Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPA- and CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days posttransplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10–60 μg/L. Rabbits having trough whole-blood concentrations of <10 μg/L rejected their grafts. A much wider therapeutic range for CsA (50–300 μg/L) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.
Forty-one heart transplant recipients were monitored serially for the expression of transferrin receptors and T-helper/T-suppressor cytotoxic ratios on circulating lymphocytes during the hospitalization periods after heart transplantations (60.5 +/- 18.9 days). These values were retrospectively correlated with the patients' clinical status with respect to rejection and infection. During clinically stable periods the average values of percentage of transferrin receptor-positive lymphocytes and T-helper/T-suppressor cytotoxic ratios were 5.9 +/- 4.3 and 1.5 +/- 1.0, respectively. The percentage of transferrin receptor-positive lymphocytes increased to a level of 12.0 +/- 5.4 (p less than 0.001) during the early prerejection phase and remained at this level throughout the rejection period. T-helper/T-suppressor cytotoxic ratios increased to 1.96 +/- 0.92 during the early prerejection phase (p less than 0.05), peaked at 2.30 +/- 1.21 during the late prerejection phase (p less than 0.01), but began to decline by the rejection period. After rejection treatment percentage of transferrin receptor-positive lymphocytes decreased to 8.4 +/- 5.3 (p less than 0.05), and T-helper/T-suppressor cytotoxic ratios decreased to normal levels. In contrast, in patients with infectious complications, a remarkably elevated percentage of transferrin receptor-positive lymphocytes (20.7 +/- 11.7) and relatively low T-helper/T-suppressor cytotoxic ratios (1.3 +/- 0.5) were noted. The data show an association between the clinical status, such as rejection and infection, and these immunologic measurements as transferrin receptor-positive lymphocytes and T-helper/T-suppressor cytotoxic ratios in heart transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
PASCOE, EDWARD A.; BARNHART, GLENN R.; CARTER, W. HANS JR.; THOMPSON, JAMES A.; HESS, MICHAEL L.; HASTILLO, ANDREA; SZENTPETERY, SZABOLCS; LOWER, RICHARD R. Author Information
