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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808965

RESUMO

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.


Assuntos
Endométrio/efeitos dos fármacos , Infertilidade Feminina/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Tacrolimo/uso terapêutico , Relação Dose-Resposta a Droga , Endométrio/anormalidades , Endométrio/patologia , Feminino , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Resistência à Insulina/genética , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Gravidez , Doenças Uterinas/genética
2.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800389

RESUMO

Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/imunologia , Linfócitos T/imunologia , Tacrolimo/uso terapêutico , Animais , Humanos , Isoformas de Proteínas
3.
Braz J Med Biol Res ; 54(4): e9369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681893

RESUMO

Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.


Assuntos
Transplante de Rim , Tacrolimo , Quimioterapia Combinada , Everolimo/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico
4.
Medicine (Baltimore) ; 100(9): e24989, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655969

RESUMO

RATIONALE: Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare. PATIENT CONCERNS: A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity. DIAGNOSIS: The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established. INTERVENTION: At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards. OUTCOMES: Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased. LESSONS: Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.


Assuntos
Epilepsia/induzido quimicamente , Glomerulonefrite Membranosa/tratamento farmacológico , Tacrolimo/efeitos adversos , Eletroencefalografia , Epilepsia/diagnóstico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tacrolimo/uso terapêutico
5.
Ann Hematol ; 100(4): 969-978, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33594448

RESUMO

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.


Assuntos
Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Idoso , Aloenxertos , Bussulfano/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Infecções/epidemiologia , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Agonistas Mieloablativos/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Linfócitos T , Tacrolimo/uso terapêutico , Resultado do Tratamento , Doadores não Relacionados , Vidarabina/efeitos adversos , Vidarabina/uso terapêutico , Irradiação Corporal Total
6.
Yonsei Med J ; 62(3): 274-277, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33635018

RESUMO

Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.


Assuntos
Infecções por Citomegalovirus/virologia , Citomegalovirus/fisiologia , Transplante de Rim/efeitos adversos , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/virologia , Adulto , Antivirais/uso terapêutico , Biópsia , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Tacrolimo/uso terapêutico , Tomografia Computadorizada por Raios X
7.
N Engl J Med ; 384(1): 11-19, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406328

RESUMO

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fosfato de Sitagliptina/uso terapêutico , Adulto , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Sirolimo/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos , Análise de Sobrevida , Tacrolimo/uso terapêutico , Transplante Homólogo , Adulto Jovem
8.
Ann Hematol ; 100(4): 933-939, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33420879

RESUMO

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.


Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Imunossupressores/uso terapêutico , Pirazóis/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Soro Antilinfocitário/uso terapêutico , Benzoatos/efeitos adversos , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Erupção por Droga/etiologia , Feminino , Hipertrofia Gengival/induzido quimicamente , Hirsutismo/induzido quimicamente , Humanos , Hidrazinas/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Estudos Retrospectivos , Tacrolimo/efeitos adversos
10.
Med Oral Patol Oral Cir Bucal ; 26(3): e357-e360, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340078

RESUMO

BACKGROUND: Exfoliative and erosive cheilitis, may be a source of speech and chewing discomfort, but may also be an aesthetic issue for the patients affected. Such a clinical presentation may implicate a variety of inflammatory conditions, including atopic (eczematous) cheilitis. Topical and systemic agents, e.g. corticosteroids, have been used to treat inflammatory lip conditions. Topical tacrolimus has also been used in some inflammatory lip conditions. MATERIAL AND METHODS: We performed a retrospective clinical analysis of atopic cheilitis patients. RESULTS: Between 2015 and 2020, we addressed 7 (seven) patients with atopic dermatitis affecting only lips and were diagnosed as atopic-eczematous cheilitis. They were treated with 0.03 per cent topical tacrolimus ointment and responded completely. CONCLUSIONS: These cases represent an underreported atopy / eczema event;-few cases of atopic cheilitis without concomitant dermal lesions appear in the literature. We are also showing and discussing yet another application of tacrolimus in a local atopic form of inflammation affecting the lips.


Assuntos
Queilite , Tacrolimo , Administração Tópica , Queilite/tratamento farmacológico , Estética Dentária , Humanos , Imunossupressores , Lábio , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Resultado do Tratamento
11.
Rev Gastroenterol Mex ; 85(4): 437-442, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33032841

RESUMO

Coronavirus disease 2019 (COVID-19) is a serious respiratory illness caused by SARS-CoV-2. There is controversy about whether their immunosuppressive status is a risk factor or a protective factor for developing severe disease. We report herein the clinical outcome of three family members that had COVID-19 infection, presenting with and without different risk factors that have been described in more severe disease. Paradoxically, the patient with more risks of developing a severe disease, a 64-year-old woman, 2-years liver transplant recipient under treatment with tacrolimus, presented a similar outcome compared to the two other members of the family. She showed shorter hospitalization time, similar clinical outcome with fewer oxygen needs. The present clinical observation raises the question about the possible beneficial effect of tacrolimus in patients with COVID-19. Indeed, tacrolimus (FK-506) have an inhibitory effect on human coronaviruses by: 1) an antiviral effect by binding to the FK-506-binding proteins (FKBP) with a subsequent inhibition of their peptidyl-prolyl cis/trans isomerase (PPIase) activity, which seems to be important for the coronavirus life cycle; and 2) regulating the immune response by the inhibition of the activity of the nuclear factor of activated T-cells (NFAT) required for immunosuppression. The present observation states that liver recipients' patients with COVID-19 may not have worse outcomes when compared with other patients that have COVID-19 risk factors and puts in evidence the two mechanisms related to tacrolimus.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Imunossupressores/uso terapêutico , Transplante de Fígado , Pneumonia Viral/terapia , Complicações Pós-Operatórias/terapia , Tacrolimo/uso terapêutico , Adulto , Betacoronavirus/isolamento & purificação , Terapia Combinada , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Prognóstico , Índice de Gravidade de Doença
12.
Niger J Clin Pract ; 23(10): 1387-1394, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33047695

RESUMO

Background: Chronic kidney disease (CKD) is a common late complication in liver-transplanted patients who have received long-term therapy with calcineurin inhibitors (CNIs). Aims: To analyze kidney disease progression after liver transplantation. Methods: We analysed the clinical data of adult single-organ liver transplant recipients performed at our centre between October 2003 and September 2009. The patients with the estimated glomerular filtration rate (eGFR) greater than 60 ml/min/1.73 m2 before surgery were included in the study. Results: 69 patients with complete follow-up data were analysed. We found that eGFR at 1 or 2 years after liver transplantation correlated well with eGFR at 5 years. In addition, our results showed that patients whose eGFR declined below 60 at 2 years after liver transplantation would develop an irreversible renal injury in the following years. At 2 years, 12 patients had an eGFR less than 60, which were maintained in 11 patients at 5 years (Sensitivity = 11/12, 91.67%; Specificity = 57/58, 98.28%, Youden's index = 89.95%). The annual rate of eGFR reduction of the tacrolimus group was greater than that of the tacrolimus sparing group based on the value-time variation curve in our study. Moreover, the tacrolimus concentration influenced the CKD progression at 1 and 2 years with an under the ROC curve of 0.73 and 0.78 when Youden's index was at its maximum and the tacrolimus concentrations were 8.55 and 5.96 ng/ml, respectively. Conclusion: We confirmed that eGFR at 2 years after liver transplantation is useful for observing a meaningful change in eGFR and renal damage. Obtaining the appropriate serum concentration of an early decrease of the dose of CNIs and transforming non-nephrotoxic immunosuppressants would help improve renal function to prevent CKD progression and end-stage renal disease (ESRD).


Assuntos
Inibidores de Calcineurina/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Transplante de Fígado/efeitos adversos , Insuficiência Renal Crônica/complicações , Tacrolimo/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Inibidores de Calcineurina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Fatores de Risco
13.
Gastroenterol. hepatol. (Ed. impr.) ; 43(8): 457-463, oct. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-196902

RESUMO

La infección por el virus SARS-CoV-2 ha producido una pandemia con graves consecuencias sobre nuestro sistema sanitario. Aunque el colectivo de pacientes trasplantados hepáticos representa solo una minoría de la población, los hepatólogos que seguimos a estos pacientes hemos intentado coordinar esfuerzos para protocolizar el manejo de la inmunosupresión durante la infección por SARS-CoV-2. Aunque no hay estudios sólidos que avalen recomendaciones generales, las experiencias con otras infecciones víricas (hepatitis C, citomegalovirus) sugieren que el manejo de la inmunosupresión sin micofenolato mofetilo ni inhibidores m-Tor (fármacos que además se asocian a leucopenia y linfopenia) puede resultar beneficiosa. Es importante además prestar atención a las posibles interacciones farmacológicas, especialmente en el caso de tacrolimus, con algunos de los tratamientos con efecto antiviral que se administran en el contexto de la covid-19 (lopinavir/ritonavir, azitromicina). Finalmente, deberá tenerse en cuenta el efecto inmunosupresor de fármacos inmunomoduladores (tocilizumab y similares) que se administran en pacientes con enfermedad pulmonar severa. En el artículo se revisan los mecanismos de actuación de los diferentes fármacos inmunosupresores, su potencial efecto sobre la infección por SARS-CoV-2 y se sugieren unas pautas en el manejo de la inmunosupresión


SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression


Assuntos
Humanos , Imunossupressão/métodos , Transplante de Fígado/métodos , Infecções por Coronavirus/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Leucopenia/complicações , Linfopenia/complicações , Tacrolimo/uso terapêutico , Fatores Imunológicos/uso terapêutico , Glucocorticoides/antagonistas & inibidores , Inibidores de Calcineurina/uso terapêutico , Serina-Treonina Quinases TOR/uso terapêutico
14.
Eur J Drug Metab Pharmacokinet ; 45(6): 749-760, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32886348

RESUMO

BACKGROUND AND OBJECTIVE: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Feminino , Genótipo , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Retrospectivos , Tacrolimo/administração & dosagem
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 964-969, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933627

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus in the treatment of children with myasthenia gravis (MG). METHODS: A total of 28 children with MG were treated with tacrolimus. MG-Activities of Daily Living (MG-ADL) scale was used to assess clinical outcome and safety after 1, 3, 6, 9, and 12 months of treatment. RESULTS: After tacrolimus treatment, the MG-ADL score at 1, 3, 6, 9 and 12 months was lower than that at baseline (P<0.05), and the MG-ADL score showed a gradually decreasing trend. The response rates to tacrolimus treatment at 1, 3, 6, 9, and 12 months were 59%, 81%, 84%, 88%, and 88% respectively. At 6, 9, 12, and 18 months of treatment, 4, 13, 14, and 15 children respectively were withdrawn from prednisone. No recurrence was observed during treatment. Major adverse reactions/events were asymptomatic reduction in blood magnesium in 5 children and positive urine occult blood in 1 child, which turned negative without special treatment, and tacrolimus was not stopped due to such adverse reactions/events. One child was withdrawn from tacrolimus due to recurrent vomiting. According to CYP3A5 genotypes, all of the patients were divided into two groups: slow metabolic type (n=19) and non-slow metabolic type (fast metabolic type + intermediate type; n=9). The non-slow metabolism group received a higher dose of tacrolimus, but had a lower trough concentration of tacrolimus than the slow metabolism group (P<0.05). The slow metabolism group had a higher response rates to tacrolimus treatment than the non-slow metabolism group (P<0.05). CONCLUSIONS: Tacrolimus appears to be effective and safe in the treatment of children with MG and is thus an option for immunosuppressive therapy. CYP3A5 genotyping has a certain guiding significance for determining the dosage of tacrolimus.


Assuntos
Miastenia Gravis , Tacrolimo/uso terapêutico , Atividades Cotidianas , Criança , Humanos , Imunossupressores , Miastenia Gravis/tratamento farmacológico , Recidiva Local de Neoplasia
16.
Medicine (Baltimore) ; 99(37): e22159, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925777

RESUMO

BACKGROUND: Long-term use of corticosteroid ointment for external using or skin management products and cosmetics containing corticosteroid will produce a hormone-dependent effect on facial skin and destroy the barrier function of the skin. It is easy to cause repeated attacks of facial skin inflammation after drug withdrawal because corticosteroid hormones can cause the expression of inflammatory factors in the body, which has a serious impact on patients. The general treatment method is to stop using hormone drugs for psychotherapy and inform patients of the basic knowledge of hormone-dependent dermatitis and daily facial care, but the effect is not good. At present, non-steroidal ointment tacrolimus (a calcineurin inhibitor) is widely used in the treatment of hormone-dependent dermatitis. Tacrolimus ointment is effective for corticosteroid-dependent dermatitis, but adverse events can also occur. METHODS: We plan to searched all randomized controlled trials (RCTs) fortacrolimus ointment therapy of hormone-dependent dermatitis in: MEDLINE, PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Springer and Web of Science, China Biomedical Literature Database (CBM), China Science Journal Database (VIP database) and Wanfang Database, China National Knowledge Infrastructure (CNKI), without the limitation of publication status and language until September 1, 2020. The systematic review will also search will also search for identify publications, meeting minutes, and grey literature (including unpublished meeting articles). DISCUSSION: The systematic review mainly to access the safety and efficacy of tacrolimus ointment for hormone-dependent dermatitis (facial corticosteroid addiction dermatitis and facial steroid dermatitis). The results of our research will facilitate evidence-based management of patients with facial corticosteroid-dependent dermatitis and provide clinical advice on their treatment options. REGISTRATION: PROSPERO CRD42020171813.


Assuntos
Corticosteroides/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Erupção por Droga/tratamento farmacológico , Erupção por Droga/etiologia , Tacrolimo/uso terapêutico , Administração Cutânea , Corticosteroides/administração & dosagem , Inibidores de Calcineurina/administração & dosagem , Humanos , Pomadas , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Tacrolimo/administração & dosagem
17.
Medicine (Baltimore) ; 99(35): e21844, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871907

RESUMO

RATIONALE: The heart transplantation is the most important treatment for patients with end-stage severe heart disease who failed to conventional therapy. Post-transplant lymphoproliferative disorder is the second most common malignancy in heart transplant recipients. However, primary central nervous system lymphoma (PCNSL) after heart transplantation is an extremely rare condition. PATIENTS CONCERNS: This report described a 53-year-old male who was diagnosed as PCNSL 17 months after heart transplantation. DIAGNOSES: The patient was admitted to the local hospital presenting with dizziness, headache, and reduced left-sided power and sensation for 1 week. He had a medical history of heart transplantation because of the dilated cardiomyopathy 17 months ago and had a 17-month history of immunosuppressive therapy with tacrolimus. A computed tomography scan of the brain revealed a bulky mass in the right temporal lobe. The emergency intracranial mass resection and cerebral decompression were performed in our hospital. The histopathology of the brain lesions showed diffuse large B-cell lymphoma. A further FDG positron emission tomography-computed tomography scan of the whole body showed no significantly increased metabolic activity in other regions. The final diagnosis of this patient was PCNSL after heart transplantation. INTERVENTIONS: Given the poor health condition, with the patient's consent, the whole brain radiotherapy was performed with supportive care. OUTCOMES: The disease deteriorated rapidly during the period of receiving radiotherapy, and he died within 2 months from the diagnosis. LESSONS: PCNSL after heart transplantation is an extremely rare phenomenon with extremely poor prognosis. We should pay close attention to the heart recipients, especially when the patients present with neurological symptoms and signs. The available treatment options for PCNS-post-transplant lymphoproliferative disorder include the reduction of immunosuppressive drugs, immune-chemotherapy, operation, radiotherapy. However, individual treatments for heart transplant recipients with PCNSL should be based on the performance status and tolerance to treatment, combined with the doctor's experience and supportive care.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Transplante de Coração , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tacrolimo/uso terapêutico , Tomografia Computadorizada por Raios X
18.
Brasília; s.n; 11 ago. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117979

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Avaliação da Tecnologia Biomédica , Ácido Ursodesoxicólico/uso terapêutico , Imunoglobulinas/uso terapêutico , Prednisolona/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Cloroquina/uso terapêutico , Estudos Transversais , Estudos de Coortes , Interferon-alfa/uso terapêutico , Tacrolimo/uso terapêutico , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Células-Tronco Mesenquimais , Lopinavir/uso terapêutico , Ácido Fólico/uso terapêutico , Meropeném/uso terapêutico , Hidroxicloroquina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ácido Micofenólico/uso terapêutico
19.
Medicine (Baltimore) ; 99(27): e21056, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629733

RESUMO

Primary nephrotic syndrome (PNS) is one of the most common primary glomerular diseases in children. Patients complicated nephrotic syndrome with pancreatic lesions are rarely reported, and the clinical manifestations in children are atypical. This study has observed the incidence, clinical types, and prognosis of acute pancreatitis (AP) in children with primary nephrotic syndrome, and analyzed its related factors, early diagnosis, and treatment.Seven children with PNS and AP in Shanghai Children's Hospital from January 2015 to December 2017 were reviewed. The clinical data including age, height, weight, body mass index (BMI), diet, biliary tract disease, PNS durations, drugs, proteinuria, creatinine, glucose, glycated hemoglobin, amylase and lipase, albumin, cholesterol, triglyceride, ultrasound, computerized tomography (CT), renal pathology and estimated glomerular filtration rate (eGFR) were retrospectively analyzed. All patients were followed for >2 years.Ten in 589 patients with PNS were detected pancreatic lesions by abdominal ultrasound. Seven were diagnosed as AP, which the incidence was 1.2%. Only 1 of 7 patients had elevated serum amylase. Lesions of pancreas were found by ultrasound and/or enhanced CT. Four of 7 patients had been treated with tacrolimus. All patients with AP were improved after octreotide acetate injection and supportive treatment. Only 1 patient suffered recurrent AP during the relapse of PNS 10 months later.AP in children with PNS is not common, and the clinical manifestations are not typical. Abdominal ultrasound and enhanced CT are of high value in diagnosis. The adverse effects of tacrolimus should be concerned. Early diagnosis and timely treatment can be helpful for a prognosis.


Assuntos
Rim/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/metabolismo , Pancreatite/metabolismo , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Masculino , Síndrome Nefrótica/diagnóstico por imagem , Síndrome Nefrótica/fisiopatologia , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Pancreatite/diagnóstico por imagem , Pancreatite/tratamento farmacológico , Pancreatite/epidemiologia , Prognóstico , Recidiva , Estudos Retrospectivos , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico
20.
Ann Hematol ; 99(10): 2315-2322, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32728937

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by lower platelet count resulting from immune cells-mediated platelet clearance. Tacrolimus is an immunosuppressive agent which selectively inhibits T cell activation. Whether tacrolimus plays a role in ITP remains unclear. This study aimed to investigate the effect of tacrolimus on ITP in mice. An ITP mouse model was established by injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin and treated with tacrolimus followed by isolation of peripheral blood mononuclear cells and plasma. The mRNA expression of T-bet, GATA3, and Foxp3 was measured by RT-PCR, and level of IFN-γ, IL-12p70, IL-4, IL-13, and TGF-ß in plasma was measured by ELISA. Tacrolimus inhibited antiplatelet antibody-mediated platelet clearance in ITP mouse model. Meanwhile, tacrolimus-treated ITP mice displayed a significant decrease in the mRNA expression of T-bet and plasma level of IFN-γ and IL-12p70 compared with ITP mice but without differences when compared with normal mice. Furthermore, the expression of GATA3, Foxp3, and plasma level of IL-4 and TGF-ß were upregulated in tacrolimus-treated ITP mice without significant differences to normal mice (except TGF-ß). Tacrolimus prevents antiplatelet antibody-mediated thrombocytopenia in ITP mice possibly through regulating T cell differentiations, suggesting it might be a novel approach for preventing ITP.


Assuntos
Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Tacrolimo/uso terapêutico , Animais , Plaquetas/imunologia , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoanticorpos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Organismos Livres de Patógenos Específicos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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