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1.
Acta Ophthalmol ; 100(7): e1463-e1469, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35638110

RESUMO

PURPOSE: To investigate potential risk factors, particularly antimetabolite choice, with regard to the development of adverse bleb morphology in eyes that had undergone trabeculectomy surgery. METHODS: A single-centre, observational cohort study of 631 consecutive eyes, which had undergone trabeculectomy over an 11-year period. For each case, bleb morphology was recorded at 2 years, and its association with the per-operative antimetabolite as well as potential confounding risk factors was analysed using univariate (unadjusted) and multivariate (adjusted) logistical regression analyses to identify those that could contribute to the development of adverse blebs. A standard protocol for 5-fluorouracil and mitomycin-C utilization was employed in the majority of cases. RESULTS: When 5-fluorouracil was used (n = 257), 24% of patients formed cystic or partially cystic blebs, whereas with mitomycin-C (n = 299), only 12% formed such adverse blebs, the difference being statistically significant (OR = 3.54, p = 0.002 unadjusted; OR = 7.49, p = 0.00 adjusted). Of the other potential confounding factors, care within the private sector (OR = 0.30 p = 0.02) and a history of previous ocular surgery involving a conjunctival incision were identified as potential risk factors for the formation of adverse cystic blebs (OR = 0.28, p = 0.02). CONCLUSIONS: Modern use of mitomycin-C appeared to be better than 5-fluorouracil as an adjunctive antimetabolite used at the time of trabeculectomy, with respect to the development of preferable final bleb morphology. The only potential preoperative risk factors found to be significant with respect to adverse cystic bleb development were care in the private health sector and previous ocular surgery involving a conjunctival incision.


Assuntos
Glaucoma , Trabeculectomia , Humanos , Antimetabólitos/efeitos adversos , Túnica Conjuntiva/cirurgia , Análise Fatorial , Fluoruracila , Glaucoma/etiologia , Glaucoma/cirurgia , Pressão Intraocular , Mitomicina , Fator Regulador X1 , Fatores de Risco , Trabeculectomia/efeitos adversos , Trabeculectomia/métodos
2.
Dig Dis Sci ; 67(1): 241-251, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532972

RESUMO

BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.


Assuntos
Azatioprina , Colite Ulcerativa , Doença de Crohn , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Mercaptopurina/análogos & derivados , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Antimetabólitos/farmacocinética , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/farmacocinética , Biomarcadores Farmacológicos/sangue , Criança , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Substituição de Medicamentos/métodos , Substituição de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Mercaptopurina/farmacocinética , Países Baixos/epidemiologia , Estudos Retrospectivos , Tionucleotídeos/sangue
3.
Rev. cuba. oftalmol ; 34(4)dic. 2021.
Artigo em Espanhol | CUMED, LILACS | ID: biblio-1409013

RESUMO

La retinopatía por descompresión es una complicación infrecuente de la cirugía ocular. Aunque después de una trabeculectomía con o sin antimetabolitos se ha reportado la mayoría de los casos, también se ha comunicado en otros procederes oculares. La presión intraocular preoperatoria elevada y sus bruscas variaciones intra- y posoperatorias juegan un rol en su fisiopatología. Las hemorragias retinales son su signo distintivo y la oclusión de la vena central de la retina su diagnóstico diferencial más complejo. En la mayoría de los pacientes se resuelve el cuadro clínico en las primeras ocho semanas sin necesidad de intervención terapéutica. Para minimizar su riesgo, se recomienda una reducción gradual y controlada de la presión intraocular pre- e intraoperatoria. Para la actualización del conocimiento sobre retinopatía por descompresión se realizó una revisión de las publicaciones más relevantes relacionadas con el tema durante los últimos años, con el objetivo de profundizar y mejorar el entendimiento sobre retinopatía por descompresión(AU)


Decompression retinopathy is an infrequent complication of ocular surgery. Most cases have been reported after trabeculectomy with or without antimetabolites, but it has also been described in other ocular procedures. High preoperative intraocular pressure and its sudden intra- and postoperative variations play a role in its physiopathology. Retinal hemorrhage is its distinguishing sign, and central retinal vein occlusion its most complex differential diagnosis. In most patients the clinical picture is resolved within the first eight weeks without any therapeutic intervention. A gradual, controlled reduction in pre- and intraoperative intraocular pressure is recommended to minimize risk. With the purpose of updating knowledge about decompression retinopathy, a review was conducted of the most relevant studies about the topic published in recent years(AU)


Assuntos
Humanos , Hemorragia Retiniana , Trabeculectomia/métodos , Diagnóstico Diferencial , Antimetabólitos/efeitos adversos , Literatura de Revisão como Assunto , Pressão Intraocular
4.
Br J Haematol ; 195(3): 378-387, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34340254

RESUMO

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos/efeitos adversos , Antimetabólitos/farmacologia , Artralgia/induzido quimicamente , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Constipação Intestinal/induzido quimicamente , Metilação de DNA/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Risco
5.
Rev Neurol ; 73(5): 174-183, 2021 Sep 01.
Artigo em Espanhol | MEDLINE | ID: mdl-34328206

RESUMO

INTRODUCTION: Neurological complications are some of the most important complications that can occur in a patient undergoing haematopoietic stem cell transplantation (HSCT), not only because of the high mortality rate, but also because of the sequelae that appear in survivors. The causes of such complications are manifold and very often coexist in the same patient: toxicity of the conditioning regimen, graft-versus-host disease and its treatment, infections and their treatment, platelets and coagulation disorders, liver failure or arterial hypertension with low platelet count. AIMS: The aim of the present study is to provide a clinical description and to describe the risk factors for complications involving the central nervous system that may occur during the course of HSCT, in order to assist in the early detection of these disorders that may have a negative influence on the morbidity and mortality of these patients. DEVELOPMENT: The following types of neurological complications are described: central nervous system infections, vascular complications, pharmacological toxicity, metabolic complications, immune-mediated disorders and post-HSCT carcinogenesis, and effects of graft-versus-host disease and thrombotic microangiopathy on the nervous system. CONCLUSIONS: The patient undergoing HSCT is at particular risk for the development of neurological complications. Early diagnosis and treatment are needed to try to reduce the high morbidity and mortality in these patients.


TITLE: Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.Introducción. Las complicaciones neurológicas son algunas de las más importantes que se pueden presentar en un paciente sometido a un trasplante de progenitores hematopoyéticos (TPH), no sólo porque conllevan una mortalidad elevada, sino también por las secuelas que aparecen en los supervivientes. Las causas de dichas complicaciones son múltiples y, muy frecuentemente, coexisten en el mismo paciente: toxicidad del régimen de acondicionamiento, enfermedad del injerto contra el hospedador y su tratamiento, infecciones y su tratamiento, plaquetopenia y trastornos de la coagulación, fallo hepático o hipertensión arterial con plaquetopenia. Objetivos. El objetivo del presente estudio es el de aportar una descripción clínica y de los factores de riesgo de las complicaciones sobre el sistema nervioso central que pueden presentarse en el curso de un TPH, para ayudar en la detección precoz de estos trastornos que pueden influir negativamente en la morbimortalidad de estos pacientes. Desarrollo. Se describen los siguientes tipos de complicaciones neurológicas: infecciones sobre el sistema nervioso central, complicaciones vasculares, toxicidad farmacológica, complicaciones metabólicas, trastornos inmunomediados y carcinogenia pos-TPH, y efectos de la enfermedad del injerto contra el hospedador y de la microangiopatía trombótica sobre el sistema nervioso. Conclusiones. El paciente sometido a TPH es de especial riesgo para el desarrollo de complicaciones neurológicas. Se precisan un diagnóstico y un tratamiento precoces para intentar disminuir la elevada morbimortalidad de estos pacientes.


Assuntos
Doenças do Sistema Nervoso Central/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Antibacterianos/efeitos adversos , Antimetabólitos/efeitos adversos , Encefalopatias Metabólicas/etiologia , Neoplasias Encefálicas/etiologia , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/epidemiologia , Infecções do Sistema Nervoso Central/diagnóstico por imagem , Infecções do Sistema Nervoso Central/epidemiologia , Infecções do Sistema Nervoso Central/etiologia , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Criança , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressores/efeitos adversos , Agonistas Mieloablativos/efeitos adversos , Neoplasias Induzidas por Radiação/etiologia , Neuroimagem , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/etiologia , Fatores de Risco , Microangiopatias Trombóticas/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Irradiação Corporal Total/efeitos adversos
6.
J Crohns Colitis ; 15(1): 88-98, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32687146

RESUMO

BACKGROUND AND AIMS: The microbial ecosystem seems to be an important player for therapeutic intervenption in inflammatory bowel disease [IBD]. We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine [AZA] or anti-tumour necrosis factor [anti-TNF] antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome. METHODS: Faecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as Crohn's Disease Activity Index [CDAI] < 150 in Crohn´s disease [CD], partial Mayo score <2 in ulcerative colitis [UC], and faecal calprotectin values <150 µg/g and C-reactive protein <5 mg/dl. 16S rRNA amplicon sequencing was performed. To predict microbial community metabolic processes, we constructed multispecies genome-scale metabolic network models. RESULTS: Paired Bray-Curtis distance between baseline and follow-up time points was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared with patients without remission [p = 0.041]. In this model, the difference in butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA [p = 0.008]. CONCLUSIONS: In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD.


Assuntos
Azatioprina , Vias Biossintéticas , Butiratos/metabolismo , Colite Ulcerativa , Doença de Crohn , Microbioma Gastrointestinal , Inibidores do Fator de Necrose Tumoral , Adulto , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Bacteroidetes/isolamento & purificação , Bacteroidetes/metabolismo , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Simulação por Computador , Correlação de Dados , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteobactérias/isolamento & purificação , Proteobactérias/metabolismo , Indução de Remissão , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/efeitos adversos
7.
Dig Dis Sci ; 66(9): 3124-3131, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32920717

RESUMO

BACKGROUND: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. METHODS: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. RESULTS: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). CONCLUSION: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD.


Assuntos
Azatioprina , Doença de Crohn , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infliximab , Mercaptopurina , Adulto , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Monitoramento de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Japão/epidemiologia , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
8.
J Oncol Pharm Pract ; 27(3): 588-595, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32484382

RESUMO

INTRODUCTION: Delayed methotrexate clearance in several patients admitted to the oncology unit at a regional medical center necessitated the development of a pharmacist-driven protocol for supportive therapy with high-dose methotrexate. This performance improvement project evaluated the impact of the protocol on inpatient length of stay, patient safety, and clinical outcomes. METHODS: Retrospective data were collected over 14 months pre-implementation and prospective data were collected over 19 months post-implementation. Primary outcomes included mean length of stay and incidence of kidney injury. Secondary outcomes included myelosuppression, treatment delays, mucositis, protocol adherence, and pharmacist interventions. Chi-squared and unpaired two sample t-test were used for data analysis. INTERVENTION: A literature review of consensus recommendations for supportive care post high-dose methotrexate administration was conducted to develop the protocol. Education on implementation was provided to involved disciplines. RESULTS: One-hundred ten high-dose methotrexate admissions for 23 patients were analyzed: 24 pre-protocol and 86 post-protocol. Mean length of stay was 5.17 nights pre-protocol and 3.91 nights post-protocol (p = 0.026). Incidence of kidney injury significantly decreased (16.7% pre-protocol versus 3.5% post-protocol; p = 0.0394). Lower incidences of all-grade anemia (83.3% versus 58.1%), neutropenia (62.5% versus 29.1%), and thrombocytopenia (58.3% versus 33.7%) as well as treatment delays (29.2% versus 11.6%; p = 0.036) were reported post protocol. No statistically significant difference in mucositis was detected. Pharmacist adherence to protocol was ≥80% resulting in 348 interventions with 99.4% provider acceptance. CONCLUSION: The implementation of a pharmacist-driven high-dose methotrexate management protocol resulted in a statistically significant decrease in inpatient length of stay and kidney injury. Further studies are needed to assess the impact on additional outcomes.


Assuntos
Antimetabólitos/administração & dosagem , Antimetabólitos/uso terapêutico , Conduta do Tratamento Medicamentoso , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico , Farmacêuticos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Idoso , Antimetabólitos/efeitos adversos , Estudos de Coortes , Feminino , Fidelidade a Diretrizes , Humanos , Incidência , Tempo de Internação , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
9.
Hematology Am Soc Hematol Educ Program ; 2020(1): 319-327, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33275674

RESUMO

Corticosteroids constitute a first-line therapy for adults and children suffering from nonmalignant immune-mediated hematologic diseases. However, high disease relapse rates during the tapering period or upon drug discontinuation result in long-term corticosteroid use that increases the risk of infection. This same concept applies to other immunosuppressive agents, such as antimetabolites, calcineurin inhibitors, and cyclophosphamide. Corticosteroids are associated with a length-of-treatment and dose-dependent risk for infection. Screening and antimicrobial prophylaxis against tuberculosis, hepatitis B, Strongyloides stercoralis, and Pneumocystis jirovecii pneumonia (PJP) might be indicated in patients who are scheduled to be on high-dose corticosteroids for >4 weeks (>30 mg of prednisone-equivalent dose [PEQ]) or in patients chronically treated (≥8 weeks of continuous or intermittent corticosteroid use) with moderate doses (≥15 to <30 mg PEQ). Antimetabolites (azathioprine, mycophenolate) increase the risk of progressive multifocal leukoencephalopathy (PML); however, other opportunistic infections and viral reactivation have also been reported. In case of new onset of neurological symptoms, PML needs to be considered, and an urgent neurology consultation should be obtained. Cyclophosphamide-induced myelosuppression can lead to serious infections related to neutropenia. PJP prophylaxis should be considered with combination therapy of cyclophosphamide and corticosteroids until a PEQ dose ≤ 5 mg/d is reached. Data on infectious risk when cyclosporine is used in patients with nonmalignant hematologic diseases are lacking. Discontinuation of any immunosuppressive agent during an episode of infection is recommended. In all patients, adherence to an age-based immunization schedule is appropriate.


Assuntos
Corticosteroides/efeitos adversos , Antimetabólitos/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Infecções/induzido quimicamente , Corticosteroides/uso terapêutico , Idoso , Antimetabólitos/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Doenças Hematológicas/tratamento farmacológico , Herpes Zoster/induzido quimicamente , Herpes Zoster/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Controle de Infecções , Pneumonia por Pneumocystis/induzido quimicamente , Pneumonia por Pneumocystis/prevenção & controle , Estrongiloidíase/induzido quimicamente , Estrongiloidíase/prevenção & controle
10.
Br J Haematol ; 189(5): 869-878, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32191819

RESUMO

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).


Assuntos
Antimetabólitos/uso terapêutico , Cladribina/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Idade de Início , Idoso de 80 Anos ou mais , Antimetabólitos/efeitos adversos , Cladribina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , França/epidemiologia , Histiocitose de Células de Langerhans/mortalidade , Humanos , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Modelos de Riscos Proporcionais , Indução de Remissão , Estudos Retrospectivos , Sepse/etiologia , Sepse/mortalidade , Viroses/etiologia
11.
Environ Mol Mutagen ; 61(4): 456-464, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31743483

RESUMO

The rodent Pig-a assay has been used extensively as a potential regulatory assay for evaluating the in vivo mutagenicity of test substances. Although the assay can be conducted in different mammalian species, there have been only a few reports describing its use in humans, and rarely in genotoxicant-exposed human populations. In this study, PIG-A mutation frequencies (MFs) were evaluated in 36 azathioprine (AZA; human carcinogen)-treated inflammatory bowel disease (IBD) patients and 36 healthy volunteers. IBD patients exhibited a slight but statistically higher MF (6.10 ± 4.44 × 10-6 ) than healthy volunteers (4.97 ± 2.74 × 10-6 ) (P = 0.0489). The estimated relative risk for the exposed patients was 1.22 which indicated that AZA is a risk factor for inducing PIG-A mutation. However, the PIG-A MF showed no associations with AZA treatment duration or total AZA exposure. In addition, we performed the cytokinesis-block micronucleus test on the same samples. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in IBD patients (MN: 4.70 ± 2.86‰; NBUD: 1.89 ± 0.95‰) were significantly higher than in healthy volunteers (MN: 1.47 ± 0.77‰, P < 0.001; NBUD: 0.90 ± 0.58‰, P = 0.004). MN frequency also had significant correlations with AZA treatment duration (P = 0.011) and total AZA exposure (P = 0.018). Our findings indicate that AZA-treated IBD patients have only a marginally significant increase in PIG-A MF; in contrast, a much stronger AZA-associated increase in genotoxicity was detected with the lymphocyte MN assay. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Antimetabólitos/efeitos adversos , Azatioprina/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Proteínas de Membrana/genética , Mutagênicos/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Pessoa de Meia-Idade , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Taxa de Mutação , Adulto Jovem
12.
Pharmacotherapy ; 40(2): 125-132, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31885095

RESUMO

BACKGROUND: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout. OBJECTIVE: To determine the clinical impact of the febuxostat-thiopurine DI. DESIGN AND SETTING: Case series derived from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature. PATIENTS: Nineteen patients who received concomitant febuxostat and either AZA or 6-MP. MEASUREMENTS: Laboratory and clinical data. RESULTS: Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only. LIMITATIONS: Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostat-thiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting. CONCLUSION: Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.


Assuntos
Antimetabólitos/efeitos adversos , Azatioprina/efeitos adversos , Febuxostat/efeitos adversos , Supressores da Gota/efeitos adversos , Mercaptopurina/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Interações Medicamentosas , Humanos , Estados Unidos/epidemiologia , United States Food and Drug Administration
13.
PLoS Pathog ; 15(4): e1007717, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009520

RESUMO

Infectious complications are a common cause of morbidity and mortality in cancer patients undergoing chemotherapy due to increased risk of oral and gastrointestinal candidiasis, candidemia and septicemia. Interactions between C. albicans and endogenous mucosal bacteria are important in understanding the mechanisms of invasive infection. We published a mouse intravenous chemotherapy model that recapitulates oral and intestinal mucositis, and myelosuppression in patients receiving 5-fluorouracil. We used this model to study the influence of C. albicans on the mucosal bacterial microbiome and compared global community changes in the oral and intestinal mucosa of the same mice. We validated 16S rRNA gene sequencing data by qPCR, in situ hybridization and culture approaches. Mice receiving both 5Fu and C. albicans had an endogenous bacterial overgrowth on the oral but not the small intestinal mucosa. C. albicans infection was associated with loss of mucosal bacterial diversity in both sites with indigenous Stenotrophomonas, Alphaproteobacteria and Enterococcus species dominating the small intestinal, and Enterococcus species dominating the oral mucosa. Both immunosuppression and Candida infection contributed to changes in the oral microbiota. Enterococci isolated from mice with oropharyngeal candidiasis were implicated in degrading the epithelial junction protein E-cadherin and increasing the permeability of the oral epithelial barrier in vitro. Importantly, depletion of these organisms with antibiotics in vivo attenuated oral mucosal E-cadherin degradation and C. albicans invasion without affecting fungal burdens, indicating that bacterial community changes represent overt dysbiosis. Our studies demonstrate a complex interaction between C. albicans, the resident mucosal bacterial microbiota and the host environment in pathogenesis. We shed significant new light on the role of C. albicans in shaping resident bacterial communities and driving mucosal dysbiosis.


Assuntos
Candida albicans/patogenicidade , Candidíase Bucal/etiologia , Disbiose/induzido quimicamente , Fluoruracila/efeitos adversos , Mucosa Intestinal/microbiologia , Mucosa Bucal/microbiologia , Animais , Antimetabólitos/efeitos adversos , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Candidíase Bucal/patologia , Modelos Animais de Doenças , Feminino , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia
14.
Aliment Pharmacol Ther ; 49(9): 1188-1194, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891808

RESUMO

BACKGROUND: Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. AIM: To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. METHODS: We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged <60 vs ≥60 years randomised to early combined immunosuppression or conventional management, using Cox proportional hazard analysis or modified Poisson model. In the early combined immunosuppression arm, patients with failure to achieve clinical remission within 4-12 weeks of corticosteroids were treated with a combination of tumour necrosis factor-α antagonist plus anti-metabolite and sequentially escalated in a stepwise algorithm. RESULTS: Of 1981 patients, 311 were ≥60 years (15.7%; 173 randomised to early combined immunosuppression and 138 to conventional management). Over 24 months, 10% of older patients developed Crohn's disease-related complications (early combined immunosuppression vs conventional management: 6.4% vs 14.5%) and 14 patients died (3.5% vs 5.8%). There was no difference between younger and older patients in risk of achieving corticosteroid-free clinical remission (<60 years, early combined immunosuppression (72.6%) vs conventional management (64.4%): relative risk [RR], 1.06 [95% CI, 0.98-1.15] vs ≥60 years, early combined immunosuppression (74.8%) vs conventional management (63.0%): RR, 1.09 [0.90-1.33], P-interaction = 0.78) or time to major adverse outcome (<60 years: hazard ratio [HR], 0.71 [0.53-0.96] vs ≥60 years: HR, 0.69 [0.31-1.51], P-interaction = 0.92) with early combined immunosuppression vs conventional management. CONCLUSIONS: We observed no difference in efficacy and safety of early combined immunosuppression compared to conventional management in older and younger patients. Early combined immunosuppression may be considered as a treatment option in selected older patients with Crohn's disease with suboptimal disease control. Clinical Trial Identifier: NCT01030809.


Assuntos
Doença de Crohn/tratamento farmacológico , Terapia de Imunossupressão , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Doença de Crohn/epidemiologia , Doença de Crohn/imunologia , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Terapia de Imunossupressão/métodos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
15.
Ann Hematol ; 98(6): 1383-1392, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877373

RESUMO

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that participates in the DNA repair of malignant cells, with various consequences on their survival. We have recently shown that PARP1 mRNA levels in the bone marrow of patients with myelodysplastic syndrome (MDS) are correlated to prognosis. To evaluate PARP1 as a biomarker of response to 5-azacytidine in patients with MDS, we measured PARP1 mRNA levels by a quantitative real-time PCR in diagnostic bone marrow samples of 77 patients with MDS treated with 5-azacytidine. Patients with higher PARP1 mRNA levels had a better response to 5-azacytidine per the IWG criteria (p = 0.006) and a longer median survival after 5-azacytidine initiation (p = 0.033). Multivariate analysis revealed that PARP1 mRNA level was the only factor affecting response to treatment and survival after treatment with 5-azacytidine. A next-generation sequencing for 40 genes of interest in MDS and quantification of the methylation levels of the PARP1 promoter were also carried out in a subset of samples (16 and 18 samples respectively). It is the first time that a single, easily measurable biomarker shows a clear correlation with response to treatment and survival in a patient population consisting of previously untreated patients with MDS homogeneously treated with 5-azacytidine. The fact that PARP1 is also a treatment target in several malignancies underscores the importance of our finding for the potential use of PARP1 inhibitors in MDS.


Assuntos
Antimetabólitos/uso terapêutico , Azacitidina/uso terapêutico , Medula Óssea/química , Síndromes Mielodisplásicas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/biossíntese , RNA Mensageiro/análise , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos/efeitos adversos , Azacitidina/efeitos adversos , Biomarcadores , Dano ao DNA , Metilação de DNA/efeitos dos fármacos , Reparo do DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Prognóstico , Regiões Promotoras Genéticas/efeitos dos fármacos , Modelos de Riscos Proporcionais , Regulação para Cima/efeitos dos fármacos
16.
J Clin Rheumatol ; 25(7): 279-283, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29965854

RESUMO

OBJECTIVE: Hyperuricemia has been epidemiologically associated with multiple comorbidities including chronic renal failure and cardiovascular disease. Cause and effect are difficult to address, given comorbidities associated with and prevalence of metabolic syndrome. One impediment to achieving serum uric acid (sUa) levels less than or equal to 6.0 mg/DL is the concept that allopurinol might be nephrotoxic. We examined the relation of sUa less than or equal to 6.0 mg/dL to renal function over time. METHODS: This is a medical records review study of 348 hyperuricemia patients identified in 2015, as having been followed with serial uric acid measurements. After 1 year of serial urate levels, to allow for treatment, patient cohorts were defined: sUa less than or equal to 6.0 mg/dL and sUa greater than 6.0 mg/dL. A repeated measure model was used to test for an association between uric acid level and serum creatinine, while adjusting for covariates. RESULTS: There was a significant difference in the least square means of serum creatinine comparing those who achieved an sUa less than or equal to 6.0 mg/dL versus sUa greater than 6.0 mg/dL (1.39 mg/dL [95% confidence interval, 1.30-1.48] vs 1.57 mg/dL [95% confidence interval, 1.46-1.69]; p = 0.0015). This is a between-group difference in creatinine of 0.18 mg/dL. If a change in serum creatinine of 0.2 is considered significant, this short-term between-group progression of renal failure approaches clinical significance. CONCLUSIONS: Given that most serial measures were within the first few years of follow-up, and change in renal function occurs slowly over time, the between group difference of sUa of 0.18 mg/dL is close to a clinically significant creatinine difference of 0.2 mg/dL.


Assuntos
Alopurinol , Creatinina/sangue , Hiperuricemia , Falência Renal Crônica , Ácido Úrico/sangue , Idoso , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Comorbidade , Correlação de Dados , Progressão da Doença , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/epidemiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Masculino , Síndrome Metabólica/epidemiologia , Avaliação de Resultados em Cuidados de Saúde , Prevalência , Estados Unidos/epidemiologia
17.
World J Gastroenterol ; 24(44): 4979-4988, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30510373

RESUMO

Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.


Assuntos
Antimetabólitos/efeitos adversos , Antioxidantes/farmacologia , Cálcio/metabolismo , Glutationa/antagonistas & inibidores , Absorção Intestinal/efeitos dos fármacos , Antimetabólitos/farmacocinética , Glutationa/metabolismo , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Oxidantes/efeitos adversos , Oxidantes/farmacocinética
18.
Cochrane Database Syst Rev ; 8: CD005984, 2018 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-30098021

RESUMO

BACKGROUND: Prevention of relapse is a major issue in the management of quiescent Crohn's disease (CD). Current therapies (e.g. methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant adverse events. Interventions that are effective and safe for maintenance of remission in CD are desirable. OBJECTIVES: The primary objectives were to evaluate the efficacy and safety of enteral nutrition for the maintenance of remission in CD and to assess the impact of formula composition on effectiveness. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to 27 July 2018. We also searched references of retrieved studies and reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) including participants of any age with quiescent CD were considered for inclusion. Studies that compared enteral nutrition with no intervention, placebo or any other intervention were selected for review. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included anthropometric measures (i.e. height and weight), quality of life (QoL), adverse events, serious adverse events and withdrawal due to adverse events. We calculated the risk ratio and 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference and 95% CI. A random-effects model was used for the statistical analysis. We used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes. MAIN RESULTS: Four RCTs (262 adult participants) met the inclusion criteria. One study (N = 33) compared an elemental diet to a non-elemental (polymeric) diet. One study (N = 51) compared a half elemental diet to a regular free diet. Another study (N = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group. One study (N= 83) compared a polymeric diet to mesalamine. Two studies were rated as high risk of bias due to lack of blinding or incomplete outcome data. The other two studies were judged to have an unclear risk of bias. The studies were not pooled due to differences in control interventions and the way outcomes were assessed.The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to adverse events is uncertain. Fifty-eight per cent (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57% (8/14) of participants in the polymeric diet group (RR 1.01, 95% CI 0.56 to 1.84; very low certainty evidence). Thirty-two per cent (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95% CI 0.59 to 159.93; low certainty evidence). Anthropometric measures, QoL, adverse events and serious adverse events were not reported as outcomes.The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates is uncertain. Thirty-five per cent (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64% (16/25) of participants in the free diet group (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). No adverse events were reported. This study reported no differences in weight change between the two diet groups. Height and QoL were not reported as outcomes.The effect of an elemental diet compared to 6-MP on relapse rates or adverse events is uncertain. Thirty-eight per cent (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23% (7/30) of participants in the 6-MP group (RR 1.61; 95% CI 0.73 to 3.53; very low certainty evidence). Three per cent (1/32) of participants in the elemental diet group had an adverse event compared to 13% (4/30) of participants in the 6-MP group (RR 0.23, 95% CI 0.03 to 1.98; low certainty evidence). Adverse events in the elemental diet group included surgery due to worsening CD. Adverse events in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1). No serious adverse events or withdrawals due to adverse events were reported. Weight, height and QoL were not reported as outcomesThe effect of a polymeric diet compared to mesalamine on relapse rates and weight is uncertain. Forty-two per cent (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55% (22/40) of participants in the mesalamine group (RR 0.76; 95% CI 0.49 to 1.19; low certainty evidence). The mean difference in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95% CI -4.62 to 8.42; low certainty evidence). Two participants in the polymeric diet group experienced nausea and four had diarrhoea. It is unclear if any participants in the mesalamine group had an adverse event. Height, QoL, serious adverse events and withdrawal due to adverse events were not reported as outcomes. AUTHORS' CONCLUSIONS: The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.


Assuntos
Doença de Crohn/terapia , Nutrição Enteral , Prevenção Secundária , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antimetabólitos/efeitos adversos , Antimetabólitos/uso terapêutico , Doença de Crohn/prevenção & controle , Dieta , Alimentos Formulados , Humanos , Quimioterapia de Manutenção/métodos , Mercaptopurina/efeitos adversos , Mercaptopurina/uso terapêutico , Mesalamina/efeitos adversos , Mesalamina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Int J Mol Sci ; 19(8)2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127309

RESUMO

Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG (p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group (p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.


Assuntos
Antimetabólitos/efeitos adversos , Desoxiglucose/efeitos adversos , Dieta Cetogênica/métodos , Animais , Antimetabólitos/administração & dosagem , Glicemia/metabolismo , Desoxiglucose/administração & dosagem , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Corpos Cetônicos/metabolismo , Cetose/etiologia , Cetose/metabolismo , Camundongos Nus , Neoplasias/metabolismo
20.
BMC Pediatr ; 18(1): 231, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-30001695

RESUMO

BACKGROUND: Lesch-Nyhan syndrome is a rare inborn error of purine metabolism marked by a complete deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Inherited as an X-linked recessive genetic disorder that primarily affects males, patients with Lesch-Nyhan syndrome exhibit severe neurological impairments, including choreoathetosis, ballismus, cognitive dysfunction, and self-injurious behavior. Uric acid levels are usually abnormally high, leading to kidney and bladder stones which often necessitate urological intervention. Factor V Leiden is an autosomal dominant disorder of blood clotting associated with hypercoagulability, thrombophilia, and renal disease. CASE PRESENTATION: We present the first reported case of xanthine calculi in a patient with Lesch-Nyhan syndrome and Factor V Leiden who was treated with allopurinol. A renal ultrasound and CT scan demonstrated bilateral staghorn calculi in the kidneys as well as nephrocalcinosis. Two years earlier the patient underwent cystoscopy with bilateral ureteroscopy and laser lithotripsy, and he was stone free afterwards. The patient subsequently underwent bilateral percutaneous nephrolithotomy (PCNL) and was stone free following the procedure. Patients with endogenous overproduction of uric acid who are being treated with allopurinol have a higher chance of developing xanthine stones. CONCLUSIONS: Pediatricians treating these children should be aware of these rare conditions and promptly manage the potential complications that may require medical or surgical intervention.


Assuntos
Alopurinol/efeitos adversos , Antimetabólitos/efeitos adversos , Fator V/genética , Cálculos Renais/etiologia , Síndrome de Lesch-Nyhan/complicações , Mutação Puntual , Xantina Oxidase/antagonistas & inibidores , Alopurinol/uso terapêutico , Antimetabólitos/uso terapêutico , Criança , Humanos , Cálculos Renais/sangue , Cálculos Renais/química , Cálculos Renais/terapia , Síndrome de Lesch-Nyhan/sangue , Síndrome de Lesch-Nyhan/tratamento farmacológico , Masculino , Xantina/metabolismo
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