Protopic
Time-related changes in pulmonary function after conversion to tacrolimus in bronchiolitis obliterans syndrome.

Cairn J, Yek T, Banner NR, Khaghani A, Hodson ME, Yacoub M.

Department of Transplant Medicine, National Heart and Lung Institute, Harefield, Middlesex, UK.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a leading cause of morbidity and mortality after lung and heart-lung transplantation. Present treatment is directed at the augmentation of pharmacologic immunosuppression. METHODS: This study examines the effect of substituting cyclosporine with tacrolimus on the forced expiratory volume in 1 second (FEV(1)) and on the forced expiratory flow between 25% and 75% of vital capacity (FEF(25%-75%)) in 32 patients who developed BOS. The proportional rates of decline of FEV(1) and FEF(25%-75%) before and after treatment with tacrolimus were calculated. The actuarial survival of responders and non-responders to tacrolimus was compared. Pre-operative and post-operative factors were investigated to determine any difference between the 2 groups. RESULTS: There were significant reductions in the rates of decline of FEV(1) and FEF(25%-75%) when the rates in the 3 months before conversion to tacrolimus were compared with subsequent rates at 0 to 3 months, 3 to 6 months, 6 to 9 months and 9 to 12 months after conversion. The rates of decline of FEV(1) and FEF(25%-75%) in the 3 months before conversion were 0.11 liters/month and 0.13 liters/s per month, respectively. This compares with the rates of decline for FEV(1) and FEF(25%-75%) for the 3 months after conversion to tacrolimus of 0.04 liters/month (p = 0.023) and 0.04 liters/s per month (p = 0.022), respectively. The actuarial survival at 1 year from the time of conversion to tacrolimus for the responder sub-group and the non-responder sub-group were 89.2% and 75%, respectively, and at 4 years after conversion were 61.3% and 56.3%, respectively (p = 0.92). CONCLUSIONS: Tacrolimus rescue therapy is effective at stabilizing lung function in patients with BOS, and this effect is apparent up to 12 months after conversion from cyclosporine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12531413&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

Simon N, Morin C, Urien S, Tillement JP, Bruguerolle B.

Laboratoire de Pharmacologie, Faculte de Medecine de Marseille, 27 Bd Jean Moulin, F-13385 Marseille cedex, France. Nicolas.simon medecine.univ-mrs.fr

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12540528&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus ointment (Protopic) for atopic dermatitis.

Pascual JC, Fleisher AB.

Department of Dermatology, Hospital General de Alicantem, Alicante, Spain.

Tacrolimus ointment (Protopic, Fujisawa) is an effective agent in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in decreased T-cell activation and inflammatory cytokine release. Tacrolimus ointment is safe and effective for short- and long-term treatment of atopic dermatitis (AD) in pediatric and adult patients. The most common adverse events associated with its use are a transient burning sensation and pruritus at the site of application. Unlike topical corticosteroid agents, tacrolimus ointment does not cause a reduction in collagen synthesis or skin thickness. Because tacrolimus ointment does not cause skin atrophy, it may be safely used for months or years on all skin areas, including the face and intertriginous areas.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15550992&dopt=Abstract tacrolimus Protopic



Protopic
Angioedema in pediatric liver transplant recipients under tacrolimus immunosuppression.

Lykavieris P, Frauger E, Habes D, Bernard O, Debray D.

Service d'Hepatologie pediatrique, Hopital de Bicetre, Le Kremlin Bicetre Cedex, France.

BACKGROUND: The authors report on their experience with food-induced angioedema in tacrolimus-immunosuppressed pediatric liver recipients. METHODS: Among 121 children treated with tacrolimus after liver transplantation, those who presented with angioedema are reported. RESULTS: Twelve children (10%) experienced angioedema related to food allergy while on tacrolimus. Mean ages at transplantation and angioedema were 1.3 years and 3.75 years, respectively. Angioedema occurred within a mean of 28 months from onset of tacrolimus. Eleven children experienced two or more angioedema attacks without consequences. One child presented with anaphylactic shock that caused postischemic cerebral damage. Besides eviction of food allergens, eight children were switched from tacrolimus to cyclosporine, whereas tacrolimus dosage was decreased in four. Reintroduction of food allergens was successfully performed only in those who were switched to cyclosporine. CONCLUSION: A causal relationship between tacrolimus and the occurrence of food-induced angioedema is suggested. The switch from tacrolimus to cyclosporine should be considered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12544888&dopt=Abstract tacrolimus Protopic



Protopic
Outcome of 3 years of immunosuppression with tacrolimus in more than 1,000 renal transplant recipients in japan.

Sonoda T, Takahara S, Takahashi K, Uchida K, Ohshima S, Toma H, Tanabe K, Yoshimura N; Japanese Tacrolimus Study Group.

Osaka Prefectural General Hospital, Osaka, Japan.

BACKGROUND: In Japan, the new macrolide immunosuppressant, tacrolimus, was approved for the prevention and treatment of allograft rejection in renal transplant recipients in April 1996. This article summarizes efficacy and safety data for tacrolimus gathered since its approval. METHOD: Data from 1,007 patients who received tacrolimus-based treatment after kidney transplantation at 35 leading Japanese transplant centers between April 1996 and December 2000 were retrospectively analyzed. RESULTS: The renal transplants consisted of 856 living (756 ABO compatible, 100 ABO incompatible) and 151 cadaveric (146 non-heart-beating, 5 brain dead) donor grafts. Mean follow-up duration was 24.4 months. Overall patient and graft survival rates were 98.4% and 94.8% at 1 year, 98.0% and 92.6% at 2 years, and 97.6% and 90.4% at 3 years, respectively. Graft survival rates in living and non-heart-beating donor graft transplantations were 95.9% and 88.8% at 1 year, 94.0% and 85.0% at 2 years, and 92.2% and 80.0% at 3 years, respectively. Graft survival rates in living ABO-compatible donor graft transplantation ranged from 93.4% to 97.5%, and in ABO-incompatible cases, rates were stable at 83.2% throughout the 3-year assessment period. Median serum creatinine levels ranged from 1.30 to 1.37 mg/dL during this time. Percentages of patients receiving antihyperlipidemics, antihypertensives, and insulin were 12.6%, 41.1%, and 6.5% at 1 year, respectively, and remained low at 3 years after transplantation. CONCLUSION: Three years of tacrolimus therapy demonstrated excellent efficacy and safety in more than 1,000 renal transplant recipients, including recipients of living ABO-incompatible and non-heart-beating donor grafts, with favorable graft function maintained.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12548123&dopt=Abstract tacrolimus Protopic



Protopic
Toward better outcomes with tacrolimus therapy: population pharmacokinetics and individualized dosage prediction in adult liver transplantation.

Staatz CE, Willis C, Taylor PJ, Lynch SV, Tett SE.

School of Pharmacy, University of Queensland, Princess Alexandra Hospital, Queensland, Australia. c.staatz pharmacy.uq.edu.au

Patient outcomes in transplantation would improve if dosing of immunosuppressive agents was individualized. The aim of this study is to develop a population pharmacokinetic model of tacrolimus in adult liver transplant recipients and test this model in individualizing therapy. Population analysis was performed on data from 68 patients. Estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F) using the nonlinear mixed effects model program (NONMEM). Factors screened for influence on these parameters were weight, age, sex, transplant type, biliary reconstructive procedure, postoperative day, days of therapy, liver function test results, creatinine clearance, hematocrit, corticosteroid dose, and interacting drugs. The predictive performance of the developed model was evaluated through Bayesian forecasting in an independent cohort of 36 patients. No linear correlation existed between tacrolimus dosage and trough concentration (r(2) = 0.005). Mean individual Bayesian estimates for CL/F and V/F were 26.5 +/- 8.2 (SD) L/hr and 399 +/- 185 L, respectively. CL/F was greater in patients with normal liver function. V/F increased with patient weight. CL/F decreased with increasing hematocrit. Based on the derived model, a 70-kg patient with an aspartate aminotransferase (AST) level less than 70 U/L would require a tacrolimus dose of 4.7 mg twice daily to achieve a steady-state trough concentration of 10 ng/mL. A 50-kg patient with an AST level greater than 70 U/L would require a dose of 2.6 mg. Marked interindividual variability (43% to 93%) and residual random error (3.3 ng/mL) were observed. Predictions made using the final model were reasonably nonbiased (0.56 ng/mL), but imprecise (4.8 ng/mL). Pharmacokinetic information obtained will assist in tacrolimus dosing; however, further investigation into reasons for the pharmacokinetic variability of tacrolimus is required.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12548506&dopt=Abstract tacrolimus Protopic