Disease relevance of leflunomide

• Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%) [1].
• Leflunomide is a novel immunosuppressive and anti-inflammatory agent for the treatment of autoimmune disease [2].
• We have previously found that the antirheumatic drug leflunomide is a potent inhibitor of APAP toxicity in cultured human hepatocytes, protecting them from mitochondria-mediated cell death by inhibiting the mitochondrial permeability transition [3].
• We undertook this double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of leflunomide in patients with PsA and psoriasis [4].
• Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis [5].

High impact information on leflunomide

• After donor antigen infusion, temporary NK-cell depletion and a 4-week administration of Leflunomide, hamster heart grafts survived even after withdrawal of immunosuppression [6].
• Leflunomide in treatment of rheumatoid arthritis [7].
• In the past 2 years, three new disease-modifying antirheumatic drugs (DMARDs) have been approved: leflunomide, etanercept, and infliximab [8].
• The purpose of this study was to explore whether leflunomide protects against APAP hepatotoxicity in vivo and to define the molecular pathways of cytoprotection [3].
• Activation of nuclear factor kappaB (NF-kappaB), which regulates TNF-alpha production, was inhibited in the liver of mice treated with leflunomide, resulting in a reduction of TNF-alpha production from lymphocytes infiltrating the liver [2].

Chemical compound and disease context of leflunomide

• Leflunomide and peripheral neuropathy: a potential interaction between uracil/tegafur and leflunomide [9].
• Uridine substitution prevented lethal VSV encephalitis under Leflunomide treatment by restoring the neutralizing IgM and IgG responses [10].
• The treatment of BKV nephritis (BKVN) consists of reduction in immunosuppressive therapy and antiviral therapy with cidofovir or leflunomide or a combination of both [11].
• Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors [12].
• Open-labeled studies have reported success of newer immunosuppressive drugs, immunomodulatory therapies, and the biological agents such as mycophenolate mofetil (MMF), calcineurin inhibitors, leflunomide, intravenous immunoglobulin, immunoadsorption, and rituximab in the treatment of cyclophosphamide (CYC) resistant proliferative lupus nephritis [13].

Biological context of leflunomide

• We previously reported that leflunomide inhibits LPS-stimulated B cell proliferation, cell cycle progression, and IgM secretion [14].
• Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis [15].
• In this study, we characterized the inhibitory effects of leflunomide on Src family (p56lck and p59fyn)-mediated protein tyrosine phosphorylation [16].
• Treatment of the anti-Fas-resistant NALM-6-UM1 cells with the leflunomide metabolite analog alpha-cyano-beta-methyl-beta-hydroxy-N-(2, 5-dibromophenyl)propenamide, a potent inhibitor of BTK, abrogated the BTK-Fas association without affecting the expression levels of BTK or Fas and rendered them sensitive to Fas-mediated apoptosis [17].
• Leflunomide is a novel immunosuppressive and antiinflammatory agent currently being tested for treatment of autoimmune diseases and transplant rejection [18].

Anatomical context of leflunomide

• These findings were supported by the results in which leflunomide administration decreased the number of T lymphocytes infiltrating the liver as well as inhibiting their production of TNF-alpha [2].
• Treatment with leflunomide markedly reduced serum transaminase activities and the numbers of dead liver cells [2].
• The mechanism of protection by leflunomide was not through inhibition of cytochrome P450 (CYP)-catalyzed APAP bioactivation or an apparent suppression of the innate immune system [3].
• Hence, after 4 wk of LF, the rats developed partial B cell tolerance, as they were unable to produce T-independent (CsA-resistant) XAbs [19].
• Moreover, splenocytes taken from rats that rejected Xgs despite a treatment with LF + ASGM-1 provoked an acceleration of Xg rejection when transferred to newly transplanted LF + ASGM-1-treated nude rats, and finally, the latter accelerating effect disappeared when macrophages were first depleted from the adoptively transferred splenocytes [20].

Associations of leflunomide with other chemical compounds

• Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group [1].
• Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria [21].
• The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms [22].
• It was previously reported that treatment with leflunomide (LF; 10 mg/kg/day) together with cyclosporine (CsA; 10 mg/kg/day) resulted in long term survival of hamster heart xenografts (Xg) in rats and that LF could be withdrawn 2 to 4 wk after transplantation [19].
• RESULTS: Leflunomide blocked de novo pyrimidine synthesis and RANKL-induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF-ATc1) was strongly inhibited [23].

Gene context of leflunomide

• Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers [21].
• Previously, we have demonstrated that leflunomide inhibits TNF-induced NF-kappaB activation by suppressing I-kappaBalpha (inhibitory subunit of NF-kappaB) degradation [24].
• Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis [24].
• We further demonstrate that leflunomide suppresses HA synthase activity, as determined by (14)C-glucuronic acid incorporation assays [25].
• More importantly, two tyrosine kinase inhibitors mimicked the effect of leflunomide in that both blocked IL-1beta-induced HAS1 activation without affecting HAS2 or HAS3 [25].

Analytical, diagnostic and therapeutic context of leflunomide

• To study the mechanisms allowing withdrawal of LF, second hamster heart Xgs were transplanted 6 wk after the first xenograft [19].
• Leflunomide, a novel immunosuppressive drug, is able to prevent and reverse allograft and xenograft rejection in rodents, dogs, and monkeys [16].
• OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA) [21].
• Together with the findings in adoptive transfer EAN, this indicates that the antiproliferative effect is probably not the only mechanism of immunosuppressive action by leflunomide [26].
• Leflunomide-treated rats did not mount autoantibodies as specified by ELISA (enzyme-linked immunosorbent assay) with a mixture of peripheral myelin proteins, including P2 and myelin basic protein [26].

References