Protopic
Primary immunosuppression with tacrolimus after liver transplantation: 12-years follow-up.

Jonas S, Neuhaus R, Junge G, Klupp J, Theruvat T, Langrehr JM, Settmacher U, Neuhaus P.

Department of General, Visceral and Transplantation Surgery, Charite Virchow-Klinikum, University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. sven.jonas charite.de

The early safety and efficacy of tacrolimus after liver transplantation has been shown in two multicenter trials. Herein, we report our single-center long-term follow-up of a randomized controlled trial. As part of a European multicenter trial, 121 patients entered the study at our institution and were randomly assigned to receive either tacrolimus and steroids (n=61) or a quadruple protocol (n=60) using ciclosporin A, steroids, azathioprine, and antithymocyte globulin (ATG). Twelve-year figures of patient survival were 74% in the tacrolimus group and 66% in the cyclosporine-based group. Graft survival after 12 years was 69% in the tacrolimus group compared to 56% in the cyclosporin-based group (not significant, p=0.15). The total rate of graft loss and retransplantation decreased significantly in the tacrolimus arm (p<0.05). De novo malignancies increased significantly in the ciclosporin-based group and dominated as single cause of death beyond 5 years posttransplant. The use of tacrolimus after liver transplantation resulted in a decreased rate of graft loss over the long-term. An increased number of de novo malignancies in the ciclosporin-based group may be attributable to the use of ATG as induction therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15589470&dopt=Abstract tacrolimus Protopic



Protopic
Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids.

Hricik DE, Anton HA, Knauss TC, Rodriguez V, Seaman D, Siegel C, Valente J, Schulak JA.

Departments of Medicine and Surgery, Case Western Reserve University and the Transplantation Service, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA. deh5 po.cwru.edu.

BACKGROUND: African American kidney transplant recipients generally exhibit poor long-term graft survival compared with other ethnic groups. The combination of sirolimus, tacrolimus, and corticosteroids has proven to be effective in reducing rejection episodes in high-risk organ and islet cell transplant recipients but has not yet been tested in a large number of African American patients. METHODS: The outcomes of 56 African American adult, primary kidney transplant recipients treated with corticosteroids, sirolimus, and tacrolimus targeted to relatively low trough blood levels were compared with those of a concurrent group of 65 white patients treated with steroids, mycophenolate mofetil, and tacrolimus targeted to relatively high blood levels. Induction antibody therapy was not routinely used in either group. RESULTS: The incidence of acute rejection in the first 3 posttransplantation months was 7.1% in African Americans and 16.9% in whites (P=NS). Actuarial 2-year patient, graft, and rejection-free graft survival rates were equivalent in the two groups. Posttransplantation diabetes mellitus occurred in 36% of the African American patients, despite similar doses of corticosteroids and lower trough levels of tacrolimus, compared with 15% of white patients (P=0.024). CONCLUSIONS: The combination of corticosteroids, sirolimus, and relatively low doses of tacrolimus results in acute rejection, graft survival, and patient survival rates equivalent to those achieved in white patients receiving steroids, mycophenolate mofetil, and relatively high doses of tacrolimus, even without the routine use of induction antibody therapy. Posttransplantation diabetes mellitus remains a problem for African Americans receiving this combination of immunosuppressants, despite relatively low tacrolimus blood levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12151730&dopt=Abstract tacrolimus Protopic



Protopic
Topical tacrolimus in the management of peristomal pyoderma gangrenosum.

Lyon CC, Stapleton M, Smith AJ, Mendelsohn S, Beck MH, Griffiths CE.

Dermatology Centre, University of Manchester, Manchester, UK. clyon fs1.ho.man.ac.uk

BACKGROUND: Peristomal pyoderma gangrenosum (PPG) is a potentially disabling disease in stoma patients. Topical tacrolimus has been shown to be effective in the management of pyoderma gangrenosum. Unfortunately, greasy topical treatments may be impractical for PPG because of impaired appliance adhesion. OBJECTIVE: The purpose of this open study was to evaluate the therapeutic effectiveness of topical tacrolimus 0.3% formulated in carmellose sodium paste compared with topical corticosteroid preparations in the management of PPG. RESULTS: A total of 11 patients with PPG received treatment with topical tacrolimus 0.3% in Orabase trade mark and 13 with topical clobetasol propionate 0.05% as monotherapy in each case. Seven of the tacrolimus-treated group healed completely (mean time to healing: 5.1 weeks) compared with five of the clobetasol propionate-treated group (mean time to healing: 6.5 weeks). Topical tacrolimus was significantly more effective than clobetasol propionate in managing larger PPG lesions (ulcer diameter > 2 cm). In six patients, who had failed to respond adequately to multiple systemic and topical treatments for PPG, the addition of topical tacrolimus was associated with healing of PPG within 6 weeks. CONCLUSION: These results suggest that topical tacrolimus 0.3% in Orabase trade mark is a more effective and expeditious treatment than clobetasol propionate 0.05% for PPG. It is significantly more effective than clobetasol propionate 0.05% in managing lesions larger than 2 cm in diameter. Topical tacrolimus may be highly effective when other systemic or topical treatments have been unsuccessful.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12171681&dopt=Abstract tacrolimus Protopic



Protopic
Long-term use of FK 506 in living related liver transplantation.

Uemoto S, Tanaka K, Tokunaga Y, Nishizawa T, Sawada H, Katoh H, Yamamoto E, Yamaoka Y, Ozawa K.

Department of Surgery, Faculty of Medicine, Kyoto University, Shogoin, Japan.

FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 +/- 0.277 mg/kg daily at 1 month after transplantation to 0.078 +/- 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 +/- 7.1 ng/ml and 4.1 +/- 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11271341&dopt=Abstract tacrolimus Protopic



Protopic
Combined host-conditioning with CTLA4-Ig, tacrolimus, anti-lymphocyte serum, and low-dose radiation leads to stable mixed hematopoietic chimerism.

Li S, Thanikachalam M, Pang M, Carreno M, Aitouche A, Pham SM.

Department of Surgery, University of Miami School of Medicine, 1801 N.W. 9th Ave., Miami, FL 33136, USA.

The toxic dose of irradiation required to achieve stable mixed hematopoietic chimerism is the major limitation to its clinical application in transplantation and other nonmalignant conditions such as hemoglobinopathies. This study examines the additive effect of costimulatory blockage, to our previously described tacrolimus-based conditioning regimen, in further reducing the dose of total-body irradiation to achieve stable mixed chimerism in rats.Fully mismatched, 4- to 6-week-old ACI and Wistar Furth rats were used as donors and recipients, respectively. Recipients were administered CTLA4-Ig 2mg/kg/day (alternate days) in combination with tacrolimus 1 mg/kg/day (daily) from day 0 through day +10, anti-lymphocyte serum 10 mg at day +10 (single dose), and total-body irradiation ranging from 100-600 cGy, prior to bone marrow transplantation (day 0) with 100 x 10(6) of T-cell-depleted bone marrow cells. Levels of donor chimerism were determined over a period of 12 months.The short course of CTLA4-Ig, tacrolimus, and ALS led to dramatic engraftments at reduced doses of irradiation: 100% (5/5) and 93% (13/14) of the animals developed mixed chimerism at 400 cGy and 300 cGy, respectively. At 300 cGy, recipients exhibited durable, multilineage mixed chimerism at 365 days with donor cells ranging from 19-42% (mean 23.4%) with no evidence of graft-vs-host disease. These mixed chimeras exhibited in vitro (mixed lymphocyte reaction) and in vivo (skin grafts) donor-specific tolerance.This study suggests that addition of costimulatory blockade to a tacrolimus-based conditioning regimen reduces the dose of irradiation required to achieve stable multilineage chimerism in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11301194&dopt=Abstract tacrolimus Protopic



Protopic
Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus.

Arima H, Yunomae K, Hirayama F, Uekama K.

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

We recently reported that of all hydrophilic cyclodextrin (CyD) derivatives examined, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) most significantly increased the aqueous solubility and the dissolution rate, resulting in the improvement of oral bioavailability of the immunosuppressive drug tacrolimus in rats. In the present study, we showed that DM-beta-CyD increased the dissolution rate and oral bioavailability of tacrolimus in rats with increases in the molar ratio of the complexes (DM-beta-CyD:tacrolimus). However, nonlinear pharmacokinetic behavior of tacrolimus after oral administration in rats was observed. Thus, an additional mechanism of the solubilizing effect of DM-beta-CyD on oral bioavailability of tacrolimus was postulated. To gain insight into this additional mechanism of action of DM-beta-CyD, its effects on the efflux of tacrolimus and rhodamine 123, a P-glycoprotein (P-gp) substrate, were examined using both Caco-2 and vinblastine-resistant Caco-2 (Caco-2R) cell monolayers. Pretreatment of the apical membranes of the monolayers with DM-beta-CyD decreased the efflux of tacrolimus and rhodamine 123 without an associated cytotoxicity. DM-beta-CyD decreased the P-gp level in the apical membranes of both Caco-2 and Caco-2R cell monolayers, probably by allowing release of P-gp from the apical membrane into the transport buffer. DM-beta-CyD, however, did not decrease the MDR1 gene expression in Caco-2 or Caco-2R cells. These results suggested that the enhancing effect of DM-beta-CyD on the oral bioavailability of tacrolimus is due not only to its solubilizing effect but also, at least in part, to its inhibitory effect on the P-gp-mediated efflux of tacrolimus from intestinal epithelial cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11303042&dopt=Abstract tacrolimus Protopic



Protopic
Liver transplantation using sirolimus and minimal corticosteroids (3-day taper).

Trotter JF, Wachs M, Bak T, Trouillot T, Stolpman N, Everson GT, Kam I.

Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO, USA. James.Trotter uchsc.edu

At our center, we have performed liver transplantation since 1995 with a rapid-taper steroid protocol (weaning steroids by day 14 posttransplantation). Beginning in 2000, we further reduced the use of corticosteroids to 3 days and added sirolimus to our immunosuppressive regimen. We report our experience with 39 patients who underwent liver transplantation with either tacrolimus or cyclosporin A (Neoral; Novartis Pharmaceuticals Corp., Summit, NJ) and sirolimus, with a 3-day tapered dose of corticosteroids. Thirty-two patients received a cadaveric graft and 7 patients received a right hepatic lobe from a living donor. All patients initially were administered either tacrolimus (0.1 mg/kg/d) or cyclosporin A (10 mg/kg/d) and sirolimus (6 mg/d for 1 day, followed by 2 mg/d), in addition to methylprednisolone on the first 3 days (1, 0.5, and 0.5 g/d) after transplantation. Patients were administered corticosteroids for presumptive or biopsy-proven evidence of acute cellular rejection (methylprednisolone, 1, 0.5, and 0.5 g on 3 successive days). Seventeen patients were administered tacrolimus and 22 patients were administered cyclosporin A. Six patients were excluded from analysis because they were administered sirolimus for less than 2 weeks. Mean duration of follow-up was 124 days. Patient survival was 36 of 39 patients (92%), and graft survival was 35 of 39 grafts (89%). Ten of 33 patients (30%) experienced 12 episodes of rejection (7 biopsy proven, 5 presumptive) compared with 70% in historical controls (P <.01). OKT3 was required in 1 of 33 patients (3%) compared with 37% in controls (P <.01). Twenty-six of 33 patients (79%) were not administered prednisone, and 7 of 33 patients (21%) were administered prednisone for reasons other than rejection. Posttransplantation, there was no significant change in values for creatinine, glucose, aspartate aminotransferase, bilirubin, cholesterol, and white blood cell counts. Platelet counts were significantly reduced, and hematocrits were significantly elevated (P <.05). Liver transplantation may be successfully performed with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporin A. Despite the absence of prednisone from our immunosuppressive protocol, the incidence of rejection and OKT3 use was lower than in historical controls. Patient and graft survival rates were identical to those of historical controls. The findings in this report will serve as the basis for a formal trial evaluating the efficacy of sirolimus in liver transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11303295&dopt=Abstract tacrolimus Protopic