Successful topical tacrolimus (FK506) therapy in a child with pyoderma gangrenosum

The inflammatory skin disease pyoderma gangrenosum is characterized by destructive ulceration, typically occurring on the calves and thighs and less commonly on the buttocks and face. Lesions vary in size and may be multiple, often rapidly ulcerating to form deep painful wounds. Ulcers characteristically have ragged purple edges that overhang. In many patients a concomitant condition can be identified such as inflammatory bowel disease, rheumatoid arthritis, chronic autoimmune hepatitis, and various hematologic and solid tumours (1,2). Treatment of these ulcers in the past has been disappointing. The large lesions usually run a chronic course and heal very slowly, with traditional dressings often in combination with systemic steroids or immunosuppressants. Since 1998, a small number of case have been reported of adults with pyoderma gangrenosum whose lesions heal with the use of topical tacrolimus (FK506) (2–4). We report, to the best of our knowledge, the first successful treatment of a child with pyoderma gangrenosum using topical tacrolimus.

Tacrolimus ointment for long-term treatment of atopic dermatitis

Atopic dermatitis (AD) or atopic eczema is characterised by a superficial skin inflammation with an overall Th2 cell dominance and impaired function of the epidermal barrier. Patients also are at an increased risk for asthma and allergic rhinitis. Treatment with tacrolimus ointment inhibits T cell activation and blocks the production of several inflammatory cytokines in the skin, without suppressing collagen synthesis. The aims of this thesis were to determine: (1) long-term efficacy, safety, and effects on cell-mediated immunity and serum IgE levels in patients with moderate-to-severe AD treated for 1 year with tacrolimus ointment or a corticosteroid regimen, (2) the 10-year outcome of eczema, respiratory symptoms, and serum IgE levels in AD patients initially treated long-term with tacrolimus ointment, and (3) pharmacokinetics and long-term safety and efficacy of 0.03% tacrolimus ointment in infants under age 2 with AD. Cell-mediated immunity, reflecting Th1 cell reactivity, was measured by recall antigens and was at baseline lower in patients with AD compared to healthy controls. Treatment with either 0.1% tacrolimus ointment or a corticosteroid regimen for one year enhanced recall antigen reactivity. Transepidermal water loss (TEWL), an indicator of skin barrier function, decreased at months 6 and 12 in both tacrolimus- and corticosteroid-treated patients; TEWL for the head and neck was significantly lower in tacrolimus-treated patients. Patients in the 10-year open follow-up study showed a decrease in affected body surface area from a baseline 19.0% to a 10-year 1.6% and those with bronchial hyper-responsiveness at baseline showed an increase in the provocative dose of inhaled histamine producing a 15% decrease in FEV1, indicating less hyper-responsiveness. Respiratory symptoms (asthma and rhinitis) reported by the patient decreased in those with active symptoms at baseline. A good treatment response after one year of tacrolimus treatment predicted a good treatment response throughout the 10-year follow-up and a decrease in total serum IgE levels at the 10-year follow-up visit. The 2-week pharmacokinetic and the long-term study with 0.03% tacrolimus ointment showed good and continuous improvement of AD in the infants. Tacrolimus blood levels were throughout the study low and treatment well tolerated. This thesis underlines the importance of effective long-term topical treatment of AD. When the active skin inflammation decreases, cell-mediated immunity of the skin improves and a secondary marker for Th2 cell reactivity, total serum IgE, decreases. Respiratory symptoms seem to improve when the eczema area decreases. All these effects can be attributed to improvement of skin barrier function. One potential method to prevent a progression from AD to asthma and allergic rhinitis may be avoidance of early sensitisation through the skin, so early treatment of AD in infants is crucial. Long-term treatment with 0.03% tacrolimus ointment was effective and safe in infants over age 3 months.

Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus

Background: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA), Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

AIMS
The aim of this study was to investigate the in?uence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation.
METHODS
Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular ?ltration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes.
RESULTS
The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls,P = 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%,P = 0.057). Carriers of the G2677->T variant allele also had a signi?cant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P = 0.031). Haplotype analysis showed a signi?cant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P = 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were signi?cantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation.
CONCLUSIONS
These ?ndings suggest that ABCB1 polymorphisms in the native intestine signi?cantly in?uence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the ?rst year posttransplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant

Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining inter-individual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.

Methods: The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates.

Results: The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation:

TVCL=12.9×(Weight /13.2)^0.75×EXP(-0.00158×TPT)×EXP(0.428×CYP3A5)

where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where*1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h kg (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%.

Conclusion: Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. © 2013 The British Pharmacological Society.

Tacrolimus is not associated with gingival overgrowth in renal transplant patients

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients.

METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models.

RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension.

CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Exposição de fibroblastos provenientes de pterígios recidivados e da cápsula de Tenon normal ao tacrolimus (FK-506)

OBJETIVO: Avaliar a taxa de proliferação de fibroblastos provenientes de pterígios recidivados e da cápsula de Tenon normal, quando expostos in vitro ao tacrolimus (FK 506). MÉTODOS: Foi realizado estudo prospectivo, controlado, avaliando-se 8 amostras de explantes de cápsula de Tenon de pterígios recidivados e 6 de cápsula de Tenon normal, obtidas na Faculdade de Medicina de Botucatu - UNESP. A cápsula de Tenon normal foi colhida da região temporal inferior, do mesmo portador de pterígio. As amostras foram cultivadas em meio específico e posteriormente expostas ao tacrolimus 1M (FK 506), em única exposição, com avaliação da taxa de proliferação celular 1, 5, 12 e 19 dias após a exposição. RESULTADOS: Avaliando-se a proliferação dos fibroblastos provenientes de cápsula de Tenon de pterígios recidivados e da cápsula de Tenon normal, os fibroblastos expostos ao tacrolimus tiveram taxa de proliferação significativamente menor (p<0,05) do que quando não houve exposição a droga, quando a avaliação foi feita 1 dia após a exposição. Quando a avaliação foi feita 19 dias após a exposição, a taxa de proliferação foi maior nos grupos expostos a droga. CONCLUSÃO: Os fibroblastos provenientes da cápsula de Tenon de pterígios recidivados apresentaram taxa de proliferação significativamente menor um dia após a exposição ao tacrolimus. Novos estudos devem ser realizados para definir dose e tempo de exposição dos fibroblastos a droga, com o intuito de definir se o tacrolimus pode ser útil como tratamento coadjuvante do pterígio.

Protective effects of Tacrolimus, a calcineurin inhibitor, in experimental periodontitis in rats

Objective: Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation with pathogenic features similar to those observed in other inflammatory diseases, such as arthritis. Since Tacrolimus, is an immunomodulatory drug used for the treatment of some cases of arthritis, we hypothesized that it may modulate periodontal disease.Design: Using a murine model of ligature-induced periodontal disease, we assessed the effects of daily administrations of Tacrolimus (1 mg/kg body weight) on bone loss, enzymatic (myeloperoxidase) analysis, differential white blood cells counts, airpouch exudate and cytokine expression for 5-30 days.Results: Radiographic, enzymatic (myeloperoxidase) and histological analysis revealed that Tacrolimus reduced the severity of periodontitis. More specifically, Tacrolimus suppressed the expression of serum interleukin (IL-1 beta), tumour necrosis factor (TNF-alpha), IL-6, airpouch exudate PGE(2) and leukocytosis usually observed after the induction of periodontitis. Tacrolimus treatment in periodontitis-induced rats conferred protection against the inflammation-induced tissue and bone loss associated with periodontitis, through a mechanism involving IL-1 beta, TNF-alpha and IL-6.Conclusions: the effects of Tacrolimus on periodontal disease pathogenesis may provide clues to a novel approach to host modulation therapy in destructive periodontal disease. (C) 2007 Elsevier Ltd. All rights reserved.

Immunosuppressant Prograf (R) (Tacrolimus) Induces Histopathological Disorders in the Peritubular Tissue of Rat Testes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Structural alterations in the seminiferous tubules of rats treated with immunosuppressor tacrolimus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Interaction of the Anti-Inflammatory Annexin A1 Protein and Tacrolimus Immunosuppressant in the Renal Function of Rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Oral health in renal transplant recipients administered cyclosporin A or tacrolimus

OBJECTIVE: the aim of this study was to determine the oral status of renal transplant recipients receiving cyclosporin A (CsA) or tacrolimus (FK-506) as immunosuppressant.SUBJECTS AND METHODS: A total of 88 renal transplant recipients receiving CsA (63 men and 25 women, mean age 51.4 years) and 67 receiving FK-506 (57 men and 10 women, mean age 33.5 years) were included in the study. Donor type, histocompatibility, cold ischemia time and prior delayed graft function were similar between the two groups. Demographics and pharmacological data were recorded for all subjects.RESULTS: the results demonstrated that CsA caused a greater number of oral diseases. A greater number of gingival overgrowth was present in patients treated with CsA. However, the combined use with calcium channel blockers increased the gingival overgrowth number. The occurrence of candida in saliva was observed in 80 renal recipients treated with CsA and 20 treated with FK-506. The presence of squamous oral carcinoma (n = 3) and herpes simplex (n = 10) was observed in patients treated with CsA. These alterations were not observed in renal recipients treated with FK-506.CONCLUSIONS: Renal recipients constitute a high-risk group for oral diseases, as they are immunocompromised. However, the FK-506 regime appears to ameliorate this effect, compared with CsA. Adequate pre- and post-transplant oral health care is recommended for these subjects, irrespective of the time interval for which the drug is administered.