Agents and Actions

The studies were undertaken to investigate the influence of compound 48/80 on histamine (Hi) and collagen levels of chick embryos after administration of lathyrogen factor, β-aminopropionitrile (BAPN). Hi and soluble collagen levels in bones (tibia and femur) and skin were significantly higher in the embryos treated with BAPN. Compound 48/80 administered together with BAPN lowered Hi and soluble collagen in the bones and skin as compared with the embryos treated with BAPN alone. Both, in the skin and bones, 48/80 was found to be a protective factor against the changes in biosynthesis of collagen.

The extent of the small intestinal injury following experimental acetic acid induction of colitis in rats was examined. Following intraluminal colonic administration of radiolabelled acetic acid, high levels of radioactivity were identified in the colon and in the liver, while low background levels were found in jejunum, ileum, caecum, and heart. The increased level of radioactivity in the liver relative to that of the heart suggests that a significant portion of the colonic intraluminal acetic acid was absorbed directly into the portal circulation. The colon, which was the only segment of intestine in direct contact with the acetic acid, had the highest levels of radiolabelled acetic acid, demonstrated a marked macroscopic mucosal ulceration, an enhanced myeloperoxidase activity, and a fall inin vivo fluid absorption. The jejunum, which demonstrated low levels of radiolabelled acetic acid was normal without evidence of injury. In contrast, the ileum, which displayed the same levels of radiolabelled acetic acid as did the jejunum, also demonstrated a significant fall inin vivo fluid absorption but showed no mucosal ulceration or increased myeloperoxidase activity. These studies have shown that acetic acid induction of colitis produces evidence of ileal injury but that this injury is not the result of inadvertent delivery of acetic acid or recruitment of neutrophils to the ileal mucosa.

It was found that ergotropic arousal inducing drugs, such as psilocybin, a Ditran®-type ‘glycolate’ andd-amphet-amine, significantly lower human spatial distortion thresholds, i.e. these drugs, interfere with counter-adaptation to optical distortion, or the expectation to see the world undistorted. The trophotropic arousal inducing chlorpromazine® on the other hand promotes such counter-adaptation, i.e. the optimization of visual information. Optimization is independent from the rat at which the distorting stimulus is presented. Optimization is regarded here as a cortical (perceptual-behavioral) interpretive process while interference with and promotion of the optimization are subcortical influences.

We have studied the antiangiogenetic effects of hydrocortisone and protamine given intra-arterially. The cornea of male, Sprague-Dawley rats were cauterized with silver nitrate. The following treatments were given :30 μg hydrocortisone topical (t.p.), b.i.d., 50 mg/kg/day intraperitoneally (i.p.) or intra-arterially (i.a.), 10 mg/ kg/day protamine i.p. or i.a. Saline was administered to the control groups. In separate experiments we also evaluated the anti-inflammatory effects of hydrocortisone, i.p., on the cauterized corneas. Five days after cauterization, the animals were killed, exsanguinated and India ink was injected to show the network of neovessels. The percentage area of the cornea covered by neovessels was measured morphometrically and evaluated statistically. Hydrocortisone t.p. (−84%), i.a. (−60%) and protamine i.a. (−44%) significantly inhibited angiogenesis in the cauterized cornea. Either drugs, i.p., had any antiangiogenetic effects, but hydrocortisone significantly reduced cell infiltration of the corneas. The results suggest that locoregional administration of antiangiogenetic drugs might be clinically useful.

Mice selected for a strong (AIRmax) or weak (AIRmin) acute inflammatory response present different susceptibilities to bacterial infections, autoimmune diseases and carcinogenesis. Variations in these phenotypes have been also detected in AIRmax and AIRmin mice rendered homozygous for Slc11a1 resistant (R) and susceptible (S) alleles. Our aim was to investigate if the phenotypic differences observed in these mice was related to the complement system. AIRmax and AIRmin mice and AIRmax and AIRmin groups homozygous for the resistance (R) or susceptibility (S) alleles of the solute carrier family 11a1 member (Slc11a1) gene, formerly designated Nramp-1. While no difference in complement activity was detected in sera from AIRmax and AIRmin strains, all sera from AIRmax Slc11a1 resistant mice (AIRmaxRR) presented no complement-dependent hemolytic activity. Furthermore, C5 was not found in their sera by immunodiffusion and, polymerase chain reaction and DNA sequencing of its gene demonstrated that AIRmaxRR mice are homozygous for the C5 deficient (D) mutation previously described in A/J. Therefore, the C5D allele was fixed in homozygosis in AIRmaxRR line. The AIRmaxRR line is a new experimental mouse model in which a strong inflammatory response can be triggered in vivo in the absence of C5.

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)-α 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-α 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.