AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral cons...AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG(donor) and DA(recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later(C_2). The blood levels of Cs A(Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay(EMIT) on Cobas Mira. Statistical analyses of interactions were done by an acceleratedfailure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and Cs A in the prolongation of cardiac allograft survival for dose ranges of Cs A by castanospermine of(0 to 2) mg/kg by(0 to 200) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and(0 to 3) mg/kg by(0 to 100) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of Cs A. On the contrary, cessation of castanospermine in the presence of Cs A at 2 mg/kg significantly increased the Cs A level(P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between castanospermine and Cs A in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of Cs A provides an explanation.展开更多
基金Supported by Kiriwina Investments Limited of Australia
文摘AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG(donor) and DA(recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later(C_2). The blood levels of Cs A(Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay(EMIT) on Cobas Mira. Statistical analyses of interactions were done by an acceleratedfailure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and Cs A in the prolongation of cardiac allograft survival for dose ranges of Cs A by castanospermine of(0 to 2) mg/kg by(0 to 200) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and(0 to 3) mg/kg by(0 to 100) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of Cs A. On the contrary, cessation of castanospermine in the presence of Cs A at 2 mg/kg significantly increased the Cs A level(P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between castanospermine and Cs A in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of Cs A provides an explanation.
