Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A77 1726 is a malononitrilarnide (MNA) and the active metabolite of leflunomide. Leflunomide has been extensively investigated and shown to be a potent immunosuppressive drug. However, the half-life of A77 1726 is about 15-18 days in humans and the leflunomide is, therefore, currently being evaluated for the treatment of autoimmune disease and not for transplantation. The search for analogues has led to the development of MNA 715 and 279, derivatives of A77 1726. Previous limited experimental experience has shown these MNAs to prevent skin allograft and xenograft rejection and graft-versus-host disease in rodents, and to reverse ongoing allograft rejection. The aim of the present study was to verify the efficacy of these MNAs in a cardiac retransplant model of sensitized rats, concerning prevention of accelerated rejection, inhibition of antibody production and interaction with cyclosporin A (CsA). Heterotopic cardiac transplantation and retransplantation in Dark Agouti (DA) to Piebald Virol Glaxo (PVG) rats was used. Subgroups of rats were given either CsA, MNA 715, MNA 279 or combined CsA/MNA for 10 days starting either day 0 or day -1, as of regrafting or no treatment. Titres of allospecific IgM and IgG were quantitated by flow cytometry. Ten days of MNA 715 or 279 from day -1 prevented accelerated rejection of the retransplant, as did CsA. Neither treatment given from day 0 prevented rejection within 24 h. However, a combination of MNA 715 or 279 and CsA from day 0 effectively prevented accelerated regraft rejection. Production of specific alloantibodies was reduced in all immunosuppressed subgroups, IgG titres at day 7 in MNA-treated subgroups being significantly lower compared with those in the CsA-treated subgroup. In conclusion, MNA 715 and 279 were shown to be potent immunosuppressants with the capacity to prevent accelerated regraft rejection in rat cardiac transplants, most efficiently in combination with CsA, and to suppress specific alloantibody production.
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PMID:Malononitrilamides 715 and 279 prevent accelerated cardiac allograft rejection synergistically with cyclosporin A in presensitized rats. 977 97

Ganciclovir-resistant cytomegalovirus (CMV) infection is an emerging problem in transplant recipients. Foscarnet resistance and cidofovir resistance have also been described, but no previous reports have suggested treatment regimens for patients with CMV refractory to all three of these drugs. Leflunomide, an immunosuppressive drug used in rheumatoid arthritis and in rejection in solid-organ transplantation, has been reported to have novel anti-CMV activity. However, its clinical utility in CMV treatment has not been described previously. We report an allogeneic bone marrow transplant recipient who developed CMV infection refractory to sequential therapy with ganciclovir, foscarnet, and cidofovir. The patient was ultimately treated with a combination of leflunomide and foscarnet. Both phenotypic and genotypic virologic analysis was performed on sequential CMV isolates. The patient's high CMV-DNA viral load became undetectable on leflunomide and foscarnet, but the patient, who had severe graft-versus-host disease (GVHD) of the liver, expired with progressive liver failure and other complications. We concluded that leflunomide is a new immunosuppressive agent with anti-CMV activity, which may be useful in the treatment of multiresistant CMV. However, the toxicity profile of leflunomide in patients with underlying GVHD remains to be defined.
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PMID:Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection. 1548 72

BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation. So far, no specific antiviral drug with proven efficacy has been approved for treating BKV-HC. Leflunomide is an immunosuppressive drug with antiviral activity and has been used in treating BKV-associated nephropathy after renal transplantation. This is the first report on the efficacy and safety of leflunomide in the treatment of BKV-HC. From January 2006 to January 2009, 89 patients received allogeneic hematopoietic stem cell transplantation, and among them, 18 patients were identified as having BKV-HC, with a 20% cumulative incidence. Fourteen patients were treated with oral leflunomide. Three days of 100 mg/day leflunomide was used as loading doses and followed by maintenance doses of 20 mg/day. The urinary BKV-DNA load was monitored weekly by real-time quantitative PCR. The efficacy was evaluated on day 20 after leflunomide treatment. Seven patients (50%) achieved complete remission, 5 patients (35.7%) achieved partial remission, and 2 patients (14.3%) had more than a 1-log reduction in urinary BKV-DNA loads after treatment. During the leflunomide treatment, the graft-versus-host disease of the patients did not progress, and the dosages of the immunosuppressant were reduced simultaneously. One patient discontinued treatment because of intolerable gastrointestinal symptoms. Neutropenia occurred in 2 cases. These preliminary data suggest that leflunomide may be a potentially effective medication for treating BKV-HC without significant toxicity, but evidence supporting its use requires randomized controlled trials.
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PMID:Efficacy and safety of leflunomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. 2342 38