Protopic
Prevalence of gingival overgrowth in transplant patients immunosuppressed with tacrolimus.

Ellis JS, Seymour RA, Taylor JJ, Thomason JM.

School of Dental Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4BW, UK. j.s.ellis ncl.ac.uk

AIMS: The study aims to determine the prevalence and severity of gingival overgrowth in a group of adult organ transplant recipients immunosuppressed with tacrolimus in comparison with ciclosporin, and to examine various risk factors for the development of gingival overgrowth. METHODS: Forty patients taking tacrolimus were compared with 197 ciclosporin patients. Demographic, pharmacological and periodontal data were recorded for all patients. Comparison between the groups was made using independent sample t-tests, chi2 statistic or Mann-Whitney test. The effects of risk variables on overgrowth severity were examined using forward and backward stepwise regression analysis. RESULTS: Those taking tacrolimus had a significantly lower mean gingival overgrowth score (14.1%) compared with ciclosporin (22.4%). Fifteen percent of the tacrolimus group had clinically significant gingival overgrowth compared with 30% in the ciclosporin group (p=0.053). CONCLUSIONS: The prevalence and severity of gingival overgrowth is less in adult transplant patients taking tacrolimus compared with ciclosporin. Concomitant use of calcium channel blockers and previous medication with ciclosporin are significant risk factors for the presence and severity of gingival overgrowth. Patients who have alteration of their immunosuppressant from ciclosporin to tacrolimus may persist in demonstrating gingival overgrowth attributable to their ongoing therapy with calcium channel blockers. Copyright Blackwell Munksgaard, 2004.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15016038&dopt=Abstract tacrolimus Protopic



Protopic
Basiliximab in association with tacrolimus and steroids in caucasian cadaveric renal transplanted patients: significant decrease in early acute rejection rate and hospitalization time.

Leonardi G, Messina M, Giraudi R, Pellu V, Fop F, Segoloni GP.

Renal Transplant Unit, Chair of Nephrology, University of Turin, St John Hospital, C.so Bramante, Turin, Italy. leonardigl hotmail.com

Safety and tolerability of basiliximab in renal transplantation have been proven in different immunosuppressive regimens. Few informations are available about the association of basiliximab with tacrolimus and steroids. We present a retrospective analysis performed in Caucasian cadaveric renal transplant recipients, comparing a basiliximab, tacrolimus and steroids induction protocol (GrA: 51 patients) with a tacrolimus and steroids protocol (GrB: 46 patients). A significant decrease in acute rejection rate in the first 3 months (2.0% vs. 17.4%; p < 0.01) was noted. Interestingly, the recipients in GrA were at major immunologic risk for the younger age of recipients, the greater number of mismatches and the higher rate of second transplants. The hospitalization times resulted reduced of 5.3 d in GrA vs. GrB (20.8 d vs. 26.1 d; p < 0.05). The adverse events patterns and profiles were similar in the two treatments groups. One patient in each group had a post-transplant lymphoprolipherative disorder. No significant difference was found in patient and graft survival. According to the results of this study, in a Caucasian adult population, basiliximab in association with tacrolimus and steroids is a safe and efficacious tool for acute rejection prevention and it is cost saving by reducing the hospitalization times.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15016122&dopt=Abstract tacrolimus Protopic



Protopic
The variability of liver graft function and urinary 6beta-hydroxycortisol to cortisol ratio during liver regeneration in liver transplant recipients.

Kishino S, Ogawa M, Takekuma Y, Sugawara M, Shimamura T, Furukawa H, Todo S, Miyazaki K.

Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Tokyo, Japan. skishino my-pharm.ac.jp

The urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) is considered to be the simplest and most practical method for estimation of hepatic cytochrome P450 3A4 (CYP3A4) activity as a non-invasive marker of human in vivo CYP3A4 activity. However, the inter- and intra-individual variability of the urinary 6beta-OHF/F ratio during liver regeneration and the effect of variability on optimal dose of tacrolimus have not yet been clarified. The objective of this study was to clarify the change in the urinary 6beta-OHF/F ratio during liver regeneration and to determine the effect of the liver graft function on the optimal tacrolimus dose in liver transplant recipients. Two liver transplant recipients (one male and one female) and eight healthy volunteers (five males and three females) were enrolled in this study. Urine samples were collected from the recipients from 08.00 hours for 24 h on post-transplant period, 1-10 and 21-30 days postoperatively. In the healthy volunteers, morning spot urine samples were collected at 08.00 hours. The mean urinary 6beta-OHF/F ratio in the immediate postoperative period was significantly low (p < 0.05). However, a marked difference in the regulation of CYP3A4 activity during liver regeneration was found in the two recipients. A significant correlation was found between the urinary 6beta-OHF/F ratio and the C/D ratio of tacrolimus (R = 0.658, p < 0.05). The urinary 6beta-OHF/F ratio is a useful probe for estimating the variability of CYP3A4 activity in liver transplant recipients in early postoperative phase. Future studies should evaluate the clinical usefulness of the urinary 6beta-OHF/F ratio as a predictor of tacrolimus pharmacokinetics in liver transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15016124&dopt=Abstract tacrolimus Protopic



Protopic
Pharmacokinetics of tacrolimus in kidney transplant recipients: twice daily versus once daily dosing.

Hardinger KL, Park JM, Schnitzler MA, Koch MJ, Miller BW, Brennan DC.

Department of Pharmacy, Barnes-Jewish Hospital at Washington University, St. Louis, MO, USA. klh2562 bjc.org

Tacrolimus a macrolide immunosuppressant that is routinely given in two equally divided doses every 12 h. However, the time-dependent pharmacokinetics of tacrolimus suggest that once daily morning administration of tacrolimus may produce appropriate drug exposure. The purpose of this pilot study was to compare the pharmacokinetics and safety of twice vs. once daily administration of tacrolimus in stable kidney transplant recipients. Steady-state tacrolimus pharmacokinetic parameters were estimated on two occasions in an open-label, three-arm, two-period sequential study: twice daily dosing (Phase I) and once daily dosing (Phase II). In phase II, 18 patients were assigned to one of three arms: those taking 67%, 85% and 100% of their total twice daily dose once in the morning. In phase I, the mean area under the blood concentration-time curve (AUC) was higher after the morning dose, AUC(0-12) 117 +/- 40 vs. AUC(12-24) 97 +/- 30 ng/h/mL, p=0.012. In the 85% Group, the mean AUC ratio between twice and once daily was 1.0 (95% CI, 0.9-1.1) which predicted the best conversion ratio. Tacrolimus given once daily in the morning, at 85% of the twice daily dose, provides safe and equivalent drug exposure to twice daily dosing. This convenient dosing schedule may help to increase compliance and lower costs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15023155&dopt=Abstract tacrolimus Protopic



Protopic
Additive effects of leflunomide and tacrolimus in prevention of islet xenograft rejection.

Zhang L, Qi Z, Wu D, Shan S, Ekberg H.

Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China. zhongquan.qi kir.mas.lu.se

Leflunomide is a low molecular weight immunosuppressive drug which inhibits the enzymes dehydroorotate dehydrogenase and protein tyrosine kinase, both of which are important components in the immune response. As the mechanisms of action of leflunomide and tacrolimus are different, we postulated an additive or synergistic effect of the two drugs and investigated the effects of leflunomide alone, or in combination with a suboptimal dose of tacrolimus, on xenogeneic islet transplantation in a rat-to-mouse model. A total of 1200-1500 rat islets were transplanted under the left kidney capsule of streptozotocin-induced diabetic BALB/c mice. The median survival time (MST) of the untreated group was 6 days. Leflunomide at 5, 10 and 20 mg/kg/d administrated for 10 days significantly prolonged MST to 10, 16 and 20 days. A dose of tacrolimus (2 mg/kg/d) was associated with a graft survival of 9 (range 6-12) days; most grafts rejected during ongoing therapy. When tacrolimus (2 mg/kg/d) was combined with leflunomide (10 mg/kg/d), the survival time of the islet xenografts was increased further to 22 days, significantly longer than with leflunomide or tacrolimus alone. In summary, our findings demonstrate that leflunomide prolonged xenogeneic islet graft survival, and that its immunosuppressive effect was improved when combined with tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15030575&dopt=Abstract tacrolimus Protopic



Protopic
Short- and long-term effects of T-cell modulating agents in experimental autoimmunity.

Mellergard J, Havarinasab S, Hultman P.

Division of Molecular and Immunological Pathology, Department of Molecular and Clinical Medicine, Linkoping University, SE-581 85 Linkoping, Sweden.

Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2(s)) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2(s)) mice were given 6 mg HgCl(2)/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15036746&dopt=Abstract tacrolimus Protopic



Protopic
Protocol biopsy and subclinical rejection in patients after kidney transplantation treated by tacrolimus (Prograf).

Zadrazil J, Krejci K, Al-Jabry S, Horcicka V Jr, Tichy T, Hrabalova M, Bachleda P.

3rd Clinic of Internal Medicine, Teaching Hospital, I. P. Pavlova 22, Olomouc, 775 00, Czech Republic.

The article deals with the contribution of tacrolimus (Prograf) to improvement in kidney transplant results. Tacro-limus, in comparison with cyclosporine significantly reduces the incidence of acute rejection and improves survival of grafts as well as patients. Based on the literature, the primary immunological differences between tacrolimus and cyclosporine effects are pointed out. These differences explain the better immunosuppressive effectiveness of tacrolimus. Based on analysis of the results, subclinical rejection problems and significance of protocol biopsy for present-day transplantology are discussed. There is also a critical analysis of the questions, which priority, in relationship to the expanding availability of immunosuppressive substances currently has high interest for nephrologists researching subclinical rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15037903&dopt=Abstract tacrolimus Protopic