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1.
Int J Nanomedicine ; 15: 7937-7949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116510

RESUMO

Background: Cyclosporine A (CsA) is an exceptional immunosuppressant used for the treatment of immune disorders. Niosomal vesicles are promising drug carriers that are formed by self-association of nonionic surfactants and cholesterol in an aqueous phase. The objective of the study was to formulate combined nonionic surfactant based vesicles and to evaluate their in vitro characterization, release studies and in vivo studies. Materials and Methods: Five niosomal formulations (F7 to F11) were prepared using the thin film hydration method. The molar ratio of cholesterol and non-ionic surfactant taken was 1:1. In formulation F10, the combination of surfactants Span 20 and Brij 35 was used. The niosomes were characterized by zeta sizer and SEM for particle size analysis, in vitro drug release and stability studies. The pharmacokinetic studies were conducted on healthy albino rabbits. Results: The size of niosome was found in the range of 427.1 nm to 972.3 nm. SEM image of optimized formulations F10 exhibit the spherical nature of niosomal vesicles. DSC thermograms of niosomal formulations exhibited a broadened endothermic peak. The stability study exhibited that all formulations are stable and negligible change of vesicle size and entrapment was observed with time. The percentage drug release was significantly higher as compared to CsA plain dispersion for all niosomal formulations at pH 1.2 and 7.4. The release kinetic behavior showed that all preparations were best described by zero order and can release active ingredient in a sustained manner. The pharmacokinetic data showed the test formulation (F10) possessed greater bioavailability as compared to the reference formulation (CsA aqueous dispersion). Conclusion: The formulation F10 demonstrated a comparatively more delayed rate of release with enhanced dissolution as compared to a single surfactant scheme. The F10 formulation can be a remarkable nanotechnology for prolonged delivery of CsA orally with improved dissolution profile and bioavailability.


Assuntos
Portadores de Fármacos/química , Imunossupressores/química , Imunossupressores/farmacologia , Tensoativos/química , Animais , Disponibilidade Biológica , Colesterol/química , Ciclosporina/administração & dosagem , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Liberação Controlada de Fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Lipossomos , Tamanho da Partícula , Coelhos
2.
Ann Hematol ; 99(8): 1727-1734, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32601798

RESUMO

Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) have been widely accepted as the standard first-line treatments for severe aplastic anemia (SAA). However, most of the patients with SAA had a slim chance to access these strategies in developing countries. Here, we reported 10-year results in a cohort of 232 patients with SAA who received a novel IST of CsA, levamisole, and danazol (CsA&LMS-based regimen). The cumulative incidence of response was 52.1% at 6 months, 66.4% at 12 months, and 77.1% at 24 months. The 10-year overall survival (OS) and failure-free survival was 60.2% and 48.3%, respectively. Positive predictors of OS in multivariate analysis were higher pretreatment ANC, younger age, higher pretreatment absolute reticulocyte count (ARC), and response within 6 months. The probability of CsA&LMS discontinuation was 50.2% at 10 years. With a slow CsA&LMS taper, the actuarial risk for relapse was only 9.5%. The cumulative incidence of MDS/AML was 8.2% at 10 years. The long-term follow-up information demonstrated that the CsA&LMS regimen could be a promising strategy for patients with SAA in developing countries.


Assuntos
Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Ciclosporina/administração & dosagem , Imunossupressão , Levamisol/administração & dosagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Países em Desenvolvimento , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de Sobrevida
4.
Inflamm Bowel Dis ; 26(7): 971-973, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32393973

RESUMO

First detected in Wuhan, China, the novel 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped RNA beta-coronavirus responsible for an unprecedented, worldwide pandemic caused by COVID-19. Optimal management of immunosuppression in inflammatory bowel disease (IBD) patients with COVID-19 infection currently is based on expert opinion, given the novelty of the infection and the corresponding lack of high-level evidence in patients with immune-mediated conditions. There are limited data regarding IBD patients with COVID-19 and no data regarding early pregnancy in the era of COVID-19. This article describes a patient with acute severe ulcerative colitis (UC) during her first trimester of pregnancy who also has COVID-19. The case presentation is followed by a review of the literature to date on COVID-19 in regard to inflammatory bowel disease and pregnancy, respectively.


Assuntos
Aborto Espontâneo , Colite Ulcerativa , Infecções por Coronavirus , Ciclosporina/administração & dosagem , Metilprednisolona/administração & dosagem , Pandemias , Pneumonia Viral , Complicações na Gravidez , Indução de Remissão/métodos , Adulto , Antivirais/administração & dosagem , Betacoronavirus/isolamento & purificação , Proteína C-Reativa/análise , Técnicas de Laboratório Clínico/métodos , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/fisiopatologia , Colite Ulcerativa/terapia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Imunossupressores/administração & dosagem , Gravidade do Paciente , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Gravidez , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/terapia , Sigmoidoscopia/métodos , Resultado do Tratamento
5.
Am J Transplant ; 20(7): 1864-1868, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277555

RESUMO

An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in Wuhan, China, with cases now confirmed in multiple countries. The clinical course of patients remains to be fully characterized, clinical presentation ranges from asymptomatic infection to acute respiratory distress syndrome and acute renal failure, and no pharmacological therapies of proven efficacy yet exist. We report a case of SARS-CoV-2 infection in a renal transplant recipient with excellent outcome. This case states the importance of close monitoring of the concentration of cyclosporine in patients treated with lopinavir/ritonavir; the routine treatment of corticosteroid can be continued. This is a rare report of SARS-CoV-2 infection in a renal transplant recipient. Further data are needed to achieve better understanding of the impact of immunosuppressive therapy on the clinical presentation, severity, and outcome of SARS-CoV-2 infections in solid organ transplant recipients.


Assuntos
Infecções por Coronavirus/complicações , Ciclosporina/sangue , Imunossupressão/efeitos adversos , Falência Renal Crônica/cirurgia , Transplante de Rim , Pneumonia Viral/complicações , Transplantados , Corticosteroides/administração & dosagem , Adulto , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Ciclosporina/administração & dosagem , Surtos de Doenças , Combinação de Medicamentos , Humanos , Imunossupressores/administração & dosagem , Falência Renal Crônica/complicações , Doadores Vivos , Lopinavir/administração & dosagem , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ritonavir/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
7.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32169870

RESUMO

BACKGROUND: The combination of the immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab is a mainstay of treatment for selected patients with metastatic melanoma. This combination also results in more frequent immune-related adverse events (irAEs) than either ICI alone. These irAEs can be severe and their pathogenesis is poorly understood. CASE PRESENTATION: We report a case of a woman with metastatic melanoma, treated with combined ipilimumab and nivolumab, who developed severe anaemia. While initial workup revealed autoimmune haemolytic anaemia, the anaemia persisted despite corticosteroids and paradoxical reticulocytopenia was observed. Bone marrow biopsy demonstrated a CD8+ T cell-mediated destruction of the red cell precursors implying concurrent pure red cell aplasia. Both processes resolved after the addition of cyclosporine A. CONCLUSIONS: This report describes a rare case of two concurrent mechanisms of haematological irAE in a patient treated with combined ICI therapy. Successful treatment resulted only after the second underlying mechanism of toxicity was uncovered. Prompt recognition of these unusual presentations of rare irAEs is now key to effective irAE management.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melanoma/tratamento farmacológico , Adulto , Anemia Hemolítica Autoimune/induzido quimicamente , Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/patologia , Antifúngicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclosporina/administração & dosagem , Feminino , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Melanoma/imunologia , Melanoma/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Prognóstico
8.
Transplant Proc ; 52(3): 843-849, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199645

RESUMO

BACKGROUND: Idiopathic focal segmental glomerulosclerosis (FSGS) commonly recurs in the early post-transplant period. The treatment protocols and results are conflictive in recurrent FSGS. We aimed to present the results of our treatment protocol and basic approach to the disease recurrences. METHODS: This prospective, single-center study was conducted between the years 2015 and 2018. Twelve patients who fit completely the diagnosis of idiopathic FSGS by clinical, laboratory, and biopsy findings were included. A specific treatment protocol which consists of plasma exchange and high dose intravenous cyclosporine was delivered to the patients independently of induction protocols. Twenty-four months of outcomes of graft functions were evaluated. RESULTS: Nine patients completed the treatment protocol and were documented for evaluation. All patients achieved a complete or partial remission in an average 24 months of follow-up period. CONCLUSION: Idiopathic FSGS is more commonly recurrent than thought to be. The early detection of proteinuria is crucial because the administration of a plasma exchange-based treatment protocol can reverse proteinuria. We think our treatment protocol is a well-established, efficient, and safe choice for post-transplant recurrent FSGS in adults.


Assuntos
Ciclosporina/administração & dosagem , Glomerulosclerose Segmentar e Focal/terapia , Transplante de Rim/efeitos adversos , Troca Plasmática/métodos , Complicações Pós-Operatórias/terapia , Administração Intravenosa , Adulto , Terapia Combinada , Feminino , Glomerulosclerose Segmentar e Focal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Proteinúria/etiologia , Recidiva , Resultado do Tratamento
9.
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
10.
Pediatr Hematol Oncol ; 37(3): 259-268, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32028812

RESUMO

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.


Assuntos
Ciclosporina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunomodulação , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Doadores de Tecidos , Quimeras de Transplante/sangue , Aloenxertos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Estudos Prospectivos , Recidiva
11.
Expert Opin Pharmacother ; 21(7): 761-771, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32100586

RESUMO

INTRODUCTION: The prevalence of atopic dermatitis (AD) in geriatric populations of industrialized countries is currently estimated at 3-4% and continues to increase. AD is associated with significant morbidity, increased susceptibility to infection, and symptoms of pruritus and pain. Treatments may negatively affect elderly patients; thus, plans should be optimized for this population. AREAS COVERED: This review summarizes treatment options for AD in the elderly. A systematic review of the literature was conducted using the key terms atopic dermatitis, elderly, geriatric, systemic therapy, therapy, and topical therapy in PubMed. Searches yielded articles on skincare management and topical and systemic pharmacotherapies. EXPERT OPINION: Proper use of moisturizer is crucial in all patients with AD. Topical corticosteroids are commonly prescribed; however, they carry an increased risk of adverse events such as skin atrophy. Systemic corticosteroids should be avoided in elderly patients due to questionable efficacy and increased adverse events. Topical calcineurin inhibitors and crisaborole are similarly efficacious with an excellent safety profile. Cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil are systemic agents available for the treatment of refractory AD; however, insufficient data exist to indicate the superiority of any one agent. Dupilumab is a safe and efficacious injectable therapy in elderly patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Inibidores de Calcineurina/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Humanos , Dor/prevenção & controle , Prurido/prevenção & controle , Resultado do Tratamento
12.
Adv Ther ; 37(3): 1260-1275, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31993943

RESUMO

BACKGROUND: A low level of evidence exists regarding the choice of calcineurin inhibitor (CNI) for immunosuppression after lung transplantation (LTx). Therefore, we designed a randomized clinical trial according to good clinical practice rules to compare tacrolimus with cyclosporine after LTx. METHODS: The ScanCLAD study is an investigator-initiated, pragmatic, controlled, randomized, open-label, multicenter study evaluating if an immunosuppressive protocol based on anti-thymocyte globulin (ATG) induction, once-daily tacrolimus dose, mycophenolate mofetil, and corticosteroid reduces the incidence of chronic lung allograft dysfunction (CLAD) after LTx, compared to a cyclosporine-based protocol with all other immunosuppressive and prophylactic drugs being identical between groups. All patients will be followed for 3 years to determine the main endpoint of CLAD. The study is designed for superiority, and power calculations show that 242 patients are needed. Also, the study is designed with more than 10 substudies addressing other important and unresolved issues in LTx. In addition, the ScanCLAD study enabled the synchronization of the treatment and follow-up protocols of the lung transplantation programs of all five Scandinavian lung transplantation centers. PLANNED OUTCOMES: Recruitment started in 2016. At the end of April 2019, 227 patients were randomized. We anticipate the last patient to be randomized in autumn 2019, and thus the last patient visits will be in 2022. The ScanCLAD study is enrolling and investigates which CNI is to be preferred from a CLAD perspective after LTx. TRIAL REGISTRY NUMBER: ScanCLAD trial registered at ClinicalTrials.gov before patient enrollment (NCT02936505). EUDRACT number 2015-004137-27.


Assuntos
Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Pulmão , Tacrolimo/administração & dosagem , Corticosteroides/administração & dosagem , Aloenxertos , Quimioterapia Combinada , Humanos , Incidência , Ácido Micofenólico/administração & dosagem , Projetos de Pesquisa
13.
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
14.
J Med Microbiol ; 69(6): 854-863, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31958048

RESUMO

Introduction. Management of steroid-refractory ulcerative colitis has predominantly involved treatment with systemic cyclosporine A (CyA) and infliximab.Aim. The purpose of this study was to assess the effect of using a colon-targeted delivery system CyA formulation on the composition and functionality of the gut microbiota.Methodology. Ex vivo faecal fermentations from six healthy control subjects were treated with coated minispheres (SmPill) with (+) or without (-) CyA and compared with a non-treated control in a model colon system. In addition, the in vivo effect of the SmPill+CyA formulation was investigated by analysing the gut microbiota in faecal samples collected before the administration of SmPill+CyA and after 7 consecutive days of administration from eight healthy subjects who participated in a pilot study.Results. Analysis of faecal samples by 16S rRNA gene sequencing indicated little variation in the diversity or relative abundance of the microbiota composition before or after treatment with SmPill minispheres with or without CyA ex vivo or with CyA in vivo. Short-chain fatty acid profiles were evaluated using gas chromatography, showing an increase in the concentration of n-butyrate (P=0.02) and acetate (P=0.32) in the faecal fermented samples incubated in the presence of SmPill minispheres with or without CyA. This indicated that increased acetate and butyrate production was attributed to a component of the coated minispheres rather than an effect of CyA on the microbiota. Butyrate and acetate levels also increased significantly (P=0.05 for both) in the faecal samples of healthy individuals following 7 days' treatment with SmPill+CyA in the pilot study.Conclusion. SmPill minispheres with or without CyA at the clinically relevant doses tested here have negligible direct effects on the gut microbiota composition. Butyrate and acetate production increased, however, in the presence of the beads in an ex vivo model system as well as in vivo in healthy subjects. Importantly, this study also demonstrates the relevance and value of using ex vivo colon models to predict the in vivo impact of colon-targeted drugs directly on the gut microbiota.


Assuntos
Ciclosporina/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Acetatos/metabolismo , Adulto , Butiratos/metabolismo , Colo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ácidos Graxos Voláteis/biossíntese , Fezes/química , Feminino , Humanos , Masculino , Microesferas , Pessoa de Meia-Idade , Projetos Piloto
15.
Transplantation ; 104(4): 744-753, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31929419

RESUMO

BACKGROUND: Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. METHODS: Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. RESULTS: Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45 cells, and reduced numbers of F4/80 macrophages, and CD3 T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. CONCLUSIONS: Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.


Assuntos
Glucocorticoides/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Transplante de Rim , Rim/efeitos dos fármacos , Nefrite/tratamento farmacológico , Prednisolona/administração & dosagem , Aloenxertos , Animais , Inibidores de Calcineurina/administração & dosagem , Ciclosporina/administração & dosagem , Modelos Animais de Doenças , Glucocorticoides/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Injeções Intravenosas , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lipossomos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nefrite/imunologia , Nefrite/metabolismo , Nefrite/patologia , Prednisolona/metabolismo , Distribuição Tecidual
16.
Ann Hematol ; 99(3): 443-449, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31970447

RESUMO

This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.


Assuntos
Ciclosporina/administração & dosagem , Imunossupressão , Aplasia Pura de Série Vermelha/tratamento farmacológico , Indução de Remissão , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/imunologia , Aplasia Pura de Série Vermelha/patologia
17.
Xenobiotica ; 50(4): 435-441, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31382792

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is induced by various triggers, including genetic factors, infections, autoimmune diseases, lymphoma or other malignancies. Cyclosporin is one of the clinical treatments for HLH. However, cyclosporin has considerable inter- and intra-individual variabilities in pharmacokinetics and also displays a narrow therapeutic window, making it difficult to define an optimal dose for HLH treatment. This study is aimed to establish cyclosporin population pharmacokinetic (PPK) model of pediatric HLH patients and formulate an initial dose regimen for personalized medicine.Pediatric HLH patients between June 2014 and March 2019 from Children's Hospital of Fudan University were analyzed using NONMEM. Dose recommended was investigated using Monte Carlo simulations.The final cyclosporin PPK model was: CL/F = 91×(WT/70)0.75×(1+ Piperacillin-Tazobactam × Î¸P-T); V/F = 4250×(WT/70), where WT, and θP-T were weight, and the coefficient of the Piperacillin-Tazobactam, respectively. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the first cyclosporin PPK model in pediatric HLH patients was established and the model could be used to predict individualized initial dosing regimens in children with HLH.


Assuntos
Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Linfo-Histiocitose Hemofagocítica/metabolismo , Adolescente , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Masculino
18.
Am J Ophthalmol ; 212: 116-126, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31770513

RESUMO

PURPOSE: To assess the safety and efficacy of cyclosporine A cationic emulsion (CsA CE) 0.1% eye drops in pediatric patients with severe active vernal keratoconjunctivitis (VKC). DESIGN: Multicenter, double-masked, randomized controlled trial 8-month safety analysis. METHODS: Of 169 patients (age range, 4-17 years) initially randomized in the 4-month VErnal KeratoconjunctiviTIs Study (VEKTIS), 142 entered the 8-month follow-up period during which CsA CE patients remained on their original regimen (CsA CE 4 times daily [QID, high-dose] or CsA CE twice daily [BID, low-dose] + vehicle BID) and vehicle patients were allocated to one of these 2 active regimens. Main outcome measures were safety, including treatment-emergent adverse events, and efficacy, including corneal fluorescein staining (CFS) score. RESULTS: Improvements in CFS score, rescue medication use, key VKC symptoms (photophobia, tearing, itching, and mucous discharge), and quality of life (QoL) assessed by QUICK questionnaire observed with CsA CE compared with vehicle during the 4-month evaluation period remained stable during the 8-month follow-up period, with the high-dose regimen continuing to provide greater benefits in most efficacy measures. CsA CE was well tolerated. Treatment-related treatment-emergent adverse events during the 12-month study were reported in 15 (20.8%) and 11 (15.7%) of the CsA CE high-dose and low-dose patients, respectively, most commonly instillation site pain (13.9% and 7.1%, respectively). Laboratory data, vital signs, slit lamp examination, best-corrected distance visual acuity, and intraocular pressure raised no safety concerns. CONCLUSIONS: Improvements in keratitis, symptoms, and QoL achieved after CsA CE treatment for 4 months remained stable over the 8-month follow-up period. CsA continued to maintain a favorable safety profile.


Assuntos
Conjuntivite Alérgica/tratamento farmacológico , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Pré-Escolar , Ciclosporina/efeitos adversos , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Imunossupressores/efeitos adversos , Ceratite/tratamento farmacológico , Masculino , Segurança do Paciente , Resultado do Tratamento
19.
Ocul Immunol Inflamm ; 28(3): 370-378, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986119

RESUMO

Purpose: To evaluate the efficacy and safety of a novel topical cyclosporin A 0.05% nanoemulsion in comparison with a conventional emulsion in primary Sjögren's syndrome dry eyes.Methods: Prospective, randomized, double-blinded study was conducted.Results: Corneal and conjunctival staining score was improved in both groups, with a faster change noted in the nanoemulsion group at 12 weeks (p < 0.05). Tear film break-up time was significantly improved in the nanoemulsion group at 12 weeks (p < 0.05), while ocular surface disease index score was improved in both groups without a difference at 12 weeks. Schirmer I value and goblet cell grade did not change in both groups. IL-6 and MMP-9 were significantly decreased in both groups at 12 weeks.Conclusions: Both nanoemulsion and conventional cyclosporin A improved ocular signs, symptoms, and conjunctival inflammation. However, the novel cyclosporin A nanoemulsion showed faster improvement of ocular surface staining scores than the conventional emulsion.


Assuntos
Ciclosporina/administração & dosagem , Síndromes do Olho Seco/tratamento farmacológico , Síndrome de Sjogren/complicações , Administração Tópica , Contagem de Células , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Síndromes do Olho Seco/diagnóstico , Síndromes do Olho Seco/etiologia , Emulsões , Feminino , Seguimentos , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Pessoa de Meia-Idade , Nanopartículas , Estudos Prospectivos , Síndrome de Sjogren/diagnóstico , Resultado do Tratamento
20.
Ann Rheum Dis ; 79(1): 3-18, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672775

RESUMO

The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.


Assuntos
Antirreumáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Lubrificantes Oftálmicos/uso terapêutico , Agonistas Muscarínicos/uso terapêutico , Saliva Artificial/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Administração Oftálmica , Corticosteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Ciclosporina/administração & dosagem , Humanos , Hidroxicloroquina/uso terapêutico
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