Home About us Contact
|
Home About us Contact | ||
|
|
||
Antiinflammatory Effects (antiinflammatory + effects)
Selected AbstractsAntinociceptive and antiinflammatory activities of pine (Pinus densiflora) pollen extractPHYTOTHERAPY RESEARCH, Issue 5 2007Eun-Mi Choi Abstract The study aimed to evaluate the antinociceptive and antiinflammatory activity of pine (Pinus densiflora) pollen in mice. The antinociceptive activity was determined using acetic acid-induced abdominal constriction and formalin-induced licking, and the hot plate test. Antiinflammatory effects were evaluated using carrageenan- and formalin-induced paw edema, and arachidonic acid-induced ear edema in mice. The ethanol extract of pine pollen (100 and 200 mg/kg, p.o.) produced a significant inhibition of both phases of the formalin pain test in mice, a reduction in mouse writhing induced by acetic acid and an elevation of the pain threshold in the hot plate test in mice. The pine pollen extract also produced a significant inhibition of carrageenan- and formalin-induced paw edema as well as arachidonic acid-induced ear edema in mice. The inhibitions were similar to those produced by aminopyrine and indomethacin, p.o. The different polyphenols found in pine pollen could account for the antinociceptive and antiinflammatory actions. The results obtained indicate that the extract possesses analgesic and antiinflammatory effects. Copyright © 2007 John Wiley & Sons, Ltd. [source] Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritisARTHRITIS & RHEUMATISM, Issue 6 2010Stephan Blüml Objective To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA). Methods We performed bone marrow transplantations in human TNF,transgenic mice using hematopoietic cells from wild-type, TNFRI,/,, TNFRII,/,, and TNFRI/II,/, mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays. Results Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis. Conclusion Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA. [source] Bifidobacterium lactis inhibits NF-,B in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice,,INFLAMMATORY BOWEL DISEASES, Issue 9 2010Seung Won Kim MS Abstract Background: The aim of this study was to investigate the antiinflammatory effects of Bifidobacterium lactis on intestinal epithelial cells (IECs) and on experimental acute murine colitis and its tumor prevention effects on colitis-associated cancer (CAC) in mice. Methods: Human HT-29 cells were stimulated with IL-1,, lipopolysaccharides, or tumor necrosis factor-, with and without B. lactis, and the effects of B. lactis on nuclear factor kappa B (NF-,B) signaling in IEC were examined. For in vivo study, dextran sulfate sodium (DSS)-treated mice were fed with and without B. lactis. Finally, we induced colonic tumors in mice by azoxymethane (AOM) and DSS and evaluated the effects of B. lactis on tumor growth. Results: B. lactis significantly suppressed NF-,B activation, including NF-,B-binding activity and NF-,B-dependent reporter gene expression in a dose-dependent manner, and suppressed I,B-, degradation, which correlated with the downregulation of NF-,B-dependent gene products. Moreover, B. lactis suppressed the development of acute colitis in mice. Compared with the DSS group, the severity of DSS-induced colitis as assessed by disease activity index, colon length, and histological score was reduced in the B. lactis -treated group. In the CAC model, the mean number and size of tumors in the B. lactis -treated group were significantly lower than those in the AOM group. Conclusions: Our data demonstrate that B. lactis inhibits NF-,B and NF-,B-regulated genes in IEC and prevents acute colitis and CAC in mice. These results suggest that B. lactis could be a potential preventive agent for CAC as well as a therapeutic agent for inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source] Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient miceINFLAMMATORY BOWEL DISEASES, Issue 11 2008Hitoshi Ichikawa MD Abstract Background: Tetomilast (OPC-6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects. Methods: Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10,/, chronic colitis. Results: Tetomilast suppressed TNF-, and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed TNF-,, IFN-,, and IL-10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on TNF-, and IL-12. Tetomilast ameliorated IL-10,/, chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-, mRNA expression. Conclusions: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases. (Inflamm Bowel Dis 2008) [source] Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2003G. J. Brewer Abstract The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines. [source] Estimation of the relative antiinflammatory efficacies of six commercial preparations of Harpagophytum procumbens (Devil's Claw)PHYTOTHERAPY RESEARCH, Issue 3 2010Nassima Abdelouahab Ouitas Abstract The current work compared the relative efficacies of six commercial formulations of H. procumbens. Each formulation was assayed for the content of harpagoside (1), harpagide (2), verbascoside (3) and 8- O-p -coumaroyl harpagide (4) and, based on the recommended dosages, the total daily amounts were determined and used to establish anti-/proinflammatory (A/P) factors. The formulations were compared using ex vivo porcine skin for their activities towards COX-2 by Western blotting. The results showed great variation in the amounts of compounds 1,4 within the six formulations examined. The relative proportions of 1,4 also varied widely between the products and this inconsistency was reflected in the A/P factors, which correlated with the COX-2 expression (R2 = 0.9496). Although the data support the beneficial antiinflammatory effects from the use of some of the brands tested, others would appear potentially to exacerbate inflammation. To conclude, a ratio based upon the amount and relative proportions of anti- and proinflammatory compounds can be used to predict relative antiinflammatory properties. Also, with access to a diversity of ostensibly similar commercial products, the patient may experience varying therapeutic responses. Finally, current pharmacopoeia monographs, which are generally concerned with a minimum harpagoside content, are inadequate for ensuring the quality of products based on H. procumbens. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effect of pine bark extract (Pycnogenol®) on symptoms of knee osteoarthritisPHYTOTHERAPY RESEARCH, Issue 8 2008Peter Cisár Abstract Objective. The safe and efficacious use of Pycnogenol® (French maritime pine bark extract) in other inflammatory diseases prompted this study of its antiinflammatory effects in patients with osteoarthritis (OA). The aim of the study was to evaluate whether Pycnogenol® reduces the symptoms of OA in a double-blind, placebo-controlled, randomly allocated trial with patients suffering from knee osteoarthritis stages I and II. Methods. 100 patients were treated for 3 months either by 150 mg Pycnogenol® per day at meals or by placebo. Patients had to report any change of use of previously prescribed antiinflammatory medication during the study period. Patients filled the Western Ontario and Mc Masters University (WOMAC) questionnaire for osteoarthritis every 2 weeks and evaluated weekly pain symptoms using a visual analogue scale for pain intensity. Results. Following treatment with Pycnogenol® patients reported an improvement of WOMAC index (p < 0.05), and a significant alleviation of pain by visual analogue scale (p < 0.04), the placebo had no effect. The use of analgesics diminished in the verum group but increased under the placebo. Treatment with Pycnogenol® was well tolerated. Conclusion. Results show that Pycnogenol® in patients with mild to moderate OA improves symptoms and is able to spare NSAIDs. Copyright © 2008 John Wiley & Sons, Ltd. [source] A systematic review on the Rosa canina effect and efficacy profilesPHYTOTHERAPY RESEARCH, Issue 6 2008Cosima Chrubasik Abstract Rose hip, rose hip and seed and rose hip seed, all were negatively monographed by the German Commission E due to insufficient evidence of effects and effectiveness. Therefore a comprehensive review of the literature was conducted to summarize the pharmacological and clinical effects of Rosa canina L. to reevaluate its usefulness in traditional medicine. For various preparations of rose hip and rose hip and seed, antioxidative and antiinflammatory effects have been demonstrated. Lipophilic constituents are involved in those mechanisms of action. The proprietary rose hip and seed powder LitozinR has been employed successfully in a number of exploratory studies in patients suffering from osteoarthritis, rheumatoid arthritis and low back pain. However, the sizes of the clinical effects for the different indications need to be determined to assure clinical significance. There is also a rationale behind the use of LitozinR as part of a hypocaloric diet based on the rose hip probiotic, stool regulating and smooth muscle-relaxing actions, as well as the rose hip seed lipid-lowering, antiobese and antiulcerogenic effects. Further research is needed to clarify the importance of the reported promising experimental effects in clinical use and to characterize the optimum rose hip seed oil preparation for topical use in the treatment of skin diseases. Copyright © 2008 John Wiley & Sons, Ltd. [source] Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat modelsPHYTOTHERAPY RESEARCH, Issue 9 2007Ibrahim Tekeoglu Abstract Many studies have been carried out in recent years on the pharmacological effects of Nigella sativa seeds that have uncovered their antiinflammatory and immunological effects. The objective of this study was to explore the antiinflammatory effects of thymoquinone on arthritis in rat models. Rats with arthritis induced by Freund's incomplete adjuvant were assigned to five groups: group 1: controls 0.9% NaCl (n = 7); group 2: 2.5 mg/kg thymoquinone (n = 7); group 3: 5 mg/kg thymoquinone (n = 7); group 4: Bacilli Chalmette Guerin (BCG) 6 × 105 CFU (n = 7); group 5: methotrexate 0.3 mg/kg (n = 7). Signs of inflammation on the claw and radiological signs were searched for and TNF-alpha and IL-1beta were measured. The results of the control and other groups were compared. As a result, thymoquinone, confirmed clinically and radiologically, suppressed adjuvant-induced arthritis in rats. Copyright © 2007 John Wiley & Sons, Ltd. [source] Antinociceptive and antiinflammatory activities of pine (Pinus densiflora) pollen extractPHYTOTHERAPY RESEARCH, Issue 5 2007Eun-Mi Choi Abstract The study aimed to evaluate the antinociceptive and antiinflammatory activity of pine (Pinus densiflora) pollen in mice. The antinociceptive activity was determined using acetic acid-induced abdominal constriction and formalin-induced licking, and the hot plate test. Antiinflammatory effects were evaluated using carrageenan- and formalin-induced paw edema, and arachidonic acid-induced ear edema in mice. The ethanol extract of pine pollen (100 and 200 mg/kg, p.o.) produced a significant inhibition of both phases of the formalin pain test in mice, a reduction in mouse writhing induced by acetic acid and an elevation of the pain threshold in the hot plate test in mice. The pine pollen extract also produced a significant inhibition of carrageenan- and formalin-induced paw edema as well as arachidonic acid-induced ear edema in mice. The inhibitions were similar to those produced by aminopyrine and indomethacin, p.o. The different polyphenols found in pine pollen could account for the antinociceptive and antiinflammatory actions. The results obtained indicate that the extract possesses analgesic and antiinflammatory effects. Copyright © 2007 John Wiley & Sons, Ltd. [source] Antiinflammatory and Anticoagulant Effects of Transgenic Expression of Human Thrombomodulin in MiceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010S. Crikis Thrombomodulin (TBM) is an important vascular anticoagulant that has species specific effects. When expressed as a transgene in pigs, human (h)TBM might abrogate thrombotic manifestations of acute vascular rejection (AVR) that occur when GalT-KO and/or complement regulator transgenic pig organs are transplanted to primates. hTBM transgenic mice were generated and characterized to determine whether this approach might show benefit without the development of deleterious hemorrhagic phenotypes. hTBM mice are viable and are not subject to spontaneous hemorrhage, although they have a prolonged bleeding time. They are resistant to intravenous collagen-induced pulmonary thromboembolism, stasis-induced venous thrombosis and pulmonary embolism. Cardiac grafts from hTBM mice to rats treated with cyclosporine in a model of AVR have prolonged survival compared to controls. hTBM reduced the inflammatory reaction in the vein wall in the stasis-induced thrombosis and mouse-to-rat xenograft models and reduced HMGB1 levels in LPS-treated mice. These results indicate that transgenic expression of hTBM has anticoagulant and antiinflammatory effects that are graft-protective in murine models. [source] Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritisARTHRITIS & RHEUMATISM, Issue 6 2010Stephan Blüml Objective To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA). Methods We performed bone marrow transplantations in human TNF,transgenic mice using hematopoietic cells from wild-type, TNFRI,/,, TNFRII,/,, and TNFRI/II,/, mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays. Results Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis. Conclusion Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA. [source] Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptorsARTHRITIS & RHEUMATISM, Issue 3 2010Sandra Sacre Objective Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA). Methods Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs. Results Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-,,inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action. Conclusion Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development. [source] Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signalingARTHRITIS & RHEUMATISM, Issue 2 2010George D. Kalliolias Objective Interleukin-27 (IL-27) has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effects of IL-27 on human osteoclastogenesis, to determine whether IL-27 can stimulate or attenuate the osteoclast-mediated bone resorption that is a hallmark of RA. Methods Osteoclasts were generated from blood-derived human CD14+ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of tartrate-resistant acid phosphatase,positive multinucleated cells and measuring the expression of osteoclast-related genes. The induction of nuclear factor of activated T cells c1 (NFATc1) and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, and immunoreceptor tyrosine,based activation motif,harboring adaptor proteins) was measured by real-time reverse transcription,polymerase chain reaction. Murine osteoclast precursors obtained from mouse bone marrow and synovial fluid macrophages derived from RA patients were also tested for their responsiveness to IL-27. Results IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, down-regulated the expression of RANK and triggering receptor expressed on myeloid cells 2 (TREM-2), and inhibited RANKL-mediated activation of ERK, p38, and NF-,B in osteoclast precursors. Synovial fluid macrophages from RA patients were refractory to the effects of IL-27. In contrast to the findings in humans, IL-27 only moderately suppressed murine osteoclastogenesis, and this was likely attributable to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors. Conclusion IL-27 inhibits human osteoclastogenesis by a direct mechanism that suppresses the responses of osteoclast precursors to RANKL. These findings suggest that, in addition to its well-known antiinflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as in RA synovitis. [source] Estrone/17,-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritisARTHRITIS & RHEUMATISM, Issue 10 2009Martin Schmidt Objective The role of estrogens in rheumatoid arthritis (RA) is debated since both proinflammatory and antiinflammatory effects have been reported. Important evidence of the dual role of estrogens is conversion to various proinflammatory or antiinflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA). Methods We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17,-estradiol, and conversion of estrone/17,-estradiol to various estrogen metabolites in RA and OA synovial cells. The effect of estrogen metabolites on tumor necrosis factor (TNF) secretion was also studied in RA and OA synovial cells. Results Serum levels of estrone sulfate were similar in healthy controls and RA patients. Estrone sulfate transporters were present in synovial tissue. Interconversion of estrone and 17,-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17,-estradiol as substrates, RA and OA synovial cells produced 16,-, 4-, and 2-hydroxylated estrogens and their 4- and 2-methylation products. The levels of 16,-hydroxylated estrone/17,-estradiol (16,OH-estrone/16,OH-17,-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16,OH-estrone than did OA synovial cells. Importantly, the 16,OH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects. Conclusion Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16,OH-estrone, which, in addition to 16,OH-17,-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16,-hydroxylated estrogens is an unfavorable sign in synovial inflammation. [source] Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivoARTHRITIS & RHEUMATISM, Issue 9 2009Roland Axmann Objective To investigate the efficacy of a murine anti,interleukin-6 receptor (anti,IL-6R) antibody in directly blocking tumor necrosis factor (TNF), and RANKL-mediated osteoclastogenesis in vitro and in vivo. Methods The efficacy of a murine antibody against IL-6R in blocking osteoclast differentiation of mononuclear cells stimulated with RANKL was tested. In addition, arthritic human TNF,,transgenic mice were treated with anti,IL-6R antibody, and osteoclast formation and bone erosion were assessed in arthritic paws. Results Blockade of IL-6R dose dependently reduced osteoclast differentiation and bone resorption in monocyte cultures stimulated with RANKL or RANKL plus TNF. In human TNF,,transgenic mice, IL-6R blockade did not inhibit joint inflammation, but it strongly reduced osteoclast formation in inflamed joints as well as bone erosion in vivo. Neither the cell influx into joints nor the synovial expression of IL-6 and RANKL changed with IL-6R blockade, while the synovial expression of IL-1 was significantly reduced. In contrast, TNF-mediated systemic bone loss was not inhibited by IL-6R blockade. Conclusion These data suggest that blockade of IL-6R directly affects osteoclast formation in vitro and in vivo, suggesting a direct and specific effect of anti,IL-6R therapy on osteoclasts independently of its antiinflammatory effects. This effect adds significantly to the structure-sparing potential of pharmacologic blockade of IL-6R in arthritis. [source] Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68ARTHRITIS & RHEUMATISM, Issue 1 2003M. Carmen Montesinos Objective Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX-68 (N -[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H -1,4-benzothiazin-7-yl]-carbonyl]- L -homoglutamic acid). Methods We studied the effects of low-dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX-68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air-pouch model in A2A and A3 receptor knockout mice. Results Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor , accumulation in the exudates of wild-type mice, but not in those of A2A or A3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A2A knockout, A3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68. Conclusion These findings confirm that adenosine, acting at A2A and A3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68. [source] Triflusal: An Antiplatelet Drug with a Neuroprotective Effect?CARDIOVASCULAR THERAPEUTICS, Issue 1 2006José Antonio González-Correa ABSTRACT Triflusal is a derivative of salicylic acid with a well-established platelet aggregation inhibitory profile. Its pharmacokinetic and pharmacodynamic properties differ, however, somewhat from those of acetylsalicylic acid. A number of recent experimental and clinical studies have shown that triflusal is a potentially useful choice in the treatment and prophylaxis of brain ischemia because of its antithrombogenic as well as neuroprotective effects. Its antithrombogenic effect has been demonstrated at the clinical as well as at the experimental level, while its neuroprotective effect has been shown only in experimental models. The drug interferes with thrombogenesis by inhibiting thromboxane synthesis and increasing the levels of cAMP and nitric oxide. Its neuroprotective action is the result of its antioxidant and antiinflammatory effects in brain tissue. From a clinical standpoint triflusal is similar in efficacy to acetylsalicylic acid in preventing stroke, but has less adverse effects, especially it is less likely to cause bleeding. Because of its pharmacodynamic properties and lower rate of adverse reactions, triflusal may be a useful alternative to acetylsalicylic acid in the prevention of stroke. [source] | ||||||||||