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1.
J Gastrointestin Liver Dis ; 29(3): 470, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32830825
2.
PLoS One ; 15(7): e0235418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614859

RESUMO

BACKGROUND: Little is known regarding optimal tacrolimus (TAC) trough levels after 1 year post-transplant in stable kidney transplant recipients (KTRs) who have not experienced renal or cardiovascular outcomes. This study aimed to investigate the effect of 1-year post-transplant TAC trough levels on long-term renal and cardiovascular outcomes and opportunistic infections in stable KTRs. METHODS: KTRs receiving TAC with mycophenolate-based immunosuppression who did not experience renal or cardiovascular outcomes within 1 year post-transplant were enrolled from a multicenter observational cohort study. Renal outcome was defined as a composite of biopsy-proven acute rejection, interstitial fibrosis and tubular atrophy, and death-censored graft loss. Cardiovascular outcome was defined as a composite of de novo cardiomegaly, left ventricular hypertrophy, and cardiovascular events. Opportunistic infections were defined as the occurrence of BK virus or cytomegalovirus infections. RESULTS: A total of 603 eligible KTRs were divided into the low-level TAC (LL-TAC) and high-level TAC (HL-TAC) groups based on a median TAC level of 5.9 ng/mL (range 1.3-14.3) at 1 year post-transplant. The HL-TAC group had significantly higher TAC trough levels at 2, 3, 4, and 5 years compared with the levels of the LL-TAC group. During the mean follow-up of 63.7 ± 13.0 months, there were 121 renal outcomes and 224 cardiovascular outcomes. In multivariate Cox regression analysis, LL-TAC and HL-TAC were not independent risk factors for renal and cardiovascular outcomes, respectively. No significant differences in the development of opportunistic infections and de novo donor-specific anti-human leukocyte antigen antibodies and renal allograft function were observed between the two groups. CONCLUSIONS: TAC trough levels after 1 year post-transplant remained at a similar level until the fifth year after kidney transplantation and were not directly associated with long-term outcomes in stable Korean KTRs who did not experience renal or cardiovascular outcomes. Therefore, in Asian KTRs with a stable clinical course, TAC trough levels higher than approximately 6 ng/mL might not be required after a year of kidney transplantation.


Assuntos
Imunossupressão/efeitos adversos , Imunossupressores , Transplante de Rim/reabilitação , Tacrolimo , Adulto , Doenças Cardiovasculares/induzido quimicamente , Estudos de Coortes , Infecções por Citomegalovirus/induzido quimicamente , Feminino , Rejeição de Enxerto/induzido quimicamente , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/induzido quimicamente , Infecções por Polyomavirus/induzido quimicamente , Insuficiência Renal/induzido quimicamente , República da Coreia , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Tacrolimo/sangue
3.
Transplant Proc ; 52(6): 1855-1857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32571709

RESUMO

OBJECTIVES: Mycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. METHODS: This study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. RESULTS: Patients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. CONCLUSIONS: After LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Fígado , Ácido Micofenólico/administração & dosagem , Feminino , Humanos , Imunossupressores/sangue , Lactente , Doadores Vivos , Masculino , Ácido Micofenólico/sangue , Fatores de Tempo
4.
Vascul Pharmacol ; 130: 106682, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32438078

RESUMO

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Everolimo/farmacocinética , Inibidores do Fator Xa/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim , Rivaroxabana/farmacocinética , Tacrolimo/farmacocinética , Trombose Venosa/tratamento farmacológico , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Coagulação Sanguínea/efeitos dos fármacos , Interações Medicamentosas , Monitoramento de Medicamentos , Everolimo/efeitos adversos , Everolimo/sangue , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/sangue , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
6.
Transplantation ; 104(4): 881-887, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32224815

RESUMO

BACKGROUND: Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. METHODS: We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. RESULTS: Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability). CONCLUSIONS: These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Monitoramento de Medicamentos , Rejeição de Enxerto/prevenção & controle , Antígenos HLA/imunologia , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Transplante de Rim , Tacrolimo/uso terapêutico , Adulto , Biomarcadores/sangue , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/sangue , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Fatores de Tempo , Resultado do Tratamento
7.
Transplant Proc ; 52(5): 1402-1408, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32220480

RESUMO

Measurement of immunosuppressive drug concentrations cyclosporine A (CyA), tacrolimus (TAC), sirolimus (SIR), and everolimus (EVE) in blood is an important application of therapeutic drug monitoring. These immunosuppressive agents are used in combined regimens and nowadays the liquid chromatography and tandem mass spectrometry is the best option for simultaneous analysis of these drugs in one short run. We developed an liquid chromatography and tandem mass spectrometry methodology in-house to measure the combination of immunosuppressants in a single blood sample from transplant patients in Brazil. We analyzed 235 combinations of 4 immunosuppressive drugs in patient blood to validate this study. The measuring ranges were 9 to 1000 ng/mL for CyA and 2 to 50 ng/mL for TAC, SIR, and EVE. Accuracy of the method was between 83.87% and 126.6% (coefficient of determination [r2] > 0.995). Validation of variation was ≤15% for lower limit of quantification. In our analysis 20% of patients treated with EVE showed concentration range of 6 to 6.9 ng/mL, 28% of patients treated with SIR showed a concentration range of 4 to 4.9 ng/mL to TAC, 22% of patients showed concentration range of 5 to 5.9 ng/mL, and finally 50% of patients treated with CyA showed concentration range of 20 to 30 ng/mL. Our routine laboratory was able to implement this new methodology in-house to measure simultaneous CyA, TAC, SIR, and EVE in a single blood sample from transplant patients with a sensibility and rapid quantification analysis.


Assuntos
Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Espectrometria de Massas em Tandem/métodos , Brasil , Ciclosporina/sangue , Everolimo/sangue , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Transplante de Órgãos/efeitos adversos , Sirolimo/sangue , Tacrolimo/sangue
8.
Am J Surg ; 219(4): 583-586, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32122660

RESUMO

BACKGROUND: Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK). METHODS: This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively. RESULTS: There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07). CONCLUSIONS: Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.


Assuntos
Preparações de Ação Retardada , Imunossupressores/administração & dosagem , Transplante de Rim , Transplante de Pâncreas , Tacrolimo/administração & dosagem , Transplantados , Adulto , Creatinina/sangue , Feminino , Hemoglobina A Glicada/análise , Rejeição de Enxerto/epidemiologia , Humanos , Imunossupressores/sangue , Masculino , Complicações Pós-Operatórias , Tacrolimo/sangue
9.
Transplant Proc ; 52(3): 775-779, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143870

RESUMO

INTRODUCTION: Long-term transplant outcomes are considered a crucial point for kidney transplantation. Follow-up studies in patients receiving early conversion to once-daily tacrolimus (TAC-OD) are still limited. We aimed to investigate tacrolimus trough level (Cmin), intrapatient variability of tacrolimus dose-normalized Cmin (TAC-Cmin/D), along with other outcomes between twice-daily tacrolimus (TAC-BID) and early converted TAC-OD. MATERIAL AND METHODS: This study was a single center, retrospective, cohort study. All new kidney transplant patients who received tacrolimus and presented an estimated glomerular filtration rate of more than 45 mL/min/1.73 m2 on the day of hospital discharge were included. Studied patients were divided into the standard TAC-BID and patients who were converted from TAC-BID to TAC-OD on the day of hospital discharge. We followed patients for 1 year after transplantation. RESULTS: At the first follow-up visit, Cmin of TAC-OD was significantly lower than that of TAC-BID. However, Cmin and estimated glomerular filtration rate were comparable between TAC-BID and TAC-OD throughout 1-year follow-up. TAC-OD also provided a lower intrapatient variability of TAC-Cmin/D compared with TAC-BID when observed after 6 months post transplantation (17.40% and 23.27% for TAC-OD and TAC-BID, respectively; P = .13). The renal function, as well as other adverse outcomes, was similar between 2 formulations. DISCUSSION: TAC-OD provided a similar Cmin with comparable renal function compared with TAC-BID during 1-year follow-up. In addition, TAC-OD is likely to have a benefit of a lower intrapatient variability of tacrolimus. CONCLUSION: Early conversion from TAC-BID to TAC-OD with 1:1 ratio can be used with close long-term monitoring.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/sangue , Transplante de Rim , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Adulto , Estudos de Coortes , Esquema de Medicação , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Pharm Res ; 37(3): 64, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32140879

RESUMO

PURPOSE: The aim of the present study was to develop a new multi-unit dosage formulation, Universal ORbicular Vehicle (UniORV), to improve the biopharmaceutical properties of tacrolimus (TAC). METHODS: TAC-loaded UniORV (UO/TAC) was produced by the dripping and gelling of a solution comprising TAC, gelatin, starch syrup, and triethyl citrate at 0.5 w/w% drug loading. Its microstructure was elucidated by polarized light microscopy and the Raman mapping technique. The pharmacokinetic profiles of TAC after the oral administration of UO/TAC were evaluated in rats and healthy humans. RESULTS: The dissolution behavior of UO/TAC was similar to that of commercial capsules, and the formation of nanoparticles was detected by TEM in dissolved media. In a stability study on UO/TAC, only 2.6 and 4.7% decreases in TAC concentrations were observed at 40± 2°C/75 ± 5% relative humidity for 4 months and at 50± 2°C for 2 months, respectively. A pharmacokinetic study on rats revealed a 30-fold higher AUC than that with crystalline TAC. A randomized double-blind crossover study on 8 healthy males showed that UniORV achieved a 1.4-fold increase in AUC and 34% decrease in inter-individual variation from the reference formulation. CONCLUSION: The new dosage form UniORV is a promising approach to improve the dissolution, amorphous stability, and biopharmaceutical properties of TAC, which is a poorly water-soluble drug.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Veículos Farmacêuticos/química , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Administração Oral , Adulto , Animais , Citratos/química , Estudos Cross-Over , Método Duplo-Cego , Composição de Medicamentos , Liberação Controlada de Fármacos , Gelatina/química , Humanos , Imunossupressores/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Amido/química , Tacrolimo/sangue , Adulto Jovem
11.
Lancet Haematol ; 7(2): e157-e167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32004485

RESUMO

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco/efeitos adversos , Gerenciamento Clínico , Monitoramento de Medicamentos , Resistência a Medicamentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos
12.
Anal Bioanal Chem ; 412(4): 1011-1024, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897563

RESUMO

Cabbage flower-like Ho3+/NiO nanostructure (CFL-Ho3+/NiO NSs) with significant electrocatalytic oxidation has been published for the first time. First, structure and morphology of CFL-Ho3+/NiO-NSs have been described by XRD, SEM, and EDX methods. Then, CFL-Ho3+/NiO-NSs have been applied as a modifier for simultaneous electrochemical detection of methotrexate (MTX) and carbamazepine (CBZ). Functions of the modified electrode have been dealt with through electrochemical impedance spectroscopy (EIS). It has been demonstrated that the electrode response has been linear from 0.001-310.0 µM with a limit of detection of 5.2 nM and 4.5 nM (3 s/m) through DPV for MTX and CBZ. Diffusion coefficient (D) and heterogeneous rate constant (kh) have been detected for MTX and CBZ oxidation at the surface of the modified electrode. Moreover, CFL-Ho3+/NiO-NS/GCE has been employed for determining MTX and CBZ in urine and drug specimens. Outputs showed the analyte acceptable recovery. Therefore, the electrode could be applied to analyze both analytes in drug prescription and clinical laboratories. Graphical abstract Electrochemical sensor based on bifunctional cabbage flower-like Ho3+/NiO nanostructures modified glassy carbon electrode for simultaneous detecting methotrexate and carbamazepine was fabricated.


Assuntos
Analgésicos não Entorpecentes/farmacocinética , Carbamazepina/farmacocinética , Monitoramento de Medicamentos/métodos , Imunossupressores/farmacocinética , Metotrexato/farmacocinética , Analgésicos não Entorpecentes/análise , Analgésicos não Entorpecentes/sangue , Analgésicos não Entorpecentes/urina , Carbamazepina/análise , Carbamazepina/sangue , Carbamazepina/urina , Técnicas Eletroquímicas/métodos , Hólmio/química , Humanos , Imunossupressores/análise , Imunossupressores/sangue , Imunossupressores/urina , Limite de Detecção , Metotrexato/análise , Metotrexato/sangue , Metotrexato/urina , Nanoestruturas/química , Níquel/química , Oxirredução , Comprimidos
13.
BMC Gastroenterol ; 20(1): 7, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931737

RESUMO

BACKGROUND: The anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS. METHODS: Lewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels. RESULTS: The results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate. CONCLUSIONS: This study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = - 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/imunologia , Imunossupressores/uso terapêutico , Transplante de Fígado/efeitos adversos , Tacrolimo/uso terapêutico , Animais , Aspartato Aminotransferases/sangue , Imunossupressores/sangue , Fígado/imunologia , Transplante de Fígado/métodos , Doadores Vivos , Tamanho do Órgão/imunologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Tacrolimo/sangue , Transplantes/imunologia , Resultado do Tratamento
14.
Eur J Drug Metab Pharmacokinet ; 45(1): 123-134, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31745812

RESUMO

BACKGROUND AND OBJECTIVE: Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. METHODS: We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. RESULTS: The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). CONCLUSIONS: The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Disponibilidade Biológica , Monitoramento de Medicamentos , Feminino , Transplante de Coração , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Pulmão , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Transplante de Órgãos/métodos , Período Pós-Operatório , Tacrolimo/sangue , Tacrolimo/uso terapêutico
15.
Anal Bioanal Chem ; 412(2): 355-364, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760446

RESUMO

An innovative electrochemical sensor was proposed for simultaneous determination of mycophenolate mofetil (Mph) and tacrolimus (TAC) for the first time. A novel sensor based on electro-polymerization of multi-walled carbon nanotubes (MWCNTs) and a novel Cu-1N-allyl-2-(2,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole metal organic framework (Cu-ADPPI MOF) on disposable pencil graphite electrode (dPGE). Many techniques were used to characterize the electrochemical activity and surface structure of the fabricated sensor. The proposed sensor exhibited good catalytic performance towards Mph and TAC oxidation due to the synergistic effect. Under optimal conditions, the proposed sensor has achieved a linear range of 0.85-155 × 10-8 M and 1.1-170.0 × 10-8 M with LODs of 0.28 × 10-8 M and 0.36 × 10-8 M for Mph and TAC, respectively. The designated sensor showed good reproducibility, repeatability, stability, and selectivity for the determination of Mph and TAC. Moreover, the simultaneous determination of Mph and TAC in different human biological fluids was carried out with acceptable results. As a result, the proposed sensor opens a new venue for the use of electro-polymerized MOFs in combination with other conductive materials such as MWCNTs for electrochemical sensing of different analytes with the desired sensitivity and selectivity. Graphical abstract Construction of disposable graphite electrode, based on electro-deposition of multilayer films of multi-walled carbon nanotubes and a new generation of Cu-MOFs, for simultaneous analysis of tacrolimus and mycophenolate mofetil for the first time.


Assuntos
Eletrodos , Grafite/química , Imunossupressores/análise , Ácido Micofenólico/análise , Tacrolimo/análise , Humanos , Imunossupressores/sangue , Imunossupressores/urina , Limite de Detecção , Estruturas Metalorgânicas/química , Ácido Micofenólico/sangue , Ácido Micofenólico/urina , Nanoestruturas/química , Polimerização , Reprodutibilidade dos Testes , Tacrolimo/sangue , Tacrolimo/urina
16.
Transplantation ; 104(6): 1201-1209, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31609904

RESUMO

BACKGROUND: There is an interest in understanding the association between early calcineurin inhibitors exposure post-liver transplantation (LT) and long-term outcomes. We aimed to analyze this association exploring median calcineurin inhibitor levels and intrapatient variability (IPV) in a multicenter, retrospective cohort. METHODS: Tacrolimus (Tac) and Cyclosporine (CsA) levels obtained during the first 15 days post-LT were collected. High immunosuppression (IS) was considered as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration higher than 10, 250, or 1200 ng/mL, respectively, or a peak of Tac >20 ng/mL. Optimal IS was defined as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration levels between 7 and 10, 150 and 250, or 800 and 1200 ng/mL. Low IS was defined as below the thresholds of optimal IS. IPV was estimated during the first 15 days post-LT. RESULTS: The study included 432 patients with a median follow-up of 8.65 years. IS regimen was based on either Tac or CsA in 243 (56.3%) and 189 (43.8%), respectively. There were no differences in terms of graft loss among low versus optimal and high IS groups (P = 0.812 and P = 0.451) nor in high versus low IPV (P = 0.835). Only viral hepatitis and arterial hypertension were independently associated with higher graft loss (hazard ratio = 1.729, P = 0.029 and hazard ratio = 1.570, P = 0.021). CONCLUSIONS: In contrast to what has previously been reported, no association was found between very early postoperative over IS or high IPV and long-term outcome measures following LT. Strategies aimed at reducing these long-term events should likely focus on other factors or on a different IS time window.


Assuntos
Variação Biológica Individual , Inibidores de Calcineurina/sangue , Rejeição de Enxerto/epidemiologia , Imunossupressores/sangue , Transplante de Fígado/efeitos adversos , Inibidores de Calcineurina/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/sangue
17.
J Pharm Biomed Anal ; 177: 112890, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31563756

RESUMO

Various immunoassay methods have been developed and used for the therapeutic drug monitoring (TDM) of cyclosporine (CsA). However, there is no report on the application of a time-resolved fluoroimmunoassay (TRFIA) in routine CsA TDM. The aim of this study was to evaluate the feasibility and validate the performance of a newly developed TRFIA method for CsA analysis in human whole blood. The TRFIA method was then compared with the method of chemiluminescent microparticle immunoassay (CMIA). The calibration range of the CsA-TRFIA method was 0-1000 ng/mL. The linear range and correlation coefficients were 30-1000 ng/mL and more than 0.990, respectively. The accuracy, precision, and inter-batch range were 90.0%-110.0%, less than 10%, and no more than 15%, respectively. The lowest limit of detection was less than 10 ng/mL. The linear regression equation was YCMIA = 0.961XTRFIA + 3.357, which showed that the measurements of CMIA and TRFIA were strongly correlated (r = 0.980). The results demonstrate that TRFIA is a precise and reproducible method for detecting the CsA concentration and can be used for routinely CsA TDM.


Assuntos
Ciclosporina/sangue , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Ciclosporina/administração & dosagem , Estudos de Viabilidade , Fluorimunoensaio/métodos , Humanos , Imunossupressores/administração & dosagem , Limite de Detecção , Reprodutibilidade dos Testes
18.
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
19.
Clin Pharmacol Ther ; 107(2): 462-470, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31513279

RESUMO

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.


Assuntos
Lesão Renal Aguda/epidemiologia , Rejeição de Enxerto/epidemiologia , Imunossupressores/farmacocinética , Transplante de Pulmão/métodos , Tacrolimo/farmacocinética , Lesão Renal Aguda/prevenção & controle , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Índice de Gravidade de Doença , Tacrolimo/administração & dosagem , Tacrolimo/sangue
20.
Talanta ; 206: 120242, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514896

RESUMO

High performance liquid chromatography (HPLC) post-column photochemical reaction (PR) coupled capacitively coupled contactless conductivity detector (C4D) was used for the first time in analysis of weak ultraviolet (UV)-absorbing, non-fluorescence and nonpolar compound. A series of conditions including the radiation power of light source, the length of the reaction tube and the thickness of detection tube were investigated. HPLC-PR-C4D system was successfully applied to the determination of Cyclosporin A (CsA). Consequently, under optimal conditions, the detection system exhibited a detection limit of 0.04 µg/mL and wide linear range from 0.5 µg/mL to 100 µg/mL for CsA detection. Application of the HPLC-PR- C4D system to pharmaceutical formulation and biological samples revealed the system developed maybe reliably applied to clinical studies.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclosporina/sangue , Fotoquímica/métodos , Cromatografia Líquida de Alta Pressão/instrumentação , Ciclosporina/efeitos da radiação , Humanos , Imunossupressores/sangue , Imunossupressores/efeitos da radiação , Limite de Detecção , Fotoquímica/instrumentação
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