The interaction between FK778 and tacrolimus in the prevention of rat cardiac allograft rejection is dose dependent

TY - JOUR

T1 - The interaction between FK778 and tacrolimus in the prevention of rat cardiac allograft rejection is dose dependent

AU - Deuse, Tobias

AU - Schrepfer, Sonja

AU - Reichenspurner, Hermann

PY - 2004/2/27

Y1 - 2004/2/27

N2 - OBJECTIVE: The synthetic malononitrilamide FK778 inhibits T- and B-cell responsiveness, phagocyte effector function, exerts inhibitory activity against cytomegalovirus, and is thus one of the most promising new immunosuppressive drugs. The aim of this study was to evaluate the combination of FK778 and tacrolimus in a high-responder rat cardiac transplantation model.METHODS: The Brown Norway-Lewis rat strain combination was used to investigate graft survival after 10 days of posttransplant oral therapy with FK778 (5 or 20 mg/kg), tacrolimus (2 or 8 mg/kg), or combination regimens at varying doses (5+2 mg/kg, 10+1 mg/kg, or 20+8 mg/kg). Grafts were harvested after cessation of cardiac contractions. Combination indices (CI) were calculated for drug combinations.RESULTS: In untreated recipients, allograft survival was 6.2+/-0.4 days. FK778 at 20 mg/kg and tacrolimus at 2 or 8 mg/kg significantly prolonged graft survival to a mean survival time (MST) of 17.0+/-2.8, 18.5+/-2.7, and 25.0+/-2.5 days, respectively. The two low-dose drug combinations achieved a graft survival of 23.2+/-2.9 and 25.2+/-3.1 days, which was significantly longer compared with FK778 at 5 mg/kg, FK778 at 20 mg/kg, and tacrolimus at 2 mg/kg (P CONCLUSIONS: This study provides evidence that FK778 and tacrolimus show supportive interaction in their immunosuppressive potency that is synergistic in low-dose combinations and additive in higher doses.

AB - OBJECTIVE: The synthetic malononitrilamide FK778 inhibits T- and B-cell responsiveness, phagocyte effector function, exerts inhibitory activity against cytomegalovirus, and is thus one of the most promising new immunosuppressive drugs. The aim of this study was to evaluate the combination of FK778 and tacrolimus in a high-responder rat cardiac transplantation model.METHODS: The Brown Norway-Lewis rat strain combination was used to investigate graft survival after 10 days of posttransplant oral therapy with FK778 (5 or 20 mg/kg), tacrolimus (2 or 8 mg/kg), or combination regimens at varying doses (5+2 mg/kg, 10+1 mg/kg, or 20+8 mg/kg). Grafts were harvested after cessation of cardiac contractions. Combination indices (CI) were calculated for drug combinations.RESULTS: In untreated recipients, allograft survival was 6.2+/-0.4 days. FK778 at 20 mg/kg and tacrolimus at 2 or 8 mg/kg significantly prolonged graft survival to a mean survival time (MST) of 17.0+/-2.8, 18.5+/-2.7, and 25.0+/-2.5 days, respectively. The two low-dose drug combinations achieved a graft survival of 23.2+/-2.9 and 25.2+/-3.1 days, which was significantly longer compared with FK778 at 5 mg/kg, FK778 at 20 mg/kg, and tacrolimus at 2 mg/kg (P CONCLUSIONS: This study provides evidence that FK778 and tacrolimus show supportive interaction in their immunosuppressive potency that is synergistic in low-dose combinations and additive in higher doses.

KW - Alkynes

KW - Animals

KW - Dose-Response Relationship, Drug

KW - Drug Synergism

KW - Graft Rejection/prevention & control

KW - Graft Survival

KW - Heart Transplantation

KW - Immunosuppressive Agents/administration & dosage

KW - Isoxazoles/administration & dosage

KW - Male

KW - Nitriles

KW - Rats

KW - Rats, Inbred BN

KW - Tacrolimus/administration & dosage

U2 - 10.1097/01.tp.0000113443.70993.8c

DO - 10.1097/01.tp.0000113443.70993.8c

M3 - SCORING: Journal article

C2 - 15084926

VL - 77

SP - 509

EP - 513

JO - TRANSPLANTATION

JF - TRANSPLANTATION

SN - 0041-1337

IS - 4

ER -