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15 Deoxyspergualin

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Noboru Takasaki – One of the best experts on this subject based on the ideXlab platform.

  • Sensitization interval and administration method alter the effect of 15Deoxyspergualin on heart transplantation in sensitized recipient rats
    Transplant International, 1996
    Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Noboru Takasaki
    Abstract:

    We evaluated the effect of 15Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and that postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.

Haruhiko Ueda – One of the best experts on this subject based on the ideXlab platform.

  • Sensitization interval and administration method alter the effect of 15Deoxyspergualin on heart transplantation in sensitized recipient rats
    Transplant International, 1996
    Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Noboru Takasaki
    Abstract:

    We evaluated the effect of 15Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and that postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.

  • Sensitization interval and administration method alter the effect of 15Deoxyspergualin on heart transplantation in sensitized recipient rats.
    Transplant international : official journal of the European Society for Organ Transplantation, 1996
    Co-Authors: Haruhiko Ueda, S. Itoh, Yusaku Iwamoto, Takasaki N
    Abstract:

    We evaluated the effect of 15Deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and the postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.

  • Effect of 15Deoxyspergualin on accelerated rejection in rat heart transplantation
    European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes, 1994
    Co-Authors: Haruhiko Ueda, S. Itoh, H. Azuma, K. Isurugi, C. Yutani
    Abstract:

    The effect of 15Deoxyspergualin (DSG) on accelerated rejection was evaluated using a rat heart transplantation model. Lewis rats (LEW, RT1l) served as the organ recipient and Brown Norway rats (BN, RT1n) as the donor. In the accelerated rejection model, the LEW recipient was sensitized with BN skin and BN heart was transplanted 7 days later; the heart graft was rejected within 2 days (n = 7). Histologically, the graft showed coagulation necrosis and hemorrhage throughout the myocardium. DSG (2.5 mg/kg/day) was administered to the recipient under the following three protocols: group 1: during the sensitization period (7 days); group 2: from 3 days after the sensitization to 2 days after grafting (7 days), and group 3: immediately after heart transplantation. The mean graft survival period in groups 1, 2, and 3 was 4.3 +/- 0.8 days (n = 7, p < 0.01 vs untreated host), 11.7 +/- 2.1 days (n = 7, p < 0.001, vs. untreated host), and 2.0 +/- 0 days (n = 6), respectively. The rejected grafts in groups 1 and 3 histologically showed coagulation necrosis and hemorrhage. By contrast, in group 2, the major histological change was interstitial lymphocyte infiltration and there were few findings such as coagulation necrosis or hemorrhage. In the complement-dependent cytotoxicity test, serum obtained at the second posttransplant day from the recipients treated in group 1 showed a high cytotoxicity level, although the cytotoxicity level of serum obtained from the recipients treated in group 2 was consistently low.(ABSTRACT TRUNCATED AT 250 WORDS)

Renaut Patrice – One of the best experts on this subject based on the ideXlab platform.

  • a new efficient synthesis of the immunosuppressive agent 15 Deoxyspergualin
    Tetrahedron, 2001
    Co-Authors: Philippe Durand, Philippe Peralba, Renaut Patrice
    Abstract:

    Abstract (±)-15Deoxyspergualin is a new promising immunosuppressive agent, recently marketed in Japan for the control of corticoresistant acute renal graft rejection. We describe here a nine-step synthesis starting from 7-bromoheptanenitrile and N1,N4-bis(benzyloxycarbonyl)spermidine, suitable for the production of multigram quantities of this unstable highly polar compound with an 18% overall yield. Furthermore, it opens the way for the synthesis of α-hydroxyglycine analogues.

  • Structure-immunosuppressive activity relationships of new analogues of 15Deoxyspergualin. 2. Structural modifications of the spermidine moiety.
    Journal of medicinal chemistry, 1999
    Co-Authors: Luc Lebreton, Eric Jost, Bertrand Carboni, Jocelyne Annat, Michel Vaultier, Patrick Dutartre, Renaut Patrice
    Abstract:

    A series of new analogues of 15Deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-hosthost disease (GVHD) model in mice. Various substitutions of the spermidine “D” region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene α to the primary aminamine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated ana…

  • 15 Deoxyspergualin a new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration
    Journal of Organic Chemistry, 1998
    Co-Authors: Philippe Durand, Philippe Richard, Renaut Patrice
    Abstract:

    (±)-15Deoxyspergualin (DSG) has recently been marketed in Japan for the control of corticoresistant acute renal graft rejection. A nine-step total synthesis of its eutomer ((−)-DSG) 2 has been developed starting from 7-bromoheptanenitrile 3 and N1,N4-bis(benzyloxycarbonyl)spermidine. The use of a chiral α-alkylbenzyl group to protect the hydroxyl of the α-hydroxyglycine moiety allowed its chromatographic resolution and afforded a practical access to 2 with a high optical purity and a 7% overall yield. Moreover, X-ray structure analysis of the key crystalline intermediate 7b definitely confirmed the previously proposed absolute configuration of 2.