Protopic
Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction.

Okabe H, Yano I, Hashimoto Y, Saito H, Inui K.

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

The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11829131&dopt=Abstract tacrolimus Protopic



Protopic
Effects of thymic hormone on reactive oxygen species-scavengers and renal function in tacrolimus-induced nephrotoxicity.

Tada H, Nakashima A, Awaya A, Fujisaki A, Inoue K, Kawamura K, Itoh K, Masuda H, Suzuki T.

Department of Pharmaceutical Science, Akita University Hospital, Hondo, Japan.

The effects of a thymic hormone (Facteur thymique serique; FTS) on renal reactive oxygen species-scavenging enzymes or substances in heminephrectomized rats with and without tacrolimus-induced nephrotoxicity were studied. Rats received both oral dose of tacrolimus (5 mg/kg/day) and subcutaneous administration of three dosages of FTS (5, 50, and 250 microg/kg/day) over 28 days (Group A). In Group B, they received three dosages of FTS alone (0.5, 5, and 50 microg/kg/day) or FTS 50 microg/kg/day with tacrolimus over 28 days. Each dose of FTS (Group A) partially elevated renal creatinine clearances. Tacrolimus enhanced renal glutathione reductase (GSH-R) activities and glutathione (GSH) and depressed catalase (CAT) activities. FTS increased GSH levels and GSH-R activities. Although FTS alone did not change CAT activities, CAT activities recovered as a result of concomitant use of FTS (Groups A and B). A significant positive correlation was found between CAT activity and creatinine clearance. These findings suggest that FTS is useful for the prevention of tacrolimus-induced nephrotoxicity, and that the increase of renal CAT activity in the defense mechanism of FTS might be important for cell protection against active oxygen species.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11848304&dopt=Abstract tacrolimus Protopic



Protopic
Complete replacement of tracheal epithelia by the host promotes spontaneous acceptance of orthotopic tracheal allografts in rats.

Ito Y, Suzuki H, Hattori Y, Muhammad BA, Takahashi T, Suzuki K, Kazui T.

First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan. haigeka2 hospital.iwata.shizuoka.jp

BACKGROUND: Tracheal immunogenicity has been controversial. Although replacement of allotracheal epithelia by the host epithelia has been reported in rat orthotopic tracheal grafting, the immunological effect of epithelial replacement is still uncertain. METHODS: We performed orthotopic tracheal grafting of nine cartilage rings in the following groups: 1, Lewis --> Lewis (n = 30); 2, ACI --> DA (n = 25); 3, Lewis --> F344 (n = 23); 4-A, DA --> Lewis (n = 41); 4-B, DA --> Lewis with tacrolimus therapy (1 mg/kg/d for 10 days) starting from the day of the operation (n = 31); 4-C, retransplantation of DA allografts to secondary naive Lewis rats 10 or 15 days after primary grafting (n = 11); 4-D, DA --> Lewis with tacrolimus therapy starting from postoperative day 10 (n = 6). Survival times and histopathology were assessed. Epithelial replacement was evaluated by immunohistochemistry. RESULTS: All rats survived in groups 1, 2, and 3. Even in the fully histoincompatible group 4-A, survival ratio on day 120 was 15%. Epithelial replacement was in progress on day 10 in this group. However, all tacrolimus-treated rats died by day 54 and epithelial replacement did not occur on days 30 and 50 in group 4-B. In group 4-C, retransplantation after complete epithelial replacement increased the long-surviving rats. In group 4-D, all rats receiving tacrolimus therapy after complete epithelial replacement survived over 120 days. CONCLUSIONS: These results suggest that complete replacement of tracheal epithelia by the host promotes spontaneous acceptance of orthotopic tracheal allografts in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15561264&dopt=Abstract tacrolimus Protopic



Protopic
Increased early rejection rate after conversion from tacrolimus in kidney and pancreas transplantation.

Barone GW, Ketel BL, Abul-Ezz SR, Lightfoot ML.

Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. baronegary uams.edu

CONTEXT: A successful immunosuppression regimen for combined kidney and pancreas transplants is tacrolimus, mycophenolate mofetil, and prednisone. However, not all patients tolerate these immunosuppressants especially tacrolimus. OBJECTIVE: To evaluate the efficacy of cyclosporine as a rescue agent for tacrolimus toxicity in combined kidney and pancreas transplants. DESIGN: Retrospective. SETTING: Single center. PATIENTS: Thirty-five combined kidney and pancreas transplants were performed between July 1994 and January 1999. All patients were insulin dependent diabetics with end-stage renal disease. Twenty-eight (mean age: 36 years and 57% female) were available with at least 12 month follow-up. INTERVENTIONS: Conversion to cyclosporine following renal (biopsy proven) or pancreatic dysfunction. MAIN OUTCOME MEASURES: Toxicity, rejection rate, and patient/transplant organ survival. RESULTS: Nineteen transplant recipients (68%) were continuously maintained on tacrolimus while nine (32%) required conversion to cyclosporine 75 +/- 20 days post-transplant. Reasons for conversion included: hyperglycemia (n=2), hemolytic-uremic syndrome (n=1), and severe tacrolimus nephrotoxicity (n=6). By 12 months post-transplant, the 19 patients maintained on tacrolimus had 5 rejections (26%). Three of the 9 patients (33%) converted to cyclosporine had an acute rejection prior to conversion. Seven of these 9 patients (78%; P=0.017 vs. patients maintained on tacrolimus) had rejections an average of 25 +/- 4 days post-conversion. Four of the 7 patients had no previous rejections prior to conversion. In spite of increased rejections, the 1- and 2-year patient/graft survivals were unchanged by converting. CONCLUSIONS: Converting to cyclosporine from tacrolimus was associated with an increased risk of acute rejection especially within the first 30 days post conversion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11884766&dopt=Abstract tacrolimus Protopic



Protopic
Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management.

First MR, Gerber DA, Hariharan S, Kaufman DB, Shapiro R.

University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0585, USA.

BACKGROUND: Posttransplant diabetes mellitus (PTDM), associated with the use of immunosuppressants, occurs at varying rates in kidney transplant recipients. METHODS: Five transplant centers conducted a retrospective review of 435 kidney recipients completing at least 6 months of follow-up to determine risk factors, incidence, and management strategies for posttransplant glucose intolerance. A distinction was made between hyperglycemia and diabetes. RESULTS: The incidence of PTDM was found to be 4.9%. Among tacrolimus-treated patients it was 5.7%, compared with 3.3% among cyclosporine-treated patients (P=0.453). Mean daily maintenance doses of prednisone and mycophenolate mofetil (MMF) were significantly lower in tacrolimus-treated patients. Significantly more tacrolimus-treated patients were prednisone-free (9.0%/0%; P<0.001). Logistic regression analysis revealed that the absence of an antiproliferative agent correlated with the development of PTDM (odds ratio=3.56; P=0.01). CONCLUSIONS: Based on this study, we propose management guidelines specifically for glucose intolerance developing after renal transplantation. Maintenance of blood glucose levels within strict limits is recommended, and the contribution of immunosuppressive agents to the development of PTDM is accounted for. Gradual tapering of prednisone and tacrolimus is proposed for patients who develop PTDM but also bear minimal risk of rejection. Tapering and eventual withdrawal of insulin should be attempted once blood glucose levels normalize. Switching to the alternative calcineurin inhibitor should only be considered as a late intervention. Tacrolimus therapy should be considered even in patients at high risk for diabetes, because the benefit of reduced acute rejection incidence and severity, as demonstrated in other studies, outweighs the risk of PTDM.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11884934&dopt=Abstract tacrolimus Protopic



Protopic
Long-term viability of articular cartilage after microsurgical whole-joint transplantation and immunosuppression with rapamycin, mycophenolate mofetil, and tacrolimus.

Vogelin E, Jones NF, Rao UN.

UCLA Hand Center, Department of Orthopaedic Surgery and Division of Plastic and Reconstructive Surgery, University of California, Los Angeles, CA 90095, USA.

The survival or rejection of articular cartilage in heterotopic vascularized joint transplants in rats immunosuppressed with rapamycin (SDZ RAD), mycophenolate mofetil (MMF), and tacrolimus was evaluated histologically up to 1 year after surgery. The vascularized knee joint of an ACI donor rat was transplanted to the groin of a Lewis recipient rat. Nonimmunosuppressed allografts were evaluated after 6 weeks and 3 months, and immunosuppressed allografts and control isografts were evaluated after 6 weeks, 3 months, 6 months, and 1 year. No rejection was seen in the control isografts. All allografts without immunosuppression were rejected at 6 weeks and 3 months. Eighteen of 21 knee joint transplants immunosuppressed with SDZ RAD and 17 of 22 knee joint transplants immunosuppressed with MMF were rejected between 6 weeks and 1 year. SDZ RAD and MMF caused significant side effects including compromised wound healing and bone marrow suppression culminating in weight loss and death. Eighteen of 19 knee joints immunosuppressed with tacrolimus showed no signs of rejection up to 1 year after surgery. Long-term intermittent immunosuppression with tacrolimus was significantly superior to SDZ RAD and MMF in preventing rejection of the transplanted articular cartilage of a vascularized knee joint allograft up to 1 year after surgery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11901390&dopt=Abstract tacrolimus Protopic



Protopic
Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channel.

Fuhrer DK, Kobayashi M, Jiang H.

Basic Research, Fujisawa Research Institute of America, Northwestern University/Evanston Research Park, Evanston, IL 60201-3135, USA.

AIM: By focusing on the pancreatic beta cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. METHODS: A glucose responsive beta cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. RESULTS: It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50- 80 nm for tacrolimus, 100-300 nm for rapamycin, and 7-12 mm for CsA in RIN-5F cells. Optimal insulin release for HIT-T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non-toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l-type calcium channels. Continued studies showed that the specific ATP-sensitive potassium channel agonist diazoxide (150 mm) also blocked immunosuppressant-induced insulin release. CONCLUSIONS: A model that fits this data is a novel calcineurin-independent immunophilin mediated partial closing of the ATP-sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11903410&dopt=Abstract tacrolimus Protopic