RESUMEN
A 36-year-old woman presented to the emergency department with a 1-day history of purulent perianal and vulvar discharge. She had a 25-year history of Crohn's disease (CD), and 13 years prior had received a total colectomy with end ileostomy. She had vulvar biopsies 5 years prior to presentation, demonstrating noncaseating granulomas consistent with metastatic Crohn's disease (MCD). Throughout the course of her disease, she had a failed treatment with adalimumab, certolizumab, methotrexate, and 6-mercaptopurine. She had received a radical vulvectomy 1 year prior to presenting to control recurrent vulvar abscesses and MCD while receiving monthly subcutaneous infliximab 10 mg/kg body weight. Dermatology was consulted at presentation, and the physical examination revealed tender, linear ulcerations with a granulated appearance and depigmentation on the natal cleft and vulva (Figures 1 and 2). Computerized tomography (CT) scan of the abdomen and pelvis indicated thickening of soft tissue without evidence of abscesses, fluid collection, or fistulae. Given the distribution and morphology of lesions with a history of biopsy-proven MCD, the patient was diagnosed with a flare of MCD.
Asunto(s)
Enfermedad de Crohn , Neoplasias , Femenino , Humanos , Adulto , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/cirugía , Absceso/etiología , Infliximab , Mercaptopurina , Metotrexato , RecurrenciaRESUMEN
Azathioprine (AZA) and 6-mercaptopurine (6-MP) are drugs widely used in the treatment of autoimmune diseases. Among the enzymes involved in the metabolism of AZA and 6-MP are thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). The existence of single nucleotide polymorphisms in the genes that code for these enzymes could decreased enzymatic activity AND lead to severe myelosuppression. The most relevant polymorphism is NUDT15*3 (rs116855232), where the replacement of cytosine for thymine at position 415, which in turn leads to a loss of enzymatic activity. In a previous study, it was identified that together the polymorphisms in the TPMT gene reach an allelic frequency of 3.81%. There is no information regarding the rs116855232 polymorphism in the NUDT15 gene, so this corresponds to the objective of this report. Blood samples from Chilean adult patients with indications for the use of AZA or 6-MP for different pathologies and who had undergone a TPMT gene polymorphism study were retrospectively analyzed. A total of 253 blood samples were analyzed. Of the 253 patients, 47 presented the c.415C>T polymorphism in the NUDT15 gene, 3 being homozygous and 44 heterozygous. Four of the heterozygous patients for NUDT15 also had the *3A variant in the TPMT gene, also heterozygous. The allelic frequency of the minor T allele found (9.88%) was very similar to that found in patients of Asian origin, and much higher than that reported for the European Caucasian or Latin American population.
Asunto(s)
Azatioprina , Mercaptopurina , Metiltransferasas , Pirofosfatasas , Adulto , Humanos , Azatioprina/efectos adversos , Chile , Mercaptopurina/efectos adversos , Metiltransferasas/genética , Polimorfismo de Nucleótido Simple , Pirofosfatasas/genética , Estudios RetrospectivosRESUMEN
Inflammatory bowel disease (IBD) is a chronic condition that affects the digestive tract and can lead to inflammation and damage to the intestinal lining. IBD patients with cancer encounter difficulties since cancer treatment weakens their immune systems. A multidisciplinary strategy that strikes a balance between the requirement to manage IBD symptoms and the potential effects of treatment on cancer is necessary for effective care of IBD in cancer patients. To reduce inflammation and avoid problems, IBD in cancer patients is often managed by closely monitoring IBD symptoms in conjunction with the necessary medication and surgical intervention. Anti-inflammatory medications, immunomodulators, and biologic therapies may be used for medical care, and surgical options may include resection of the diseased intestine or removal of the entire colon. The current study provides a paradigm for shared decision-making involving the patient, gastroenterologist, and oncologist while considering recent findings on the safety of IBD medicines, cancer, and recurrent cancer risk in individuals with IBD. We hope to summarize the pertinent research in this review and offer useful advice. (AU)
Asunto(s)
Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/terapia , Neoplasias del Cuello Uterino , Neoplasias Urológicas , Neoplasias Gastrointestinales , Metotrexato , Factores de Riesgo , Inhibidores del Factor de Necrosis Tumoral , MercaptopurinaRESUMEN
Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults. Historically, this patient group has been treated using adult-based regimens, which entails a high rate of treatment-related mortality and a poor overall survival (OS). The use of the CALGB 10403, a pediatric-inspired regimen, has been proven effective in this patient subgroup. Nonetheless, low- and middle-income countries (LMICs) may present limited access to standard care treatments implemented elsewhere, warranting the need for further research to improve outcomes among vulnerable populations. In this study, we present the outcomes in terms of safety and effectiveness of using a modified CALGB 10403 regimen to reflect drug and resource availability in LMICs. Modifications included the use of Escherichia coli asparaginase,6-mercaptopurine instead of thioguanine and the use of rituximab among patients with CD20+. A total of 95 patients with a median age of 23 (range, 14-49) years treated with this modified scheme were prospectively assessed at 5 centers in Mexico and 1 in Guatemala. Among these, 87.8% achieved a complete response after induction. During follow-up, 28.3% of patients relapsed. Two-year OS rate was 72.1%. Factors associated with worse OS included hyperleukocytosis (hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.81-10.10) and postinduction minimal residual disease (HR, 4.67; 95% CI, 1.75-12.44). Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation, respectively), and the treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Asparaginasa/efectos adversos , Mercaptopurina , Rituximab/uso terapéutico , Inducción de RemisiónRESUMEN
The use of thiopurines is an independent risk factor for active tuberculosis in patients with inflammatory bowel disease.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Tuberculosis , Humanos , Azatioprina , Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Factores de Riesgo , Tuberculosis/epidemiología , Nucleósidos de Purina , Mercaptopurina/efectos adversosRESUMEN
Alkylation of thiopurine derivatives with alcohols by the Mitsunobu reaction are reported in moderated to good yields. The method was applied in synthesis of number of thiopurine and thiopurine ribosides derivatives.
Asunto(s)
Alcoholes , Mercaptopurina , Alquilación , Espectroscopía de Resonancia MagnéticaRESUMEN
An 18-year-old male was admitted for his second induction chemotherapy treatment for an acute lymphoblastic leukaemia with cyclophosphamide, cytarabine, and mercaptopurine. He presented with high fever, abdominal pain, non-bloody diarrhoea, portal hypertension and leukopenia. Stool sample analysis, blood cultures and extensive work-up were negative. The only microbiologic evidence was the presence of cytomegalovirus DNA detected by PCR. A profound hypogammaglobulinemia was documented. Pathology material reported non-caseating granulomas in liver, bone marrow, duodenum and colon with negative cytomegalovirus immunostaining. What is your diagnosis?
Un varón de 18 años se internó para recibir el segundo ciclo de inducción por una leucemia linfoblástica aguda con ciclofosfamida, citarabina y mercaptopurina. Desarrolló fiebre alta, dolor abdominal, diarrea no sanguinolenta, hipertensión portal y leucopenia. El análisis de materia fecal, cultivos de sangre y una evaluación exhaustiva fueron negativas. La única evidencia microbiológica fue la detección de ADN de citomegalovirus en sangre por PCR. También se documentó una hipogamaglobulinemia profunda. El material de patología reportó granulomas no caseificantes en hígado, médula ósea, duodeno y colon con inmunohistoquímica negativa para citomegalovirus. ¿Cuál es su diagnóstico?
Asunto(s)
Fiebre de Origen Desconocido , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Ciclofosfamida , Citarabina/uso terapéutico , Granuloma/diagnóstico , Humanos , Masculino , Mercaptopurina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there is an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects are associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgammanull mice measuring human lymphoblasts by flow cytometry; and the expression of HOX genes by qPCR after treatment in an adult model of ALL with t(4;11). LBH589 combination with MTX or 6MP did not promote synergistic effects in RS4;11 cell line. LBH589 treatment leads to increased overall survival and reduction of blasts in xenotransplanted mice but caused no significant changes in HOXA7, HOXA9, HOXA10, and MEIS1 expression. The LBH589, alone, showed promising antineoplastic effects in vivo and may represent a potential agent for chemotherapy in ALL patients with t(4;11).
Asunto(s)
Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Animales , Humanos , Mercaptopurina/farmacología , Metotrexato/farmacología , Ratones , Ratones Endogámicos NOD , Panobinostat/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.
Asunto(s)
Asparaginasa , Leucemia-Linfoma Linfoblástico de Células Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida , Citarabina , Daunorrubicina , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Humanos , Mercaptopurina , Metotrexato/uso terapéutico , Pacientes Ambulatorios , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Prednisona , Vincristina/uso terapéuticoRESUMEN
Background and objectives: The multidrug resistance protein 4 (MRP4) is a member of the ABC transporter, which has been extensively related to many types of cancer including leukemia. MRP4 overexpression and activity over the efflux of some chemotherapeutic drugs are the main causes of chemoresistance. 6-mercaptopurine (6-MP) is a chemotherapeutic drug widely used in the consolidation and maintenance phases of leukemia treatment. However, 6-MP is a substrate of MRP4, which decreases its chemotherapeutic efficacy. Current research is focused on the development of MRP4 inhibitors to combat chemoresistance by allowing the accumulation of the drug substrates inside the cells. To date, the only specific MRP4 inhibitor that has been developed is ceefourin-1, which has been reported to inhibit MRP4 in many cancer cells and which makes it an excellent candidate to enhance the activity of 6-MP in a combined treatment in vitro of leukemic cells. Materials and methods: in the present work, we determined the enhancing activity of ceefourin-1 on the antiproliferative and apoptotic effect of 6-MP in leukemic Jurkat cells by trypan blue assay and flow cytometry. Besides, we determined the 6-MP and ceefourin-1 binding sites into MRP4 by molecular docking and molecular dynamics. Results: ceefourin-1 enhanced the apoptotic activity of 6-MP in Jurkat cells, while in CRL-1991 cells both antiproliferative and apoptotic effect were significantly lower. Ceefourin-1 additively cooperates with 6-MP to induce apoptosis in leukemic cells, but normal lymphoblast CRl-1991 showed resistance to both drugs. Conclusion: ceefourin-1 and 6-MP cooperates to trigger apoptosis in leukemic Jurkat cells, but the full mechanism needs to be elucidated in further works. In addition, our perspective is to test the cooperation between ceefourin-1 and 6-MP in samples from patients and healthy donnors.
Asunto(s)
Leucemia , Mercaptopurina , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Apoptosis , Línea Celular , Humanos , Células Jurkat , Mercaptopurina/farmacología , Mercaptopurina/uso terapéutico , Simulación del Acoplamiento Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismoRESUMEN
BACKGROUND: Thiopurines are effectively prescribed for immune and oncology diseases but their toxicity leads to severe myelosuppression. Therefore, TPMT genetic variants have been used to adjust dosing for poor and intermediate metabolizers, significantly preventing adverse drug reactions. In 2018, the Clinical Pharmacogenetics Implementation Consortium included NUDT15 rs116855232 to also guide thiopurines dosing. This variant is not present in Caucasians but have been identified in 10% of Asian and Latin American populations. Despite research efforts to portrait the world's genetic variation, few studies include the investigation of NUDT15 in large samples. METHODS: Fifteen NUDT15 and TPMT variants were retrieved for 1270 Mestizos and 20 Natives genotyped from previous studies using the GSA-Illumina microarray. After bioinformatic quality controls, genotypes were available for 12 variants, TPMT rs2842949, rs2842950, rs2842934, rs1800460, rs12201199, rs12663332, rs2518463, rs4449636, rs12529220, rs3931660, rs200591577, and NUD15 rs116855232. Allele frequencies and haplotypes were assessed using PLINK, R, and Haploview. Dosing inferences were described according to the Clinical Pharmacogenomics Implementation Consortium. RESULTS: We report relevant populations differences in actionable TPMT*3B and NUDT15 rs116855232 as the allele frequency of the former is higher in Mestizos compared to Caucasians, and for the latter we report twofold and 1.35-fold higher allele frequencies in Natives and Mestizos compared to Mexicans from Los Angeles. CONCLUSIONS: TPMT*3B and NUDT15 rs116855232 actionable markers showed population differences that ought to be considered as dosing inferences highlight the relevance of routine genotyping of these variants for the prescription of thiopurines in Mexican populations.
Asunto(s)
Mercaptopurina/farmacología , Metiltransferasas/genética , Pirofosfatasas/genética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , México/epidemiología , Farmacogenética/métodos , Variantes FarmacogenómicasRESUMEN
RESUMO Objetivo descrever as necessidades de aprendizagem de familiares de crianças e adolescentes com câncer quanto ao tratamento com quimioterápicos antineoplásicos orais. Método pesquisa qualitativa descritiva desenvolvida em um hospital federal do Rio de Janeiro, Brasil. Os dados foram coletados nos meses de julho a setembro de 2020 a partir de entrevistas semiestruturadas com vinte e três familiares de crianças e adolescentes com câncer em quimioterapia antineoplásica oral. Os dados foram processados no software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires pela Classificação Hierárquica Descendente. Resultados dentre os temas que demandam aprendizagem pelos familiares estão administração oral, armazenamento e manipulação dos quimioterápicos orais, além dos efeitos adversos e emergências que demandam atendimento hospitalar. Conclusão e implicações para a prática no tratamento com quimioterápicos orais, as necessidades de aprendizagem dos familiares de crianças e adolescentes precisam ser problematizadas em práticas educativas dialógicas para, assim, favorecer a segurança, a adesão e a eficácia do tratamento.
RESUMEN Objetivo describir las necesidades de aprendizaje de familiares de niños y adolescentes con cáncer en cuanto al tratamiento con quimioterápicos antineoplásicos orales. Método investigación cualitativa descriptiva desarrollada en un hospital federal de Río de Janeiro, Brasil. Los datos fueron recogidos en los meses de julio a septiembre de 2020 a partir de entrevistas semiestructuradas con veintitrés familiares de niños y adolescentes con cáncer en quimioterapia antineoplásica oral. Los datos fueron procesados en el software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires por la Clasificación Jerárquica Descendente. Resultados entre los temas que demandan aprendizaje por los familiares están administración oral, almacenamiento y manipulación de los quimioterápicos orales, además de los efectos adversos y emergencias que demandan atención hospitalaria. Conclusión e implicaciones para la práctica en el tratamiento con quimioterápicos orales, las necesidades de aprendizaje de los familiares de niños y adolescentes necesitan ser problematizadas en prácticas educativas dialógicas para, así, favorecer la seguridad, la adhesión y la eficacia del tratamiento.
ABSTRACT Objective to describe the learning needs of family members of children and adolescents with cancer regarding treatment with oral antineoplastic chemotherapies. Method a descriptive qualitative research developed in a federal hospital in Rio de Janeiro, Brazil. Data were collected in the months from July to September 2020 from semi-structured interviews with twenty-three family members of children and adolescents with cancer undergoing oral antineoplastic chemotherapy. Data was processed in the software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires by the Descending Hierarchical Classification. Results among the themes that demand learning by the family members are oral administration, storage and handling of oral antineoplastic drugs, as well as adverse effects and emergencies that require hospital care. Conclusion and implications for practice in oral antineoplastic treatment, the learning needs of family members of children and adolescents need to be problematized in dialogic educational practices in order to favor the safety, adherence, and efficacy of the treatment.
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Educación en Salud , Cuidadores/educación , Neoplasias/terapia , Antineoplásicos/uso terapéutico , Cuidado del Niño , Metotrexato/uso terapéutico , Administración Oral , Investigación Cualitativa , Almacenaje de Medicamentos , Temozolomida/uso terapéutico , Mercaptopurina/uso terapéutico , Antineoplásicos/administración & dosificaciónRESUMEN
INTRODUÇÃO: A retocolite ulcerativa (RCU), ou colite ulcerativa, é uma doença caracterizada pela ocorrência de episódios de inflamação restrita à mucosa do cólon, podendo envolver o reto e se estender por outras partes proximais do cólon. Os pacientes apresentam diarreia, podendo ser associada com a presença de sangue. Os sintomas incluem dor abdominal, urgência, incontinência e tenesmo, que apresentam de forma gradual e progressiva, podendo estender-se por várias semanas. Febre, fadiga, perda de peso, dispneia, palpitação, anemia e deficiência de ferro podem ocorrer. A RCU pode ser dividida em fase ativa e estádio de remissão. A fase ativa é caracterizada pela presença de sintomas e lesões ativas da mucosa e a remissão é caracterizada pela resolução dos sintomas e desaparecimento de achados na mucosa. A doença ocorre gradualmente, seguida de períodos de remissão espontânea e recaídas subsequentes. A incidência da doença é semelhante entre homens e mulheres, sendo que a idade de início é entre 30 e 40 anos. O tratamento da RCU consiste em aminossalicilatos orais e por via retal, corticoides, imunossupressores e medicamentos biológicos, e é feito d
Asunto(s)
Humanos , Proctocolitis/tratamiento farmacológico , Azatioprina/efectos adversos , Corticoesteroides/efectos adversos , Quinasas Janus/antagonistas & inhibidores , Mercaptopurina/efectos adversos , Sistema Único de Salud , Brasil , Análisis Costo-BeneficioRESUMEN
Objective: This study aimed to correlate the genetic profile of the NUDT15 and TPMT genes with the side effects of the treatment of pediatric patients with acute lymphoid leukemia who were undergoing maintenance therapy at a tertiary care hospital in 2017. Methods: This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated. Results: Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for NUDT15 and TPMT (rs1800462 and rs1800460) on 68 patients, while for the rs1142345 polymorphism, typing was achieved in 42 patients. 4/68 patients were heterozygous for NUDT15, and the same number of patients were heterozygous for rs1800462 and rs1142345, while for rs1800460, 6 heterozygous patients were identified. No statistically significant association was identified between the genetic variants and the outcomes of interest. Conclusion: Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy.
Objetivo: la finalidad de este estudio fue evaluar las asociaciones entre los perfiles de los genes NUDT15 y TPMT con los efectos adversos del tratamiento de mantenimiento en pacientes pediátricos con Leucemia Linfoblástica Aguda atendidos en un hospital de referencia durante el 2017. Métodos: Este fue un estudio observacional analítico, de corte longitudinal en el que los genotipos de los genes de interés fueron determinados mediante PCR de discriminación alélica con sondas TaqMan® en pacientes que estaban recibiendo quimioterapia de mantenimiento en la Unidad de Oncohematología Pediátrica durante el 2017. Los datos clínicos y sociodemográficos correspondientes a los primeros 6 meses de sus tratamientos de mantenimiento fueron colectados, y se evaluó la correlación entre los genotipos identificados y el desarrollo de efectos secundarios en estos pacientes. Resultados: setenta pacientes fueron incluidos en el estudio, de estos, los análisis genéticos para NUDT15 y TPMT (rs1800462 and rs1800460) fueron realizados en 68 pacientes, en tanto que para el polimorfismo rs1142345 se logró la tipificación en 42 pacientes. 4/68 pacientes fueron heterocigotos para NUDT15 y el mismo número de pacientes fueron heterocigotos para rs1800462 and rs1142345, mientras que para rs1800460, 6 pacientes heterocigotos fueron identificados. No se identificaron asociaciones estadísticamente significantes entre las variants genéticas y los resultados clínicos de interés. Conclusiones: Estos hallazgos resaltan la importancia de realizar estudios de este tipo con un mayor número de sujetos de estudio, así como plantean la necesidad de evaluar otras variantes genéticas que podrían tener algún impacto en el desarrollo de efectos secundarios durante la quimioterapia de mantenimiento.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antimetabolitos Antineoplásicos/efectos adversos , Niño , Colombia , Humanos , Mercaptopurina/efectos adversos , Metiltransferasas/genética , Metiltransferasas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genética , Pirofosfatasas/uso terapéuticoRESUMEN
INTRODUÇÃO: A retocolite ulcerativa (RCU) é uma doença crônica que consiste na inflamação da camada mucosa do cólon, que afeta o reto e outras partes proximais do cólon. A diarreia sanguinolenta ou não, juntamente com o pequeno volume de cada evacuação e o aumento da frequência, caracterizam a doença. Além desses sintomas, observa-se febre, perda de peso, anemia, alterações laboratoriais, dores abdominais, dentre outros. A doença pode ser classificada de acordo com sua gravidade, o que auxilia no tratamento, em leve, moderada ou grave, a partir da aplicação de um índice específico. O tratamento atualmente preconizado no Sistema Único de Saúde é o uso de corticoides e aminossalicilatos. PERGUNTA: Citrato de tofacitinibe é eficaz e seguro para o tratamento da RCU ativa moderada a grave com resposta inadequada, perda de resposta ou intolerância a aminossalicilatos, corticosteroides, azatioprina, 6-mercaptopurina ou medicamentos biológicos da classe dos anti-TNF? TECNOLOGIA: Citrato de Tofacitinibe (Xeljanz®). EVIDÊNCIAS CI
Asunto(s)
Humanos , Adulto , Proctocolitis/tratamiento farmacológico , Azatioprina/efectos adversos , Corticoesteroides/efectos adversos , Quinasas Janus/antagonistas & inhibidores , Mercaptopurina/efectos adversos , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economíaRESUMEN
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 21 artigos.
Asunto(s)
Neumonía Viral/tratamiento farmacológico , Infecciones por Coronavirus/tratamiento farmacológico , Progresión de la Enfermedad , Betacoronavirus/efectos de los fármacos , Azatioprina/uso terapéutico , Zinc/uso terapéutico , Metilprednisolona/uso terapéutico , Metotrexato/uso terapéutico , Corticoesteroides/uso terapéutico , Azitromicina/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Ritonavir/uso terapéutico , Combinación de Medicamentos , Oseltamivir/uso terapéutico , Lopinavir/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Hidroxicloroquina/uso terapéutico , Mercaptopurina/uso terapéuticoRESUMEN
INTRODUCTION: The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. METHODS: The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software. RESULTS: Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world. CONCLUSION: Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.
Asunto(s)
Pueblos Indígenas/genética , Pirofosfatasas/genética , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Brasil , Humanos , Mercaptopurina/farmacología , Mercaptopurina/uso terapéutico , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirofosfatasas/metabolismoRESUMEN
Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Asparaginasa/administración & dosificación , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Neoplasia Residual/patología , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Prednisona/administración & dosificación , Pronóstico , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
OBJECTIVE: To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL). STUDY DESIGN: The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing. RESULTS: TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P < .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia. CONCLUSIONS: White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.