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1.
J Coll Physicians Surg Pak ; 31(9): 1046-1050, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34500519

RESUMO

OBJECTIVE: To investigate the relationship of beta-hCG changes between the first, fourth and seventh days as a predictor of the additional dose requirement in single-dose methotrexate protocol in tubal ectopic pregnancy. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynecology, Bursa Yüksek Ihtisas Training and Research Hospital, between January 2017 and June 2020. METHODOLOGY: Data of 123 patients with tubal ectopic pregnancy, treated with a single-dose methotrexate protocol, were retrospectively analysed. Patients who received methotrexate on the first day and achieved treatment success constituted one group. Patients who received additional doses on the seventh day and achieved treatment success, constituted the other group. Treatment success was defined as normalisation of beta-hCG levels without surgical intervention. RESULTS: The percentage of beta-hCG change between day-one and day-four was a significant independent variable for the additional dose treatment requirement (OR:1.07, CI:1.01-1.13, p=0.022). The cut-off value of the beta-hCG change percentage between the first and fourth day, was calculated as 4% (sensitivity 72.9%, specificity 78.9%, positive predictive value [PPV] 88.6%, negative predictive value [NPV] 56.6%). CONCLUSION: In the single-dose methotrexate protocol applied in the medical treatment of tubal ectopic pregnancy, the change in beta-hCG value between the first and fourth days may predict the need for additional doses. Administration of an additional dose of methotrexate on the fourth day may be considered, if there is less than a 4% decrease or any increase in beta-hCG value between the first and fourth days. Key Words: Ectopic pregnancy, Methotrexate, Beta human chorionic gonadotropin, Tubal pregnancy, Single-dose protocol.


Assuntos
Metotrexato/uso terapêutico , Gravidez Ectópica , Gravidez Tubária , Gonadotropina Coriônica Humana Subunidade beta , Feminino , Humanos , Metotrexato/administração & dosagem , Gravidez , Gravidez Ectópica/tratamento farmacológico , Gravidez Tubária/tratamento farmacológico , Estudos Retrospectivos
2.
JAMA ; 326(5): 390-400, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342619

RESUMO

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.


Assuntos
Abortivos não Esteroides/administração & dosagem , Metotrexato/administração & dosagem , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/cirurgia , Conduta Expectante , Aborto Espontâneo , Adulto , Gonadotropina Coriônica/sangue , Terapia Combinada , Dilatação e Curetagem , Feminino , Humanos , Satisfação do Paciente , Gravidez , Ultrassonografia Pré-Natal , Hemorragia Uterina
3.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201550

RESUMO

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.


Assuntos
Encéfalo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Metotrexato/toxicidade , Bainha de Mielina/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Bainha de Mielina/patologia , Síndromes Neurotóxicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/genética
4.
Res Vet Sci ; 138: 39-48, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34091228

RESUMO

Methotrexate (MTX), an antifolate drug, is widely used in chemotherapeutic protocols for metastatic and primary brain tumors and some autoimmune diseases. Its efficacy for brain tumors is limited by the high incidence of central nervous system (CNS) complications. This investigation aimed to observe the morphological effects, including astroglial and microglial responses, following systemic short-term MTX administration in adult rats. Male Wistar rats received 5 or 10 mg/kg/day of MTX by intraperitoneal route for 4 consecutive days (respectively, MTX5 and MTX10 groups) or the same volume of 0.9% saline solution (control group). On the 5th day, brain samples were collected for hematoxylin-eosin and luxol fast blue staining techniques, as well as for immunohistochemical staining for glial fibrillary acidic protein (GFAP) expression in astrocytes and Iba1 (ionized calcium binding adaptor molecule 1) for microglia in the frontal cortex, hippocampus, hypothalamus and molecular/granular layers of the cerebellum. Morphometric analyses were performed using Image Pro-Plus software. Brain levels of the proinflammatory cytokines TNF-α and IL-1ß were determined by ELISA. No signs of neuronal loss or demyelination were observed in all groups. Increased GFAP and Iba1 expression was found in all areas from the MTX groups, although it was slightly higher in the MTX10 group compared to the MTX5. Both TNF-α and IL-1ß levels were decreased in the MTX5 group compared to controls. In the MTX10 group, TNF-α decreased, although IL-1ß was increased relative to controls. MTX administration induced microglial reaction and astrogliosis in several CNS areas. In the MTX5 group, it apparently occurred in the presence of decreased proinflammatory cytokines.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Astrócitos/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/fisiopatologia , Metotrexato/administração & dosagem , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Relação Dose-Resposta a Droga , Gliose/induzido quimicamente , Gliose/patologia , Masculino , Microglia/metabolismo , Microglia/patologia , Ratos , Ratos Wistar
5.
Int J Hematol ; 114(2): 252-262, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34086252

RESUMO

The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m2 on day 1, 3 and 6) to a short-MTX group (10 mg/m2 on day 1 and 7 mg/m2 on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p < 0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1 year, p = 0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p = 0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/administração & dosagem , Metotrexato/administração & dosagem , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Gerenciamento Clínico , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Recidiva , Resultado do Tratamento , Adulto Jovem
6.
Medicine (Baltimore) ; 100(20): e25790, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011040

RESUMO

BACKGROUND: It is known that Bi Qi Capsules (BQC) have synergistic effects when combined with Methotrexate, but there is a lack of clinical studies on the long-term efficacy and safety of the combination of the 2 in the treatment of rheumatoid arthritis (RA). Therefore, the purpose of this randomized controlled trial was to evaluate the long-term efficacy and safety of this treatment. METHODS: This was a prospective, double-blind, single-simulation, randomized controlled trial investigating the efficacy and safety of BQC in combination with Methotrexate in the treatment of RA, and was approved by the Clinical Research Ethics Committee of the hospital. Patients were randomized in a 1:1 ratio to either the observation or control group and were respectively followed up for 6 months after receiving 12 weeks of treatment. The observation indexes included: total effective rate, DAS-28 score, inflammatory indexes, and adverse reactions. Finally, the collected data was statistically analyzed by SPSS version 18.0. DISCUSSION: This study evaluated the long-term efficacy of BQC in combination with Methotrexate in the treatment of RA. The trial results of this study will provide new ideas for choosing a combination of Chinese and Western medicine protocols for the treatment of RA. TRIAL REGISTRATION: OSF Registration number: DOI 10.17605/OSF.IO/U85GX.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Metotrexato/administração & dosagem , Adolescente , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Cápsulas , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
7.
AAPS PharmSciTech ; 22(5): 164, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34041632

RESUMO

Psoriasis is a life-threatening autoimmune inflammatory skin disease, triggered by T lymphocyte. Recently, the drugs most commonly used for the treatment of psoriasis include methotrexate (MTX), cyclosporine (CsA), acitretin, dexamethasone, and salicylic acid. However, conventional formulations due to poor absorptive capacity, inconsistent drug release characteristics, poor capability of selective targeting, poor retention of drug molecules in target tissue, and unintended skin reactions restrict the clinical efficacy of drugs. Advances in topical nanocarriers allow the development of prominent drug delivery platforms can be employed to address the critical issues associated with conventional formulations. Advances in nanocarriers design, nano-dimensional configuration, and surface functionalization allow formulation scientists to develop formulations for a more effective treatment of psoriasis. Moreover, interventions in the size distribution, shape, agglomeration/aggregation potential, and surface chemistry are the significant aspects need to be critically evaluated for better therapeutic results. This review attempted to explore the opportunities and challenges of current revelations in the nano carrier-based topical drug delivery approach used for the treatment of psoriasis.


Assuntos
Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Nanocápsulas/administração & dosagem , Psoríase/tratamento farmacológico , Administração Cutânea , Animais , Ciclosporina/administração & dosagem , Ciclosporina/metabolismo , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Humanos , Lipossomos/administração & dosagem , Lipossomos/metabolismo , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Psoríase/metabolismo , Ácido Salicílico/administração & dosagem , Ácido Salicílico/metabolismo
8.
Expert Rev Clin Pharmacol ; 14(9): 1105-1112, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34006152

RESUMO

Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.


Assuntos
Antirreumáticos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Metotrexato/administração & dosagem , Animais , Antirreumáticos/farmacologia , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/patologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Metotrexato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Psoríase/complicações , Psoríase/tratamento farmacológico , Psoríase/patologia
9.
Life Sci ; 279: 119576, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965376

RESUMO

Cancer-targeted co-delivery of therapeutic agents has been recognized as an effective strategy for increasing efficacy and reducing side effects of therapeutic agents. In this study, we used methotrexate (MTX) alone as a targeting moiety and chemotherapeutic agent and in combination with docetaxel (DTX) and doxorubicin (DOX) as chemotherapeutic agents to stop cancer cell proliferation with the aid of newly designed nanostructured lipid carriers (NLCs). The physicochemical properties of our designed nanocomplexes were evaluated by DLS, FT-IR spectroscopy, SEM, and TEM. Moreover, the targeting efficiency of the designed and synthesized nanoplatforms was evaluated on the folate receptor (FR) positive human breast cancer cell line (MCF-7) and FR negative human alveolar basal epithelial cells (A549). The NLCs/DTX/DOX/CS and NLCs/DTX/DOX/CS-MTX complexes significantly increased the cell cytotoxicity and the cell apoptosis rate. However, the complexes significantly reduced the capability of colony formation and cell migration. Our results revealed that NLCs/DTX/DOX/CS-MTX had synergistic cytotoxicity, reactive oxygen spaces, autophagy, and the apoptosis induction ability with an enhanced cellular internalization rate in FR-positive cancer cells, thorough MTX recognition capability. We conclude that the NLCs/DTX/DOX/CS-MTX complex is a new promising paradigm for breast cancer-targeted co-delivery.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Lipídeos/química , Nanoestruturas/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Apoptose , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Humanos , Metotrexato/administração & dosagem , Células Tumorais Cultivadas
10.
JAMA ; 325(17): 1755-1764, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33944875

RESUMO

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Exacerbação dos Sintomas , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Leflunomida/administração & dosagem , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Radiografia , Sulfassalazina/administração & dosagem , Ultrassonografia
11.
Am J Hematol ; 96(7): 823-833, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33864703

RESUMO

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Linfoma Intraocular/tratamento farmacológico , Metotrexato/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Feminino , Humanos , Linfoma Intraocular/diagnóstico , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Retina/diagnóstico , Resultado do Tratamento
12.
Am J Hematol ; 96(7): 764-771, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811794

RESUMO

Central nervous system (CNS) relapse affects 5% of diffuse large B-cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS relapse based upon CNS-IPI score, double-hit lymphoma, or testicular involvement. Among 906 patients with median follow-up 35.3 months (range 0.29-105.7), CNS relapse occurred in 1.9% with CNS-IPI 0-1, 4.9% with CNS-IPI 2-3, and 12.2% with CNS-IPI 4-6 (p < .001). HD-MTX was administered to 115/326 (35.3%) high-risk patients, of whom 96 (83.5%) had CNS-IPI score 4-6, 45 (39.1%) had double-hit lymphoma, and four (3.5%) had testicular lymphoma. The median number of HD-MTX doses was two (range 1-3). Central nervous system relapse risk was similar with versus without HD-MTX (11.2% vs. 12.2%, p = .82) and comparable to previous reports of high-risk patients who did not receive CNS prophylaxis (10-12%). In multivariate and propensity score analyses, HD-MTX demonstrated no association with CNS relapse, progression-free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD-MTX in this high-risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/prevenção & controle , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma Difuso de Grandes Células B/etiologia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
13.
Medicine (Baltimore) ; 100(17): e25564, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907104

RESUMO

BACKGROUND: Osteosarcoma is one of the most common primary bone tumour in children and young patients, and the third most common among adults. Its main treatment option is currently based on neoadjuvant or adjuvant chemoradiotherapy along with the lesion's surgical resection. The current study's primary aim is to examine the clinical therapeutic impacts of combined methotrexate, along with other chemotherapeutic agents to treat children and young adults suffering from osteosarcoma. METHODS: We will perform a comprehensive literature search in English database (PubMed, EMBASE, Cochran Library CINAHL, and PsycINFO) and Chinese database (Chinese National Knowledge Infrastructure, VIP information database, Chinese Biomedical Database, and WanFang Database) with no language restriction from their inception to the search date. Additionally, two independent authors will screen the works of literature obtained from these databases, obtain information, and examine the risks of data included for the studies' bias. Furthermore, we intend to employ the Q statistics as well as I2 statistics to calculate heterogeneity among each study's analysis. Accordingly, we will utilize the funnel plots and Egger test to assess the possibility of publication bias where relevant. RESULTS: The current study aims to provide significant information regarding the clinical therapeutic impacts of combines methotrexate along with other chemotherapeutic agents to treat children and young adults suffering from osteosarcoma. CONCLUSIONS: The present study will generate compelling evidence of combined methotrexate as well as other chemotherapeutic agents for osteosarcoma among children and young adults. Also, it will provide clinical practice suggestions. ETHICS AND DISSEMINATION: The study is founded upon published data. Therefore, there is no requirement for ethics approval. OSF REGISTRATION NUMBER: March 26, 2021.osf.io/a23rc. (https://osf.io/a23rc/).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Metotrexato/administração & dosagem , Osteossarcoma/tratamento farmacológico , Adolescente , Criança , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Adulto Jovem
14.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800115

RESUMO

Graphene oxide (GO), due to its 2D planar structure and favorable physical and chemical properties, has been used in different fields including drug delivery. This study aimed to investigate the impact of different process parameters on the average size of drug-loaded PEGylated nano graphene oxide (NGO-PEG) particles using design of experiment (DoE) and the loading of drugs with different molecular structures on an NGO-PEG-based delivery system. GO was prepared from graphite, processed using a sonication method, and functionalized using PEG 6000. Acetaminophen (AMP), diclofenac (DIC), and methotrexate (MTX) were loaded onto NGO-PEG particles. Drug-loaded NGO-PEG was then characterized using dynamic light scattering (DLS), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), XRD. The DLS data showed that the drug-loaded NGO-PEG suspensions were in the size range of 200 nm-1.3 µm. The sonication time and the stirring rate were found to be the major process parameters which affected the average size of the drug-loaded NGO-PEG. FTIR, DSC, XRD, and SEM demonstrated that the functionalization or coating of the NGO occurred through physical interaction using PEG 6000. Methotrexate (MTX), with the highest number of aromatic rings, showed the highest loading efficiency of 95.6% compared to drugs with fewer aromatic rings (diclofenac (DIC) 70.5% and acetaminophen (AMP) 65.5%). This study suggests that GO-based nano delivery systems can be used to deliver drugs with multiple aromatic rings with a low water solubility and targeted delivery (e.g., cancer).


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Grafite/química , Nanopartículas/química , Acetaminofen/administração & dosagem , Acetaminofen/química , Varredura Diferencial de Calorimetria , Diclofenaco/administração & dosagem , Diclofenaco/química , Portadores de Fármacos/química , Metotrexato/administração & dosagem , Metotrexato/química , Microscopia Eletrônica de Varredura , Estrutura Molecular , Nanopartículas/administração & dosagem , Tamanho da Partícula , Polietilenoglicóis/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
15.
Cancer Chemother Pharmacol ; 87(6): 807-815, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33677616

RESUMO

PURPOSE: High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed. METHODS: Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured. RESULTS: Patients (n = 12), median (range) age 12.4 (5.7-19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4) mM at the end of 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum [MTX] < 0.1 µM was 83 (80.7, 90.7) h and 87 (82.8, 92.4) h for 4 and 12 h infusions. GFRCr was highly variable, increased after cisplatin, and exceeded 150 ml/min/1.73 m2. GFRcysC was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12 h infusions. Radiographic and histological response were similar for patients receiving 4 h or 12 h infusions; the median percent tumor necrosis was > 95%. CONCLUSIONS: Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity. CLINICAL TRIAL: NCT01848457.


Assuntos
Abortivos não Esteroides/administração & dosagem , Abortivos não Esteroides/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Biomarcadores/metabolismo , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Osteossarcoma/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Osteossarcoma/metabolismo , Adulto Jovem
16.
Am J Clin Dermatol ; 22(3): 415-423, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33712987

RESUMO

BACKGROUND: Placebo-controlled studies have reported the efficacy of apremilast in the management of palmoplantar psoriasis but studies comparing efficacy with a conventional agent are lacking. OBJECTIVE: The objective of this article was to  compare the efficacy and safety of apremilast and methotrexate in patients with palmoplantar psoriasis. METHODS: In this prospective, randomized, active-controlled, observer-blinded clinical trial, conducted at a psoriasis clinic of a tertiary care institute in India from 1 July, 2019 to 1 June, 2020, 84 patients with palmoplantar psoriasis were randomized (1:1) to receive either methotrexate (0.4 mg/kg/week orally) or apremilast (30 mg twice daily). The treatment protocol was continued for 16 weeks or until achieving a ≥ 75% improvement in the Modified Palmoplantar Psoriasis Area and Severity Index (m-PPPASI 75), whichever was earlier. Changes in m-PPPASI and Dermatology Life Quality Index scores from baseline, the proportion of patients achieving m-PPPASI 75, and adverse events were assessed. RESULTS: Eighty-four patients were included (76 palmoplantar psoriasis and 8 palmoplantar pustulosis). The mean age (standard deviation) was 44.5 (12.9) years and 53 (63%) were women. The m-PPPASI score [median (interquartile range)] after 16 weeks of treatment showed a significant improvement from baseline in both apremilast [- 6.3 (10.9), p < 0.001] and methotrexate groups [- 8.5 (9.9), p < 0.001]. The estimated median difference between the groups was - 1.2 (p = 0.39, 95% confidence interval - 4.2 to 2.1). At 16 weeks, m-PPPASI 75 was achieved by 14/42 (33%) and 17/42 (41%) patients in the apremilast and methotrexate groups, respectively (p = 0.49). A significant reduction in the Dermatology Life Quality Index score [median (interquartile range)] was observed in both groups [apremilast: - 3.0 (6.0), p < 0.001; methotrexate: - 3.0 (6.3), p < 0.001] with an estimated median difference of 0.0 (p = 0.99, 95% confidence interval - 1.0 to 2.0). The proportion of patients experiencing adverse events was comparable (p = 0.49). CONCLUSIONS: Apremilast showed a comparable efficacy and safety profile to methotrexate in the management of palmoplantar psoriasis. CLINICAL TRIAL REGISTRATION: CTRI/2019/06/019830, date of registration: 24 June, 2019; trial registered prospectively.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Metotrexato/administração & dosagem , Psoríase/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Fármacos Dermatológicos/efeitos adversos , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/diagnóstico , Índice de Gravidade de Doença , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
17.
Pediatr Hematol Oncol ; 38(5): 434-443, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33764242

RESUMO

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Estudos Retrospectivos
18.
Am J Hematol ; 96(6): 680-689, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33735476

RESUMO

We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Indução de Remissão , Rituximab/administração & dosagem , Talidomida/administração & dosagem , Talidomida/toxicidade , Vincristina/administração & dosagem , Adulto Jovem
19.
Biomed Pharmacother ; 138: 111456, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33714108

RESUMO

Methotrexate is used as first-line treatment of moderate to severe psoriasis. Despite the marked variability in treatment outcomes, no pharmacogenetic markers are currently used for personalised management of therapy. In this retrospective study, we investigated the effects of genetic predisposition on efficacy and toxicity of low-dose methotrexate in a cohort of 137 patients with moderate to severe plaque psoriasis. We genotyped 16 polymorphisms in genes for enzymes involved in the folate-methionine pathway and in methotrexate transport, and analysed their association with treatment efficacy and toxicity using classification and regression tree analysis and logistic regression. The most pronounced effect observed in this study was for GNMT rs10948059, which was identified as a risk factor for inadequate efficacy leading to treatment discontinuation. Patients carrying at least one variant allele had ~7-fold increased risk of treatment failure compared to patients with the wild-type genotype, as shown by the classification and regression tree analysis and logistic regression (odds ratio [OR], 6.94; p = 0.0004). Another risk factor associated with insufficient treatment responses was DNMT3b rs2424913, where patients carrying at least one variant allele had a 4-fold increased risk of treatment failure compared to patients with the wild-type genotype (OR, 4.10; p = 0.005). Using classification and regression tree analysis, we show that DNMT3b rs2424913 has a more pronounced role in patients with the variant GNMT genotype, and hence we suggest an interaction between these two genes. Further, we show that patients with the BHMT rs3733890 variant allele had increased risk of hepatotoxicity (OR, 3.17; p = 0.022), which is the most prominent reason for methotrexate discontinuation. We also show that variants in the genes for methotrexate transporters OATP1B1 (rs2306283/rs4149056 SLCO1B1 haplotypes) and ABCC2 (rs717620) are associated with increased risk of treatment failure. The associations identified have not been reported previously. These data suggest that polymorphisms in genes for enzymes of the methionine cycle (which affect cell methylation potential) might have significant roles in treatment responses to methotrexate of patients with psoriasis. Further studies are warranted to validate the potential of the pharmacogenetic markers identified.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Glicina N-Metiltransferase/genética , Metotrexato/administração & dosagem , Polimorfismo de Nucleotídeo Único/genética , Psoríase/tratamento farmacológico , Psoríase/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Fármacos Dermatológicos/administração & dosagem , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Psoríase/diagnóstico , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
20.
Int J Hematol ; 114(1): 79-84, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33743109

RESUMO

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Nefropatias/induzido quimicamente , Metotrexato/efeitos adversos , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Nefropatias/sangue , Nefropatias/urina , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Ácido Úrico/sangue , Adulto Jovem
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