Protopic
Increase in tacrolimus trough levels after steroid withdrawal.

van Duijnhoven EM, Boots JM, Christiaans MH, Stolk LM, Undre NA, van Hooff JP.

Department of Internal Medicine, University Hospital of Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. evd groupwise.azm.nl

Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12827231&dopt=Abstract tacrolimus Protopic



Protopic
Case report of unchanged tacrolimus clearance in a hypoxemic pediatric liver transplant recipient with hepatopulmonary syndrome.

Sugimoto K, Ohmori M, Fujimura A, Sakamoto K, Hishikawa S, Mizuta K, Kita Y, Uno T, Kawarasaki H.

Center for Clinical Pharmacology and Therapeutics, Jichi Medical School Hospital, 3311-1 Minamikawachi, 329-0498 Tochigi, Japan. ksugi jichi.ac.jp

Reductions in hepatic oxygen supply may reduce the oxidative metabolism of drugs, including tacrolimus. We encountered a patient (2.3-year-old girl) with hypoxemia [arterial oxygen tension (PaO2) 40.9 mmHg in room air] due to hepatopulmonary syndrome who had undergone living related liver transplantation. After transplantation, tacrolimus was initially administered by continuous intravenous infusion, and her PaO2 was maintained at more than 50 mmHg [72.8+/-10.4 (SD) mmHg] by oxygen supplementation. Apparent clearance of tacrolimus (calculated as: the infusion rate of tacrolimus/blood concentration) in the patient (0.075 l/h per kg) was comparable to those of non-hypoxemic control pediatric cases (0.092+/-0.014 l/h per kg, n=7, mean age 2.2 years, PaO2 149.2+/-41.5 mmHg), except for the acute decline in the early period after transplantation. These findings suggest that the reduction in tacrolimus clearance is negligible when arterial oxygen tension is maintained at more than 50 mmHg, even in patients with hypoxemia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15502939&dopt=Abstract tacrolimus Protopic



Protopic
Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats.

McLaughlin GE, Kashimawo LA, Steele BW, Kuluz JW.

Department of Pediatrics, University of Miami School of Medicine, Miami, FL 33101, USA. gmclaugh med.miami.edu

OBJECTIVE: To determine whether theophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, reverses the acute declines in renal blood flow and glomerular filtration rate induced by high-dose tacrolimus in rats. DESIGN: Prospective, randomized, placebo-controlled experimental study. SETTING: University-based basic science research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: After mechanical ventilation and instrumentation under isoflurane and nitrous oxide anesthesia, animals received either tacrolimus 0.5 mg/kg intravenously or vehicle and 1 hr later either theophylline 4 mg/kg intravenously or vehicle. MEASUREMENTS AND MAIN RESULTS: By using radiolabeled microspheres, renal blood flow was measured in three groups: control (n = 5), tacrolimus plus vehicle (n = 6), and tacrolimus plus theophylline (n = 6) at four time points-baseline and 60, 75, and 90 mins after tacrolimus or vehicle (the latter two time points being 15 and 30 mins after theophylline or vehicle, respectively). Whole blood tacrolimus and serum theophylline concentrations were measured. In a separate group of animals, by using (51)Cr-EDTA, glomerular filtration rate was measured in two groups: tacrolimus plus vehicle (n = 5) and tacrolimus plus theophylline (n = 5) at baseline and over two consecutive 20-min time periods beginning 61 mins posttacrolimus. Urine flow rate also was measured. Following tacrolimus, both renal blood flow and glomerular filtration rate declined in parallel by approximately 33% and 50% from baseline after 75 and 90 mins, respectively (p <.05 by two-way repeated-measures analysis of variance). Theophylline completely reversed these tacrolimus-induced decreases in renal blood flow and glomerular filtration rate. Urine flow rate also increased in response to theophylline. CONCLUSIONS: Low-dose theophylline reverses tacrolimus-induced declines in renal blood flow and glomerular filtration rate observed in an acute model of tacrolimus toxicity. Theophylline's effect in chronic toxicity remains to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12831420&dopt=Abstract tacrolimus Protopic



Protopic
Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation.

Abou-Jaoude MM, Almawi WY.

Mutli-Organ Transplant Unit, St. George Hospital, Beirut, Lebanon.

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12835078&dopt=Abstract tacrolimus Protopic



Protopic
Pimecrolimus inhibits the elicitation phase but does not suppress the sensitization phase in murine contact hypersensitivity, in contrast to tacrolimus and cyclosporine A.

Meingassner JG, Fahrngruber H, Bavandi A.

Novartis Research Institute, Vienna, Austria. josef.meingassner pharma.novartis.com

Pimecrolimus (SDZ ASM 981, Elidel) is a nonsteroid inflammatory cytokine inhibitor specifically developed for the treatment of inflammatory skin diseases. Its effect on the elicitation and sensitization phases of oxazolone-induced contact hypersensitivity was compared with tacrolimus and cyclosporine A (CyA) in BALB/c mice using the ear swelling assay. The compounds were administered orally. Elicitation was dose-dependently inhibited by all three compounds. The minimal effective doses were 30 mg per kg (pimecrolimus, tacrolimus) and 90 mg per kg (CyA), respectively. There was no impairment of sensitization by pimecrolimus up to the highest dose tested (120 mg per kg), in contrast to CyA (60% inhibition at 60 mg per kg) and tacrolimus (71% inhibition at 30 mg per kg). Weight and cellularity of the draining lymph nodes in mice treated with tacrolimus or CyA during sensitization were reduced. In addition, proliferation of T cells after secondary stimulation was inhibited in cell cultures from lymph nodes of mice treated with tacrolimus or CyA. Thus, in contrast to tacrolimus and CyA, pimecrolimus exerts a more selective immunomodulatory effect. It does not impair the primary immune response (sensitization phase) but effectively inhibits the secondary phase, the elicitation phase that is the clinical manifestation of contact hypersensitivity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12839566&dopt=Abstract tacrolimus Protopic



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Inflammatory bowel disease after liver transplantation: the effect of different immunosuppressive regimens.

Haagsma EB, Van Den Berg AP, Kleibeuker JH, Slooff MJ, Dijkstra G.

Department of Gastroenterology and Hepatology, University Hospital Groningen, The Netherlands. e.b.haagsma int.azg.nl

BACKGROUND: Seemingly conflicting results have been reported on the prevalence and severity of inflammatory bowel disease after liver transplantation. Regimens with different combinations of drugs can be used for immunosuppression after transplantation. AIM: To study retrospectively the prevalence of inflammatory bowel disease after liver transplantation, and the possible relationship with maintenance immunosuppressive regimens. METHODS: All 78 patients with end-stage primary sclerosing cholangitis (48 patients) or autoimmune cirrhosis (30 patients), transplanted between 1979 and July 2001, and with a follow-up of at least 1 year, were eligible for this study. In addition to patient and transplant characteristics, data on inflammatory bowel disease and immunosuppression before and after transplantation were collected. The Kaplan-Meier method was used for survival analysis. Possible risk factors for inflammatory bowel disease after transplantation were analysed by Cox univariate and multivariate regression. RESULTS: The median follow-up after transplantation was 7.2 years (range, 1.1-22.3 years). Nine of 25 patients with pre-transplant inflammatory bowel disease experienced flare-ups after transplantation. Six of 53 patients without pre-transplant inflammatory bowel disease developed de novo inflammatory bowel disease after transplantation. The cumulative risks (standard errors in parentheses) for inflammatory bowel disease were 6% (3%), 12% (4%) and 20% (5%) at 1, 3 and 5 years after transplantation, respectively. The inflammatory bowel disease-free survival was significantly higher in patients not receiving tacrolimus vs. those receiving tacrolimus, in patients receiving azathioprine vs. those not receiving azathioprine and in patients taking the regimen prednisolone-azathioprine-ciclosporin A vs. those taking tacrolimus-prednisolone. Pre-transplant inflammatory bowel disease and the use of tacrolimus were found to be independent predictors for inflammatory bowel disease after transplantation. CONCLUSIONS: The prevalence of inflammatory bowel disease after liver transplantation is affected by the immunosuppression used. Azathioprine seems to have a protective effect and tacrolimus a promoting effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12848624&dopt=Abstract tacrolimus Protopic



Protopic
Mucosal villus microcirculatory disturbances associated with rat intestinal ischaemia-reperfusion injury are not prevented by tacrolimus.

Kalia N, Wood RF, Pockley AG, Brown NJ.

Department of Biomedical Science, Alfred Denny Building, Western Bank, University of Sheffield, Sheffield, UK. n.kalia sheffield.ac.uk

BACKGROUND/AIMS: Microcirculatory disturbances following small intestinal ischaemia-reperfusion (I/R) injury lead to tissue damage that may affect short- and long-term outcome after transplantation. The immunosuppressive drug Tacrolimus (FK506) attenuates I/R injury in a number of organs, raising the possibility that it might be able to control both I/R injury and rejection after small bowel transplantation. However, its effects on intestinal I/R injury have not been evaluated. METHODS: PVG rats were subjected to 30 min intestinal ischaemia. Animals received Tacrolimus (1 mg/kg i.p.) 4 and 1 h prior to ischaemia. The mucosa was visualised in an exteriorised ileal segment using in vivo microscopy. FITC-BSA or Acridine orange was used to quantitate macromolecular leak (MML) and leucocyte adhesion respectively every 15 min for 2 h during reperfusion. Heart rate and mean blood pressure (mBP) were monitored throughout the experiment. RESULTS: Ten of 12 untreated animals subjected to intestinal I/R injury failed to survive the 2-hour reperfusion period. MML and leucocyte adhesion were increased in untreated animals (p < 0.001) and blood flow stasis eventually ensued. Similar results were obtained for Tacrolimus pre-treated I/R animals, with 10 of 12 animals again failing to survive reperfusion. CONCLUSIONS: Despite previous evidence that Tacrolimus reduces I/R injury in other organs, it did not improve survival rates or prevent villus microcirculatory disturbances following intestinal I/R injury. The severity of microcirculatory damage suffered by the small intestine highlights the importance of alternative therapies to combat I/R in this organ. Copyright 2003 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12853727&dopt=Abstract tacrolimus Protopic