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We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels

Twelve renal transplant recipients randomised to receive immunosuppression with either tacrolimus (FK506) or cyclosporin underwent oral glucose tolerance tests (OGTT) a median of 8 months (range 7-9) after transplantation. Six healthy subjects acted as controls. Compared with the controls, both transplant groups had significantly elevated fasting (p < 0.05 for both groups) and postprandial (p < 0.001 for tacrolimus and p < 0.05 for cyclosporin) blood glucose concentrations. Fasting hyperinsulinaemia was observed in both transplant groups (p < 0.05) relative to the control subjects. Glucose-stimulated plasma immunoreactive insulin concentrations in the tacrolimus-treatment group were significantly higher than in the cyclosporin group (p < 0.05) and the controls (p < 0.001). Postprandial blood alanine concentrations were also significantly elevated in the tacrolimus group compared with both the controls (p < 0.001) and cyclosporin-treated patients (p < 0.001). The raised insulin concentrations with normal or increased blood glucose concentrations after renal transplantation suggests that insulin resistance was more marked in patients receiving tacrolimus-based immunosuppression.

Background: The new microemulsion formulation of cyclosporine (Neoral) has been developed in an effort to improve the reliability of drug absorption. The objectives of this study were to assess the efficacy, safety, and tolerability of Neoral compared to the original formulation (Sandimmun) in liver transplant recipients., Methods: In a double-blind, parallel group study conducted in 28 centers across Europe and the United States, patients receiving primary orthotopic liver allografts were randomized within 24 hr of transplantation, 198 to Neoral and 192 to Sandimmun. Patients with and without T-tube biliary drainage were included. Postoperatively, all patients also received intravenous (i.v.) cyclosporine, together with prednisolone and azathioprine. Antibody induction was excluded. Efficacy measures were rejections, graft failure, patient survival, and the efficacy of the study medication in achieving the desired cyclosporine blood levels. Safety was assessed by reported adverse events, blood pressure, serum creatinine, and other routine laboratory measurements., Results: Kaplan-Meier analyses showed that the Neoral group performed better than the Sandimmun group, with the estimates for patients free of treated rejection and histologically confirmed rejection either showing or approaching statistical significance at the 5% level. By 52 weeks, 5.8% (95% confidence limits: -4.4-15.9%) fewer patients required treatment of acute rejection in the Neoral group. The proportion of patients experiencing at least one treated rejection episode by 2 weeks was 29.8% for Neoral and 43.2% for Sandimmun. For histologically confirmed rejection, these proportions were 32.8% and 44.3%, respectively. The proportion of patients experiencing at least one steroid-resistant rejection was 2.0% for Neoral and 6.3% for Sandimmun at week 2, and 3.0% and 9.9%, respectively, at week 3. All these differences were significant at P<0.05. By 52 weeks, graft failure was 6.3% on Neoral and 11.4% on Sandimmun, with respective patient survival figures of 85.4% and 85.8%. The median duration of the initial episode of i.v. cyclosporine was 4.0 days for Neoral, compared to 6.5 days for Sandimmun (P<0.001). Within the first 2 weeks, a larger percentage of patients in the Neoral group reached the lower target level of cyclosporine (P< or =0.01). The weight-adjusted daily doses of study medication were lower in the Neoral group (median dose: 4.86 vs. 5.42 mg/kg/day, P=0.001), but the blood levels of cyclosporine showed no difference. For those with a T-tube, more of the patients on Neoral remained free of treated rejection throughout the study period (P=0.042, Wilcoxon). By week 2, 44.9% of these patients in the Sandimmun group required treatment for rejection compared to 30.2% in the Neoral group (P=0.007). There was no significant difference between the groups for serum creatinine, blood pressure, other biochemical and hematological variables, or reported adverse events., Conclusions: In liver transplantation in the normal clinical setting, the pharmacokinetic advantages of Neoral translate into clinical superiority over Sandimmun without a negative impact on safety. Recent data indicate that it is not optimal to use i.v. cyclosporine initially in this type of study, but the benefit was seen despite this. In keeping with the previous pharmacokinetic studies, patients managed by T-tube biliary drainage, and hence with no or limited bile available in the gastrointestinal tract, did particularly well with Neoral.

Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandimmune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine.

Background: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection., Methods: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids., Results: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment., Conclusions: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

Background: Recurrence of primary biliary cirrhosis in the liver allograft remains controversial., Methods: We have examined the liver allograft biopsies taken at 1 and 2 years after transplantation from patients receiving either FK506 or cyclosporin as part of a multi-centre trial., Results: Histological features characteristic for primary biliary cirrhosis, including bile duct damage, ductopenia, bile duct proliferation and portal granulomas, were found more commonly and earlier after transplantation in patients receiving FK506 than cyclosporin. During the 2-year period, seven of 16 patients receiving FK506 and only one of 11 on cyclosporin had a graft biopsy suggestive of recurrent primary biliary cirrhosis., Conclusions: These findings confirm earlier reports that features of primary biliary cirrhosis recur in the liver allograft in some patients and suggest that the rate of recurrence may be affected by the immunosuppression regimen used.

Initial clinical trials of FK did not incorporate available FK levels, and difficulties were quickly experienced particularly with neurotoxicity and nephrotoxicity. The introduction of routine assay allowed broad parameters to be identified, which assisted in evaluating effective therapeutic parameters. Levels approximately 20 ng/ml were frequently associated with toxicity and the initial therapeutic range between 10-25 ng/ml was probably excessive. Reliable effective assay > 5 ng/ml using the Abbott IMx is not available, and many patients will have excellent hepatic or renal function with what are currently undetectable levels of FK. However, IncStar have an ELISA assay with a sensitivity of 0.5 mg/ml. Clinical practice does not, at this time, dictate elevation of FK, although careful monitoring continues. Education of oral administration from 0.15 mg/kg to 0.1 mg/kg in combination therapy with steroids and 0.05 mg/kg with azathioprine and steroids has led to revision of therapeutic parameters, e.g., 5-15 ng/ml is now widely used. Therapeutic drug monitoring is important to avoid unnecessary toxicity, but the lower limit has not been fully defined. Clearly, many patients with < 5 ng/ml have excellent hepatic function.

Eighty-one liver recipients were randomised to FK 506 or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-seven FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-sparing effect.

We assessed the immunomodulatory effect of leflunomide (LEF) in a heterotopic abdominal model of rat heart transplantation using a major histocompatibility mismatch (DA X LEW). The endpoint of this study was cardiac rejection assessed by abdominal palpation of the ventricular impulse and confirmed by laparotomy and histology. In this study, LF was investigated using four dosages (5, 10, 20 and 30 mg/kg per day orally) against cyclosporine (CsA) (15 mg/kg per day orally) and FK 506 (1 mg/kg per day orally). The ability of LEF to prevent rejection and reverse ongoing acute rejection was assessed. The results showed that untreated hearts were fully rejected by day 5 and that LEF at 5 mg/kg was significantly better than any other dose tested, was superior to FK 1 mg/kg, and was as effective as CsA 15 mg/kg in preventing rejection after a short course of treatment. After a longer course, 10 and 20 mg/kg LEF proved more effective than 5 mg/kg in controlling rejection and as efficacious as 1 mg/kg FK and 15 mg/kg CsA. In the control of ongoing established early rejection. LEF proved to be equally effective, even at lower doses (5 mg/kg), to CsA 15 mg/kg and FK 1 mg/kg. In the control of ongoing established late rejection, 20 mg/kg LEF proved to be superior to 10 mg/kg LEF and 15 mg/kg CsA, and was as effective as FK 1 mg/kg. However, when higher doses of CsA (25 mg/kg) and FK (2 mg/kg) were tested against 20 mg/kg LEF in this mode of rescue, LEF proved as effective as CsA and superior to FK. In the assessment of drug toxicity using body weight as a parameter, 20 mg/kg LEF proved safer than any other LEF dose tested, and safer than 15 mg/kg CsA and 1 mg/kg FK in both short- and long term administration. We conclude that LEF is a relatively safe and potent immunosuppressant with promising clinical potential.

Steroid therapy was withdrawn in 85% of 152 orthotopic liver transplant recipients with grafts surviving for more than 3 months, and 87% of these remained steroid-free. Steroid therapy was restarted in 8% for reasons other than rejection. The most common was conversion of immunosuppression because of cyclosporine nephrotoxicity. The incidence of rejection after steroid withdrawal was low: 3.8% for chronic rejection (CR) and 4.5% for acute rejection. Only 3 grafts (1.9%) were lost because of CR. No risk factors have been identified for the development of CR after steroid withdrawal, but a protective role for azathioprine has been suggested.