Protopic
A comparison of the pharmacokinetics of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients.

Renton KW, Crocker JF, McLellan H, Acott PD.

Department of Pharmacology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, Halifax, Nova Scotia, B3H 4H7, Canada. Ken.renton dal.ca

OBJECTIVE: Our objective was to identify common factors that determine the dose of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients. METHODS: The concentration profiles of tacrolimus and cyclosporin in blood were determined in 68 children who had received a renal transplant. To avoid disruption of therapy, measurements were made at 2-h intervals over an 8-h period during normal dosing regimens. Direct comparisons of the two drugs were made in 14 of the subjects who were switched from cyclosporin to tacrolimus. RESULTS: The ratio of peak to trough levels for tacrolimus was approximately twofold compared with over threefold for cyclosporin. Area under the curve (AUC) for tacrolimus remained relatively constant in each 2-h period of the dosage interval compared with the AUC for cyclosporin, which varied by over twofold in the same time period. In the 14 subjects who received both drugs, there was a poor correlation between C2/C0, C2, t(1/2) and AUC for tacrolimus and cyclosporin in the same individual. In a multivariate analysis, there were no significant associations for tacrolimus concentrations, AUC or C2/C0 with age, gender, calcium-channel blocker, quinolone or statin. For cyclosporin, there was some association for AUC with gender and quinolone use and a weak association with calcium-channel blocker or statin use. CONCLUSIONS: Tacrolimus and microemulsified cyclosporin display a wide intra- and inter-individual variation in pharmacokinetic properties in young subjects. In the case of absorption represented by the peak-trough ratios, the values for tacrolimus are significantly less than those obtained with cyclosporin. The pharmacokinetic parameters obtained for one of these agents is not predictive for the behaviour of the other in young renal transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15232662&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus ointment: new preparation. Too many unknowns.

[No authors listed]

(1) Drug therapy for exacerbations of atopic dermatitis (atopic eczema) should only be considered when simple measures and emollients are inadequate. The first-line option is a topical corticosteroid with a level of potency appropriate for the affected site and the patient's age. (2) Tacrolimus, an immunosuppressant used orally or parenterally to prevent graft rejection, is now marketed in France as an ointment, in two dose strengths, for the treatment of atopic dermatitis. It is approved for use when topical corticosteroids fail, in patients aged at least two years. (3) According to a comparative trial in adults, tacrolimus, when used as a first-line treatment, is no more effective than a class II (strong) topical corticosteroid. Several clinical trials show that it is better than the excipient in both adults and children. The 0.1% strength seems to be slightly more active than the 0.03% strength in adults. (4) It is not known whether tacrolimus is effective after topical corticosteroid failure. (5) In comparative trials the main systemic adverse events in patients using tacrolimus ointment were flu-like syndromes and headache. Local adverse events included burning or pruritus at the site of application in about 50% of patients. These local effects are due to both the excipient and tacrolimus. (6) Severe skin infections and skin cancer cannot be ruled out as serious side effects. (7) Tacrolimus uptake through the skin exposes patients to systemic adverse effects and drug interactions. (8) In practice, patients with atopic dermatitis, however severe, have no reason to use tacrolimus, at least pending studies showing it is effective after topical corticosteroid failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15233141&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus ameliorates cerebral vasodilatation and intracranial hypertension in the rat with portacaval anastomosis and hyperammonemia.

Dethloff T, Hansen BA, Larsen FS.

Department of Hepatology, Copenhagen University Hospital, Copenhagen, Denmark.

Arterial hyperammonemia and cerebral vasodilatation correlate with cerebral herniation in patients with fulminant hepatic failure (FHF). Tacrolimus is a calcineurin inhibitor that passes the blood-brain barrier and may increase cerebrovascular tone and restrict cerebral ammonia influx. In this study, we determined if tacrolimus prevents cerebral vasodilatation and high intracranial pressure (ICP) in the rat with portacaval anastomosis (PCA) challenged to high arterial ammonia (NH4+) concentration. Seven groups of mechanically ventilated rats, with 6-9 rats in each group, were investigated within 48 hours after construction of a PCA (4 groups) or after sham operation (3 groups). Three groups of the rats received infusion of NH4+ and 4 groups received saline for approximately 180 minutes. Two groups of the PCA rats receiving either NH4+ or saline had an i.v. injection of tacrolimus (0.4 mg/kg) or vehicle before start of NH4+ or saline infusion. Cerebral blood flow (CBF) was monitored by a laser Doppler probe in brain cortex. ICP was monitored by placement of a catheter in the cerebrospinal fluid. CBF and ICP increased in PCA rats receiving NH4+ infusion compared to PCA controls and to all groups of sham-operated animals (P <.05). In the group of PCA rats pre-treated with tacrolimus before receiving ammonia infusion, the increase in ICP was ameliorated compared to the ammonia infused group receiving vehicle (P <.03). Tacrolimus also prevented an increase in CBF in the PCA group receiving NH4+ (P <.05) compared to the control groups. In conclusion, Tacrolimus prevents cerebral vasodilatation and ameliorates intracranial hypertension in PCA rats receiving NH4+ infusion. These findings indicate that tacrolimus could be of clinical value in the prevention of cerebral hyperemia, high ICP, and serious brain damage in patients with FHF.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15237379&dopt=Abstract tacrolimus Protopic



Protopic
Glucose metabolism after pancreas transplantation: cyclosporine versus tacrolimus.

Dieterle CD, Schmauss S, Veitenhansl M, Gutt B, Illner WD, Land W, Landgraf R.

Diabetes Center, Medizinische Klinik, Ziemssenstr. 1, 80336 Munich, Germany. christoph.dieterle med.uni-muenchen.de

BACKGROUND: The results of the new immunosuppressants in simultaneous pancreas-kidney transplantation (SPK) concerning organ survival and rejection rates are excellent. Tacrolimus as well as cyclosporine are assumed to be diabetogenic; however, there are no comparative studies investigating their effects on glucose metabolism. METHODS: One hundred thirty-six type 1 diabetic patients who had undergone successful SPK were investigated. Glucose and insulin levels during an oral glucose tolerance test as well as hemoglobin (Hb) A1c were analyzed. Investigations were performed early (3 months, n = 136) and late (3 years, n = 83) after transplantation. Graft recipients were grouped according to the first-line immunosuppression: group 1, cyclosporine; group 2, tacrolimus. There were no differences concerning age, gender, body mass index, and renal function between the groups. RESULTS: Early after transplantation, there was no difference between the groups concerning fasting glucose, HbA1c levels, basal and stimulated insulin secretion, and incidence of normal glucose tolerance. Late after transplantation, the incidence of a normal glucose tolerance tended to be lower (70% vs. 78%), whereas HbA1c (5.3% vs. 5.0%) and fasting glucose (81 vs. 78 mg/dL) levels tended to be higher in tacrolimus-treated patients. However, these differences were not significant. Insulin secretion was not reduced in the tacrolimus group. CONCLUSIONS: Concerning glucose metabolism and secretory capacity of the pancreas graft, no significant differences were found comparing tacrolimus- versus cyclosporine-treated graft recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15239622&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis.

Schuller E, Oppel T, Bornhovd E, Wetzel S, Wollenberg A.

Department of Dermatology, Ludwig-Maximilian-University, Munich, Germany.

BACKGROUND: The topical immunomodulators tacrolimus and pimecrolimus are novel therapeutic options for atopic dermatitis (AD). The inhibition of nuclear factor of activated T cell-dependent proinflammatory cytokine production in cutaneous lymphocytes is an established effect of topical immunomodulators, which additionally influence mast cells, eosinophils, and dendritic cells (DCs). The latter include a reduced expression of the high-affinity IgE receptor FcepsilonRI, a reduced stimulatory capacity of lesional DCs, and a selective depletion of the inflammatory dendritic epidermal cells (IDECs) but not of Langerhans cells (LCs) from the lesional skin. OBJECTIVE: Because induction of apoptosis in lymphocytes is a reported tacrolimus effect, we asked whether tacrolimus ointment induces apoptosis of LCs or IDECs in AD lesions. METHODS: Epidermal single-cell suspensions were prepared from AD lesions of 9 tacrolimus-treated and 5 hydrocortisone butyrate-treated patients with AD before and after 1 week of treatment. Cell numbers, apoptosis rate, and immunophenotype were assessed by using the standardized FACS technique with terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, Annexin V, and 3-color immunophenotyping. Freshly isolated LCs and monocyte-derived DCs served as in vitro controls. RESULTS: Tacrolimus and steroid ointment induced a selective depletion of IDECs from the epidermis and reduced the expression of the costimulatory molecules CD80 and CD86. Tacrolimus ointment did not increase the rate of apoptotic DCs, whereas steroid ointment did so. The isolation-induced high apoptosis rate of freshly isolated LCs was unaffected by both drugs. CONCLUSION: Tacrolimus ointment selectively depletes IDECs and alters the immunophenotype of epidermal DCs in AD lesions, but there is no evidence for tacrolimus-induced DC apoptosis in this phenomenon. Copyright 2004 American Academy of Allergy, Asthma and Immunology

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15241357&dopt=Abstract tacrolimus Protopic



Protopic
Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines.

Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metzger A.

Vitiligo and Pigmentation Institute of Southern California, and the Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, USA. pegrimesmd earthlink.net

BACKGROUND: Previous studies have documented humoral and cell-mediated immunologic defects in patients with vitiligo. OBJECTIVE: This 24-week study assessed the efficacy and safety of tacrolimus 0.1% ointment in patients with generalized vitiligo as well as the pretreatment and post-treatment expression of cytokines in the depigmented and normal skin of patients compared with controls. METHODS: Twenty-three patients were enrolled in this investigation, and 19 patients completed the study; 8 were male and 11 were female. Fifteen age-, race-, and sex-matched control subjects were also included. Patients were treated with tacrolimus 0.1% ointment applied twice daily. Repeat evaluations were performed at 4, 8, 12, 16, 20, and 24 weeks. Three-millimeter punch biopsy specimens were taken from the depigmented, non-sun-exposed skin and adjacent normal skin of patients at baseline and 24 weeks, and from normal, non-sun-exposed skin of controls. Cellular messenger RNA expression for interleukin 2 (IL-2), IL-4, IL-10, tumor necrosis factor alfa (TFN-alpha), and interferon gamma (IFN-gamma) were determined by real-time quantitative polymerase chain reaction. RESULTS: At 24 weeks, 17 of 19 patients (89%) achieved varying levels of repigmentation. There was a statistically significant decrease in overall disease severity scores at 24 weeks. Thirteen patients (68%) had greater than 75% repigmentation of face and/or neck lesions. Signs and symptoms of irritation were minimal. At baseline, compared with healthy controls, vitiligo patients demonstrated a statistically significant increase in the expression of IFN-gamma in involved and adjacent uninvolved skin (P=.05 and P=.02, respectively); significantly increased TNF-alpha expression in involved and uninvolved skin (P=.01 and P=0.02, respectively); and significantly increased IL-10 expression in involved and uninvolved skin (P=.01 and P=.04, respectively). Posttreatment, TNF-alpha expression decreased in the depigmented and adjacent uninvolved skin (P <.001). There was no statistically significant change in IL-10 or IFN-gamma posttreatment. These data suggest that tacrolimus 0.1% ointment is a safe and effective therapy for patients with vitiligo. It further suggests that an imbalance in local cytokine expression may play a role in the pathogenesis of vitiligo. Suppression of TNF-alpha after topical tacrolimus application may be associated with repigmentation of vitiligo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15243524&dopt=Abstract tacrolimus Protopic



Protopic
Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein.

Egashira K, Ohtani H, Itoh S, Koyabu N, Tsujimoto M, Murakami H, Sawada Y.

Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

We recently reported a case of increase in the blood level of tacrolimus following intake of pomelo in a renal transplant recipient. To clarify the mechanism of this increase in the blood level of tacrolimus, we investigated the effect of pomelo juice extract on the activities of CYP3A4 and P-glycoprotein, in comparison with that of extract of grapefruit juice (GFJ). The 10% ethyl acetate extracts of the juice of three pomelos of different origins (Banpeiyu, pomelo I; Hirado Buntan, pomelo II; and Tosa Buntan, pomelo III) and GFJ significantly inhibited 6beta-hydroxylation of testosterone in human liver microsomes by 76.4, 67.2, 37.5, and 83.9%, respectively. The extract of pomelo I was as potent as that of GFJ. The metabolism of tacrolimus itself was also inhibited by the extract of pomelo I, as well as that of GFJ. Furthermore, the inhibition of both 6beta-hydroxylation of testosterone and metabolism of tacrolimus by pomelo I and GFJ was preincubation time-dependent. On the other hand, the extract of pomelo I had little effect on the transcellular transport of tacrolimus or [(3)H]digoxin across a monolayer of LLC-GA5-COL150 cells (a porcine kidney epithelial cell line, LLC-PK1, transfected with human MDR1 cDNA and overexpressing human P-glycoprotein). In conclusion, pomelo constituents inhibit the activity of CYP3A4 and may thereby produce an increase in the blood level of tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15258108&dopt=Abstract tacrolimus Protopic