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Fifty-one WG patients with relapses under MTX (n=36) or LEF (n=15) maintenance monotherapy were identified. They were subsequently treated with MTX+LEF to reintroduce remission. Mean follow-up was 26.0 (3-93) months. MTX+LEF controlled relapsing WG in 43/51 (84%) patients: 28/51 achieved a Birmingham Vasculitis activity index (BVAS)=0 and 15/51 a response (BVAS reduction of > = or). 8/51 patients did not respond to MTX+LEF (<50% BVAS reduction) and were switched to cyclophosphamide and/or a biological for ongoing disease activity. Follow up showed a sustained remission (BVAS=0 >3 months) in 14/51 patients, a minor relapse in 27/51, and a major relapse in 2/51 (subsequently switched to cyclophosphamide). Fifty adverse effects were observed. MTX+LEF therapy was discontinued in 18/51 patients because of adverse effects (main causes: gastro-intestinal complaints, hypertension, infections).
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Leflunomide(Arava) is a novel immunomodulatory drug, the primary action of which is inhibition of de-novo pyrimidine synthesis by selective inhibition of dihydro-orotate dehydrogenase. It has been shown that leflunomide is effective in treating active rheumatoid arthritis(RA) in a placebo-controlled phase II study. Subsequent multinational, randomized, controlled phase III clinical trials demonstrated that leflunomide is as effective and safe as methotrexate and sulfasalazine in treatment of RA. Frequently reported adverse effects included diarrhea, nausea and vomiting, skin rash, reversible alopecia, and transient lever enzyme elevations. However, accumulating concerns about its toxic effects, especially hepatotoxicity, have been raised recently. In addition, rheumatologists should be aware that leflunomide has a much longer half life than any other disease modifying antirheumatic drug.
Evaluation of effectiveness and safety of leflunomide treatment in patients with active rheumatoid arthritis in whom methotrexate was ineffective or contraindicated.
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The review is based on a MEDLINE (PubMed) search of the English-language literature from 1965 to 2005, using the index keywords "rheumatoid arthritis" and "surgery". As co-indexing terms the different disease-modifying antirheumatic drugs (DMARDs) as well as nonsteroidal anti-inflammatory drugs (NSAIDs) and "glucocorticoids" were used. In addition, citations from retrieved articles were scanned for additional references. Furthermore, because the number of published articles is so limited, relevant abstracts presented at congresses were included in the analysis.
High levels of active MMP-9, COMP and SAA were detected in the sera of the patients with RA prior to the start of the leflunomide therapy compared to normal control sera. A significant reduction of the MMP-9 activity levels was seen after 3 months immunomodulation with leflunomide and was maintained after 6 months (p < 0.01). The degradation marker COMP and the inflammation marker SAA decreased significantly after 6 months (p < 0.04, respectively p < 0.01). There was also an insignificant tendency of MMP-1 reduction in serum after 6 months.
Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide.
DiHydroOrotate DeHydrogenase [huDHODH] is a therapeutic target for Rheumatoid arthritis [RA]. Leflunomide [A771726] is a widely used synthetic inhibitor against huDHODH. We to find more efficient lead like compounds. A four featured E-Pharmacophore A1D4H6R7 was built based on the inhibitor A771726. This pharmacophore was validated by checking its ability to identify known highly active inhibitors of huDHODH and assigning higher fitness scores to them. A reverse validation was also performed where random 4 featured pharmacophores were built and its efficiency in identifying actives was compared with our E-Pharmacophore. Our Epharmacophore was very efficient, since it passed both validations by picking the known active molecules with high fitness scores. This validated E- pharmacophore was searched against the KEGG phytochemicals subset database. This search resulted in 18 molecules which were subjected to docking with huDHODH. The molecules with docking score greater than that of A771726 were selected. The docking results were further validated using MM/GBSA which gave similar ranking with high binding free energy values. The four molecules 6-Methoxytaxifolin, Rhamnetin, Rhamnazin and Pinoquercetin were taken for explicit 3ns simulation and it was observed that all four molecules had acceptable RMSD values and stable interactions. Thus our study, suggests four phytomolecules that might inhibit huDHODH more efficiently than A771726. Interestingly, some of the obtained hits have already been proven in vitro anti-inflammatory activity which confirms that, the developed E-pharmacophore can be used to identify novel small molecules against inflammatory target, huDHODH.
In population dynamics, inverse density dependence can be manifested by individual fitness traits (component Allee effects), and population-level traits (demographic Allee effects). Cooperatively breeding species are an excellent model for investigating the relative importance of Allee effects, because there is a disproportionately larger benefit to an individual of being part of a large group. As a consequence, larger groups have greater performance than small groups, known as the group Allee effect. Although small populations of cooperative breeders may be prone to all levels of Allee effects, empirical evidence for the existence of a demographic Allee effects is scarce. To determine the extent to which Allee effects are present in a cooperatively breeding species, we used a comprehensive 35-year life history database for cooperatively breeding Arabian babblers (Turdoides squamiceps). Firstly, we confirmed the existence of a component Allee effect by showing that breeding individuals in large groups receive greater benefits than those in small groups; second, we confirmed the existence of group Allee effect by showing that larger groups survive longer. And thirdly, we identified a demographic Allee effect by showing that per capita population growth rate is positively affected by population density. Finally, we found that emigration and immigration rates, although dependent on group size, do not buffer against component and group-level Allee effects becoming a demographic Allee effect. Our finding of the existence of all three levels of Allee effects in a cooperative breeder may have important implications for future research and conservation decisions.
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A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data.
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It is very difficult to predict future treatment modalities especially in diseases like rheumatoid arthritis (RA) with unknown etiology and pathogenesis. In the near future, traditional disease-modifying antirheumatic drugs (DMARD) alone, in combination with each other, or together with cyclosporine, FK506, Rapamycin, or Leflunomide, will probably be the main treatment for RA. Currently biological anti-TNFalpha agents like humanized MAb and recombinant TNF-receptor constructs are now launched in the market. This therapy alone, or in combination with methotrexate is very effective in RA patients. There are, however, concerns over increase in serious infections. Autologous stem cell transplantation will probably be used in certain patient with serious autoimmune diseases.
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The study involved a retrospective analysis of data collected over a period of four years in 17 patients with DRESS. Clinical features, laboratory findings, responses to treatment, and outcomes were investigated.
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AA amyloidosis was induced in Swiss male mice using amyloid enhancing factor and AgNO(3). Suppression of amyloid formation was studied in comparison to saline, using i.p. injections of several non-steroidal anti-inflammatory agents, TNF-α inhibitors, interferon-α, leflunomide and a variety of chemotherapeutic agents, commonly used in the treatment of inflammatory illnesses such as methotrexate, azathioprine, chlorambucil and cyclophosphamide. The degree of splenic amyloid deposition was determined using Congo red staining of smears and a 5 grade scale.
Between 1990 and 2004 146 bone marrow examinations in 3638 patients were performed due to abnormal laboratory results. Medical history, results of bone marrow examination (morphology, histology) and cytogenetic data were investigated retrospectively.
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To determine the cost effectiveness of treatment strategies for rheumatoid arthritis patients satisfying the indication for tumor necrosis factor (TNF)-blocking treatment.
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Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor alpha) and chemokines (interleukin-8).
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We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial.
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Eotaxin-2/CCL24 and eotaxin-3/CCL26 are CC chemokines and their receptor, CC chemokine receptor 3 is preferentially expressed on eosinophils. It was reported that vascular endothelial cells and dermal fibroblasts produced CCL26. However, the regulation of CCL24 and CCL26 production in keratinocytes has not been well documented. We investigated the expression and production of CCL24 and CCL26 in the human keratinocyte cell line, HaCaT cells. Reverse transcription and polymerase chain reaction was performed using these cells and Enzyme-linked immunosorbent assay was carried out using supernatant of these cells. The production of CCL24 in HaCaT cells was slightly enhanced by IL-4 and that of CCL26 was strongly enhanced by IL-4 and IL-13. Furthermore, TNF-alpha generated a synergistic effect on IL-4 enhanced CCL26 production. Dexamethasone, IFN-gamma and the p38 mitogen-activated protein kinase inhibitor SB202190 inhibited IL-4 enhanced CCL26 production. IL-4 enhanced production of CCL26 was inhibited by leflunomide and JAK inhibitor 1, but not by JAK3 inhibitor, which indicates that it is mediated by JAK1-STAT6-dependent pathway. This result also strongly suggests the involvement of the type 2 IL-4 receptor in IL-4 enhanced production of CCL26. These results suggest that keratinocytes are involved in the migration of CC chemokine receptor 3 positive cells such as eosinophils in a Th2-dominant situation like atopic dermatitis.
The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active alpha-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma,t1/2 = 36 min; human plasma, t1/2 = 12 min) and whole blood (rat blood, t1/2 = 59 min; human blood, t1/2 = 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t1/2 = 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, Vmax = 1797 pmol/min/mg and Km = 274 microM). Leflunomide metabolism in microsomes was sensitive to furafylline treatment, suggesting p4501A2 involvement. 3-Methylleflunomide, which contained a 3-methyl substituent on the isoxazole ring, was resistant to ring opening in base, plasma, blood, and liver microsomes. In microsomes, two monohydroxylated metabolites were formed, and metabolite identification studies established the 3- and the 5-methyl groups on the isoxazole ring as sites of hydroxylation. These results indicate that the C3-H in leflunomide is essential for ring opening. Although A771726 formation in human liver microsomes or recombinant p4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the p450Fe(II) form of the enzyme. A mechanism for the p450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from p450Fe(II) to the C=N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.
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We undertook this study to evaluate the effects of leflunomide, an oral pyrimidine synthesis inhibitor, on the serum chemokine levels in patients with active rheumatoid arthritis (RA) who were refractory to treatment with methotrexate (MTX) or did not tolerated MTX treatment. RA patients were supposed to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally for the 12 months). Serum concentrations of RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) were assessed by enzyme-linked immunosorbent assay before and after 3, 6, 9, and 12 months of treatment with leflunomide. Three months therapy with leflunomide caused reduction in serum RANTES and MCP-1 (in both cases, p < 0.001) levels. Decrease in the concentration of these chemokines persisted until the end of the study period but was less significant. In the case of IL-8, its serum levels significantly diminished after 6 months of therapy with leflunomide (p < 0.01) and remained stable to the end of the study. Changes in serum chemokine levels were accompanied by significant decrease of disease activity score (DAS; p < 0.001). Prior to the first dose of leflunomide, serum concentrations of studied chemokines correlated with marker of RA activity such as the erythrocyte sedimentation rate and IL-8 level with DAS. Furthermore, we demonstrated significant correlations between serum levels of RANTES, MCP-1, and IL-8. During study period, such associations were far less or not significant. Leflunomide, beside a clinical improvement, reduce serum chemokines concentrations in RA patients. Leflunomide seems to be an effective treatment for RA, alternative to current therapies.
Obliterative bronchiolitis (OB) is the main chronic complication after heart-lung (HLTx) and lung transplantation (LTx), limiting the long-term success of both transplant procedures.
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Some studies have reported that adding leflunomide (LEF) to the treatment of rheumatoid arthritis (RA) in patients who do not respond to methotrexate (MTX) improved efficacy but increased the risk of liver toxicity. This study aimed at assessing the incidence of liver toxicity in patients with active RA using the LEF and MTX combination therapy in comparison with that of patients on MTX monotherapy.
Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ.
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This is the first description of the development of rheumatoid nodules in 3 rheumatoid arthritis patients following leflunomide therapy. The nodules were localized at typical sites with preference of the extensor side of hands and elbow. One nodule examined histologically revealed the typical architecture of RA nodules. In all 3 patients the time of onset of nodulosis was about 6 months after initiating the leflunomide therapy. In all 3 patients leflunomide was clinically efficacious concerning RA: remission or near remission was achieved. Due to the extent of nodulosis, the leflunomide therapy had to be stopped in 2 patients. Progression and acceleration of nodulosis is well known following MTX therapy in RA patients. It is caused by adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes. Leflunomide has no known influence on adenosine metabolism, so different pathogenetic mechanisms must be assumed for the induction of nodulosis by leflunomide.
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To estimate the incidence of pancytopenia in patients taking leflunomide with or without methotrexate in Australia.
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Leflunomide has been reported as an immunomodulating agent which acts on a variety of cells including T- and B-lymphocytes. CD4+ T-lymphocytes are essential for the type of disease that develops after infection with the protozoan parasite Leishmania major. A variety of immunological interventions has been shown to modulate disease development. Therefore, the effect of leflunomide on the development of parasite-induced lesions and the ensuing immune response was investigated in genetically susceptible BALB/c mice. Oral feeding for 7 to 10 days of leflunomide (30 mg/kg per day) beginning 2 days prior to or at the day of infection led to the development of a stable resistant phenotype, i.e. to long-lasting (> 13 months) regression of the lesions and clinical cure. Starting leflunomide treatment 3 days after infection was ineffective. The main bioactive metabolite, 1726 B, did not inhibit viability or growth of L. major promastigotes and amastigotes in vitro. Quantitative analysis of CD4+ and CD8+ cells in spleens and lymph nodes of parasite-infected animals treated with leflunomide for 5 days showed no significant effect. In vitro, 1726 B dose-dependently inhibited growth of stimulated T-cells, which could not be restored by saturating amounts of exogenous IL-2 and IL-4. No effect was observed on the killing function of activated macrophages. Taken together, the data indicate that leflunomide is a potent prophylactic agent to prevent an otherwise lethal infection of BALB/c mice.
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We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2005 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
The project was set to construct an extensive wetland in the southernmost region of Israel at Kibbutz Neot Smadar (30 degree 02'45" N and 35 degree 01'19" E). The results of the first period of monitoring, summary, and perspectives are presented. The constructed wetland (CW) was built and the subsequent monitoring performed in the framework of the Southern Arava Sustainable Waste Management Plan, funded by the EU LIFE Fund. The specific aims were: (1) To end current sewage disposal and pollution of the ground, the aquifer, and the dry river bed (wadi) paths by biologically treating the sewage as part of the creation of a sustainable wetland ecosystem. (2) Serve as an example of CW in the Negev highlands and the Arava Valley climates for neighboring communities and as a test ground for plants and building methods appropriate to hyper arid climate. (3) Serve as an educational resource and tourist attraction for groups to learn about water reuse, recycling, local wildlife and migrating birds, including serving the heart of a planned Ecological-Educational Bird Park. This report is intended to allow others who are planning similar systems in hyper arid climates to learn from our experience.
A total of 465 (29%) of the sarcoidosis patients experienced ocular disease. Of these, 365 patients were treated with methotrexate (MTX) for their eye disease with 281 (77% of those started on MTX) still receiving MTX at the end of the study. Methotrexate was the only systemic therapy prescribed in 115 patients while 101 patients also received concurrent prednisone. Other combinations administered include MTX plus azathioprine and/or leflunomide. A total of 25 patients were treated with the monoclonal anti-TNF antibodies infliximab (19 patients) or adalimumab (6 patients). While all patients initially responded to anti-TNF therapy, only ten patients experienced a sustained response with ongoing therapy or complete remission of ocular disease. Recurrent infections, adverse drug events, or financial constraints were responsible for most drug discontinuations.
Granulumatosis with polyangiitis (wegener's)/GPA microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are primary systemic vasculitides which predominantly affect small vessels, showing a high association with a positive C/PR3-ANCA in GPA and P/MPO-ANCA in MPA, so called ANCA-associated vasculitides (AAV). The diagnostic work-up relies on an interdisciplinary approach including imaging techniques and laboratory tests in order to assess disease stage and extent. The golden standard remains the histological proof of a necrotizing, pauci-immune small vessel vasculitis, in GPA additionally non-caseating granuloma is found mainly in the respiratory tract. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of glucocorticosteroids. Induction of remission in "early systemic" disease without organ- and life-threatening organ manifestations and a near normal kidney function can be achieved with methotrexate. In the generalized phase with significant renal dysfunction cyclophosphamide is the mainstay of therapy, in rapidly progressive glomerulonephritis with an imminent dialysis indication plasmapheresis is performed additionally. When remission is achieved, usually after 3-6 months of induction treatment, cyclophosphamide is switched to azathioprine as maintenance of remission drug. Alternative therapies are methotrexate provided the kidney function is normal or Leflunomide in the long-term follow-up the relapse rate in ANCA-associated vasculitis is approximately 50% in 5 years, irrespective of the drug used for maintenance treatment. The relapse rate is significantly higher in GPA than in MPA and CSS.
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Patients with rheumatoid arthritis (RA) suffer from pain and joint disability. The transient receptor potential ankyrin 1 (TRPA1) channel expressed on sensory neurones and non-neuronal cells mediates pain transduction and inflammation and it has been implicated in RA. However, there is little information on the contribution of TRPA1 for human disease. Here, we investigated the expression of TRPA1 on peripheral blood leukocytes and the circulating levels of its endogenous activators 4-hydroxynonenal (4-HNE) and hydrogen peroxide (H2O2) in RA patients treated or not with the anti-rheumatic leflunomide (LFN) or the anti-TNFα adalimumab (ADA). We also assessed whether TRPA1 expression correlates with joint pain and disability, in addition to the immune changes in RA. TRPA1 expression on peripheral blood leukocytes correlated with pain severity and disability. TRPA1 levels on these cells were associated with the numbers of polymorphonuclear and the activation of CD14(+) cells. No correlations were found between the lymphocyte population and TRPA1 expression, pain or disability. Patients recently diagnosed with RA expressed increased levels of TRPA1 on their leukocytes whilst treatment with either LFN or ADA down-regulated this receptor probably by reducing the numbers of polymorphonuclears and the activation of CD14(+) cells. We suggest that the activation levels of CD14(+) cells, the numbers of PMNs in the peripheral blood and the expression of TRPA1 on peripheral blood leukocytes correlate with RA progression, affecting joint pain sensitivity and loss of function.
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Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p<0.05). Likewise, preincubation of PBMC induced a reduction in their TEM of 39 (9)% (p<0.005). Incubation of both PBMC and EC with LEF-M had an additive effect (mean reduction of 48 (6)%, p<0.005). Incubation of PBMC with LEF-M also decreased monocytic CD44 expression (p<0.005) and PBMC-hyaluronan binding (p<0.05). Incubation of cells with LEF-M and uridine in addition to LEF-M reversed the inhibition of migration, suggesting that the observed effects were due to DHODH inhibition. Fluorocytometric analysis of PBMC subsets within the migrated population showed a decrease of monocytes, but not of B or T cells, after LEF-M treatment.