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Mechanistic Study of Malononitrileamide FK778 in Cardiac Transplantation and CMV Infection in Rats

Mechanistic Study of Malononitrileamide FK778 in Cardiac Tra...

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首届全国中青年风湿病学学术大会

作者： James Waldman deborah a knight Anita S Chong James W Williams Department of Pathology Ohio State University Lab of Transplantation Immunology University of Chicago

Background: FK778 is a malononitrilamide, a class of immune suppressive compounds with anti viral featuresand experimental activity in chronic rejection, a potentially interesting combination for organ *** goal of this project was to study the tolerability, immune suppressive efficacy, and anti CMV activity ofFK778 and to assess the in vivo relevance of its previously described inhibition of de novo ***: Heart transplants were performed in rats (BN to Lewis) and treated with varying doses of FK778 orleflunomide for 28 days. At 28 days, at the time of rejection or at the death of the animal, the allograft andother vital organs were obtained for study by light microscopy and immunohistochemistry. In separateexperiments, Lewis rats were given sub-lethal irradiation, inoculated with rat CMV (Maastricht strain) andtreated with varying doses of FK778 and leflunomide. In both the transplant and CMV studies, IP uridinewas given at 250 mg/kg to cohorts or animals receiving FK778 and ***: FK778 controls acute rejection, and inhibits CMV replication at 20 mg/kg but is toxic at 25 mg/*** is manifested as anemia, changes in hepatic and intestinal histology and mortality. The toxicity butnot the immune suppressive or anti viral efficacy, is reduced significantly by exogenous uridine ***: FK778 has both immune suppressive and anti viral activities, neither of which are dependent oninhibition of pyrimidine synthesis. These, and other published observations, suggest that the antiviral activityand a considerable part of the efficacy of the malononitrilamide family of drugs is attributable to activities otherthan drug induced pyrimidine deficiency.

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Mechanistic Study of Malononitrileamide FK778 in Cardiac Traasplantation and CMV Infection Rats

Mechanistic Study of Malononitrileamide FK778 in Cardiac Tra...

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中华医学会第十四次全国儿科学术会议

作者： Anita S Chong James W Williams James Waldman deborah a knight 广州市儿童医院内科免疫性疾病专业(过敏免疫风湿科) ImmunologY LabDepartment of Organ Tranplantation University of Chicago Department Of PatholOgYOh．o State University

Background: FK778 is a malononitrilamide, a class ofimmune suppressive compounds with anti Viral features alld experimental amiVity in chronic rejection, a potentiallyinteresting combination for organ *** goal ofthisproject Was to studythetolcrabilit) , immune suppressiVeemcacy, and anti CMV activityofFK778 andt0 assess the in vivo relevance ofits previOIlSly described *** of de novo pyrimidine ***: Hearttransplants wereperformed in rats (BN to Lewis) and treated with varying doses of FK778 orlenunomide for 28 days. At 28 days, at the time ofrejection or at the death of the allimal, the allograft and other VitaJ organs were obtained for study by

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