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Increased tacrolimus levels during diarrhea.

Hochleitner BW, Bosmuller C, Nehoda H, Fruhwirt M, Simma B, Ellemunter H, Steurer W, Hochleitner EO, Konigsrainer A, Margreiter R.

Department of Transplant Surgery, Innsbruck University Hospital, Anichstrasse 35, 6020 Innsbruck, Austria. Boris.Hochleitner uibk.ac.at

While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11512055&dopt=Abstract tacrolimus Protopic



Protopic
Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation.

Staatz C, Taylor P, Tett S.

School of Pharmacy, University of Queensland, Brisbane, Queensland 4072, Australia.

BACKGROUND: A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. METHODS: A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. RESULTS: Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs non-rejecters (P=0.04). The average median concentration (+/-SD) in the biopsy-proven rejecter group was 5.09+/-1.16 ng/ml, compared to 9.20+/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57+/-1.47 ng/ml, compared with 9.20+/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. CONCLUSION: A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11522877&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells.

Szabo G, Gavala C, Mandrekar P.

Division of Gastroenterology, Memorial Health Center, University of Massachusetts Medical School, Worcester 01655, USA. gyongyi.szabo umassmed.edu

Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 microg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P<0.02). Production of inflammatory cytokines, tumor necrosis factor alpha (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 microg/mL) or staphylococcal enterotoxin B (1 microg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor alpha, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11523700&dopt=Abstract tacrolimus Protopic



Protopic
Corticosteroid-free immunosuppression with tacrolimus following induction with daclizumab: A large randomized clinical study.

Boillot O, Mayer DA, Boudjema K, Salizzoni M, Gridelli B, Filipponi F, Trunecka P, Krawczyk M, Clavien PA, Ducerf C, Margarit C, Margreiter R, Pallardo JM, Hoeckerstedt K, Pageaux GP.

Service de Transplantation, Hopital Edouard Herriot, Lyon, France.

This open, randomized (1 : 1), multicenter, 3-month study compared a dual tacrolimus plus steroids (Tac / steroids) regimen with a steroid-free immunosuppressive regimen of tacrolimus following daclizumab induction therapy (Tac / Dac) in adult liver transplant recipients. The full analysis set comprised 347 patients in the Tac / steroids group and 351 in the Tac / Dac group. Mean tacrolimus dose during month 3 was 0.11 mg/kg/day in both groups; mean whole-blood trough levels during month 3 were 10.9 ng/mL (Tac / steroids) and 10.6 ng/mL (Tac / Dac). The incidence of biopsy-confirmed acute rejection that required treatment was similar in both groups: 26.5% in the Tac / steroids group and 25.4% in the Tac / Dac group (P = .727). However, the incidence of biopsy-confirmed corticosteroid-resistant acute rejection was higher in the Tac / steroids group than in the Tac / Dac group (6.3 vs. 2.8%; P = .027). Kaplan-Meier estimates of graft survival (92.2 vs. 90.5%) and patient survival (94.5 vs. 93.7%) were similar in both groups. While also the overall adverse event profiles were similar, the incidences of diabetes mellitus (15.3 vs. 5.7%, respectively; P < .001) and cytomegalovirus infection (11.5 vs. 5.1%, respectively; P = .002) were higher in the Tac / steroids group compared with the Tac / Dac group. Mean cholesterol levels increased by 16% in the Tac / steroids group, but were unchanged in the Tac / Dac group during the study. In conclusion, tacrolimus monotherapy following daclizumab induction is an effective and safe regimen, with an advantage over concomitant steroid-maintenance therapy in terms of a lower incidence of diabetes and viral infection, and a lower incidence of steroid-resistant acute rejection. (Liver Transpl 2005;11:61-67.).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15617147&dopt=Abstract tacrolimus Protopic



Protopic
Safe and effective treatment of refractory facial lesions in atopic dermatitis using topical tacrolimus following corticosteroid discontinuation.

Kawakami T, Soma Y, Morita E, Koro O, Yamamoto S, Nakamura K, Tamaki K, Yajima K, Imaizumi A, Matsunaga R, Murakami N, Kashima M, Mizoguchi M.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan.

BACKGROUND: Topical corticosteroids are commonly applied in atopic dermatitis (AD) treatment. However, their chronic use may be associated with significant side effects at the application site. Skin atrophy and other undesirable effects are frequently seen after long-term corticosteroid treatment. In addition, when application of corticosteroids is discontinued, a rebound phenomenon in the facial lesions can occur within several days. Topical tacrolimus, an immunosuppressant currently used to prevent rejection after solid-organ transplantation, presents a potential alternative therapeutic agent for AD. OBJECTIVE: The present study is the first trial designed to evaluate the efficacy and safety of topically applied tacrolimus ointment after corticosteroid discontinuation without a washout phase in severe, long-term facial AD. PATIENTS/METHODS: Forty-seven patients with facial refractory AD were recruited, of whom 38 had undergone topical corticosteroid treatment for at least 4 weeks before enrollment (group 1) and the other 9 had not received steroid treatment (group 2). All 47 patients received 0.1% tacrolimus ointment, and the severity index and pruritus score were assessed as an AD clinical activity index every week and compared with baseline data. RESULTS: Both the severity index and pruritus score improved significantly in group 1 after 1 and 2 weeks of application (p < 0.01, respectively). Group 2 showed the greatest improvement at 4 weeks (p < 0.05). In this trial, none of the patients experienced a rebound phenomenon associated with tacrolimus treatment. A transient sensation of burning at the application site was the only adverse event in 31 of the 47 (66%) enrolled patients, but this condition improved after several days. Spectrophotometric assessment of the facial lesion following treatment revealed significant improvement in group 1 (p < 0.05). CONCLUSION: The present results indicate that topical tacrolimus treatment following corticosteroid discontinuation is safe and effective in refractory facial AD. Copyright 2001 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11549797&dopt=Abstract tacrolimus Protopic



Protopic
Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis.

Kollum M, Farb A, Schreiber R, Terfera K, Arab A, Geist A, Haberstroh J, Wnendt S, Virmani R, Hehrlein C.

Department of Cardiology and Angiology, University of Freiburg, Freiburg, Germany.

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents. Catheter Cardiovasc Interv 2005;64:85-90. (c) 2004 Wiley-Liss, Inc.

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Protopic
Topical tacrolimus in the treatment of bovine collagen hypersensitivity.

Moody BR, Sengelmann RD.

Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUND: Soft tissue augmentation with bovine collagen is a common and safe aesthetic procedure. Despite adequate pretreatment testing, allergic reactions can develop. The medical literature provides little guidance to the clinician in the management of bovine collagen hypersensitivity. OBJECTIVE: We describe a case of bovine collagen allergy treated with 0.1% topical tacrolimus and corticosteroids. METHODS: Clinical evaluation and management of a patient with bovine collagen hypersensitivity. RESULTS: Our patient responded to combined therapy with oral corticosteroids and topical tacrolimus. CONCLUSION: Topical tacrolimus may be a useful first-line or adjuvant therapy in the management of bovine collagen allergic reactions. Further clinical experience with its use for bovine collagen hypersensitivity is required to determine its true efficacy in this condition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11553165&dopt=Abstract tacrolimus Protopic