Protopic
Neuropsychologic side-effects of tacrolimus in pediatric renal transplantation.

Kemper MJ, Sparta G, Laube GF, Miozzari M, Neuhaus TJ.

Nephrology Unit, University Children's Hospital and Department of Nephrology, University Hospital, Zurich, Switzerland. markus.kemper kispi.unizh.ch

Calcineurin inhibition with tacrolimus has been used after renal transplantation (RTPL) as rescue therapy for insufficient immunological control or if cyclosporin A (CSA) toxicity occurred. Neurologic side-effects occur but are rare in children, usually presenting as tremor; however, serious complications, e.g. the posterior leukoencephalopathy syndrome are also documented. Twenty children (10 girls) were switched to tacrolimus: 11 (55%) for immunological reasons (n = 9: steroid-resistant rejection; n = 2: recurrent rejections) and nine for CSA side-effects. Tacrolimus was started at a median of 8 wk (range 10 d to 8.7 yr) after RTPL and was continued for a median of 2.5 yr (range 5 wk to 4.6 yr). Renal function significantly improved over a period of 12 months following conversion to tacrolimus (glomerular filtration rate 56 +/- 19 vs. 66 +/- 16 mL/min/1.73 m2; p < 0.03; n = 13). Fifteen of 20 (75%) patients tolerated tacrolimus well. The most frequent side-effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms with weight loss, amenorrhea, depression and school problems to severe insomnia and to aggressive and anxious behavior in one child. Only the latter child was exposed to toxic tacrolimus blood levels. All side-effects were fully reversible after discontinuation of tacrolimus. In conclusion, tacrolimus had a beneficial effect on renal function and was well tolerated in the majority of pediatric patients. However, neuropsychologic and behavioral side-effects are important and maybe underrecognized in children.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12709079&dopt=Abstract tacrolimus Protopic



Protopic
Significant prolongation of renal allograft survival by delayed combination therapy of FK778 with tacrolimus in nonhuman primates.

Qi S, Zhu S, Xu D, Wang X, Ouyang J, Jiang W, Vu MD, Bilolo K, Ma A, Johnson S, Daloze P, Bekersky I, Fitzsimmons WE, Chen H.

Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.

BACKGROUND: Malononitrilamide 715 (FK778) is a new class of low-molecular-weight immunosuppressant that is a derivative of the active metabolite of leflunomide, A77 1726. In this study, the authors evaluated the combined effect of FK778 with tacrolimus in prevention of renal allograft rejection in Vervet monkeys. METHODS: Male Vervet monkeys were obtained from Caribbean Primates Ltd. Donor and recipient monkeys were from different breeding colonies. Eleven groups (n>or=4 per group) were involved in this study. FK778 and tacrolimus were administered orally for 60 days according to protocol. RESULTS: Naive controls rejected renal grafts, with a median survival time (MST) of 8.0 days in group 1. When recipient monkeys were treated with tacrolimus 1.0 mg/kg/day in group 2 or FK778 2.5 mg/kg/day in group 3, the MST was 16.0 days (P=0.001) and 11.0 days (P=0.266), respectively. Combination therapy of these two agents at the same doses immediately after transplantation resulted in an MST of 25.0 days (P=0.016) in group 4. When tacrolimus was initiated immediately after transplantation and FK778 treatment was delayed until day 7 after surgery in group 5, recipient survivals were significantly prolonged to 38.0 days (P=0.02). These results were repeatable when FK778 5.0 mg/kg/day (9.0 days, P=0.544 in group 6) was combined with tacrolimus 1.0 mg/kg/day immediately after transplantation (8.0 days, P=0.339) in group 7, or when FK778 was delayed 7 days (60.0 days, P=0.002) in group 8. Furthermore, it was also repeatable when FK778 10 mg/kg/day was combined with tacrolimus 1.0 mg/kg/day with a 7-day delay. CONCLUSIONS: A significant prolongation of renal allograft survival was produced when FK778 administration was delayed by 7 days combined with tacrolimus in Vervet monkeys.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12717189&dopt=Abstract tacrolimus Protopic



Protopic
Tailoring tacrolimus-based immunotherapy in renal transplantation.

Yang HC.

Pinnacle Health Systems at Harrisburg, Harrisburg, Pennsylvania 17104-1696, USA. hyang pinnaclehealth.org

Tacrolimus is a cornerstone immunosuppressive agent in renal transplantation and compared with cyclosporin, its use is associated with a reduced incidence of acute rejection. Optimizing immunosuppressive management in the early post-transplant period is important for achieving long-term graft function and survival. In attempts to improve the long-term outcomes of renal transplantation further, tacrolimus has been combined with two novel immunosuppressive agents, mycophenolate mofetil (MMF) and sirolimus, with encouraging results in terms of patient and graft survival, acute rejection rates and renal graft function. Tacrolimus in combination with MMF adjunctive therapy showed significantly better graft survival in patients with delayed graft function, fewer episodes of corticosteroid-resistant rejection and better renal function at the 3-year follow-up compared with cyclosporin microemulsion plus MMF immunosuppression. A tacrolimus plus MMF regimen was also effective for renal transplant recipients at our centre in Pennsylvania, resulting in excellent survival and rejection rates at 1 year post-transplantation. The 3-month results of a US multicentre study comparing tacrolimus in combination with either MMF or sirolimus showed these two treatment regimens to be equivalent in terms of patient and graft survival, delayed graft function, the incidence of biopsy-confirmed acute rejection and renal graft function, although differences were apparent in terms of acute tubular necrosis and hyperlipidaemia. In conclusion, the development of a new immunosuppressive regimen in renal transplantation should take account of factors that influence graft function, both in the short and long term, as a way of optimizing individual maintenance therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12738759&dopt=Abstract tacrolimus Protopic



Protopic
Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease.

Baumgart DC, Wiedenmann B, Dignass AU.

Charite Medical Center-Virchow Hospital, Medical School of the Humboldt University of Berlin, Department of Medicine, Division of Hepatology and Gastroenterology, Berlin, Germany.

BACKGROUND: Oral tacrolimus, approved for the prophylaxis of organ rejection in liver or kidney transplants, has been reported to be effective in anecdotal cases of refractory inflammatory bowel disease. AIM: To evaluate the usefulness of low-dose oral tacrolimus in refractory inflammatory bowel disease. METHODS: Thirty-one adult Caucasian patients with steroid-dependent (n = 15) or steroid-refractory (n = 16) inflammatory bowel disease (Crohn's disease, n = 6; ulcerative colitis, n = 23; pouchitis, n = 2) were enrolled. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in 30 patients and initially intravenously in one patient (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-6 ng/mL. The median treatment duration was 12 months (range, 1-137 months). RESULTS: Twenty-eight patients (90.3%) experienced a clinical and laboratory response and 20 (64.5%) went into remission. One ulcerative colitis patient and two Crohn's disease patients did not improve. Three ulcerative colitis patients (9.7%) were colectomized at 1, 12 and 24 months after tacrolimus initiation. In 19 of 23 patients (82.6%) taking steroids, steroids were reduced or discontinued. Side-effects included a temporary rise of creatinine (n = 3, 9.7%), tremor or paraesthesias (n = 3, 9.7%), hyperkalaemia (n = 1, 3.2%), hypertension (n = 1, 3.2%) and an opportunistic infection (n = 1, 3.2%). CONCLUSION: Oral tacrolimus is safe and effective in refractory inflammatory bowel disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12755840&dopt=Abstract tacrolimus Protopic



Protopic
Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice.

Oetjen E, Baun D, Beimesche S, Krause D, Cierny I, Blume R, Dickel C, Wehner S, Knepel W.

Department of Molecular Pharmacology, Robert-Koch-Strasse 40, 37075 Gottingen, Germany.

Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs. They share a diabetogenic action as one of their most serious adverse effects. The underlying mechanism is unknown. Previous studies have shown that tacrolimus can inhibit insulin gene transcription at high concentrations in tumor cell lines. To study insulin gene transcription in normal, mature pancreatic islet cells, we used a novel approach in the present study. Transgenic mice that carry a human insulin promoter-reporter gene were generated. The human insulin promoter directed transcription in pancreatic islets and conferred a normal, physiological glucose response to reporter gene expression in isolated islets. After stimulation with glucose, human insulin promoter-mediated gene expression was inhibited in normal, mature islet cells by both tacrolimus and cyclosporin A to a large extent (approximately 70%) and with high potency at concentrations that are known to inhibit calcineurin phosphatase activity (IC50 values of 1 and 35 nM, respectively). Furthermore, glucose stimulated calcineurin phosphatase activity in mouse pancreatic islets, further supporting the view that calcineurin phosphatase activity is an essential part of glucose signaling to the human insulin gene. The high potency of cyclosporin A and tacrolimus in normal islets suggests that inhibition of insulin gene transcription by cyclosporin A and tacrolimus is clinically important and is one mechanism of the diabetogenic effect of these immunosuppressive drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12761338&dopt=Abstract tacrolimus Protopic



Protopic
Effect of experimental acute renal and hepatic failure on absorption of tacrolimus in rat small intestine.

Tamura S, Ohike A, Tokunaga Y, Ibuki R, Amidon GL, Sezaki H, Yamashita S.

Fujisawa Pharmaceutical Co., LTD., Osaka, Japan. shigeki_tamuru po.fujisawa.co.jp

The objective of this study is to evaluate the effect of acute renal or hepatic failure on the intestinal absorption of tacrolimus. Simultaneous perfusion study in rat small intestine revealed that the extent of absorption into blood vessels was decreased in the jejunum and the ileum of rat of acute renal failure due to the decrease in the uptake of tacrolimus into enterocytes. In contrast, there observed no significant changes in tacrolimus absorption in rat of acute hepatic failure. Since it has been reported that tacrolimus absorption is regulated mainly by Cytochrome P-450 (CYP) mediated metabolism in the jejunum, but by P-glycoprotein (P-gp) mediated efflux in the ileum, these factors might contribute to the changes in intestinal absorption of tacrolimus in rat of acute renal failure. Enzyme inhibitor, ketoconazole, was co-perfused with tacrolimus to specify the effect of CYP and P-gp. However, since ketoconazole failed to recover the permeability in the jejunum and ileum of rat of acute renal failure, it is considered that the changes in CYP or P-gp functions might not be involved in the decreased uptake of tacrolimus. This type of kinetic study in rats should be valuable to identify the precise mechanisms of drug absorption and the effects of various diseases on it, such as acute renal or hepatic failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15499186&dopt=Abstract tacrolimus Protopic



Protopic
Combination therapy of malononitrilamide FK778 with tacrolimus on cell proliferation assays and in rats receiving renal allografts.

Vu MD, Qi S, Wang X, Jiang W, Ma A, Xu D, Bekersky I, Fitzsimmons WE, Wu J, Chen H.

Laboratory of Experimental Surgery, Research Center of Centre Hospitalier de l'Universite de Montreal, Notre-Dame Hospital, Quebec, Canada.

BACKGROUND: Malononitrilamide FK778, an analogue of leflunomide's active metabolite, is a promising novel small molecule with immunosuppressive and immunomodulatory properties. In this study, we evaluated the ability of combination therapy of FK778 with tacrolimus to inhibit lymphocyte proliferation and to prevent acute allograft rejection. METHODS: Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on murine splenocytes, monkey lymphocytes, and human peripheral blood mononuclear cells, after activation with T or B cell-specific mitogens. A rat kidney transplantation model was used to evaluate the ability of FK778 combined with tacrolimus to prolong allograft survival. Median-effect principle and combination index (CI) were used to determine synergism, summation, or antagonism. RESULTS: A total of 58 combinations of FK778 plus tacrolimus were evaluated. Of the combinations tested, 82.8% (24/29) produced additive to synergistic effects in B cells, whereas 79.3% (23/29) produced moderate antagonistic effects in T cells. A concomitant 14-day therapy of FK778 (10 mg/kg/day) and tacrolimus (1 mg/kg/day) synergistically prolonged renal allograft survival to 25.5+/-5.9 days (CI=0.458). However, when addition of FK778 to tacrolimus therapy was delayed to day 7 after transplantation, a strong synergism was obtained (mean survival time=74.9+/-14.8 days, CI<0.001). CONCLUSIONS: This study demonstrates that the combination of FK778 with tacrolimus in vitro produces synergistic inhibition on B-cell proliferation but not on T cell proliferation in mice, nonhuman primates, and humans. When the addition of FK778 treatment was delayed to day 7 after transplantation, a strong synergism was produced in prolongation of renal allograft survival in the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12792496&dopt=Abstract tacrolimus Protopic