title: Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection.
abstract: Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2-5 mg/kg) is much lower than that of MMF (20-60 mg/kg). The purpose of this study was to examine whether high-dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti-donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high-dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 mug/ml. Treatment with high-dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.
authors.affiliation: Department of Surgery II, Nagoya University School of Medicine, Japan.
authors.forename: DaGe
authors.initials: D
authors.lastname: Liu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takaharu
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Itsuo
authors.initials: I
authors.lastname: Yokoyama
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miwa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Kunio
authors.initials: K
authors.lastname: Morozumi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Oikawa
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Shimano
authors.forename: Oki
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Uchida
authors.forename: Akimasa
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000208:Acute Disease; D000818:Animals; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000188:drug therapy*; D006470:Hemorrhage / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007518:Isoantibodies / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology; D009336:Necrosis; D051437:Renal Insufficiency / Q000401:mortality / Q000473:pathology; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000627:therapeutic use; D016879:Salvage Therapy; D016019:Survival Analysis; D013552:Swine; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D012263:Ribonucleosides; C010052:mizoribine; D003404:Creatinine