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1.
Medicine (Baltimore) ; 99(12): e19441, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195940

RESUMO

We hypothesized that area under the concentration time curve (AUC(0-12)) is more accurate pharmacokinetic predictor vs trough level of mycophenolic acid (C0).Study was performed at the University Hospital of Limoges (France) and included 238 renal recipients aged 22 to 82 years. Risk of nephropathy was evaluated by analyzing data of protocol biopsies according to the Banff 97 classification.Assessment of immunosuppressants' exposures was based on the calculation of the mean of AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine and tacrolimus analyses were performed using liquid chromatography-mass spectrometry method. The measurement of total mycophenolic acid was performed using a validated high-performance liquid chromatography method with ultraviolet detection. IBM SPSS 20.0 was used for statistical analysis.The most accurate dosing of mycophenolate mofetil (MMF) was observed in patients receiving MMF with tacrolimus, 70.6% of patients' AUC(0-12) exposures were within the therapeutic range. The highest rates of low dosing were observed in patients receiving MMF with cyclosporine, 30.9% of patients had AUC(0-12) exposures below the therapeutic range. The assessment of AUC(0-12) revealed 38% of chronic nephropathy cases, while C0 enables to identify only 20% of chronic nephropathy cases.Probability test results showed that more likely AUC(0-12) and C0 will be maintained within the therapeutic width if patients receive MMF with tacrolimus vs MMF with cyclosporine: 0.6320 vs 0.6410 for AUC(0-12) determination and 0.8415 vs 0.4827 for C0 determination.Combination of MMF with tacrolimus is dosed more precisely vs dosing of MMF with cyclosporine. 72 (70.6%) patients AUC(0-12) and 79 (77.5%) patients C0 out of 102 patients were within the therapeutic range. The AUC(0-12) monitoring of mycophenolic acid in patients receiving MMF with tacrolimus or in patients receiving MMF with cyclosporine enabled to identify more overdosing and possible risky cases.Study results show that standard MMF dosing without monitoring and with mycophenolic acid level within the therapeutic width is possible and demonstrates less risky cases in patients receiving MMF with tacrolimus, while patients receiving MMF with cyclosporine should be intensively monitored to achieve the highest safety. However, AUC(0-12) monitoring is advised showing better compliance vs C0 monitoring.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Ácido Micofenólico/farmacocinética , Tacrolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Ciclosporina/administração & dosagem , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Tacrolimo/administração & dosagem
2.
Nat Rev Rheumatol ; 16(3): 167-178, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32055040

RESUMO

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.


Assuntos
Azatioprina/uso terapêutico , Ácido Micofenólico/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Reumatologia , Tacrolimo/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Azatioprina/farmacocinética , Quimioterapia Combinada , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Ácido Micofenólico/farmacocinética , Tacrolimo/farmacocinética
3.
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
4.
Neurosciences (Riyadh) ; 24(4): 324-326, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31872814

RESUMO

Tacrolimus is an immunosuppressant agent utilized for solid organ transplantations. It has been associated with rare neurotoxic effects. This case highlights one possible delayed neurotoxic effect. A 52-year-old lady on tacrolimus (3mg daily) among her immunosuppressive regimen for her kidney transplant 16 year ago. She presented with unilateral left paracentral black dots progressing over a week, associated with periorbital and temporal pain. The patient was diagnosed with left papillitis. Tacrolimus was tapered and then changed to cyclosporine. However, patient did not show any improvement of any parameter. Reports have indicated such neurotoxic effects with Tacrolimus use. Here, the report emphasizes on the unilateral optic neuropathic effect of tacrolimus even after one decade.


Assuntos
Imunossupressores/efeitos adversos , Doenças do Nervo Óptico/etiologia , Tacrolimo/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Pessoa de Meia-Idade , Doenças do Nervo Óptico/diagnóstico por imagem , Doenças do Nervo Óptico/patologia , Tacrolimo/uso terapêutico
5.
BMC Infect Dis ; 19(1): 974, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744480

RESUMO

BACKGROUND: Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN. METHODS: All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4+ and CD8+ T cells, after stimulation with large-T antigen (LT) and viral capsid protein 1 (VP1), were performed both at the time of diagnosis and after adjustment of immunosuppression. RESULTS: We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4+ T cells to LT at a median of 3 (IQR: 1-4) months after adjustment of immunosuppression compared with at the time of diagnosis (0.004 vs. 0.015; p = 0.047). However, the difference between the median percentage of IFN-γ-producing CD4+ T cells to VP1 and CD8+ T cells to LT and VP1 did not reach statistical significance. Four (33%) patients achieved plasma BKPyV DNA clearance, and the remaining eight (67%) patients had persistent BKPyV DNAemia. Although eight (67%) patients developed allograft dysfunction, none required hemodialysis. CONCLUSIONS: We observed a marginal trend of BKPyV-specific CD4+ T cell recovery after adjustment of immunosuppression in KT recipients diagnosed with BKPyVAN. A further study would be benefited to confirm and better assess BKPyV-specific immune response after KT.


Assuntos
Vírus BK/imunologia , Linfócitos T CD8-Positivos/imunologia , Transplante de Rim/efeitos adversos , Nefrite Intersticial/diagnóstico , Infecções por Polyomavirus/diagnóstico , Adulto , Vírus BK/genética , Vírus BK/isolamento & purificação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , DNA Viral/sangue , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/etiologia , Nefrite Intersticial/virologia , Infecções por Polyomavirus/etiologia , Infecções por Polyomavirus/virologia , Tacrolimo/uso terapêutico , Transplante Homólogo , Proteínas Virais/imunologia
6.
Transplant Proc ; 51(9): 2917-2920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711577

RESUMO

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/metabolismo , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/metabolismo , Tacrolimo/uso terapêutico , Adulto , Idoso , Monitoramento de Medicamentos , Feminino , Genótipo , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Medicina de Precisão/métodos , Estudos Retrospectivos
7.
Prensa méd. argent ; 105(9 especial): 576-581, oct 2019.
Artigo em Inglês | LILACS, BINACIS | ID: biblio-1046621

RESUMO

This work is aimed at studying the problems of timely diagnostics and therapy of various forms of rosacea, identifying the factors that influence the compliance, prognosis, and quality of life of the patients, as well as the stages of combination therapy. The efficiency of rosacea therapy is determined by the timely identification of patients, as well as the clinical variety of the disease. Complex therapy of rosacea includes identification of the precipitating factors, basic skincare, and the use of systemic and local pathogenetic preparations. The "Gold Standard" of topical rosacea therapy is the antimicrobial and antiprotozoal drug called metronidazole. An important role in disease therapy is played by active cooperation between the doctor and the patient. Comprehensiveness, timeliness, and rationality of rosacea therapy are defined not only by the mechanisms of the disease development but also by aggravating factors, the need for basic care and photosensitivity of the patients


Assuntos
Transtornos de Fotossensibilidade , Retinoides/uso terapêutico , Isotretinoína/uso terapêutico , Cooperação do Paciente , Tacrolimo/uso terapêutico , Rosácea/diagnóstico , Terapia Combinada , Metronidazol/uso terapêutico
8.
Transplant Proc ; 51(7): 2318-2320, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400970

RESUMO

PURPOSE: In healthy individuals, glomerular filtration rate decreases by 1 mL/min/y after a peak level of 125.0 mL/min has been reached in adulthood. Any reduction greater than this is a progressive slope (slope more negative than -1 mL/min/y, stable [-1 to +1]), or an improvable slope if it shows more of an increase, that is, greater than +1.0 mL/min/y). The aim of the study was to determine the factors affecting estimated glomerular filtration rate (eGFR) slope during the first 2 years of renal transplant in patients with negative pretransplant panel-reactive antibody. MATERIALS AND METHODS: The characteristics of 59 renal transplant patients, such as age, sex, etiology, and 2 years of laboratory data, were collected retrospectively. For each patient, the eGFR decline rate (slope) (mL/min-1/1.73 m2-1/y-1) was determined by linear regression analysis using all calculated eGFR values over the study period. FINDINGS: Of 59 patients, 7 (11.8%) had a progressive slope, 22 (37.2%) had a stable slope, and 30 (50.8%) had an improvable slope. The first-year mean tacrolimus level was lower in patients with progressive slope than in the patients with stable slope and improvable slope (P < .022). The determinants of eGFR slope in multiple regression analysis were post-transplant hypertension (ß = -0.393; P = .002) and the first-year mean tacrolimus level (ß = 0.320; P = .01), whereas age, serum albumin, and 2-year mean tacrolimus level did not reach the level of significance. CONCLUSION: Keeping tacrolimus levels high in the first year to prevent eGFR declining is important.


Assuntos
Taxa de Filtração Glomerular , Sobrevivência de Enxerto/fisiologia , Transplante de Rim , Adulto , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tacrolimo/uso terapêutico
9.
Transplant Proc ; 51(7): 2295-2297, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400975

RESUMO

PURPOSE: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic anemia, thrombocytopenia, and acute kidney injury. HUS is mostly associated with diarrhea (90%). However, 10% of cases are not associated with diarrhea and are thus called as atypical HUS (aHUS); these cases are usually caused by dysregulation of the complement system. Eculizumab, a monoclonal antibody against C5, is the drug of choice for treating aHUS. Herein we aimed to present 8 cases of renal transplantation performed on patients with aHUS. MATERIALS AND METHODS: A total of 8 patients who had been diagnosed with aHUS between the years 2012 to 2018 were enrolled and underwent transplantations. All patients received induction treatment, standard immunosuppresive treatment (tacrolimus, mycophenolic acid, prednisolone), and eculizumab. Eculizumab was administered at a dosage of 900 mg/wk for the first month and 1200 mg every 2 weeks thereafter. Patients were followed up and recorded in terms of demographic features, serum creatinine, lactate dehydrogenase, acute rejection episodes, and allograft outcomes. RESULTS: Mean age was 34 ± 8 years (Male/Female: 6/2). One of the patients had a second transplantation. Median hemodialysis vintage (25%-75% interquartile range) was 37 (9-63) months. Four patients had pretransplant plasmapheresis and 2 patients had posttransplant plasmapheresis. Induction treatment was ATG in 7 patients, and basiliximab was used only in 1 patient. The median follow-up period was 25 (13-59) months. Mean serum creatinine levels were 1.9 ± .6, 1.2 ± .7, and 1 ± .1 mg/dL for the first day, first month, and last values, respectively. Mean lactate dehydrogenase levels were 286 ± 203, 239 ± 27, and 218 ± 86 U/L for first day, first month, and last values, respectively. None of the patients had an acute rejection episode. Currently, all patients have functioning allografts. CONCLUSION: Patients with aHUS may be transplanted successfully with eculizumab with good allograft outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/cirurgia , Inativadores do Complemento/uso terapêutico , Transplante de Rim , Adulto , Terapia Combinada , Creatinina/análise , Feminino , Humanos , Masculino , Ácido Micofenólico/uso terapêutico , Plasmaferese , Período Pós-Operatório , Prednisolona/uso terapêutico , Tacrolimo/uso terapêutico , Resultado do Tratamento
10.
Transplant Proc ; 51(8): 2697-2703, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31439330

RESUMO

BACKGROUND: Compared to tacrolimus, cyclosporine increases cardiovascular risk. Furthermore, tacrolimus has a negative effect on glucose metabolism compared to cyclosporine. This study investigated the effect of the conversion from cyclosporine to tacrolimus for immunosuppressive therapy on glucose metabolism and cardiovascular risk profiles in long-term stable kidney transplant recipients (KTRs). METHODS: In this prospective, open-label, single-arm study, 36 KTRs were enrolled; 3 were excluded. Patients were evaluated for glucose metabolism and cardiovascular risk factors at baseline, 3, and 6 months after conversion of medication. Serial changes were analyzed by repeated analysis of variance. RESULTS: The mean duration from transplantation was 12.6 ± 4.0 years and baseline serum creatinine levels were 1.10 ± .23 mg/dL. After conversion, fasting plasma glucose levels increased sequentially from 101.7 ± 18.5 to 107.4 ± 21.3 mg/dL (P = .007), and glycated hemoglobin levels increased from 5.7 ± .8 to 6.0 ± 1.2% (P = .016). Among cardiovascular risk factors, fibrinogen levels were decreased (P = .015), but other factors, including blood pressure and lipid profile, did not change (all P > .05). There was no change in renal function, including serum creatinine (P = .611) and urine protein-to-creatinine ratio (P = .092). Body mass index levels were decreased (P = .037) and body weight tended to decrease (P = .063). CONCLUSIONS: Switching immunosuppressant therapy to tacrolimus has an apparent negative effect on glucose metabolism and imparts an unclear advantage on cardiovascular risk profiles for long-term stable KTRs.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Ciclosporina/uso terapêutico , Glucose/metabolismo , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/uso terapêutico , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Testes de Função Renal , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
11.
Transplant Proc ; 51(8): 2731-2734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447189

RESUMO

BACKGROUND: There is little evidence about whether mammalian target of rapamycin (mTOR) inhibitor could prevent post-kidney transplant (KT) urothelial carcinoma (UC) or not. The aim of this study is to analyze the role of mTOR inhibitor add-on in tacrolimus-based kidney transplant recipients. METHOD: The data were obtained from the Kaohsiung Chang Gung Memorial Hospital using the Chang Gung Research Database and retrospectively reviewed from January 2000 to December 2015. Patients then were categorized into 2 groups: group FK (more than 2-year tacrolimus [FK] prescription) and group FK + mTOR inhibitor (more than 2-year tacrolimus plus at least 6-month continued sirolimus prescription). The primary end point is post-KT UC development. The secondary end point is mTOR inhibitor add-on effect on renal function deterioration episode. RESULTS: There were 140 patients with tacrolimus-based immunosuppressant (group FK) and 82 patients with tacrolimus-based and add-on mTOR inhibitor regimen (group FK + mTOR inhibitor). The follow-up duration, sex distribution, and combined mycophenolate mofetil rate are similar in both groups. Younger age, lower tacrolimus trough level, lower UC incidence, and longer KT-to-UC interval were observed. Short- to intermediate-term results revealed noninferior graft outcome by creatinine level or creatinine deterioration. CONCLUSIONS: In our preliminary result, mTOR inhibitor add-on in patients with tacrolimus-based regimen revealed less post-KT UC occurrence. In addition, noninferior graft outcome was also observed. In Taiwan, a high UC prevalence area, mTOR inhibitor add-on strategy can be considered as a preventive strategy for UC after KT.


Assuntos
Carcinoma de Células de Transição/epidemiologia , Imunossupressores/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/epidemiologia , Sirolimo/uso terapêutico , Adulto , Carcinoma de Células de Transição/etiologia , Carcinoma de Células de Transição/imunologia , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Hospedeiro Imunocomprometido , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/imunologia , Estudos Retrospectivos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tacrolimo/uso terapêutico , Taiwan
12.
Int Urol Nephrol ; 51(11): 2063-2072, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385180

RESUMO

PURPOSE: In large observational studies of adult kidney transplant recipients (KTRs) where older adults (65 years old and older) were not well represented, the mammalian target of rapamycin inhibitors (mTOR inhibitors) has poorer outcomes than the standard tacrolimus-mycophenolate-steroids (TAC-MPA-S) regimen. We conducted this study to compare the outcomes of regimens containing the common mTOR inhibitor, sirolimus (SRL) against TAC-MPA-S in older adult KTRs. METHODS: Using the 2000-2016 Scientific Registry of Transplant Recipients, Cox multivariable regression models were conducted to analyze the patient and graft outcomes associated with regimens containing SRL, steroids (S) and cyclosporine (CSA), tacrolimus (TAC), or mycophenolate (MPA) vs. the standard (TAC-MPA-S) regimen in older adult KTRs. RESULTS: Included in the analysis were 15,008 (95.19%) older adult KTRs on standard (TAC-MPA-S) regimen, 242 (1.53%) on SRL-MPA-S, 300 (1.90%) on SRL-TAC-S, and 217 (1.38%) on SRL-CSA-S. Compared with the standard regimen, the adjusted risks of all-cause death and overall graft loss over a maximum 5-year follow-up were highest with SRL-MPA-S, intermediate with SRL-TAC-S and not significantly different with SRL-CSA-S. The adjusted risks of all-cause death and overall graft loss were modified by a pre-transplant history of malignancy in older adult KTRs on SRL-TAC-S, not in those on SRL-MPA-S or SRL-CSA-S. CONCLUSIONS: In older adult kidney transplant recipients, SRL-TAC-S or SRL-MPA-S, but not SRL-CSA-S is associated with higher risks of death and allograft loss than standard TAC-MPA-S regimen and a pre-transplant malignancy history worsens these risks in patients on SRL-TAC-S. Confirmation of our findings by a prospective randomized trial is needed before translation into clinical practice can be recommended.


Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Idoso , Feminino , Humanos , Masculino , Ácido Micofenólico/uso terapêutico , Sistema de Registros , Estudos Retrospectivos , Esteroides/uso terapêutico , Tacrolimo/uso terapêutico , Resultado do Tratamento
13.
Transplant Proc ; 51(7): 2358-2360, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402252

RESUMO

BACKGROUND: In intensive care unit (ICU), although there is no standard protocol for maintenance of immunosuppressive (IS) treatments for the kidney transplant recipients (KTx), the dose and the number of IS drugs are decreased according to the center's experience. The aim of this study is to evaluate the changes in IS treatment during stays in the ICU and to evaluate the safety and results of this modification on the IS treatment in the ICU arbitrarily. METHOD: We evaluated retrospectively our kidney transplant recipients in ICU between 2012 and 2017. The immunosuppressive protocols and the results were taken from the ICU documents. RESULTS: A total of 31 (18 male, 13 female) patients were suitable for the analysis. They were all under the triple IS protocol including Tacrolimus (Tac) + Mycophenolate mofetil (MMF) + steroid before the admission. The reason for ICU admission were severe sepsis in all patients. In ICU, 16 patients (51.6%) died, and a total of 10 patients were lost with functional graft. Change in IS treatment is as follows: a total of the 23 patients (74.2%) were given only steroids, and 8 patients (25.8%) were changed from triple to 2 drugs. Acute kidney injury developed in 42% (13 patients) of the patients in ICU. CONCLUSION: In our study, we observed that life-threatening severe infections were the main cause of ICU admission in KTx. Reduction in IS treatments are common practice, and reduction to a single dose of steroid was the most frequently chosen IS treatment. Eighty percent of patients are discharged with reduction of steroid gradually. None of the patients developed acute rejection and permanent graft injury.


Assuntos
Cuidados Críticos/métodos , Imunossupressores/uso terapêutico , Unidades de Terapia Intensiva/estatística & dados numéricos , Transplante de Rim , Adulto , Protocolos Clínicos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Período Pós-Operatório , Estudos Retrospectivos , Esteroides/uso terapêutico , Tacrolimo/uso terapêutico
14.
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
15.
Transplant Proc ; 51(7): 2302-2307, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358448

RESUMO

PURPOSE: HLA antibodies have been shown to be associated with late graft loss. In this study, we defined the incidence and profiles of anti-HLA antibodies and their impact on graft outcome in long-term kidney recipients. METHODS: The sera of 118 kidney transplant recipients were screened for anti-HLA antibody presence. The antigen specificity of the detected HLA class I and class II antibodies was identified using a Luminex assay (Luminex Corp, Austin, TX, United States). Presence of donor specific antibodies (DSA) was examined in individuals with anti-HLA antibodies using the Luminex method. RESULTS: Anti-HLA class I and/or class II antibodies were detected in serum of 16.1% of the kidney transplant patients. The antibodies were directed against HLA class I antigens in 4 patients (21.1%), HLA class II antigens in 9 patients (47.4%), and both class I and class II antigens in 6 patients (31.6%). The overall prevalence of DSA was 10.2%. Anti-HLA antibodies were significantly associated with higher rate of cyclosporine use. Presence of DSA was associated with a lower rate of tacrolimus use, a higher rate of cyclosporine use, and lower donor age. Presence of anti-HLA antibodies was associated with higher acute cellular rejection and higher chronic active humoral rejection rates. Presence of DSA was associated with chronic active humoral rejection. CONCLUSION: The presence of either HLA antibodies or DSA significantly correlated with lower graft survival, poor transplant function, and proteinuria.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Adulto , Especificidade de Anticorpos , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/imunologia , Rim/imunologia , Transplante de Rim/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Proteinúria/imunologia , Tacrolimo/uso terapêutico , Transplantes/imunologia , Resultado do Tratamento
16.
Intern Med ; 58(21): 3189-3194, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292376

RESUMO

A 69-year-old Japanese woman was admitted to our hospital with progressive muscle weakness and dysphagia. She was taking pitavastatin for dyslipidemia. Her serum creatine kinase was 6,300 U/L. Pitavastatin was stopped, but her symptoms deteriorated, and cardiac congestion appeared. A muscle biopsy showed necrotizing myopathy (NM), and anti-signal recognition particle (SRP) antibody was positive. 18F-fluorodeoxyglucose-positron emission tomography showed an abnormal uptake, and magnetic resonance imaging showed abnormal gadolinium enhancement in the left ventricular wall. An endomyocardial biopsy revealed inflammatory cardiomyopathy. Steroid, tacrolimus, and intravenous immunoglobulins were effective against the symptoms. This is the first case of biopsy-proven secondary cardiomyopathy due to anti-SRP-positive NM.


Assuntos
Cardiomiopatias/etiologia , Imagem Multimodal , Músculo Esquelético/patologia , Doenças Musculares/patologia , Idoso , Autoanticorpos/sangue , Biópsia , Cardiomiopatias/diagnóstico por imagem , Meios de Contraste , Ecocardiografia , Feminino , Gadolínio , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Imagem por Ressonância Magnética , Debilidade Muscular/patologia , Doenças Musculares/complicações , Doenças Musculares/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Partícula de Reconhecimento de Sinal/imunologia , Tacrolimo/uso terapêutico
17.
Orv Hetil ; 160(30): 1178-1183, 2019 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-31327249

RESUMO

Tacrolimus is an important part of immunosuppressive therapy after solid organ transplantation. The therapeutic range of the drug from the calcineurin inhibitor group is narrow. Adjustment of the blood concentration can be very complicated but to be able to avoid the occurrence of side effects or ineffective immunosuppression it is inevitable. This article summarizes the properties of tacrolimus pharmacokinetics, pharmacogenetics and pharmacodynamics. We will focus on individual variations of cytochrome enzymes. In the following part, a new method for screening high risk patients will be introduced. We will present the publications of the determination of the concentration/dose (C/D) ratio. By determining the C/D ratio, researchers identify fast and slow metabolizing patient groups. Fast metabolizers require higher doses in general and the occurrence of complications is also more frequent in this group. Long-term results are lagging behind the slow metabolizing group. The long-term results of renal transplantation nowadays contribute to the postoperative period and the later years rather than the surgery itself. It includes the proper management of previous illnesses (e.g., hypertension, diabetes, endocrinological problems), detection of complications (e.g., infections, malignancies), and the precise regulation of immunosuppressive therapy. Orv Hetil. 2019; 160(30): 1178-1183.


Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim , Rim/efeitos dos fármacos , Tacrolimo/farmacologia , Tacrolimo/farmacocinética , Inibidores de Calcineurina/farmacocinética , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Farmacogenética , Tacrolimo/uso terapêutico , Resultado do Tratamento
18.
Intern Med ; 58(22): 3331-3336, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31327821

RESUMO

A 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment.


Assuntos
Artrite Reumatoide/complicações , Transtornos Linfoproliferativos/complicações , Úlcera Péptica Perfurada/etiologia , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biópsia , Feminino , Humanos , Doença Iatrogênica , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/cirurgia , Metotrexato/uso terapêutico , Tacrolimo/uso terapêutico
19.
Drug Des Devel Ther ; 13: 2179-2186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308629

RESUMO

Background: As one of the therapeutic drugs for idiopathic membranous nephropathy (IMN), tacrolimus (TAC) has not been fully vindicated for its efficacy and tolerability. A meta-analysis was performed to detect the efficacy and safety of TAC plus glucocorticoid vs cyclophosphamide (CTX) plus glucocorticoid in therapy of patients with IMN. Methods: A literature search with a pre-defined search strategy was conducted using English databases (PubMed, EMBASE, ClinicalKey and the Cochrane Library) and Chinese databases (China National Knowledge International, Wanfang, Chinese Scientific Journal Database (VIP)) from inception to Nov 19, 2018. Any high-quality randomized controlled trials (RCTs) comparing the effectiveness or safety of TAC with CTX in IMN patients were included. Data were extracted by two authors independently and analyzed using RevMan 5.3. Results: Four randomized controlled studies were included. In this analysis, we did not find that the statistically significant difference between TAC and CTX groups on 6-month and 12-month treatment complete remission (CR) was evident (6-month: OR=1.53, 95% CI: 0.85-2.76, P=0.15; 12-month: OR=2.17, 95% CI: 0.56-8.44, P=0.27). But TAC had better 6-month total remission (TR; total CR plus partial remission [PR]) than CTX (6-month: OR=2.62, 95% CI: 1.38-4.96, P=0.003; 12-month: OR=1.74, 95% CI: 0.29-10.48, P=0.54), and got a lower proteinuria after 6-month treatment (OR=-0.80, 95% CI: -1.53 to -0.07, P=0.03). TAC had a lower incidence rate on leucopenia than CTX, but had a tendency towards higher blood creatinine. In the meantime, tremor in TAC group was higher than that in CTX group. The differences on other adverse effects such as gastrointestinal syndrome, infection, herpes zoster, hypertension, liver function disorder and hyperglycemia were also analyzed. However, none of them were statistically significant. Conclusion: TAC treatment could get high value of TR and had low value of proteinuria level when compared with those in CTX on 6-month treatment in therapy of patients with IMN.


Assuntos
Ciclofosfamida/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos
20.
Transplant Proc ; 51(7): 2495-2497, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351771

RESUMO

Posterior reversible encephalopathy syndrome (PRES) is a neuroradiologic syndrome. The etiology of PRES is still unclear. Some factors were described. We present a case of a pediatric patient with liver transplant who developed PRES following blood transfusion while receiving tacrolimus therapy. A 5½-year-old boy who underwent living donor liver transplantation, and PRES developed on the sixth day post transplant under tacrolimus treatment after 6 hours of red blood transfusion. PRES is a rare condition; it should be kept in mind about patients who have received organ transplants and develop sudden neurologic symptoms.


Assuntos
Transplante de Fígado/efeitos adversos , Síndrome da Leucoencefalopatia Posterior/etiologia , Transfusão de Sangue , Pré-Escolar , Humanos , Imunossupressores/uso terapêutico , Doadores Vivos , Masculino , Tacrolimo/uso terapêutico
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