Protopic
Tacrolimus ointment: the treatment of atopic dermatitis and other inflammatory cutaneous disease.

Carroll CL, Fleischer AB Jr.

Department of Dematology, Wake Forest University School of Medicine, Wiston-Salem, North Carolina 27157-1071, USA.

Topical tacrolimus (FK506, Protopic) has been developed and marketed for the treatment of atopic dermatitis (AD). Tacrolimus works as an inhibitor of calcineurin, which creates a downregulation of the inflammatory cascade. Numerous trials have shown the efficacy and safety of tacrolimus in treating AD in both adults and children. Additionally, comparison data with other medications commonly used for AD, such as topical steroids and pimecrolimus, show improved efficacy of tacrolimus. A comprehensive review of the off-label uses of tacrolimus in other dermatoses, including psoriasis, lichen planus and seborrhoeic dermatitis, is provided. The efficacy of tacrolimus in treating these diseases is based on Phase IV clinical trials and on case reports or series in the literature. Overall, tacrolimus has proven to be a safe and useful topical therapy for many inflammatory dermatological conditions, with AD being the principal indication.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15461548&dopt=Abstract tacrolimus Protopic



Protopic
Does conversion of immunosuppressive monotherapy from cyclosporine A to tacrolimus improve bone mineral density in long-term stable liver transplant recipients?

Ott R, Bussenius-Kammerer M, Koch CA, Yedibela S, Kissler H, Hohenberger W, Muller V.

Department of Surgery II, University of Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany. ottr medizin.uni-leipzig.de

The effects of converting cyclosporine A to tacrolimus on bone mineral density (BMD) have not yet been evaluated thoroughly in liver transplant patients. Interfering factors in this patient population often are concomitant glucocorticoid treatment or exposure to estrogens. Here, we investigated in a homogeneous population of 10 male liver transplant recipients the impact of converting low-dose cyclosporine A monotherapy to low-dose tacrolimus monotherapy on BMD by using dual-energy x-ray absorptiometry. During the 12-month study period, an increase in BMD at the lumbar spine was observed in 9 out of 10 men (P <.01), whereas BMD at the femoral neck remained stable. Converting cyclosporine A to tacrolimus appears to be safe and efficaceous with regard to maintaining or even increasing BMD in male liver transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14697971&dopt=Abstract tacrolimus Protopic



Protopic
Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus.

Billich A, Aschauer H, Aszodi A, Stuetz A.

Novartis Research Institute Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. andreas.billich pharma.novartis.com

For treatment of skin diseases with topical drugs, penetration of the agents into the relevant layers of the skin is required. Permeation through the skin should, however, be kept to a minimum, in order to avoid the risk of systemic side effects. Here we compared the in vitro skin penetration and permeation of two novel drugs used in the therapy of atopic eczema (pimecrolimus and tacrolimus) and three representative corticosteroids (betamethasone-17-valerate, clobetasol-17-propionate, and diflucortolon-21-valerate). Drug concentrations of pimecrolimus and corticosteroids in human skin were found to be in the same order of magnitude. Permeation of pimecrolimus through human skin was, however, lower by factors of 70-110 as compared to the steroids. When pimecrolimus was compared with tacrolimus in human, pig, or rat skin, similar concentrations of the two compounds were measured in the skin, whereas permeation of pimecrolimus through skin was consistently lower by factors of 9-10. Lipophilicity was found to be highest for pimecrolimus, its octanol-water distribution coefficient being higher by factors of 8 and 25-450 than that of tacrolimus and the corticosteroids, respectively. The low permeation of pimecrolimus may be explained by its higher lipophilicity (compared to tacrolimus and the corticosteroids) and higher molecular weight (compared to steroids). In conclusion, pimecrolimus appears to have a favourable skin penetration/permeation profile, featuring a low degree of percutaneous absorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14698574&dopt=Abstract tacrolimus Protopic



Protopic
The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.

Sanchez EQ, Levy MF, Goldstein RM, Fasola CG, Tillery GW, Netto GJ, Watkins DL, Weinstein JS, Murray NG, Byers D, Christensen LL, Klintmalm GB.

Baylor University Medical Center, Transplantation Services, Dallas, TX 75246, USA.

BACKGROUND: Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years. MATERIALS AND METHODS: The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically. RESULTS: Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11). CONCLUSIONS: Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14702528&dopt=Abstract tacrolimus Protopic



Protopic
Influence of continuous venovenous haemodiafiltration on the pharmacokinetics of tacrolimus in liver transplant recipients with small-for-size grafts.

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

Department of Pharmacy, Hokkaido University Hospital, School of Medicine, Hokkaido University, Sapporo, Japan.

In adult-to-adult living donor liver transplantation (LDLT), the graft volume is inevitably much smaller than the ideal liver mass (standard liver volume) for the recipient's metabolic demand. Patients with small-for-size grafts are treated with continuous venovenous haemodiafiltration (CVVHD) for the artificial liver support. However, little is known about the influence of CVVHD on the elimination of tacrolimus. The objective of this study was to elucidate the effect of CVVHD on the pharmacokinetics of tacrolimus in recipients of LDLT with small-for-size grafts. Three liver transplant recipients (one male and two females) and donors (two males and one female) were enrolled in this study. Blood samples from inflow port and outflow port were obtained on the first day at the start of CVVHD. Whole-blood concentrations of tacrolimus were measured immediately using the microparticle enzyme immunoassay (MEIA; Abbott Laboratories). There was no significant difference between concentrations of tacrolimus in blood sampled at inflow port and outflow port sites and t(1/2)-values of tacrolimus in the three recipients were 29.9, 63.6 and 28.8 h. CVVHD did not cause a decrease in the blood tacrolimus concentration. Adjustment to the dose or dosing interval is not required for patients treated with tacrolimus during CVVHD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14703922&dopt=Abstract tacrolimus Protopic



Protopic
Sensitivity of whole-blood T lymphocytes in individual patients to tacrolimus (FK 506): impact of interleukin-2 mRNA expression as surrogate measure of immunosuppressive effect.

Hartel C, Schumacher N, Fricke L, Ebel B, Kirchner H, Muller-Steinhardt M.

Institute of Immunology and Transfusion Medicine, University of Lubeck Medical School, Ratzeburger Allee 160, 23538 Lubeck, Germany.

BACKGROUND: To optimize immunosuppressive treatment in individual transplant patients, functional measurements of the effects of tacrolimus (FK 506) are of clinical importance. Previous investigations have demonstrated the occurrence of tacrolimus-resistant production of interleukin-2 (IL-2) in vitro, which may explain in part why rejection episodes are still a frequent problem despite attainment of therapeutic blood concentrations and HLA matching. However, an adequate surrogate marker to define the tacrolimus response in individual patients has not been established. METHODS: We investigated the immunosuppressive effects of tacrolimus on anti-CD3/anti-CD28 T-cell costimulation in a human whole-blood assay, analyzing T-cell proliferation, activation marker expression (CD25, CD69), IL-2 protein expression, and cytokine mRNA expression in vitro (n = 11 healthy individuals). We also quantified IL-2 mRNA expression in patients undergoing tacrolimus (n = 4) or cyclosporin A (CsA; n = 4) monotherapy before ex vivo living-donor kidney transplantation. RESULTS: T-cell proliferation; CD25, CD69, and IL-2 concentrations; and IL-4 mRNA were significantly decreased in vitro. In contrast, cytokine mRNA profiles revealed variable tacrolimus sensitivity. Whole-blood samples from 3 of 11 healthy individuals demonstrated marked suppression of IL-2 mRNA expression (>50%) when tacrolimus was administered in vitro. When CsA was added to whole-blood cultures, the influence on IL-2 mRNA expression was comparable to that of tacrolimus in 9 of 11 individuals. Two individuals responded conversely, indicating that differences in the in vitro response to tacrolimus and CsA among individuals may be attributable to potential heterogeneity in the involvement of the CD28 pathway. Kinetic profiles of IL-2 mRNA expression also revealed individually distinct degrees of calcineurin inhibitor sensitivity in patients undergoing tacrolimus or CsA monotherapy before living-donor kidney transplantation. CONCLUSIONS: Our results suggest an individual degree of calcineurin inhibitor sensitivity of activated whole-blood lymphocytes based on IL-2 mRNA expression. Our approach is potentially valuable for identifying transplant patients in whom IL-2 mRNA expression is unaffected or even enhanced after initiation of immunosuppressive therapy. Such individuals may be less sensitive to the immunosuppressive agent and therefore at increased risk of transplant rejection. Prospective studies are necessary to determine the correlation of IL-2 mRNA expression with the clinical risk of transplant rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14709642&dopt=Abstract tacrolimus Protopic



Protopic
In vitro release of Tacrolimus from Tacrolimus ointment and its speculated mechanism.

Yoshida H, Tamura S, Toyoda T, Kado K, Ohnishi N, Ibuki R.

Pharmaceutical Science Laboratories, Fujisawa Pharmaceuticals Co., Ltd, 1-6, 2-chome Kashima Yodogawa-ku, Osaka 532-8514, Japan. hiromitsu_yoshida po.fujisawa.co.jp

The in vitro release profiles and the bleeding phenomenon of Tacrolimus and propylene carbonate (PC) as a dispersing solvent for Tacrolimus drug substance in Tacrolimus ointment were investigated when changing concentrations of Tacrolimus and PC in the ointment were used, respectively. The bleeding test result indicated that Tacrolimus was in equilibrium between inside and outside of PC droplets in intact ointment base. A cumulative release amount of Tacrolimus from ointment, plotted against the square root of time, showed a straight line initially with a slope of q1 followed to change a slope to be q2 at a certain time, where the relation of these slopes being q1<q2. The q1 values increased with the concentration of Tacrolimus but decreased with PC concentration in Tacrolimus ointment. And the q2 values increased with Tacrolimus concentration but were independent of PC concentration. These profiles indicated that there were two phases for Tacrolimus release from ointment, namely, first phase was related with the period during PC release and the second phase was related with the state of ointment after PC release. When the PC release was applied to the Higuchi's release equation, the above slope q1 was found to be correlated to the parameter of A/phi(0), where A was a parameter of release rate of PC and phi(0) was an initial volume fraction of PC droplets. It should be indicated that more rapid release rate of PC rather than that of Tacrolimus resulted in the generation of amorphous phase of Tacrolimus outside of remaining PC droplets. During PC release, the slope q1 could be influenced by the thermodynamic activity of Tacrolimus dissolved in PC droplets. After PC release, it would be reasonable to speculate that the amorphous cluster of Tacrolimus with a constant thermodynamic activity would give constant q2 values regardless of PC contents in Tacrolimus ointment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14726122&dopt=Abstract tacrolimus Protopic