Protopic
Pediatric post-transplant diabetes: data from a large cohort of pediatric heart-transplant recipients.

Hathout EH, Chinnock RE, Johnston JK, Fitts JA, Razzouk AJ, Mace JW, Bailey LL.

Pediatric Diabetes Center & Pediatric Heart Transplant Program, Loma Linda University Children's Hospital, California, USA. EHATHOUT AHS.LLUMC.EDU

A retrospective analysis of 381 pediatric heart-transplant recipients was performed to determine the frequency, characteristics, and risk factors for post-transplant diabetes. The rate of post-transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25-13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post-transplant diabetes rate in tacrolimus-converted children (n = 45) was 8.8%. In tacrolimus-converted children, age at transplant, mean and maximum tacrolimus blood levels, and first-year rejection episodes were higher in the post-transplant diabetes group, which also consistently had DR-mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus-converted children. In conclusion, pediatric post-transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post-transplant diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12859535&dopt=Abstract tacrolimus Protopic



Protopic
Effects of cyclosporine and tacrolimus on maintenance therapy after renal transplantation.

Balal M, Paydas S, Sertdemir Y, Karayaylali I, Seyrek N.

Cukurova University, Faculty of Medicine, Adana, Turkey.

The immunosuppressive agents cyclosporine A and tacrolimus have demonstrated efficacy in preventing acute organ rejection after renal transplantation, but no comparative studies of these 2 agents have been published. This study compared the effects of tacrolimus and cyclosporine A on the renal function, blood pressure, and serum glucose and lipid levels of patients who underwent cyclosporine A therapy and C2 monitoring or tacrolimus therapy and standard monitoring during the first 24 months after transplantation. By the end of the follow-up period, no significant difference between either treatment group was noted in the measures of creatine clearance; BUN, glucose, uric acid, and lipid levels; or diastolic blood pressure (P>.05 for all), which were maintained at normal values throughout the study. Systolic blood pressure was significantly lower in the cyclosporine A group at the end of the 1 st month (P<.025) but this difference was not evident at months 6, 12, and 24 (P>.05). These results indicate that tacrolimus and cyclosporine (when combined with C2 monitoring) were equally effective and safe in preventing acute organ rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15509135&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus ointment for the treatment of atopic dermatitis: report of first clinical experience in Taiwan.

Lan CC, Huang CC, Chen YT, Wang LF, Lin CT, Chen GS.

Department of Dermatology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.

Atopic dermatitis (AD) is a pruritic recurring inflammatory skin disease. Recently, topical tacrolimus has been developed to treat AD. This report presents the first clinical experience with topical tacrolimus in Taiwan. This open-label, single-arm study was conducted at three centers from February to May 2002. The duration of each individual treatment was 4 weeks. Two groups were defined: pediatric and adult. Efficacy was evaluated on the basis of the physician's global evaluation at the end of treatment. Success was defined as at least 50% improvement. Other evaluations included the Eczema Area and Severity Index (EASI), the percentage of body surface area (BSA) involved, the patient's assessment of pruritus, and the patient's assessment of overall response. Safety profile was established by monitoring changes in hematology and biochemistry profiles and tacrolimus concentration in blood. All adverse events were recorded. Twenty-six pediatric patients and 42 adult patients were enrolled. Overall success rates were 80.8% and 82.1% in the pediatric and adult groups, respectively. The declines in EASI, percentage of BSA affected, and patient's assessment of pruritus were significant (p < 0.001); 88% and 100% of pediatric and adult patients, respectively, reported a favorable response to treatment. Changes in blood samples were unremarkable. Of pediatric and adult patients, 61.5% and 76.2%, respectively, reported adverse events. The most common adverse event reported was skin burning, which did not result in discontinuation of therapy. This report reveals that tacrolimus ointment is effective and safe for the treatment of AD in Taiwanese patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12873038&dopt=Abstract tacrolimus Protopic



Protopic
Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper oil.

Butani L, Afshinnik A, Johnson J, Javaheri D, Peck S, German JB, Perez RV.

Section of Pediatric Nephrology, University of California, Davis Medical Center, Sacramento, CA 95817, USA. lavjay.butani ucdmc.ucdavis.edu.

BACKGROUND: Calcineurin-inhibitor nephrotoxicity plays a role in the pathogenesis of chronic allograft nephropathy by causing renal ischemia mediated by vasoconstrictive metabolites of the prostanoid pathway. The purpose of our study was to evaluate whether altering the prostanoid profile using juniper oil (JO) would afford renoprotection in rats treated with tacrolimus. METHODS: Diets supplemented with biologic oils (no supplementation, JO, fish oil [FO], safflower oil [SO], and arachidonic acid [AA]) were fed to five groups of rats for 5 weeks; during the last 2 weeks, tacrolimus was administered to all groups except for a control group of animals. At week 5, urinary prostaglandin (PG)F(2-alpha) and inulin clearances were measured. The rat kidneys were harvested to determine the renal cell membrane composition for arachidonic, eicosatrienoic, and eicosapentaenoic acids. RESULTS: Both JO and FO completely reversed the decrease in inulin clearance seen with tacrolimus, the greatest effect being with JO (inulin clearance 15.1+/-3 vs. 6.0+/-1.1 ml/min in the nonsupplemented group; P<0.001); urinary PGF(2-alpha) excretion was also highest in the JO group (328+/-23 pg/mL, P<0.001 vs. the nonsupplemented group). Fatty acid membrane analysis showed greatest incorporation of eicosapentaenoic and eicosatrienoic acids in the JO- (5.7+/-0.6% and 3.1+/-0.4%, respectively) and FO- (8.1+/-0.7% and 2.8+/-0.6%, respectively) treated animals. CONCLUSIONS: JO supplementation in tacrolimus-treated rats was associated with incorporation of vasodilatory prostanoids in the renal-cell membrane and elevated urinary PGF(2-alpha) excretion, and the precipitous fall in inulin clearance induced by tacrolimus was completely prevented. Whether this benefit will translate into a reduction in chronic allograft nephropathy remains to be determined. However, our preliminary data point towards the need for human trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12883183&dopt=Abstract tacrolimus Protopic



Protopic
Long-term pharmacokinetic study of the novel combination of tacrolimus and sirolimus in de novo renal allograft recipients.

Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y.

Department of Nephrology and Renal Transplantation, University Hospital Leuven, Leuven, Belgium. Dirk.kuypers uz.kuleuven.ac.be

It was recently shown in two randomized studies that combining sirolimus (rapamycin) and tacrolimus is very efficient in renal transplantation. However, little is known about the long-term pharmacokinetics of this combination. We performed simultaneous AUC measurements (area under the concentration curves) of sirolimus and tacrolimus at 1, 3, and 12 months posttransplantation in nine de novo recipients treated with this drug combination to characterize the evolution of the pharmacokinetics of both drugs and to investigate possible interactions between the two compounds. Patients were treated with a standard-dose tacrolimus or with a reduced-dose tacrolimus in combination with sirolimus and corticosteroids. This long-term pharmacokinetic study has shown that when sirolimus is combined with tacrolimus, dose changes of sirolimus are reflected by pharmacokinetic exposure parameters. Patients taking a low dose of sirolimus in combination with a standard dose tacrolimus might require sirolimus dose increments over time to maintain constant exposure to sirolimus. Further prospective dose-controlled studies are necessary to investigate a possible effect of a standard-dose tacrolimus on long-term sirolimus bioavailability and/or metabolism. Dose reductions of tacrolimus in both study groups were reflected by concordant decreasing pharmacokinetic exposure parameters, which illustrates the common clinical practice of reducing the dose of calcineurin inhibitor as time elapses after transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12883227&dopt=Abstract tacrolimus Protopic



Protopic
Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment.

Crenesse D, Laurens M, Heurteaux C, Cursio R, Saint-Paul MC, Schmid-Alliana A, Gugenheim J.

Laboratoire de Physiologie, Faculte de Medecine, Universite de Nice-Sophia Antipolis, Av. de Valombrose 06107 Nice 2, France. dominique.crenesse unice.fr

The aim of this study was to demonstrate that tacrolimus (FK506) has a hepatoprotective effect by reducing ischemia-reperfusion-induced apoptosis and necrosis, both of which lead to post-surgical liver dysfunction. An ischemia-reperfusion model and primary cultured rat hepatocytes subjected to hypoxic and reoxygenation phases, mimicking the surgical process, were used. c-Jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK1/SAPK1) activation leads to caspase 3 activation, a trigger of apoptosis. The activation status of JNK1/SAPK1 was evaluated by immunoprecipitation or Western-blotting experiments. Apoptosis was assessed by measuring caspase activation and by TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling) reaction. Necrosis was assessed histologically. Tacrolimus improved the survival rate of rats subjected to ischemia-reperfusion. After FK506 pretreatment, the liver necrosis rate was reduced, and ischemia-reperfusion-induced JNK1/SAPK1 activation and apoptosis were significantly decreased. In hypoxia-reoxygenation-subjected hepatocytes, tacrolimus reduced JNK1/SAPK1 and caspase 3 activation. In the liver, tacrolimus prevented ischemia-reperfusion-induced apoptosis and necrosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12892836&dopt=Abstract tacrolimus Protopic



Protopic
Use of tacrolimus in rescue therapy of acute and chronic rejection in liver transplantation.

Coelho FF, Coelho RF, Massarollo PC, Mies S.

Department of Surgery, Faculty of Medicine, University of Sao Paulo, Sao Paulo, SP, Brazil.

PURPOSE: To study the indications and results of tacrolimus as rescue therapy for acute cellular or chronic rejection in liver transplantation. PATIENTS AND METHODS: Eighteen liver transplant recipients who underwent rescue therapy with tacrolimus between March 1995 and August 1999 were retrospectively studied. The treatment indication, patients, and graft situation were recorded as of October 31st, 1999. The response to tacrolimus was defined as patient survival with a functional graft and histological reversal of acute cellular, or for chronic rejection, bilirubin serum levels decreasing to up to twice the upper normal limit. RESULTS: Fourteen cases (77.8%) presented a good response. The response rate for the different indications was: (1) acute cellular + sepsis - 0/1 case; (2) recurrent acute cellular - 1/1 case; (3) OKT3-resistant acute cellular - 2/2 cases; (4) steroid-resistant acute cellular + active viral infection - 3/3 cases; (5) chronic rejection - 8/11 cases (72.7% response rate). The 4 patients who did not respond died. CONCLUSION: Tacrolimus rescue therapy was successful in most cases of acute cellular and chronic rejection in liver transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12894310&dopt=Abstract tacrolimus Protopic