title: Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation.
abstract: OBJECTIVE
  To investigate the interaction between castanospermine and cyclosporin A (CsA) 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 (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure 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 CsA in the prolongation of cardiac allograft survival for dose ranges of CsA 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 CsA. On the contrary, cessation of castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA level (P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction.
  
  
  CONCLUSIONS
  There is synergistic interaction between castanospermine and CsA in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of CsA provides an explanation.
authors.affiliation: Adrian D Hibberd, David A Clark, Paul R Trevillian, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia.
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Hibberd
authors.affiliation: Adrian D Hibberd, David A Clark, Paul R Trevillian, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Clark
authors.affiliation: Adrian D Hibberd, David A Clark, Paul R Trevillian, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Trevillian
authors.affiliation: Adrian D Hibberd, David A Clark, Paul R Trevillian, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mcelduff
keywords: Cardiac transplantation; Castanospermine; Cyclosporin A; Mixed lymphocyte reaction; Positive interaction