JTP-74057 blocked tumor necrosis factor-α and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1 mg/kg of JTP-74057 or 10 mg/kg of leflunomide. In the CIA, JTP-74057, but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production.
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The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
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To explore the effects of leflunomide active metabolite A771726 on high glucose-induced podocyte cytoskeleton and its possible signaling pathway.
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Peripheral blood cells from this patient, from 15 patients with rheumatoid arthritis, and from healthy controls were used in a bioassay, which suggested that leflunomide affected the Th1/Th2 balance. Such a side effect might be related, in part, to the anti-tumour necrosis factor alpha activity of leflunomide.
To study the effect of leflunomide on CCl4-induced hepatic fibrosis in rats.
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In this multinational, randomized, double-blind, parallel-group study, 402 RA patients were randomized equally to receive daily doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study was designed to demonstrate non-inferiority of the efficacy of 10 mg compared with 20 mg by calculating 95% confidence intervals for differences in changes in tender joint count (TJC), swollen joint count (SJC) and Health Assessment Questionnaire Disability Index (HAQ DI), comparing these confidence intervals with predefined bounds.
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A primary therapeutic goal in rheumatoid arthritis (RA) is to reduce functional disability. The recent introduction of several new drugs for RA creates a need for readily assessing the effectiveness of therapy. Because the consistent use of disease-modifying anti-rheumatic drugs (DMARDs) reduces long-term disability, we analysed the large database of 1817 RA patients from leflunomide trials to assess if changes in the Health Assessment Questionnaire (HAQ) can measure the effectiveness of RA therapy.
The clinical outcomes in patients with biopsy-proven BKVAN were unfavorable in the present study, especially in patients with advanced-stage BKVAN, poor renal function, and acute allograft rejection.
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IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.
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We performed a retrospective study of RA patients who were prescribed leflunomide between 2004 and 2011. Background clinical and laboratory features were compared between patients who suffered severe leflunomide-associated infections and those who did not.
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IL-13 is a T-helper class 2 cytokine that induces goblet cell hyperplasia and mucus production in airway epithelial cells. Because macrolide antibiotics are known to have immunomodulatory and mucoregulatory properties, the aim of this study was to examine the effect of clarithromycin on IL-13-induced goblet cell hyperplasia and mucin hypersecretion in normal human bronchial epithelial (NHBE) cells. NHBE cells were cultured to differentiation at an air-liquid interface with IL-13 plus clarithromycin or vehicle. Histochemical analysis was performed using H&E staining, periodic acid-Schiff (PAS) staining, and MUC5AC immunostaining. MUC5AC synthesis was assayed using RT-PCR and ELISA. Western blotting was used to evaluate signaling pathways. IL-13 significantly increased the number of PAS-positive, MUC5AC-positive goblet cells, and this was significantly attenuated by clarithromycin at concentrations greater than 8 μg/ml (P < 0.01). Clarithromycin also dose-dependently decreased MUC5AC mRNA expression induced by IL-13 (P < 0.001), and, at 24 μg/ml, clarithromycin significantly attenuated the amount of MUC5AC protein in cell supernatants (P < 0.01). Western blotting showed that clarithromycin affected IL-13 receptor janus kinase signal transducers, activators of transcription6 (STAT6), and epidermal growth factor receptor mitogen-activated protein kinase signaling and that inhibition of these pathways by clarithromycin decreased goblet cell hyperplasia via nuclear factor-κB inactivation. We conclude that clarithromycin inhibits goblet cell hyperplasia and may directly regulate mucus secretion by IL-13 in NHBE cells.
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Despite many advances in the treatment of JIA, there is still a lack of evidence for treatment of several disease subtypes. The treatment plan needs to be individualized based on the JIA subtype.
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RNA-binding proteins (RBPs) play important roles in every aspect of RNA metabolism and regulation. Their identification is a major challenge in modern biology. Only a few in vitro and in vivo methods enable the identification of RBPs associated with a particular target mRNA. However, their main limitations are the identification of RBPs in a non-cellular environment (in vitro) or the low efficiency isolation of RNA of interest (in vivo). An RNA-binding protein purification and identification (RaPID) methodology was designed to overcome these limitations in yeast and enable efficient isolation of proteins that are associated in vivo. To achieve this, the RNA of interest is tagged with MS2 loops, and co-expressed with a fusion protein of an MS2-binding protein and a streptavidin-binding protein (SBP). Cells are then subjected to crosslinking and lysed, and complexes are isolated through streptavidin beads. The proteins that co-purify with the tagged RNA can then be determined by mass spectrometry. We recently used this protocol to identify novel proteins associated with the ER-associated PMP1 mRNA. Here, we provide a detailed protocol of RaPID, and discuss some of its limitations and advantages.
Arthritis in children represents a diagnostic and therapeutic challenge. The diagnostic spectrum is broad and a very precise indication for diagnostic and therapeutic procedures, especially in small children, is important. In addition to acute arthritides - viral arthritis, reactive arthritis, Lyme arthritis and septic arthritis - secondary chronic arthritis related to an underlying disease as well as juvenile idiopathic arthritis (JIA), the most common chronic inflammatory systemic disease in children, need to be considered. This overview is a guide to the diagnosis of arthritis in childhood and to evidence-based therapy of JIA in particular. This consists of a combination of nonsteroidal anti-inflammatory drugs, systemic and intraarticular corticosteroids, traditional DMARDs such as sulfasalazine, methotrexate and leflunomide, the TNF inhibitors etanercept, adalimumab and, with restrictions, infliximab, other biopharmaceuticals such as anakinra, canakinumab and rilonacept, and tocilizumab and finally, abatacept.
The immunosuppressive metabolite of leflunomide, A77 1726, inhibits the enzymatic activity of protein tyrosine kinases and of dihydro-orotic acid dehydrogenase, an enzyme involved in pyrimidine biosynthesis. Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity. At low concentrations of A77 1726, pyrimidine biosynthesis is the target, since inhibition of proliferation correlates with a reduction in pyrimidine NTP levels and is reversed by uridine. At higher concentrations of A77 1726, uridine no longer reverses the inhibition of proliferation even though pyrimidine NTP levels are restored. This second mechanism for inhibiting proliferation is probably inhibition of protein tyrosine kinases, since these higher concentrations of A77 1726 inhibit IL-2-induced tyrosine phosphorylation of Jak1 and Jak3, the protein tyrosine kinases initiating signaling by the IL-2R. Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726. Cytotoxicity of a CTLL line that overexpresses the Lck protein tyrosine kinase is inhibited by A77 1726; this inhibition is not affected by uridine, but does correlate with inhibition of an Lck in vitro kinase reaction. These studies establish that inhibition of pyrimidine biosynthesis and that of protein tyrosine kinase both contribute to the effects of A77 1726 on CTLL cell lines.
The data obtained in this study suggest that the concept of diagnosing and treating RA early is accepted by a large proportion of the rheumatological community.
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Relative to the enormous acceptance of the ISO 9000 quality standard, the ISO 14001 environmental management certification has been met with only moderate enthusiasm among industrial facilities. The literature on corporate motivation for ISO 14001 participation is relatively modest considering the enormous number of publications reviewing other aspects of its adoption and implementation. It would seem that the present "marketing" package supporting ISO environmental commitments does not seem to offer sufficiently persuasive incentives for increased sales, either domestically or internationally. While researchers assume that a higher export rate of companies is positively associated with higher ISO participation rates, there have been very few empirical studies that support this inference, and conclusions have not been based on data taken from importing countries orfrom a systematic evaluation of expressed corporate preference for products sold by ISO 14001 certified companies. The present study reports the results of a survey to firms in six countries that are Israel's leading trade partners, importing chemicals, textiles, and produce. The survey results confirm that while the international market still considers price and quality as the paramount factors in selection of suppliers, environmental management systems (EMS) are an important feature that is frequently taken into consideration. EMS certification appears to signify a supplier who is managing the business well and exhibiting ethical responsibility. The European market proved to be more environmentally conscious than those in other industrialized parts of the world. EMS offer a particularly valuable advantage for producers wishing to reach European markets. As policy-makers seek to expand the voluntary adoption of EMS, a clear advantage for exporters should be highlighted among national industries.
Recent clinical development programs for new therapeutic agents in rheumatoid arthritis have included assessment of radiographic progression comparing changes with treatment to placebo and active controls. Studies now use reliable methods of assessment and sufficient study length to detect radiographic changes. Although patient populations and characteristics differ, and radiographic scoring methods vary, the direction of a series of studies appears to indicate that leflunomide (LEF), methotrexate (MTX), sulfasalazine (SSZ), etanercept, infliximab, and IL-1ra are all effective in retarding radiographic progression, as measured by erosions and joint space narrowing. Interpretation of radiograph data in future trials will be aided by utilization of common reading methods and by continuing comparison across differing rheumatoid arthritis protocol populations.
Human dihydroorotate dehydrogenase (huDHODH) is essential for de novo biosynthesis of pyrimidines and the target of two immunosuppressive drugs, brequinar and the leflunomide metabolite A77-1726 (Chen et al., 1992; Davis et al., 1996). Using a T7 RNA polymerase expression system, we produced huDHODH as a fusion protein containing an amino-terminal decahistidine tag. Escherichia coli growth and expression conditions were optimized to enhance huDHODH solubility and to permit purification of the enzyme in the absence of detergent. Soluble huDHODH, purified by a simple two-step procedure, was catalytically active, monomeric, and contained a flavin mononucleotide (FMN) cofactor in a 1:1 FMN/protein molar ratio. Kinetic analysis showed that huDHODH uses a two site ping-pong mechanism, where DHO is oxidized at one site and the second substrate, ubiquinone, is reduced at the other. This result is consistent with the mechanism proposed for bovine liver DHODH (Hines and Johnston, 1989).
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IAI is a simple and reliable index of RA activity in clinical practice.
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Defining remissions in clinical trials and clinical practice requires appropriate standardized and objective outcome measures, such as the ACR and EULAR remission criteria. Traditional DMARDs often provide symptom relief, improvements in physical function, and the slowing of radiographic progression in patients with RA, but rarely lead to the complete cessation of RA activity. Remission, as defined by the ACR criteria, has been observed in 7 to 22% of patients treated with traditional DMARD monotherapy (ie, gold, penicillamine, methotrexate [MTX], cyclosporine A, or sulfasalazine), but these remissions have often been short-lived. Treatments with DMARD combinations, biologic monotherapy, and biologic combination therapy with MTX offer greater hope and may facilitate the higher rates of remission. Clinical trial results have shown that newer DMARDs such as leflunomide or the combination of multiple DMARDs can generally elicit greater EULAR remission rates (ranging from 13 to 42%) than monotherapies. Biologic combinations with MTX have also been shown to induce significant remission (as defined by the EULAR criteria) in RA patients, with a 31% rate observed with infliximab plus MTX at 54 weeks, a 50% rate observed for adalimumab plus MTX after 2 years of therapy, and a 41% rate observed for etanercept plus MTX after 2 years of therapy.
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Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.
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The Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis (SMILE) study was a multicenter, observational, cross-sectional, retrospective safety study. The study was conducted by the Optimising Patient Outcomes in Australian Rheumatology-Quality Use of Medicines Initiative (OPAL QUMI). Data were deidentified for patient, clinic, and clinician prior to collection from 13 participating rheumatology practices (25 rheumatologists). Comparative analysis of safety for the different treatments, primarily with regard to neutropenia and liver abnormalities, was performed.
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Fujisawa is committed to improving the outcomes of transplant patients worldwide. Research and development programs are underway for a new modified release dosage form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several novel compounds (PG 490-88, AGI 1096) in collaboration with other companies. These programs are targeted to address many of the unmet medical needs in transplantation including (1) improving compliance, (2) reducing chronic rejection, and (3) improving long-term safety by reducing infectious and cardiovascular risk.
Cases of toxic neuropathy have been observed during treatment of rheumatoid arthritis with leflunomide. Their occurrence seems to be associated with known risk factors. Careful monitoring of the patient's neurological status during leflunomide treatment is therefore mandatory.
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Leflunomide may modulate the rheumatoid articular process by inhibition of local production of IL1beta, TNFalpha, NO, and MMP-3.
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The novel immunomodulatory agent leflunomide exhibits a strong anti-inflammatory action. This isoxazole derivative is chemically unrelated to any hitherto applied immunosuppressants. As a prodrug leflunomide is completely converted to its active metabolite A 77 1726 (M1) which blocks the dihydroorotate dehydrogenase, a key enzyme of the pyrimidine de novo synthesis. Drug-related adverse effects are mild, dose-related and reversible, characterising leflunomide as a safe immunosuppressant. While up to now leflunomide has just been approved for therapy of rheumatoid arthritis, its mechanism of action affects multiple inflammatory pathways, thereby suggesting it to be a potent therapeutic agent in autoimmune diseases, graft rejection, and tumour therapy. First dermatological experience has been gained in psoriasis and bullous pemphigoid. The role of leflunomide in the dermatologist's therapeutic armamentarium will evolve during the next years.