Protopic
Does topical tacrolimus induce lentigines in children with atopic dermatitis? A report of three cases.

Hickey JR, Robson A, Barker JN, Smith CH.

Skin Therapy Research Unit and Department of Dermatopathology, St Thomas' Hospital, London SE1 7EH, UK. jameshickey71 hotmail.com

Three children with severe atopic dermatitis were noted at routine follow-up to have developed multiple small pigmented macules during long-term therapy with topical tacrolimus 0.1% (Protopic, Fujisawa). Representative lesions in two of the three cases were confirmed histologically as simple lentigines. The focal distribution of lentigines to sites of tacrolimus use, and the temporal association between use of tacrolimus and development of lesions, suggest that topical tacrolimus is of direct aetiological relevance to their development. Careful long-term follow-up will be required to assess the clinical implications of these findings and whether they represent an increase in risk for melanocytic neoplasia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15656817&dopt=Abstract tacrolimus Protopic



Protopic
Topical tacrolimus.

Frankel SJ, Kerdel FA.

Department of Dermatology, University of Miami School Of Medicine, Miami, Florida, USA.

Tacrolimus, available for intravenous, oral and now topical administration, is a potent immunosuppressive agent with the ability to block the production of Interleukin-2 (IL-2) and inhibit T-cell proliferation. Originally developed for use in organ transplantation, it is currently being studied for the treatment of inflammatory dermatoses. The US FDA recently approved tacrolimus ointment (Protopic (R), Fujisawa) for the treatment of atopic dermatitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11176043&dopt=Abstract tacrolimus Protopic



Protopic
Pharmacokinetics and bioavailability of tacrolimus in rats with experimental renal dysfunction.

Okabe H, Hashimoto Y, Inui KI.

Department of Pharmacy, Kyoto University Hospital, Kyoto University, Japan.

The effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in rats. Experimental renal dysfunction was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)) into rats. The blood concentration of tacrolimus was measured after intravenous and intra-intestinal administration of the drug. The blood concentration of tacrolimus after intravenous administration (1 mg kg(-1)) was slightly increased (up to 1.3 fold) by induction of renal dysfunction. In contrast, the peak tacrolimus concentration after intra-intestinal administration (1 mg kg(-1) or 3 mg kg(-1)) in rats with renal failure was about 2-fold higher than that in normal controls. The bioavailability was increased by about 35% in rats with impaired renal function as compared with normal controls. These results suggested that the bioavailability of tacrolimus, which is mainly metabolized in the liver and intestine after oral administration, is also influenced by renal function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11197074&dopt=Abstract tacrolimus Protopic



Protopic
Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression.

Paolillo JA, Boyle GJ, Law YM, Miller SA, Lawrence K, Wagner K, Pigula FA, Griffith BP, Webber SA.

Department of Pediatrics, University of Pittsburgh School of Medicine, PA 15213, USA.

BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is a well-known complication of tacrolimus-based immunosuppression in both adult and pediatric solid organ recipients. The "natural history" of diabetes in the pediatric thoracic transplant population has not yet been described. METHODS: We identified all pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression who developed PTDM. Medical records were reviewed, with a particular focus on the clinical course of PTDM and its relationship to drug weaning. RESULTS: Diabetes developed in 24 of 143 (17%) 30-day survivors of heart (12/96, 13%) and heart-lung/lung (12/ 47, 26%) transplantation. In 17 (71%) patients, the immunosuppressive regimen at the onset of PTDM also included maintenance corticosteroids. Seventeen patients demonstrated glucose intolerance before the onset of diabetes. Nine patients (38%) developed diabetes during pulsed corticosteroid therapy. Median time of onset after transplantation was 9.0 months. All patients required s.c. insulin for glucose control. The median follow-up from transplant was 49.9 months. There was a significant decrease in mean tacrolimus dosage (P<0.01), tacrolimus level (P<0.04), and steroid dosage (P<0.02) from onset of PTDM to most recent follow-up. Despite this significant reduction in immunosuppression, only 3/24 (13%) patients were successfully weaned off insulin. CONCLUSIONS: Diabetes mellitus is a common complication in pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression. Insulin dependence in our population rarely resolved, even after lowering tacrolimus and steroid doses. Discontinuation of steroids did not guarantee resolution of diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11213069&dopt=Abstract tacrolimus Protopic



Protopic
Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells.

Lee YR, Yang IH, Lee YH, Im SA, Song S, Li H, Han K, Kim K, Eo SK, Lee CK.

College of Pharmacy, Chungbuk National University, Cheongju, Korea, Republic of.

The main targets for the immunosuppressive calcineurin inhibitors, cyclosporin A (CsA) and tacrolimus, have been considered to be activated T cells, but not antigen presenting cells. Here we demonstrate that CsA and tacrolimus, but not rapamycin, inhibit major histocompatibility complex (MHC)-restricted antigen presentation in dendritic cells (DCs). Microencapsulated ovalbumin (OVA) was efficiently captured, processed and presented on both class I MHC molecules (cross-presentation) as well as on class II MHC molecules. Addition of CsA and tacrolimus, but not rapamycin, to cultures of DCs inhibited both class I processing pathway and class II processing pathway of exogenous OVA. In addition, CsA and tacrolimus, but not rapamycin, also inhibited classical class I processing pathway of endogenous OVA. CsA and tacrolimus did not inhibit presentation of exogenously added OVA peptide, SIINFEKL, phagocytic activity of DCs, nor the total level of expression of class I MHC (H-2K(b)) molecules. CsA and tacrolimus, however, inhibited profoundly the expression of SIINFEKL-H-2K(b) complexes in OVA-phagocytized DCs. These results demonstrate clearly that CsA and tacrolimus inhibit intracellular processing events of antigens, and further suggest that the immunosuppressive activity of CsA and tacrolimus is at least in part due to inhibition of antigen processing pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15657176&dopt=Abstract tacrolimus Protopic



Protopic
Covariate effects on the apparent clearance of tacrolimus in paediatric liver transplant patients undergoing conversion therapy.

Garcia Sanchez MJ, Manzanares C, Santos-Buelga D, Blazquez A, Manzanares J, Urruzuno P, Medina E.

Pharmacy Department, University of Salamanca, Spain. mjgarcia gugu.usal.es

OBJECTIVE: To analyse the influence of covariates on the apparent clearance (CL) of tacrolimus in paediatric liver transplant recipients being converted from cyclosporin to tacrolimus. DESIGN: Retrospective modelling study. PATIENTS and PARTICIPANTS: 18 children, 13 girls and 5 boys, aged 4 months to 16 years (median 9.1 years) who required conversion to tacrolimus because of acute or chronic rejection or cyclosporin toxicity. METHODS: 287 whole-blood tacrolimus concentrations from therapeutic drug monitoring were used to build a nonlinear mixed-effects population model (NONMEM program) for the apparent clearance of tacrolimus. Variables considered were age, total bodyweight (TBW), body surface area (BSA), time after initiation of treatment (T), gender, haematocrit (Hct), albumin (Alb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gammaGT), alkaline phosphatase (ALP), bilirubin (BIL), creatinine clearance (CL(CR)) and dosage of concomitant corticosteroids (EST). RESUTLS: TBW, T, BIL and ALT were the covariates that displayed a significant influence on CL according to the final regression model: CL (L/h) = 10.4(TBW/70)3/4 x e(-0.00032 T) x e(-0.057 BIL) x (1 - 0.079 ALT). With this model, the estimates of the coefficients of variation were 24.3% and 29.5% for interpatient variability in CL and residual variability, respectively. CONCLUSIONS: The proposed model for tacrolimus CL can be applied for a priori dosage calculations, although the results should be used with caution because of the unexplained variability in the CL. We therefore recommended close monitoring of tacrolimus whole blood concentrations, especially within the first months of treatment. The best use of the model would be its application in dosage adjustment based on therapeutic drug monitoring and the Bayesian approach.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11236810&dopt=Abstract tacrolimus Protopic



Protopic
Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function.

Emre S, Gondolesi G, Polat K, Ben-Haim M, Artis T, Fishbein TM, Sheiner PA, Kim-Schluger L, Schwartz ME, Miller CM.

Recanati/Miller Transplantation Institute, The Mount Sinai Hospital of Mount Sinai-NYU Health, One Gustave L. Levy Pl., New York, NY 10029, USA. sukru.emre mountsinai.org

The addition of daclizumab (a human immunoglobulin G1 monoclonal antibody that blocks interleukin-2 receptors on T lymphocytes) to mycophenolate mofetil (MMF) and steroids is a new option for initial immunosuppression in patients undergoing liver transplantation (LT) with impaired renal function. We evaluated the efficacy and safety of daclizumab in preventing rejection in 25 patients with impaired kidney function undergoing LT. Patients with serum creatinine (Cr) levels greater than 2 mg/dL immediately before LT were administered initial immunosuppression with daclizumab, 1 mg/kg, in addition to MMF, 2 g/d, and methylprednisolone. Tacrolimus was added after kidney function improved (when Cr levels improved by >25% of initial value). Daclizumab-treated patients were compared retrospectively with 2 other groups of patients who underwent LT with kidney impairment (Cr > 2 mg/dL): 56 patients were administered OKT3 induction, and 48 patients were administered low-dose tacrolimus. The incidence of rejection and infection (bacterial, fungal, and viral), need for preoperative and postoperative dialysis, Cr level immediately post-LT and at 3 months, and graft and patient survival were analyzed. There was no difference among the groups in 3-month Cr levels or the incidence of rejection or fungal or viral infection. The daclizumab group had fewer bacterial infections (n = 13) than the tacrolimus group (n = 28) and significantly fewer than the OKT3 group (n = 58; P =.006). Only 1 patient (4%) in the daclizumab group required dialysis post-LT versus 13 patients in each of the other groups (OKT3, 23.21%; P <.05; tacrolimus, 27%). In the daclizumab group, 2-year patient and graft survival rates were statistically significant compared with the low-dose tacrolimus group (89% and 81% v 73% and 69%, respectively; P =.06). There were no side effects related to daclizumab use, and all patients tolerated the drug well. In patients with impaired renal function before LT, daclizumab-based initial immunosuppression can be used safely to reduce the risk for infection and need for dialysis post-LT, with improved long-term graft and patient survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11244163&dopt=Abstract tacrolimus Protopic