Protopic
Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

Cacciarelli TV, Reyes J, Jaffe R, Mazariegos GV, Jain A, Fung JJ, Green M.

Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 3601 Fifth Ave., Pittsburgh, PA 15213, USA. cacciarellitv msx.upmc.edu

While the overall incidence of post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients has been reported to be 4-11%, the long-term risk of PTLD associated with primary tacrolimus therapy is unknown. Therefore, in order to determine the incidence and long-term risk of PTLD, the present study examined 131 pediatric recipients who underwent liver transplantation (LTx) between October 1989 and December 1991 and received primary tacrolimus therapy. This cohort of children was evaluated over an extended time-period (until December 31 1996) with a mean follow-up of 6.3 yr. Actuarial Kaplan-Meier analysis was utilized to determine the risk of PTLD over time. The overall incidence of PTLD was 13% (17/131) with an average age of 4.3 +/- 0.75 yr at diagnosis. Pretransplant Epstein-Barr virus (EBV) serologies were negative in 82%, positive in 12%, and not available in 6% of the patients. The median time to diagnosis of PTLD post-Tx was 11.9 months (mean 16.4 +/- 3.9, range 1.7-63.0 months). Mean tacrolimus dose and plasma trough level (as evaluated by enzyme-linked immunosorbent assay [ELISA]) at the time of diagnosis was 0.32 +/- 0.06 mg/kg/day and 1.3 +/- 0.3 ng/mL, respectively. The cumulative long-term risk of PTLD was found to increase over time: 3% at 6 months, 8% at 1 yr, 12% at 2 yr, 14% at 3 yr, and 15% at 4 and 5 yr. Mortality from PTLD was 12% (two of 17 patients). Primary tacrolimus use in pediatric LTx has a long-term risk of PTLD approaching 15%, with the majority of episodes (78%) occurring in the first 2 yr, suggesting that intense EBV surveillance should occur early post-transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11560756&dopt=Abstract tacrolimus Protopic



Protopic
Lymphocyte suppression by glucocorticoids with cyclosporine, tacrolimus, pentoxifylline, and mycophenolic acid.

Briggs WA, Eustace J, Gimenez LF, Choi MJ, Scheel PJ Jr, Burdick JF.

Johns Hopkins University School of Medicine, Division of Nephrology, Baltimore, Maryland 21505-2196, USA.

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen-stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10(-7) mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 microg/ml pentoxifylline, and 10(-7) mol/L mycophenolic acid. Under each experimental condition, the mean +/- SD % inhibition of PHA-stimulated 3H-thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 +/- 17 versus prednisolone 28 +/- 14, p < 0.001; methylprednisolone + cyclosporine 76 +/- 18 versus prednisolone + cyclosporine 52 +/- 18, p < 0.001; methylprednisolone + tacrolimus 74 +/- 18 versus prednisolone + tacrolimus 50 +/- 20, p = 0.001; methylprednisolone + mycophenolic acid 69 +/- 14 versus prednisolone + mycophenolic acid 46 +/- 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11563403&dopt=Abstract tacrolimus Protopic



Protopic
Impact of tacrolimus and bone marrow augmentation on intestinal allograft survival and intragraft cytokine expression in rats.

Nakao A, Kobayashi E, Shen SD, Yoshino T, Tanaka N.

First Department of Surgery, Okayama University Medical School, Japan.

Effects of simultaneous bone marrow transplantation (BMT) with a short course of tacrolimus on a heterotopic small bowel transplantation (SBT) were tested in a high responder rat combination of ACI (RT1avl) to LEW (RTIl). Intestinal allograft survival and changes of intragraft cytokine expression by this treatment were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Only the treatment with donor specific BMT via portal vein plus a short course of tacrolimus (1.0 mg/Kg for 3 days) significantly prolonged allograft survival (mean +/- SD; 11.7 +/- 1.9 days), while the grafts were rejected at 4 to 8 days by other control treatments. More beneficial effect of donor type BMT via portal vein on allograft survival was achieved (19.0 +/- 2.2 days) by containing administration of a lower dose of tacrolimus (0.5 mg/Kg for 11 days). Both gene expression of IFN-gamma and infiltration of IFN-gamma-producing cells were strongly suppressed by this protocol, while tacrolimus treatment alone could not suppress IFN-gamma production. Tacrolimus treatment added with donor specific BMT down-regulated IL-12 and IFN-gamma transcript, resulted in a significant prolongation of intestinal allograft survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11563819&dopt=Abstract tacrolimus Protopic



Protopic
Population pharmacokinetics of tacrolimus in children who receive cut-down or full liver transplants.

Staatz CE, Taylor PJ, Lynch SV, Willis C, Charles BG, Tett SE.

School of Pharmacy, University of Queensland, Brisbane, Queensland 4072, Australia. s.tett pharmacy.uq.edu.au.

BACKGROUND: The aim of this study was to investigate the population pharmacokinetics of tacrolimus in pediatric liver transplant recipients and to identify factors that may explain pharmacokinetic variability. METHODS: Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimates were sought for the typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, postoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirubin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clearance, hematocrit, corticosteroid dose, and concurrent therapy with metabolic inducers and inhibitors of tacrolimus. RESULTS: No clear correlation existed between tacrolimus dosage and blood concentrations (r2=0.003). Transplant type, age, and liver function test values were the most important factors (P<0.01) that influenced the pharmacokinetics of tacrolimus. CL/F estimates were greater in whole liver recipients, decreased with increasing patient age and AST values, and increased with increasing GGT values. Average parameter estimates were CL/F=5.75 L/h (cut-down liver), CL/F=44 L/h (whole liver), and V/F=617 L. Marked intersubject variability (CV%=110% to 297%) and residual variability (CV%=42%) was observed. CONCLUSIONS: Pharmacokinetic information obtained in this study may assist physicians in making individualized dosage decisions in regard to tacrolimus in pediatric liver transplant recipients. Children who received a whole child's liver appeared to retain "pediatric" clearance, whereas those who received a cut-down adult liver had "adult" clearances (on average 7-fold less).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11579300&dopt=Abstract tacrolimus Protopic



Protopic
Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience.

Selzner N, Durand F, Bernuau J, Heneghan MA, Tuttle-Newhall JE, Belghiti J, Clavien PA.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

BACKGROUND: Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function. METHODS: The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France). RESULTS: Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss. CONCLUSIONS: These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11579301&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts.

Sloper CM, Powell RJ, Dua HS.

Department of Ophthalmology, Queen's Medical Centre, Nottingham, England.

OBJECTIVE: To assess the efficacy and side effects of tacrolimus in the management of patients with high-risk corneal and limbal grafts. DESIGN: Noncomparative case series. PARTICIPANTS: Seventeen patients (23 grafts) were treated with tacrolimus; 15 patients (20 host corneas) had two or more quadrants of stromal vascularization, 6 patients had stem cell deficiency, and 6 patients had glaucoma. Seven patients had received one previous graft, six patients had two previous grafts, and four patients had three previous grafts. INTERVENTION: Patients with high-risk corneal and limbal grafts were treated with systemic tacrolimus at a mean optimum dosage of 4.4 mg daily (range, 2-12 mg daily). MAIN OUTCOME MEASURES: Graft survival, visual acuity. RESULTS: No patient has had irreversible graft rejection while receiving tacrolimus. The follow-up period ranges from 12 to 46 months, with a mean of 24 months. Three patients have had reversible graft rejection associated with low tacrolimus levels. Nine patients have stopped treatment; two had reversible rejection within 2 months of stopping, and five grafts remain clear. The other four patients stopped treatment because of graft failure, which was not considered to be rejection related. Eight patients remain on treatment, and all have clear grafts. CONCLUSIONS: Tacrolimus (FK506) is effective in prevention of rejection in patients with high-risk corneal and limbal grafts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11581059&dopt=Abstract tacrolimus Protopic



Protopic
In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil.

Morissette P, Albert C, Busque S, St-Louis G, Vinet B.

Department of Biochemistry, Center Hospitalier de l'Universite de Montreal, Notre-Dame Hospital, Montreal, Quebec, Canada.

Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transplantation to prevent rejection, is being used increasingly in association with cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metabolized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentrations of MPAG in serum are many times the concentrations of MPA. Although MPAG has not shown immunosuppressant activity, it was postulated that it could displace MPA from its binding sites on albumin and hence increase the biologic effects of MPA. This effect could be important for patients with acute renal failure; under this condition, MPAG was shown to accumulate. The goal of this study was to document the MPAG/MPA concentration ratio in 100 renal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo from bound albumin in a representative renal transplant patient population under immunosuppressive therapy. Levels of MPAG and MPA were measured by high-performance liquid chromatography. The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transformation of the data, parametric analysis was possible. The average MPAG/MPA ratio was 15.0 +/- 2.2 for men versus 7.7 +/- 0.9 for women. Men treated with MMF and tacrolimus showed a lower ratio than patients treated with MMF and cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA. Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with tacrolimus must be taken into consideration when MMF is being administered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11591897&dopt=Abstract tacrolimus Protopic