Leflunomide prevents the development of experimentally induced myasthenia gravis

Vidić-Danković, Biljana; Kosec, Duško; Damjanović, Maja; Apostolski, Slobodan; Isaković, Katarina; Bartlett, Richard

doi:10.1016/0192-0561(95)00009-q

Cited by 37 publications

(15 citation statements)

References 15 publications

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“…A77 1726 suppresses autoimmune diseases in many animal models [45][46][47][48][49][50][51][52], and also decreases autoantibody production in these models. Both allo-and xenoantibody levels are also decreased in leflunomide-treated rodent recipients of allo-and xenografts [24,[53][54][55][56], but the mechanisms of action of the drug on B-cell proliferation and on antibody production are unknown.…”

Section: In Vivomentioning

confidence: 97%

Leflunomide and malononitriloamides

Silva

Morris

1997

Expert Opinion on Investigational Drugs

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Leflunomide is a new immunomodulatory drug effective in experimental models of autoimmune diseases and allo- or xenotransplantation. In a Phase II clinical trial leflunomide has shown high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite, A77 1726, a malononitriloamide. The in vitro and in vivo mechanisms of action of this class of compounds remain to be completely defined. A77 1726 and several malononitriloamide analogues inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. While no one central molecular mechanism of action has been proposed to explain all the effects of the malononitriloamides, inhibition of de novo pyrimidine biosynthesis and inhibition of cytokine- and growth factor-receptor associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered at daily doses of 10 and 25 mg to patients with active rheumatoid arthritis. The improved efficacy at the 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Due to the long plasma half-life of A77 1726 (11-16 days), loading doses are required to achieve steady-state concentrations. Phase III randomised, placebo-controlled trials using daily doses of 10 or 20 mg are underway in the US and Europe to confirm and extend the results of the Phase II study. Malononitriloamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation, because these compounds have a shorter half-life in animals than A77 1726. If these analogues show efficacies similar to leflunomide in these models and have shorter half-lives than A77 1726 in Phase I trials, the preclinical and Phase I data will be used to select the analogues for Phase II trials in organ transplant recipients.

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Section: In Vivomentioning

confidence: 97%

Leflunomide and malononitriloamides

Silva

Morris

1997

Expert Opinion on Investigational Drugs

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“…It was established that LEF could inhibit both T celldependent and -independent B-cell proliferation as well as the formation of antibodies in animal model of autoimmune disease [19]. Currently, investigators mainly focused on the acquired immune system down-regulated by LEF, however, whether LEF played a significant role in innate immune system was not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…LEF (leflunomide), a different structural and functional immunosuppressant to other known immunomodulatory drugs, was proved to significantly inhibit B-cell and T-cell proliferation [6]. Since 1998, LEF has been approved for rheumatoid arthritis treatment and showed therapeutic effects in other autoimmune diseases in animal model including experimental myasthenia gravis [7], experimental autoimmune encephalitis [8], and experimental autoimmune neuritis [9]. Some prospective multi-center observational studies showed that LEF, compared with cyclophosphamide, in combination with prednisone was effective in the induction therapy of proliferative lupus nephritis and was generally well-tolerated [10,11].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice

Yan

et al. 2010

Rheumatol Int

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Mice with chronic graft-versus-host disease (cGVHD) induced by transferring parental BALB/C lymphocytes into (C57BL/6 × BALB/C) F1 (CBF1) hybrids, develop a syndrome characterized by B-cell hyperactivity, autoantibody production, and immune complex-mediated glomerulonephritis. In this model, we evaluated the role of leflunomide on the development of lupus nephritis in system autoimmunity. Daily administration of leflunomide (15 mg/kg/d) from 2 weeks after cGVHD induction can dramatically reduce the production of autoantibodies and immune complex deposition in the kidney, leading to relieved kidney damage and reduced mortality. The therapeutic effect of leflunomide on the lupus-prone mice was partially due to the inhibition of TLR9 signaling pathway, which was an important component of innate immune system.

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“…As per study protocol, leflunomide was washed out with the addition of cholestyramine at a dose of 8 mg three times a day for 10 days, with rapid return of transaminase enzymes to the normal range while the patient continued methotrexate. 4.2% in subjects with and without a loading dose; 28 [21.5%] patients with increases into the abnormal range of ALT in subjects with loading dose and 6 [4.5%] without loading dose; 16 [12.3%] and 5 [3.8%] with increases in AST in subjects with and without a loading dose, respectively). It therefore is apparent that considerable potential toxicity may be avoided when a loading dose of leflunomide is omitted, at least when the drug is added to methotrexate.…”

Section: Follow-up Of the Double-blind Studymentioning

confidence: 89%

“…It was first shown to have disease-modifying properties in a rat model of adjuvant-induced arthritis [2] but has also been studied in several other animal models of immune-based inflammatory disease, including interstitial nephritis [3], myasthenia gravis [4], and systemic lupus erythematosus [5]. Leflunomide was tested in rheumatoid arthritis based on its usefulness in these animal models.…”

mentioning

confidence: 99%

Leflunomide

Cannon¹,

Kremer²

2004

Rheumatic Disease Clinics of North America

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Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide.

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Leflunomide prevents the development of experimentally induced myasthenia gravis

Cited by 37 publications

References 15 publications

Leflunomide and malononitriloamides

Leflunomide and malononitriloamides

Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice

Leflunomide

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