Protopic
Are keloids really "gli-loids"?: High-level expression of gli-1 oncogene in keloids.

Kim A, DiCarlo J, Cohen C, McCall C, Johnson D, McAlpine B, Quinn AG, McLaughlin ER, Arbiser JL.

Department of Dermatology, Emory University School of Medicine, 1639 Pierce Dr., Atlanta, GA 30322, USA.

BACKGROUND: Keloids are a common lesion arising from sites of previous trauma and are a considerable source of morbidity because of continued growth of lesions, pruritus, and physical appearance. They consist of mesenchymal cells embedded in a stroma of disordered collagen matrix. Clinically, keloids are distinguished from scars in that keloids demonstrate continued growth over the borders of the original injury. Keloids appear with increased frequency in patients of African and Asian descent. Currently, no entirely satisfactory method of treatment exists for these lesions. Recently, a patient who was enrolled in a clinical trial of topical tacrolimus for atopic dermatitis applied this drug to a keloid and noted clearing. OBJECTIVE: Based on this clinical observation and the observation that rapamycin, a chemically similar compound to tacrolimus, is known to inhibit signaling from the gli-1 oncogene, we examined keloids and scars for expression of Gli-1 protein. METHODS: Skin sections from keloids and scars were examined by immunohistochemical staining for gli-1. To further confirm the presence of gli-1 expression in keloids, reverse transcriptase-polymerase chain reaction was carried out. RESULTS: Expression of gli-1 was strongly elevated in keloids compared with scars. CONCLUSION: These results provide a rationale for the treatment of keloids with topical rapamycin analogs, including tacrolimus. Clinical trials of topical tacrolimus are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11606920&dopt=Abstract tacrolimus Protopic



Protopic
Can initial tacrolimus trough levels be predicted from clinical variables?

Baran DA, Galin ID, Zucker MJ, Alvi S, Arroyo LH, Lubitz S, Kaplan S, Correa R, Courtney MC, Chan M, Spielvogel D, Lansman SL, Gass AL.

Cardiothoracic Transplantation Program, Newark Beth Israel Medical Center, Newark, New Jersey 07112, USA.

In eligible patients, cardiac transplantation has become the definitive treatment for end-stage heart failure. The initial posttransplantation course is marked by many potential difficulties, including renal insufficiency, hemodynamic instability, and perioperative bleeding. It is important to prevent early rejection; calcineurin inhibitors, such as tacrolimus or cyclosporine, are integral parts of such management. However, these drugs are associated with renal toxicity in some patients. Previous work suggests that limiting the increase in tacrolimus levels is associated with less renal insufficiency. The hypothesis of the current study was that a combination of clinical or laboratory variables could identify patients at risk for rapid changes in tacrolimus target levels. No single variable was strongly associated with high resultant trough levels following a standard 1-mg oral "test dose" of tacrolimus. However, the combination of 2 indices of liver metabolism (alanine aminotransferase and total bilirubin) along with serum creatinine did identify patients who tended toward elevated levels of tacrolimus (> or =4.5 ng/dL). Other variables, such as demographics, and even functional variables, such as right ventricular function by echocardiography, did not enhance the predictive value of this simple scoring system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15621157&dopt=Abstract tacrolimus Protopic



Protopic
Comparative study analyzing effects of sirolimus-cyclosporin and sirolimus-tacrolimus combinations on bile flow in the rat.

Deters M, Nolte K, Kirchner G, Resch K, Kaever V.

Institute of Pharmacology, Medical School, Hannover, Germany.

The new immunosuppressive agent sirolimus is combined in transplant patients with the cholestatic substances cyclosporin and tacrolimus. Nothing is known about possible cholestatic effects of these combinations. Therefore, we compared their effects on bile flow and on important bile parameters in an acute bile fistula model in rats. Cyclosporin reduced bile flow, biliary excretion of bile salts, cholesterol, and GSH to 20-40% of basal values. Sirolimus decreased bile flow to 50% and excretion of GSH to 30% of the initial conditions but had no effect on cholesterol and bile salt excretion. In contrast, tacrolimus increased bile flow to 120% and GSH excretion to 220% of the basal levels. Sirolimus/cyclosporin decreased bile flow and bile parameters to the same extent as cyclosporin alone. Sirolimus/tacrolimus reversed sirolimus-induced reduction of bile flow and GSH excretion and resulted in a normal bile salt and cholesterol excretion, thus it may be the better alternative in cholestatic patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11680585&dopt=Abstract tacrolimus Protopic



Protopic
Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

Ovuworie CA, Fox ER, Chow CM, Pascual M, Shih VE, Picard MH, Tolkoff-Rubin NE.

Renal Unit and Transplantation Units, GRB 858, Massachusetts General Hospital, 55 Fruit Street, Boston MA 02114, USA.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11685108&dopt=Abstract tacrolimus Protopic



Protopic
[Treatment with tacrolimus in autoimmune diseases]

[Article in Spanish]

Sadaba B, Azanza JR, Garcia Quetglas E, Fernandez V.

Servicio de Farmacologia Clinica, Clinica Universitaria, Facultad de Medicina, Universidad de Navarra, Pamplona. bsadaba unav.es

Tacrolimus is an immunosuppressive drug used most successfully as a primary drug to suppress the rejection of transplants. Tacrolimus may also be useful as a novel therapy for autoimmune disease. There are various reports in the bibliography about the use of tacrolimus in the treatment of some autoimmune diseases: inflammatory bowel disease, autoimmune hepatitis, cutaneous, neurologic, renal, endocrine or eye disease. In this review of more than 130 papers, we discuss the rationale for the use of tacrolimus in autoimmune disease and report the clinical experience with the drug in the management of a variety of autoimmune diseases. But, although there are a lot questions that require future research (dose, duration of treatment, when to begin tacrolimus treatment, how to monitor it, etc.), there is also wide experience with tacrolimus in the treatment of this type of disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15622922&dopt=Abstract tacrolimus Protopic



Protopic
Experimental study of combined treatment with tacrolimus and donor splenocytes via the portal vein in small bowel transplantation.

Miyauchi T, Ishikawa M, Tashiro S, Hisaeda H, Himeno K.

First Department of Surgery, University of Tokushima School of Medicine, Tokushima, Japan.

We previously reported that the combined treatment of perioperative administration of donor splenocytes via the recipient's portal vein (DSPV) and a short-course Tacrolimus significantly prolonged the survival of fully allogenic grafts in rat small bowel transplantation (SBTX). In the present study we examined whether this effect depended on the quantity of the administered alloantigens in DSPV. In addition, we examined the expression of the surface antigen on T cells of the splenocytes and the induced toleragenic factor, according to the tolerant recipients which in our previous report had shown the prolongation of allogenic transplant small bowel graft survival by the combined treatment of DSPV (1 x 10(8) donor splenocytes) and a short-course Tacrolimus. Donor splenocytes were prepared from Brown-Norway (BN (RT1n)) rat spleens for Lewis (LEW (RT1l)) recipients. The recipients (n = 10), treated with a short course of Tacrolimus (0.5 mg/kg, 0 to 3 days postoperatively) only showed graft rejection with an average of 6.3 +/- 1.0 days postoperatively. However, the combined treatment, consisting of DSPV of 1 x 10(8) donor splenocytes and a short course Tacrolimus significantly prolonged graft survival to 12.7 +/- 2.1 days (n = 12, P < 0.01). DSPV of less than 1 x 10(8) donor splenocytes (5 x 10(7) cells and 2.5 x 10(7)) could not prolong the graft or animal survival under a short-course Tacrolimus treatment. In the tolerant recipients, the CD4 and CD8 percentages of splenocytes were not significantly different from those of control rats or recipients that were treated with short-course Tacrolimus alone. Nevertheless, the percentage of Tcr-alpha beta+ cells expressing IL-2 receptor (R) was significantly lower than in either control rats or the recipients with short-course Tacrolimus. In the suppression assay to one-way mixed lymphocyte response, a toleragenic factor was suggested to the present in the serum of the tolerant recipients. In the present study, it was suggested that the effects of the combined treatment of DSPV and short-course Tacrolimus for the prolongation of graft survival in the rat allogenic SBTX should depended on the quantity of the antigens administered into the portal vein. The beneficial effects of this treatment were reflected in the suppression of IL-2R on the recipient's splenocytes, and tolerogenic factor(s) might subsequently be induced in the tolerant recipient's serum.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11694955&dopt=Abstract tacrolimus Protopic



Protopic
Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation.

Fukatsu S, Yano I, Igarashi T, Hashida T, Takayanagi K, Saito H, Uemoto S, Kiuchi T, Tanaka K, Inui K, Tanaka K, Inui K.

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

OBJECTIVE: To characterize the pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation (LDLT). METHODS: Thirty-five patients were given tacrolimus as 18- to 60-h intravenous infusions after surgery, followed by a 4-week course of oral dose therapy (at 0900 hours and 2100 hours). Blood samples were collected daily in the morning (0800 hours) beginning the day after surgery. Whole blood concentration data were evaluated by nonlinear mixed-effect modeling using the program NONMEM and were characterized using a one-compartment model. RESULTS: The clearance (CL, l h(-1)) was related to the grafted hepatic weight, postoperative days (POD), and hepatic and renal dysfunction. Interindividual variabilities in CL, volume of distribution (V), and bioavailability (F) were 57.4%. 39.7%, and 63.0%, respectively, and the correlation between individual CL and F was 0.776. Residual intraindividual variability was 2.9 ng ml(-1). Based on the estimated final parameters, a typical recipient of LDLT with grafted hepatic weight of 600 g and normal hepatic and renal function would have a CL of 0.737 l h(-1) on POD 0 and 1.14 l h(-1) on POD 30, V of 1.52 l kg(-1) and F of 6.8%. CONCLUSIONS: Nonlinear mixed-effect modeling was useful for analysis of pharmacokinetic characteristics of tacrolimus in LDLT patients. Immediately after surgery, patients receiving LDLT showed a smaller CL value than other transplant patients, and CL value increased with POD within 30 days after surgery. The estimated population pharmacokinetic parameters can be applied for a priori dosage calculations in adult patients with LDLT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11699612&dopt=Abstract tacrolimus Protopic