Protopic
Evaluation for synergistic suppression of T cell responses to minor histocompatibility antigens by chloroquine in combination with tacrolimus and a rapamycin derivative, SDZ-RAD.

Hsiao CC, Su WN, Forooghian F, Bader S, Rempel J, HayGlass KT, Gilman A, Schultz KR.

Department of Pediatric Hematology and Oncology, Chang Gung Children's Hospital, Kaohsiung, Taiwan, ROC.

The 4-aminoquinolines, chloroquine and hydroxychloroquine, can suppress chronic graft-versus-host disease (GVHD) following blood and marrow transplantation (BMT) in mice and humans, respectively. We hypothesized that chloroquine in combination with tacrolimus and the rapamycin derivative SDZ-RAD can synergistically suppress T cell responses and antigen-presenting cell (APC) function in vitro. We used the APC-dependent C57BL/6 anti-BALB.B T cell response and APC-independent anti-CD3epsilon antibody-induced response to evaluate the role of synergism between chloroquine and tacrolimus or SDZ-RAD on each component of a T cell response to minor histocompatibility antigens. We found that chloroquine with tacrolimus had a greater synergistic suppression of APC-dependent compared to the APC-independent T cell responses, with a combination index (CIx) for 50% inhibition by mean effect analysis of 0.16 and 0.50, respectively (a lower number indicates greater suppression). By contrast, chloroquine with SDZ-RAD had a similar CIx between the two responsed 0.50 vs0.45) suggesting only T cell suppression. Synergy between chloroquine and SDZ-RAD involved a direct effect on T cell cytokine production, whereas synergism between chloroquine and tacrolimus was due to an effect on both T cells and APCs. We conclude that the renal-sparing 4-aminoquinolines may be used syneristically with immunosuppressive drugs currently used for BMT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12476284&dopt=Abstract tacrolimus Protopic



Protopic
Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus.

Staatz CE, Tett SE.

School of Pharmacy, University of Queensland, Brisbane, Queensland 4072, Australia. c.staatz pharmacy.uq.edu.au

OBJECTIVES: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. METHODS: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. RESULTS: A satisfactory model was developed in both programs with a single categorical covariate--transplant type--providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates--age and liver function tests--improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 l/h, CL/F (cut-down liver) = 8.5 l/h and V/F = 565 l in NONMEM, and CL/F = 8.3 l/h and V/F = 155 l in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 l/h, CL/F (cut-down liver) = 11.6 +/- 8.8 l/h and V/F = 712 +/- 792 l in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 l/h, CL/F (cut-down liver) = 8.2 +/- 3.4 l/h and V/F = 221 +/- 164 l in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. CONCLUSION: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12483452&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement.

Macphee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, Goldberg L, Holt DW.

Division of Renal Medicine St. George's Hospital Medical School, London, United Kingdom. imacphee sghms.ac.uk

BACKGROUND: There is marked heterogeneity in blood concentrations of tacrolimus following standard body-weight-based dosing. This is most apparent in black patients, who have a higher dose requirement when compared with other ethnic groups. Differences in intestinal P-glycoprotein and hepatic and intestinal cytochrome P4503A activity have been postulated as contributing to this problem. METHODS: The dose-normalized blood concentrations of tacrolimus at 3 months after renal transplantation were related to CYP3AP1 and multiple drug resistance (MDR)-1 genotypes determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: We found that a single nucleotide polymorphism in the CYP3AP1 pseudogene (A/G(44)) that previously has been noted to be more common in African Americans and strongly associated with hepatic CYP3A5 activity correlated well with the tacrolimus dose requirement. A weaker association was found for a polymorphism in the MDR-1 gene, which influences intestinal P-glycoprotein expression. CONCLUSIONS: The CYP3AP1 genotype is a major factor in determining the dose requirement for tacrolimus, and genotyping may be of value in planning patient-specific drug dosing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12490779&dopt=Abstract tacrolimus Protopic



Protopic
[Interaction between sildenafil and calcineurin inhibitors in renal transplant recipients with erectile dysfunction]

[Article in Spanish]

Cofan F, Gutierrez R, Beardo P, Campistol JM, Oppenheimer F, Alcover J.

Unidad de Trasplante Renal, Universidad de Barcelona, Barcelona. fcofan medicina.ub.es

AIM: Hepatic metabolism of sildenafil uses the same metabolic pathway as the calcineurin inhibitors (cyclosporine/tacrolimus), through the CYP3A4 isoenzyme. The aim of this pilot study was to evaluate the potential interaction between sildenafil therapy and circulating levels of cyclosporine and tacrolimus in a group of steady-state renal transplant recipients with erectile dysfunction. MATERIAL AND METHODS: A prospective pilot study of sildenafil interactions was carried out in 9 stable male renal transplant recipients with severe erectile dysfunction (mean age 50 +/- 8 years, range 38-64). All patients were receiving therapy with calcineurin inhibitors (5 with cyclosporine and 4 with tacrolimus). Erectile dysfunction was evaluated by clinical history, physical examination, International Index of Erectile Function (IIEF) questionnaire and the nocturnal penile tumescence test (RigiScan). Each patient received a first dose of 50 mg of sildenafil, one hour before sexual activity and a second dose at 72 hours of 50 or 100 mg according to the clinical response to the first dose. We evaluated the efficacy and safety of sildenafil and the evolution of cyclosporine-tacrolimus levels. Cyclosporine and tacrolimus trough whole blood concentrations were determined in basal conditions (before starting sildenafil) and on days 1, 4 and 7 after sildenafil therapy. RESULTS: Eighty-nine percent of patients (n = 8) required a complete 100 mg dose of sildenafil. There was a positive clinical response in two-thirds of cases (6 patients). In 5 patients (55%) sildenafil administration produced a complete response, in one patient the response was incomplete, and in the remaining 3 cases (33%) no clinical response was observed. Associated side effects included self-limited tachycardia in one patient and mild visual disturbances in another. Cyclosporine and tacrolimus levels remained stable in all patients. There were no significant differences in circulating levels of cyclosporine (basal 120 +/- 47; day 1: 116 +/- 55; day 4: 123 +/- 56 and day 7: 121 +/- 56 ng/ml p = NS) or tacrolimus (basal 11.6 +/- 1.3; day 1: 11.9 +/- 1.3; day 4: 11.1 +/- 1.0 and day 7: 11.8 +/- 0.9 ng/ml p = NS) over the study period. CONCLUSIONS: Sildenafil therapy is safe and effective for the treatment of erectile dysfunction in renal transplant recipients. Recommended therapeutic doses of sildenafil did not modify cyclosporine and tacrolimus trough blood levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12497749&dopt=Abstract tacrolimus Protopic



Protopic
Causes of mortality beyond 1 year after primary pediatric liver transplant under tacrolimus.

Fridell JA, Jain A, Reyes J, Biederman R, Green M, Sindhi R, Mazariegos GV.

Department of Surgery, Children's Hospital of Pittsburgh, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

BACKGROUND: Success of pediatric liver transplantation has improved significantly. Most posttransplant deaths occur early and are related to surgical complications or recipient status at the time of transplantation. The causes of mortality beyond the first year have not been well described. METHODS: Three hundred twenty-six pediatric liver transplants were performed between November 1989 and April 1998 using tacrolimus-based immunosuppression. Patients were followed until March 2002. Mean follow-up was 9.2+/-2.4 years. RESULTS: At 1 year, 279 patients (85.5%) were alive. In the subsequent 12.5 years, 10 of the remaining children died (3.58%) at a mean interval of 3.68+/-1.69 years after transplant. The mean age at transplant was 5.62+/-6.3 years. Six patients had infections as a major contributor to mortality, including two patients with posttransplant lymphoproliferative disorder (PTLD) and one patient that died after retransplantation for hepatitis. Two patients had recurrent malignancy. Other deaths were attributable to chronic rejection, liver failure after being lost to follow-up, and complications of cystic fibrosis. CONCLUSIONS: Pediatric liver transplantation using tacrolimus-based immunosuppression has demonstrated excellent success, with 1- and 10-year survival rates of 85.5% and 82.9%, respectively. Late mortality after pediatric liver transplantation overall remains low, with a rate of 0.32% per year. The most common cause of death was infection (60%), including PTLD-related disease (20%). However, in the recent cohort of patients who underwent transplantation after September 1995, there were no fatal cases of Epstein-Barr virus or PTLD or late mortality thus far, suggesting a benefit from improved infectious disease surveillance using currently available modalities. Mortality from chronic rejection and noncompliance under tacrolimus has been exceedingly rare.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499888&dopt=Abstract tacrolimus Protopic



Protopic
The role of topical calcineurin inhibitors in atopic dermatitis.

Alomar A, Berth-Jones J, Bos JD, Giannetti A, Reitamo S, Ruzicka T, Stalder JF, Thestrup-Pedersen K; European Working Group on Atopic Dermatitis.

Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Spain.

For more than five decades, topical corticosteroids and emollients have been the mainstay of therapy for atopic dermatitis. However, the potential for side-effects limits the clinical utility of corticosteroids in providing long-term disease control. With a unique mode of action that differs from that of corticosteroids, the steroid-free topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, provide skin-selective treatment that targets key factors involved in the pathogenesis of this chronic disease. An extensive series of clinical trials involving more than 16,000 patients with predominantly moderate to severe atopic dermatitis in tacrolimus studies and over 2000 patients with primarily mild to moderate disease in pimecrolimus studies has shown that both TCIs provide effective and well-tolerated treatment for atopic dermatitis. Randomized controlled trials have demonstrated that tacrolimus is superior to conventional hydrocortisone-based regimens and does not cause skin atrophy or other steroidal side-effects. Both tacrolimus and pimecrolimus prevent disease flares and provide progressive and sustained disease improvement with long-term therapy. These and other clinical benefits of TCIs are discussed, together with the safety profiles of tacrolimus and pimecrolimus and their use in clinical practice. In addition, this review summarizes findings from the many trials carried out with these agents and outlines how TCIs can provide long-term treatment and control of a chronic skin disease that may persist for years.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15548171&dopt=Abstract tacrolimus Protopic



Protopic
Topical tacrolimus for treatment of childhood vitiligo in Asians.

Kanwar AJ, Dogra S, Parsad D.

Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. ajkanwar sify.com

Childhood vitiligo is a common disorder of pigmentation in India. Considering the lack of uniformly effective and safe treatment modalities for children with vitiligo, search for newer therapeutic agents continues. This study was designed to evaluate the role of topical tacrolimus in the treatment of childhood vitiligo. Twenty-five children with vitiligo were treated with topical 0.03% tacrolimus ointment applied twice daily for 12 weeks. Response was noted as marked to complete (> 75% repigmentation), moderate (50-75% repigmentation) and mild (< 50% repigmentation). Twenty-two children (9 boys and 13 girls) of mean age 7.2 +/- 1.4 years completed the study. Twelve (54.5%) children had vitiligo vulgaris, nine (40.9%) had focal vitiligo and one (4.5%) had segmental vitiligo. The mean duration of disease was 8 +/- 3 months. Nineteen (86.4%) children showed some repigmentation at the end of 3 months and other three had no response. Of these 19 children, repigmentation was marked to complete in 11 (57.9%), moderate in five (26.3%) and mild in three (15.7%) children. Side effects were minimal, such as the pruritus and burning noted in only three patients. Topical tacrolimus is an effective and well-tolerated treatment modality in Asian children with vitiligo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15550128&dopt=Abstract tacrolimus Protopic