Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.815
Filtrar
1.
Lancet Haematol ; 7(2): e100-e111, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31958417

RESUMO

BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60­7·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9­23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9­25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2­29·2) versus 31·3% (21·9­40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5­35·1) in the anti-thymocyte globulin group and 41·3% (31·3­51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·6­78·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·8­62·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35­0·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.


Assuntos
Soro Antilinfocitário/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Imunossupressores/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adolescente , Adulto , Idoso , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressores/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Linfócitos T/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
2.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações de Medicamentos/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
3.
J Pharm Biomed Anal ; 177: 112853, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499431

RESUMO

Tacrolimus (TAC) is an immunosuppressant for preventing solid-organ transplant rejection. Because of its narrow therapeutic window, analytical methods which can detect TAC in serum samples with high accuracy and reliability are required. In this study, specific aptamers (Apt122 and Apt125) for TAC were isolated via systematic evolution of ligands by exponential enrichment method using magnetic beads to immobilize the target. After determination of binding constants of aptamers by flow cytometry analysis, Apt122 was selected and labeled with ATTO 647 N as a fluorophore to develop a fluorescent sensing platform for detection of TAC using graphene oxide (GO) as a fluorescence quencher. The designed aptasensor could detect TAC in phosphate buffer saline (10 mM PBS) and serum samples with detection limits as low as 1.4 and 2.5 nM, respectively.


Assuntos
Aptâmeros de Nucleotídeos/química , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Técnica de Seleção de Aptâmeros/métodos , Tacrolimo/sangue , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/instrumentação , Estudos de Viabilidade , Corantes Fluorescentes/química , Grafite/química , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Ligantes , Limite de Detecção , Reprodutibilidade dos Testes , Tacrolimo/administração & dosagem , Tacrolimo/química
4.
Int J Clin Pharmacol Ther ; 58(3): 183-193, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31841106

RESUMO

OBJECTIVE: The present study compared the pharmacokinetics of two (1 mg) tacrolimus formulations (test (generic from Panacea) and reference (innovator from Astellas)) after a single-dose administration as per the European Medicine Agency (EMA) guidelines to grant marketing authorization. MATERIALS AND METHODS: This study was a randomized, open-label, balanced, two-treatment, two-period, two-sequences, single-dose, truncated-area, crossover design with a washout period of 19 days between the phases. Healthy subjects aged 18 - 45 years (both inclusive) were included. Eligible subjects received a single oral dose of 5 × 1-mg capsule of tacrolimus either test or reference formulation. Blood samples were collected until 72.00 hours postdose, and peak concentration (Cmax) and area under the curve (AUC0-72) were evaluated in whole blood using validated LC-MS/MS. Safety was also assessed in each period. RESULTS: Of 56 subjects enrolled, 52 completed both study periods. The arithmetic mean (SD) Cmax for the reference and test formulations was 40.62 (11.30) and 46.20 (10.73) ng/mL, and AUC0-72 was 348.34 (156.41) and 361.04 (158.71) ng×h/mL, respectively. The geometric least square mean ratio (90% confidence interval (CI)) was 115.07% (90% CI: 109.81, 120.59) for Cmax and 103.78 (90% CI: 97.40, 110.58) for AUC0-72, which fell within the acceptance range as per EMA guidelines for narrow therapeutic index drugs (Cmax: 80.00 - 125.00%; AUC: 90.00 - 111.11%). No serious adverse event was observed. CONCLUSION: The generic tacrolimus was bioequivalent to the reference formulation, was well tolerated, and provides a well-acceptable alternative to the reference drug. Switching treatment to generic tacrolimus medication may reduce the cost and economic burden of treating transplanted patients.


Assuntos
Jejum , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida , Estudos Cross-Over , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
5.
Medicine (Baltimore) ; 98(48): e18150, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770256

RESUMO

The current research aimed to investigate the correlation between the effect of Wuzhi soft capsule (WZC) on FK506 concentration and CYP3A5 gene polymorphism in patients with membranous nephropathy (MN).Seventy-five patients with idiopathic MN were enrolled and divided according to the expression of CYP3A5 gene metabolic enzyme into group A (CP3A5 metabolic enzyme function expression types CYP3A5*1/*1 type and CYP3A5*1/*3 type), and group B (non-expression type CYP3A5*3/*3 type). All patients were given oral administration of tacrolimus capsule at the initial dose of 1 mg for twice a day 1 hour before breakfast and dinner. Afterwards, the oral administration of WZC was added at the dose of 0.5 g for 3 times a day within half an hour after 3 meals.The blood concentrations of FK506 in groups A and B were significantly higher than those before administration. Compared with that before administration, the FK506 blood concentration was increased by 3.051 ±â€Š0.774 ng/ml after adding the WZC. Besides, the blood concentrations of FK506 in group A were lower than those in group B before and after administration; meanwhile, the 24 hours total urine protein and the biochemical indexes in both groups displayed no statistically significant difference. Only 1 case of diarrhea was observed, which was relieved after the reduction of tacrolimus.Wuzhi soft capsule can significantly increase the blood concentration of FK506 in MN patients. Moreover, the CYP3A5 genotyping should be considered when WZC is used to increase the blood concentration of FK506.


Assuntos
Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas , Glomerulonefrite Membranosa , Tacrolimo , Adulto , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/farmacocinética , Cápsulas , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo Genético , Medicina de Precisão/métodos , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética
6.
Expert Rev Clin Pharmacol ; 12(11): 1047-1057, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31575290

RESUMO

Introduction: The clinical use of tacrolimus is characterized by many side effects which include neurotoxicity. In contrast, tacrolimus has also shown to have neuroregenerative properties. On a molecular level, the mechanisms of action could provide us more insight into understanding the neurobiological effects. The aim of this article is to review current evidence regarding the use of tacrolimus in peripheral nerve injuries.Areas covered: Available data on tacrolimus' indications were summarized and molecular mechanisms were elucidated to possibly understand the conflicting neurotoxic and neuroregenerative effects. The potential clinical applications of tacrolimus, as immunosuppressant and enhancer of nerve regeneration in peripheral nerve injuries, are discussed. Finally, concepts of delivery are explored.Expert opinion: It is unclear what the exact neurobiological effects of tacrolimus are. Besides its known calcineurin inhibiting properties, the mechanism of action of tacrolimus is mediated by its binding to FK506-binding protein-52, resulting in a bimodal dose response. Experimental models found that tacrolimus administration is preferred up to three days prior to or within 10 days post-nerve reconstruction. Moreover, the indication for the use of tacrolimus has been expanding to fields of dermatology, ophthalmology, orthopedic surgery and rheumatology to improve outcomes after various indications.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Tacrolimo/administração & dosagem , Animais , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Esquema de Medicação , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Tacrolimo/efeitos adversos , Tacrolimo/farmacologia
7.
Transplant Proc ; 51(9): 2971-2973, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607620

RESUMO

BACKGROUND: An extended-release formulation of tacrolimus designed for once-daily administration (LCP-TAC) is a new prolonged-release tacrolimus (TAC-PR) formulation using a drug delivery technology designed to enhance the bioavailability of drugs compared with TAC-PR. The aim of this study was to retrospectively compare de novo administration of LCP-TAC and TAC-PR for therapeutic trough levels and daily dosage during the first 30 days after first liver transplant (LT). METHODS: A total of 35 patients submitted to first LT between 2016 and 2018 were retrospectively enrolled: 16 received LCP-TAC, while 19 received TAC-PR as de novo immunosuppression. Patients were analyzed for daily dosage and trough levels at postoperative days (PODs) 3, 7, 15, and 30. RESULTS: The initial dose of tacrolimus did not differ between LCP-TAC and TAC-PR (mean, 5.19 [SD, 1.72] mg/d vs mean, 5.26 [SD, 1.91] mg/d, P = .90). On PODs 7, 15, and 30 the daily dosage was statistically lower for LCP-TAC compared with TAC-PR (mean, 5.44 [SD, 2.06] mg/d vs mean, 7.68 [SD, 2.91] mg/d, P = .01; mean, 5.33 [SD, 2.23] mg/d vs mean, 8.82 [SD, 2.35] mg/d, P < .001; and mean, 5.38 [SD, 2.50] mg/d vs mean, 9.81 [SD, 3.78] mg/d, P < .001, respectively). The therapeutic trough levels were significantly higher for LCP-TAC on POD 3 (mean, 5.05 [SD, 3.58] ng/mL vs mean, 2.42 [SD, 2.75] ng/mL, P = .03) and POD 5 (mean, 7.35 [SD, 5.12] ng/mL vs mean, 4.17 [SD, 2.05] ng/mL, P = .04), while no differences were found on PODs 7, 15, and 30.The percentage of patients on POD 3 achieving a trough level higher than 6 ng/mL was higher for LCP-TAC than TAC-PR (40% vs 13%, P = .05). CONCLUSIONS: LCP-TAC after LT is safe and might enhance bioavailability, reducing the amount of drug necessary to achieve therapeutic trough levels compared with TAC-PR.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Transplante de Fígado , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Imunossupressão/métodos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/sangue
8.
Expert Opin Drug Metab Toxicol ; 15(10): 803-811, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31595800

RESUMO

Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Tacrolimo/administração & dosagem , Adulto , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacocinética , Interações de Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Farmacogenética , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética
9.
Transplant Proc ; 51(8): 2615-2619, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31563241

RESUMO

BACKGROUND: Recently, a once-daily formulation of tacrolimus (Advagraf) was released in the Philippines. Studies have shown that these 2 formulations are bioequivalent at a 1:1 conversion. This study aims to determine the efficacy, safety, convertibility, and tacrolimus trough level of once-daily tacrolimus at the end of 6 months post transplant. METHODS: This is a randomized study among standard-risk primary kidney transplant patients performed at the National Kidney and Transplant Institute, Philippines. A total of 40 patients completed the 6-month follow-up. Patients in Group A who failed to meet the criteria for conversion to once-daily tacrolimus were considered to have reached the end of the study, while patients who satisfied the conversion criteria will be followed up for an additional 6 months. RESULTS: Baseline characteristics were similar in both groups. The area under the curve, maximum concentration, time to achieve the maximum concentration, and the coefficient of variation were similar. The twice-daily tacrolimus (Prograf) group patients had significantly higher mean tacrolimus trough levels than the Group B once-daily tacrolimus patients. An increase of a once-daily tacrolimus mean dose of 8% was required to achieve a therapeutic drug level post conversion. The graft and patient survival were 100%. There was no biopsy-proven acute rejection noted either both group. CONCLUSION: In conclusion, conversion from twice-daily tacrolimus to once-daily tacrolimus in kidney transplant in both de novo and converted patients after KT is safe, ensuring greater stability of drug blood concentrations than the standard form. The results also suggest an 8% increase when converting stable KT patients from twice-daily tacrolimus to once-daily tacrolimus.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adulto , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Filipinas , Projetos Piloto , Equivalência Terapêutica
10.
Clin Drug Investig ; 39(12): 1233-1238, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522334

RESUMO

BACKGROUND: The efficacy of topical calcineurin inhibitors (TCIs) for the treatment of infants with vitiligo aged less than 2 years remains to be fully determined. OBJECTIVE: This aim of this pilot study was to assess the efficacy and tolerability of the TCIs tacrolimus and pimecrolimus in infants with vitiligo aged under 2 years. METHODS: Infants with vitiligo aged < 2 years were randomly assigned to receive either tacrolimus ointment 0.03% or pimecrolimus cream 1% for a period of 6 months. During this period, topical treatment was applied twice daily. The proportion of body surface area of the treated lesions, locations, and possible adverse effects were recorded. In addition, the overall satisfaction scores of the patients' parents was evaluated by virtue of the visual analog scale (VAS). RESULTS: Forty-six infants with vitiligo were enrolled in this study. The overall response rate (> 0% repigmentation) was 100%, while the effective rate (> 50% repigmentation) of the tacrolimus and pimecrolimus groups was 69.6% and 65.2%, respectively. Meanwhile, the effective rates for vitiligo located on the head and neck, trunk, and extremities were 70%, 64.3% and 50%, respectively, while the response rates for non-segmental and segmental vitiligo were 74.4% and 28.6%, respectively. Only a low incidence of local adverse reactions (including mild redness and skin picking) was reported during the treatment process. CONCLUSIONS: Topical tacrolimus ointment 0.03% or pimecrolimus cream 1% have efficacy for vitiligo in infants, which serves to achieve an appropriate level of safety and tolerability during the 6-month period of applications. Thus, TCIs proved to be a therapeutic option for vitiligo in infants under 2 years of age.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Tacrolimo/análogos & derivados , Tacrolimo/administração & dosagem , Vitiligo/tratamento farmacológico , Administração Tópica , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Projetos Piloto , Tacrolimo/efeitos adversos
11.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547590

RESUMO

Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.


Assuntos
Monitoramento de Medicamentos , Leucócitos Mononucleares/imunologia , Tacrolimo , Adolescente , Adulto , Antígenos CD/imunologia , Ligante de CD40/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Receptores da Transferrina/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética
12.
Transplant Proc ; 51(8): 2620-2623, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474450

RESUMO

BACKGROUND: Converting to once-daily tacrolimus (Advagraf [Adv]) among renal transplant patients results in better drug adherence. Data regarding dosage and intrapatient variability changes after conversion among patients with CYP3A4/5 inhibitors (CYPinh) is lacking. METHOD: A retrospective chart review among all kidney transplant recipients at Siriraj Hospital was performed. Patients were enrolled who had been on standard release twice-daily tacrolimus and subsequently replaced it with Adv for at least 6 months with no change in CYPinh type or dosage. RESULTS: Fifty-three patients were eligible. Conversion occurred at a mean time after transplant of 51.25 (SD, 40.30) months. Ten patients (18.9%) did not receive CYPinh, while 19 (35.8%), 21 (39.6%), and 3 (5.7%) received diltiazem, ketoconazole or fluconazole, and both diltiazem and ketoconazole, respectively. After conversion, median increment of tacrolimus dosage was 14.29% (-50% to 167%), while no significant change in IPV was demonstrated (17.46% [SD, 11.25%] vs 14.83% [SD, 6.78]; P = .11). Patients receiving azole had less dosage increment than those not receiving CYPinh (P = .02). After conversion, 14 of 22 patients with IPV > 17% (63.6%) had reduced IPV to ≤ 17%, while 25.8% of patients with lower IPV had an increase in IPV > 17%. CONCLUSION: Conversion to Adv required a dosage increment of 30% to achieve the same trough level. Concomitant use of CYPinh significantly reduced tacrolimus dose increment. A trend was noted toward improved IPV after conversion. Conversion to Adv resulted in better IPV among patients with high IPV while receiving twice-daily tacrolimus.


Assuntos
Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adulto , Protocolos Clínicos , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tailândia , Resultado do Tratamento
13.
Transplant Proc ; 51(8): 2629-2632, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471014

RESUMO

BACKGROUND: Mycophenolic acid (MPA) is one of the main immunosuppressive regimens used after kidney transplantation (KT). The less expensive, generic form of mycophenolate mofetil (MMF) (Immucept®) is recently available in Thailand. Comparisons of the pharmacokinetic profiles between the original and generic forms of MMF among post-KT patients are limited. METHODS: This prospective cohort study recruited KT patients receiving stable doses of MMF 1000 mg daily along with tacrolimus and steroids. All participants were prescribed CellCept® 500 mg every 12 hours for at least 2 weeks before measuring the MPA area under the curve from 0 to 12 hours (AUC0-12). CellCept® was switched to Immucept® 500 mg every 12 hours for 2 weeks and MPA AUC0-12 was remeasured. RESULTS: Twenty patients with a median follow-up time of 35.4 (11.13-198.83) months were enrolled. Mean MPA AUC0-12 of Immucept® was higher than CellCept® without statistical significance (48.27 ± 2.31 µg⋅hr/mL vs 42.19±15.20 µg⋅hr/mL; P value = .59). No difference was revealed regarding the minimum measured concentration, maximum measured concentration, and time point with maximum concentration between both drugs. While on CellCept®, 5 patients (25%) had an MPA AUC0-12 < 30.0 µg⋅hr/mL, but 3 patients (15%) had MPA AUC0-12 < 30.0 µg⋅hr/mL when receiving Immucept®. However, 3 (15%) and 6 (30%) patients had MPA AUC0-12 > 60.0 µg⋅hr./mL when treated with CellCept® and Immucept®, respectively. CONCLUSION: Generic MMF exhibited a comparable pharmacodynamic profile as the original formulation. MPA AUC0-12 was more than 30.0 µg⋅hr/mL among most patients receiving MMF 1000 mg/day.


Assuntos
Medicamentos Genéricos/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/farmacocinética , Adulto , Área Sob a Curva , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos , Esteroides/administração & dosagem , Tacrolimo/administração & dosagem , Tailândia , Resultado do Tratamento
14.
Muscle Nerve ; 60(5): 613-620, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397908

RESUMO

INTRODUCTION: The objective of this study is to assess the efficacy of local tacrolimus (FK506) delivery to improve outcomes in the setting of nerve transection injury. METHODS: FK506 embedded poly(lactide-co-caprolactone) films capable of extended, localized release of FK506 were developed. FK506 rate of release testing and bioactivity assay was performed. Mouse sciatic nerve transection and direct repair model was used to evaluate the effect extended, local delivery of FK506 had on nerve regeneration outcomes. RESULTS: Linear release of FK506 was observed for 30 days and released FK506 matched control levels of neurite extension in the dorsal root ganglion assay. Groups treated with local FK506 had greater gastrocnemius muscle weight, foot electromyogram, and number of axons distal of the repair site than non-FK506 groups. DISCUSSION: Results of this study indicate that extended, localized delivery of FK506 to nerve injuries can improve nerve regeneration outcomes in a mouse sciatic nerve transection and repair.


Assuntos
Imunossupressores/farmacologia , Denervação Muscular , Músculo Esquelético/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/lesões , Tacrolimo/farmacologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Preparações de Ação Retardada , Eletromiografia , Gânglios Espinais/efeitos dos fármacos , Imunossupressores/administração & dosagem , Camundongos , Músculo Esquelético/patologia , Neuritos/efeitos dos fármacos , Neuritos/patologia , Procedimentos Neurocirúrgicos , Tamanho do Órgão , Traumatismos dos Nervos Periféricos , Poliésteres , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/cirurgia , Tacrolimo/administração & dosagem
15.
Transplant Proc ; 51(6): 1758-1762, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399163

RESUMO

BACKGROUND: Although tacrolimus is an effective immunosuppressive drug used for preventing biopsy proven acute rejection (BPAR) in kidney transplanted patients, its nephrotoxicity may compromise renal function and lead to delayed initiation because of its side effects. This study aimed to evaluate the safety of early initiation of tacrolimus in the occurrence of BPAR during the first 90 days post transplant. METHODS: We conducted a retrospective cohort study involving 315 patients who underwent kidney transplantation from 2015 to 2017. Comparisons were performed between 2 groups according to whether the start time of tacrolimus therapy was delayed or not delayed. Cox proportional hazards models were used to examine the association between variables and the occurrence of BPAR. RESULTS: The incidence of BPAR was 14.9% (n = 47) and it was significantly higher in the delayed group (19.4% vs 6.4%; P = .002). Delayed initiation tacrolimus group was significantly associated with the risk of BPAR (hazard ratio: 2.95; P < .036). The overall mortality rate was 2.5% (n = 8) and there was no association between delayed initiation therapy and death (P = .56). CONCLUSION: Our study confirmed that delayed initiation of tacrolimus in patients with delayed graft function is associated with a high risk of BPAR.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Tempo para o Tratamento , Adulto , Estudos de Coortes , Feminino , Rejeição de Enxerto/epidemiologia , Humanos , Incidência , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Transplant Proc ; 51(6): 1920-1922, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399176

RESUMO

INTRODUCTION: Following liver transplantation (LT), the majority of patients are treated with reduced-dose calcineurin inhibitors (CNIs) in combination with mycophenolate mofetil. The optimal timing for subsequent conversion to CNI monotherapy is not clearly defined. This study aims to evaluate the safety of conversion to CNI monotherapy after LT. METHODS: This was a single-center retrospective study of 100 consecutive patients who received CNI and mycophenolate mofetil combination regimen after LT at Singapore General Hospital from 2006 to 2018. Patient demographics, clinical parameters, and posttransplant complications (ie, rates of graft rejection, de novo malignancy, cytomegalovirus infection and renal impairment) were recorded. RESULTS: One hundred patients were recruited and mean follow-up time in months ± standard deviation was 60.36 ± 41.73. Patients were divided into 2 groups based on institution of CNI monotherapy within (group 1) or beyond (group 2) 6 months. Twenty-five (25%) patients were on CNI monotherapy within 6 months post-LT. Overall patient survival was 83.7% at 5-years posttransplant. There was no statistical difference in the rates of posttransplant complications including liver graft rejection (4.0% vs 18.7%, P = .11); de novo malignancy (0.0% vs 8.0%, P = .33); cytomegalovirus infection (4.0% vs 1.3%, P = .44); and renal impairment (20.0% vs 40.0%, P = .069) between the 2 groups. CONCLUSIONS: Successful institution of CNI monotherapy within 6 months is safe, and does not increase the risk of rejection.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Transplante de Fígado , Complicações Pós-Operatórias/epidemiologia , Tacrolimo/administração & dosagem , Fatores de Tempo , Adulto , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Humanos , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Complicações Pós-Operatórias/etiologia , Insuficiência Renal/epidemiologia , Insuficiência Renal/etiologia , Estudos Retrospectivos
17.
Int Immunopharmacol ; 75: 105772, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376625

RESUMO

Everolimus (EVR) is often administered with cyclosporine A (CsA), according to an established protocol. Although the administration protocol of EVR with tacrolimus (TAC) has not been established, it has been clinically demonstrated that a higher dose of EVR is necessary when used in combination with TAC than with CsA. In this study, we aimed to determine the optimal dose of EVR administered with TAC to maintain a similar EVR level in the blood to that observed when EVR is administered with CsA. Between June 2009 and January 2016, 22 patients who underwent living donor kidney transplantation were enrolled in this study. Among them, 12 patients were administered steroids, basiliximab, CsA, and EVR (CsA + EVR group) and 10 were administered steroids, basiliximab, TAC, and EVR (TAC + EVR group). Blood samples were collected at different time points from patients in both CsA + EVR and TAC + EVR groups, after drug administration. The trough EVR level in both groups was maintained within 3-8 ng/mL during the perioperative period. The optimal EVR doses for both groups were estimated by using a population pharmacokinetic analysis. Overall, the optimal dose of EVR for the TAC + EVR group was 3.59-fold higher than that for the CsA + EVR group to maintain a similar trough level to that of the latter group. Thus, administration of a higher EVR dose is recommended when provided in combination with TAC than with CsA to prevent adverse events caused by under immunosuppression, that could lead to acute kidney rejection.


Assuntos
Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Doadores Vivos , Tacrolimo/administração & dosagem , Adulto , Basiliximab/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Ciclosporina/farmacocinética , Everolimo/sangue , Everolimo/farmacocinética , Feminino , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Esteroides/administração & dosagem , Tacrolimo/sangue , Tacrolimo/farmacocinética
18.
Int J Nanomedicine ; 14: 5849-5863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440050

RESUMO

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).


Assuntos
Dermatite Atópica/tratamento farmacológico , Emulsões/química , Óleos/química , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Administração Cutânea , Animais , Cânfora/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dermatite Atópica/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Orelha/patologia , Humanos , Imunoglobulina E/sangue , Imunossupressores/administração & dosagem , Masculino , Mentol/química , Camundongos , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Baço/efeitos dos fármacos , Substância P/metabolismo , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Resultado do Tratamento , Perda Insensível de Água/efeitos dos fármacos
19.
Transplant Proc ; 51(7): 2308-2311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400977

RESUMO

BACKGROUND: This study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. METHODS: A total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients. RESULTS: Baseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040). CONCLUSION: This study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Rejeição de Enxerto/mortalidade , Imunossupressores/administração & dosagem , Transplante de Rim/mortalidade , Tacrolimo/administração & dosagem , Adulto , Função Retardada do Enxerto/etiologia , Feminino , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
20.
Transplant Proc ; 51(7): 2361-2366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402247

RESUMO

PURPOSE: Motherhood is the greatest privilege that nature gives to women. Although pregnancy is a physiological event for women, every pregnancy is a risky pregnancy. During a normal pregnancy, the health of mother and baby are monitored. In post-transplantation pregnancies, the function of the transplanted organ, along with the mother and the infant, must be monitored, since the continuation of pregnancy depends on both the maternal and infant health and an organ functioning within normal limits. The desire is for every baby to be born in due time and at normal weight, but this is not always possible in pregnancies after transplants. Publications about the pharmocokinetics of tacrolimus are very limited. In this study, we wanted to share our experiences with pregnancy in our clinic. MATERIAL AND METHOD: Patients who used tacrolimus during their pregnancies after renal transplantation (RT) at Antalya Medicapark Organ Transplantation Unit, during November 2008 to July 2018 were included in the study. Patient's gestational age, pregnancy, drug levels, is charge, and labor creatinine clearances were examined. FINDINGS: Four thousand six hundred thirty-five RT occurred between November 2008 to July 2018; 786 of the patients were female between the ages 18 and 45. Thirty-one pregnancies went full term. Twenty-six pregnant women, who used tacrolimus after RT, were included in the study. Five patients had pre-eclampsia, 1 patient had abortus immines, 2 patients had hypertansion due to pregnancy, and 1 patient had aplated placenta. There was a breech presentation in 1 patient with preeclampsia. Acute rejection developed in 3 postpartum patients, but renal values normalized with medical treatment. All the babies were born alive and healthy; postpartum graft loss was not observed. CONCLUSION: If planning to become pregnant after RT,our center recommends waiting at least 2 years after the RT, when graft function should be normal and without any signs of HT and proteinuria. Our recommendation regarding the level of tacrolimus after RT is 4.5 to 7 µg.


Assuntos
Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações na Gravidez/etiologia , Tacrolimo/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Imunossupressores/administração & dosagem , Rim/fisiopatologia , Pessoa de Meia-Idade , Período Pós-Operatório , Gravidez , Resultado da Gravidez , Tacrolimo/administração & dosagem , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA