ex vivo antibody response to ovalbumin and splenocytes proliferation to Concanavalin A (Con A)., Results: In adjuvant-induced arthritis in rats, bindarit possessed therapeutic activity resulting in a significant inhibition of paw inflammation. Evidence for a disease-modifying activity was also indicated by amelioration of radiologic alterations and by histological evaluation of joints. Additional evidence for beneficial effects in osseous inflammation was provided by an in vitro assay in which bindarit inhibited the release of MCP-1 from IL-1 stimulated osteoblast cells. Moreover, in a murine model of LPS-induced cytokine production bindarit reduced MCP-1 and tumor necrosis factor (TNF)-alpha increase without affecting IL-1 and IL-6 levels. Finally, the drug, given as a 0.5% medicated diet for 14 days, did not affect either anti-ovalbumin serum antibody production or splenocytes proliferative response in mice., Conclusions: Results obtained indicate that bindarit beneficial effects in experimental arthritis are correlated to MCP-1 and TNF-alpha inhibition and suggest that the control of cytokines and chemokines production can have considerable relevance as regards strategies for the treatment of chronic inflammatory diseases.

The production and action of primary proinflammatory cytokines are strictly controlled by a series of circuits to avoid damage that they can cause if produced in excess. Interleukin-10 and interleukin-1 receptor antagonist contribute to the control of the magnitude of the inflammatory responses in vivo. Benzydamine, a non-steroidal anti-inflammatory drug that has been shown to have suppressive activity for the proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, was investigated for its effects on interleukin-10 and interleukin-1ra production. The drug did not modify the production of interleukin-10 and interleukin-1ra by peripheral blood mononuclear cells stimulated with lipopolysaccharide, under conditions where tumor necrosis factor-alpha and interleukin-1beta were decreased. The antiinflammatory capacity of benzydamine might thus result from its ability to reduce the production of proinflammatory cytokines, without affecting antiinflammatory factors.

Suramin, a symmetrical polysulfonated urea derivative, promotes the dissociation of trimeric human tumor necrosis factor-alpha (TNF-alpha) into biologically inactive subunits and prevents the interaction of TNF-alpha with its cellular receptors. The aim of this work was to identify compounds structurally related to suramin which inhibit the binding of TNF-alpha to its receptor. Molecular modeling studies were performed on suramin and TNF-alpha molecules and likely interaction sites were identified in the docked complex. On this basis, Evans blue, trypan blue, sulfonazo III, beryllon II, and 1,3,6-naphthalenetrisulfonic acid trisodium salt were identified as polysulfonated compounds endowed, to various extents, with the structural characteristics responsible for interaction with TNF-alpha. N,N-bis(3,5-di-tert-butylphenyl)-3,4,9,10-perylenedicarboximide was used as an unrelated structure. The capacity of these molecules to inhibit the binding of TNF-alpha with its receptor p55 was tested in vitro by means of a specific immunoenzymatic assay using suramin as reference compound. Evans blue and trypan blue inhibited TNF-alpha/p55 binding with an IC50 of 0.75 and 1.00 mM, respectively (suramin IC50: 0.65 mM); no effect was observed with the other molecules. Molecular modeling analyses on Evans blue and trypan blue docked into the TNF-alpha molecule support these experimental results by demonstrating that these compounds share with suramin a similar binding mode to TNF-alpha. The results of this work provide a new insight into and useful hints for the design of new chemical entities endowed with a potent and selective activity on TNF-alpha.

Melatonin is an antioxidant. Since other antioxidants inhibit the production of tumor necrosis factor (TNF) induced by lipopolysaccharide, we investigated its effect on TNF production in vivo and in vitro and on lethality associated with endotoxic shock. Administration of melatonin to mice (5 mg/kg, s.c., 30 min before or simultaneously with lipopolysaccharide) inhibited serum TNF levels by 50-80% and improved survival of mice treated with a lethal dose of lipopolysaccharide. By studying other, structurally related, indolamines (N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine and 5-hydroxytryptamine) we found a good correlation between antioxidant activity (for which the 5-methoxy group is essential) and the inhibition of TNF production in vivo and in vitro in mononuclear cells. Melatonin did not increase serum corticosterone and did not modify the elevation of serum corticosterone levels by lipopolysaccharide or by interleukin-1. Furthermore, it exerted its inhibitory effect in adrenalectomized or hypophysectomized mice also, indicating that its effect is independent of the hypothalamus-pituitary-adrenal axis.

Benzydamine is a non-steroidal antiinflammatory drug, devoid of activity on arachidonic acid metabolism, which is extensively used as a topical drug in inflammatory conditions, particularly for the treatment of bacterial vaginosis and Candida albicans-sustained vaginitis. In the present study the effects of benzydamine on the production of several inflammatory cytokines were examined in cultures of Candida albicans-stimulated human mononuclear cells. Benzydamine (6.25-50 microM) inhibited Candida-induced tumor necrosis factor-alpha and, to a lesser extent, interleukin-1 beta production, whereas it did not affect interleukin-6 release. Benzydamine also blocked monocyte chemotactic protein-1 secretion, but it did not affect interleukin-8 production. Unlike benzydamine, ibuprofen and naproxen, two non-steroidal antiinflammatory drugs also used topically, were unable to suppress inflammatory lymphokine production from Candida-activated mononuclear cells. These data suggest that benzydamine may be effective in local Candida infections at least in part by suppressing inflammatory cytokine and monokine production in the vaginal mucosa and consequently decreasing their levels in vaginal secretions.