Zarzio Ameliorates Non-alcoholic Fatty Liver Induced By a High Fat Diet in a Rat Experimental Model: A Histological and Immunohistochemical Study

SUMMARY: The therapeutic effect of a granulocyte-colony stimulating factor (G-CSF) biosimilar drug, zarzio, on non-alcoholic fatty liver disease (NAFLD) in a rat model was investigated in this study. Thirty-two rats were randomly divided into four groups. Groups I and II were fed a standard laboratory diet, whereas groups III and IV were fed a high fat diet (HFD) for 14 weeks. After 12 weeks of feeding, groups I and III were administered normal saline, and groups II and IV were intraperitoneally administered zarzio (200 mg/kg/day) for two consecutive weeks. Hematoxylin-eosin (H&E) staining was used to assess hepatic and pancreatic morphology in all groups, oil red O (ORO) staining for lipid accumulation, Masson's staining for fibrosis, and immunohistochemistry assay for hepatic protein expression of insulin receptor substrate 1 (IRS1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumour necrosis factor alpha (TNF-α) and pancreatic caspase-3. The NAFLD rats (group III) developed hepatic steatosis with increased lipid accumulation, perisinusoidal fibrosis, upregulated IRS1, TNF-α (all P<0.05) without a significant increase in Nrf2 protein expression compared with normal control. In comparison, model rats treated with zarzio (group IV) showed significant rejuvenation of the hepatic architecture, reduction of fat accumulation, and fibrosis. This was accompanied by the upregulation of Nrf2, downregulation of IRS1 and TNF-α protein expression (all P<0.05). No correlation was detected between NAFLD and non-alcoholic fatty pancreas disease (NAFPD). However, the pancreatic β-cells in group III showed increased caspase-3 expression, which was decreased (P<0.05) in group IV. In conclusion, zarzio ameliorates NAFLD by improving the antioxidant capacity of liver cells, reducing hepatic IRS1, TNF-α protein expression and pancreatic β-cells apoptosis, suggesting that zarzio could be used as a potential therapy for NAFLD.

En este estudio se investigó el efecto terapéutico de un fármaco biosimilar del factor estimulante de colonias de granulocitos (G-CSF), zarzio, sobre la enfermedaddel hígado graso no alcohólico (NAFLD) en un modelo de rata. Treinta y dos ratas se dividieron aleatoriamente en cuatro grupos. Los grupos I y II fueron alimentados con una dieta estándar de laboratorio, mientras que los grupos III y IV fueron alimentados con una dieta alta en grasas (HFD) durante 14 semanas. Después de 12 semanas de alimentación, a los grupos I y III se les administró solución salina normal, y a los grupos II y IV se les administró zarzio por vía intraperitoneal (200 mg/kg/ día) durante dos semanas consecutivas. Se utilizó tinción de hematoxilina-eosina (H&E) para evaluar la morfología hepática y pancreática en todos los grupos, tinción con rojo aceite O (ORO) para la acumulación de lípidos, tinción de Masson para la fibrosis y ensayo de inmunohistoquímica para la expresión de la proteína hepática del sustrato 1 del receptor de insulina (IRS1), factor nuclear eritroide 2 relacionado con el factor 2 (Nrf2), factor de necrosis tumoral alfa (TNF-α) y caspasa-3 pancreática. Las ratas NAFLD (grupo III) desarrollaron esteatosis hepática con aumento de la acumulación de lípidos, fibrosis perisinusoidal, IRS1 y TNF-α regulados positivamente (todos P <0,05) sin un aumento significativo en la expresión de la proteína Nrf2 en comparación con el control normal. En comparación, las ratas modelo tratadas con zarzio (grupo IV) mostraron un rejuvenecimiento significativo de la arquitectura hepática, una reducción de la acumulación de grasa y fibrosis. Esto estuvo acompañado por la regulación positiva de Nrf2, la regulación negativa de la expresión de la proteína IRS1 y TNF-α (todas P <0,05). No se detectó correlación entre NAFLD y la enfermedad del páncreas graso no alcohólico (NAFPD). Sin embargo, las células β pancreáticas en el grupo III mostraron una mayor expresión de caspasa-3, que disminuyó (P <0,05) en el grupo IV. En conclusión, zarzio mejora la NAFLD al mejorar la capacidad antioxidante de las células hepáticas, reduciendo el IRS1 hepático, la expresión de la proteína TNF-α y la apoptosis de las células β pancreáticas, lo que sugiere que zarzio podría usarse como una terapia potencial para la NAFLD.

Neutropenia congénita de tipo IV: reporte de un caso / Congenital neutropenia type IV: case report

La neutropenia congénita grave (NCG) es una entidad heterogénea cuya característica común es un recuento absoluto de neutrófilos inferior a 0,5 x 10 9/l. Presenta gran heterogeneidad genética, las mutaciones más frecuentes son las del gen de la elastasa 2 (ELA 2). El tratamiento de primera elección es la administración de factor estimulador de colonias de granulocitos. Los pacientes con NCG presentan infecciones graves en etapas tempranas de la vida. Se presenta una paciente con NCG asociada a fenotipo peculiar con facies triangular, retromicrognatia, patrón venoso prominente en miembros inferiores, comunicación interauricular y mal progreso ponderal, en quien se diagnosticó déficit de la enzima glucosa 6 fosfato deshidrogenasa, subunidad catalítica 3 (G6PC3). A pesar de lo infrecuente de esta mutación como causa de NCG (2 %), su conocimiento cobra importancia porque la coexistencia del fenotipo característico con una NCG orienta en la solicitud del estudio genético que permite arribar al diagnóstico.

Severe congenital neutropenia (SCN) is a heterogeneous disease whose more common feature is an absolute neutrophil count less than 0.5 x 10 9/l. It presents great genetic heterogeneity. Autosomal dominant inherited mutations of the elastase 2 gene (ELA2) represent the most common etiology. The first choice treatment is the administration of granulocyte colony stimulating factor. Patients with SCN develop severe infections early in life. We present a patient who associated SCN to a peculiar phenotype, characterized by triangular facies, retromicrognathia, prominent venous pattern in the lower limbs, atrial septal defect and poor weight progress, in whom a deficiency of the enzyme glucose 6 phosphate dehydrogenase, a catalytic subunit 3 (G6PC3), was diagnosed. Despite the infrequency of this mutation as the origin of SCN (2%), its knowledge becomes important because the coexistence of the characteristic phenotype and SCN guides the request for the genetic study that allows reaching the diagnosis.

Manejo em longo prazo de glicogenose tipo 1b: experiência de um centro terciário brasileiro / Long term management of glycogen storage disease type 1b: a brazilian tertiary center experience

ABSTRACT BACKGROUND Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, in addition to the well-known metabolic manifestations of GSD. Treatment with granulocyte-colony stimulating factor (G-CSF) is often indicated in the management of neutropenia and inflammatory bowel disease. OBJECTIVE To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b), with special attention to immune-related complications. METHODS Retrospective case series of seven patients with GSD 1b diagnosed and followed at a tertiary university hospital in Brazil, from July/2000 until July/2016. RESULTS Mean age at referral was fourteen months. Diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies in five cases. All patients presented suffered from neutropenia, managed with G-CSF - specifically Filgrastim. Hospitalizations for infections were frequent. Two patients developed inflammatory bowel disease. Six patients remained alive, one died at age 14 years and 9 months. The mean age at the end of the follow-up was 11.5 years. Compliance to treatment was suboptimal: poor compliance to medications, starch and dietetic management of GSD were documented, and outpatient appointments were frequently missed. CONCLUSION Managing GSD 1b is challenging not only for the chronic and multisystemic nature of this disease, but also for the additional demands related dietary restrictions, use of multiple medications and the need for frequent follow-up visits; furthermore in Brazil, the difficulties are increased in a scenario where we frequently care for patients with unfavorable socioeconomic status and with irregular supply of medications in the public health system.

RESUMO CONTEXTO Glicogenose (GSD) tipo 1b é uma doença multissistêmica em que complicações imunológicas e infecciosas estão presentes, além das manifestações metabólicas bem conhecidas da GSD. O tratamento com fator estimulador de colônias de granulócitos (G-CSF) é frequentemente indicado no tratamento da neutropenia e doença inflamatória intestinal. OBJETIVO Relatar sobre a dados demográficos, genótipo, apresentação clínica, manejo e complicações de pacientes pediátricos com GSD tipo 1b (GSD 1b), com atenção especial às complicações relacionadas ao sistema imunológico. MÉTODOS Série de casos retrospectiva de sete pacientes com GSD 1b diagnosticados e acompanhados em um hospital universitário terciário no Brasil, de julho/2000 a julho/2016. RESULTADOS A idade média no encaminhamento foi de 14 meses. O diagnóstico de GSD 1b foi baseado em achados clínicos e laboratoriais e apoiado por estudos genéticos em cinco casos. Todos os pacientes apresentaram neutropenia, tratada com G-CSF - especificamente Filgrastim. As hospitalizações por infecções foram frequentes. Dois pacientes desenvolveram doença inflamatória intestinal. Seis pacientes permanecem vivos, um morreu aos 14 anos e 9 meses de idade. A média de idade ao final do acompanhamento foi de 11,5 anos. A adesão ao tratamento foi sub-ótima: má adesão aos medicamentos, amido e manejo dietético de GSD foram documentados, e consultas ambulatoriais foram frequentemente perdidas. CONCLUSÃO O manejo da GSD 1b é um desafio, não apenas pela natureza crônica e multissistêmica desta doença, mas também pelas demandas adicionais relacionadas a restrições dietéticas, uso de múltiplos medicamentos e a necessidade de consultas de acompanhamento frequentes; no Brasil, isso ainda é dificultado em um cenário em que frequentemente atendemos pacientes com situação socioeconômica desfavorável e com oferta irregular de medicamentos no sistema público de saúde.

Eficacia de la movilización de células madre en pacientes con Polineuropatía Desmielinizante Inflamatoria Crónica refractaria / Efficacy of mobilization of stem cells in patients with Refractory Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Introducción: La polineuropatía desmielinizante inflamatoria crónica (CIDP) es una enfermedad desmielinizante e inflamatoria de mediación autoinmune. El tratamiento convencional es basado en la inmunomodulación e inmunosupresión. El uso de células madre es una terapia novedosa en los trastornos autoinmune, siendo incluida como terapia. Objetivo: Determinar la eficacia de la movilización de células madre mediante la aplicación del factor estimulador de colonias granulocíticas (F-ECG) en pacientes con CIDP que han recibido otras líneas de tratamiento. Material y Métodos: Se realizó un estudio aleatorizado, doble ciego sobre una cohorte de 45 pacientes con CIDP, donde se administró el (F-ECG) en 25 pacientes y 20 continuaron con el tratamiento habitual, tratados anteriormente con otras variantes terapéuticas por más de tres años, sin respuesta satisfactoria. Resultados: Predominio de los hombres para 64,4 por ciento, la Diabetes Mellitus tuvo mayor asociación y la medicación más usada fueron los esteroides. Los síntomas y signos clínicos mejoraron significativamente tras el tratamiento. Los valores de la puntuación del TCSS al mes y 3 meses después del tratamiento disminuyeron significativamente; pero este decremento no se mantuvo al final del estudio. La velocidad de conducción y el potencial de acción de los nervios sensoriales y motores mejoraron considerablemente después del tratamiento. Conclusiones: La efectividad de la aplicación del (F-ECG) para la mejoría de los síntomas clínicos y resultados de estudios neurofisiológicos evolutivamente son mayores que otras variantes terapéuticas en los primeros meses, con buena seguridad y tolerabilidad, por lo que se puede incluir en la terapéutica convencional para la CIDP(AU)

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune demyelinating disease. Conventional treatment is based on immunomodulation and immunosuppression. The use of stem cells is a novel therapy in autoimmune disorders, so it is included as therapy. Objective: To determine the efficacy of mobilization of stem cells by applying granulocyte colony-stimulating factor (G-CSF) in patients with CIDP who have followed other lines of treatment. Material and Methods: A randomized, double-blind study was carried out on a cohort of 45 patients with CIDP. G-CSF was administered to 25 patients and 20 of them continued with the usual treatment. These patients were previously treated with other therapeutic variants for more than three years without satisfactory response. Results: There was a prevalence of men (64.4 percent), Diabetes Mellitus had a greater association, and the most used medications were steroids. Clinical symptoms and signs improved significantly after treatment. TCSS scores significantly decreased at one and three months after treatment, but this decrease was not maintained at the end of the study. The conduction velocity and action potential of sensory and motor nerves improved considerably after treatment. Conclusions: The effectiveness of the use of G-CSF shows an improvement of clinical symptoms. The results of neurophysiological studies have a better course than other therapeutic variants during the first months, with good safety and tolerability, so it can be included in the conventional therapy for the CIDP(AU)

A novel stem cell therapy for hepatitis B virus-related acute-on-chronic liver failure

The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.

Respuesta a Factores Estimulantes de Colonias de Granulocitos en eventos de Neutropenia Febril en pacientes Oncológicos del Instituto del Cáncer Solca-Cuenca / Response to Stimulating Factors of Granulocyte Colonies in Febrile Neutropenia Events in Oncological Patients of the Cancer Institute Solca-Cuenca

Introducción: La Neutropenia Febril es una complicación potencialmente fatal del tratamiento del cáncer, relacionada con mayor morbilidad, mortalidad, disminución de dosis o retardo en los ciclos de quimioterapia, y resultados finales pobres. Estudios anteriores han demostrado el beneficio de Factor Estimulante de Colonias de Granulocitos en la reducción de tiempo de hospitalización, antibióticos intravenosos, fiebre y recuperación del conteo absoluto de neutrófilos. Se decide realizar el presente reporte ya que no existen datos respecto al manejo y respuesta al tratamiento en nuestro medio. Métodos: El presente estudio descriptivo, retrospectivo, fue realizado en el Instituto del Cáncer SOLCA ­ Cuenca. Se revisaron las historias clínicas del período 2010 ­ 2011. Las variables analizadas fueron: número de días de hospitalización, fiebre, uso de antibióticos intravenosos, y días de recuperación de neutropenia a >500/mm3 y >1000/mm3. Resultados: La estancia hospitalaria tuvo una mediana de 6 días, los días de terapia antibiótica intravenosa fueron iguales a los días de hospitalización. 79 eventos se recuperaron a un conteo absoluto de neutrófilos >500/mm3, en una mediana de 4 días; 72 eventos se recuperaron a >1000 /mm3 en una mediana de 4 días. La mayoría de los eventos se volvieron afebriles en una mediana de 1 día. Conclusión: Los resultados de las variables estancia hospitalaria, uso de antibióticos intravenosos y la duración de la fiebre fueron similares a los ya descritos en estudios anteriores, la recuperación del conteo absoluto de neutrófilos, fue más tardía, mostrando diferencias importantes con la bibliografía.

Introduction: Febrile Neutropenia is a potentially fatal complication of cancer treatment, related to higher morbidity, mortality, dose reduction or retard in chemotherapy cycles, and poor final outcomes. Previous studies have demonstrated the benefit of G-CSF (Granulocyte ­ Colony Stimulating Factors) in reduction of hospital stay, the use of intravenous antibiotics, fever and absolute neutrophil count (ANC) recovery. There is no data about the management and treatment response in our population. Methods: This is a retrospective descriptive study, developed in SOLCA ­ Cuenca Cancer Institute. 83 febrile neutropenia events met the inclusion and exclusion criteria, medical records from years 2010 to 2011 were reviewed. The analyzed variables were: days of hospital stay, fever, intravenous antibiotics use, and neutropenia recovery to a level >500/mm3 and >1000/mm3. Results: The median of hospital stay was 6 days, the duration of IV antibiotic therapy was the same as the days of hospital stay. 79 events recovered to an ANC >500/mm3, with a median of 4 days; 72 events recovered to >1000 /mm3 with a median of 4 days. The majority of events became afebrile with a median of 1 day. Conclusion: The results in the variables hospital stay, use of intravenous antibiotics and fever duration, were similar to those described in previous studies. The ANC recovery was delayed, showing important differences with cited references.

Cost-effectiveness and budgetary impact of lipegfilgrastim for the reduction of chemotherapy-induced neutropenia in Brazil / Custo-benefício e impacto orçamentário do lipegfilgrastim para a redução de neutropenia induzida por quimioterapia no Brasil

Background: Granulocyte-colony stimulating factors (G-CSFs) reduce the risk of chemotherapy-induced neutropenia. Lipegfilgrastim is a long-acting, once-per-cycle G-CSF, while Brazil's standard of care is short-acting filgrastim. A cost-effectiveness and budget impact analysis of lipegfilgrastim was conducted with filgrastim and once-per-cycle pegfilgrastim for adults at risk of neutropenia in Brazil. Methods: The decision model used national and clinical data to evaluate the costs and outcomes of each treatment. Costs included drug and medical expenses, outpatient and inpatient neutropenia treatments, and adverse events. Health outcomes included incidence of neutropenia-related events. For the budget impact analysis, health outcomes and costs for the pre/post-lipegfilgrastim scenarios were combined to identify expenditure with lipegfilgrastim's introduction. Results: Total cost per patient during a course of four chemotherapy cycles was estimated at R$12,920 for lipegfilgrastim, R$15,168 for filgrastim, and R$13,232 for pegfilgrastim. Based on better outcomes and lower total costs with lipegfilgrastim compared with filgrastim as well as pegfilgrastim, lipegfilgrastim was the dominant treatment strategy over both filgrastim and pegfilgrastim during the duration of chemotherapy treatment. Over 5 years, the uptake of lipegfilgrastim led to savings of R$61,532,403 in overall medical costs. Neutropenic events decreased by 17,141 and deaths linked to febrile neutropenia decreased by 239. Conclusion: Due to better outcomes and lower overall cost, lipegfilgrastim was a cost-saving strategy compared with filgrastim and pegfilgrastim in the Brazilian healthcare system. Furthermore, the budget impact analysis estimated a reduction in overall medical costs and improved health outcomes over 5 years following the introduction of lipegfilgrastim.

Introdução: Fatores estimuladores de colônias de granulócitos (G-CSFs) reduzem risco de neutropenia induzida por quimioterapia. Lipegfilgrastim é um G-CSF de longa ação, de "um por ciclo", enquanto o padrão de cuidado no Brasil é filgrastim de curta ação. Realizou-se uma análise de custo/ benefício e impacto orçamentário (IO) no Brasil do lipegfilgrastim um por ciclo com filgrastim e pegfilgrastim para adultos sob risco de neutropenia. Métodos: O modelo de decisão usou dados nacionais e clínicos para avaliar resultados e custos dos tratamentos que incluíam medicamentos, médicos, tratamentos ambulatoriais e hospitalares para a neutropenia, e eventos adversos. Resultados de saúde incluíam a incidência de eventos relacionados à neutropenia. Para a análise do IO, os custos e resultados de antes/depois do lipegfilgrastim foram combinados para identificar gastos com o lipegfilgrastim. Resultados: O custo total por paciente em quatro ciclos foi estimado em R$ 12.920 para lipegfilgrastim, R$ 15.168 para filgrastim e R$ 13.232 para pegfilgrastim. Com base em melhores resultados e custos totais menores, o lipegfilgrastim, comparado ao filgrastim e ao pegfilgrastim, representou a estratégia de tratamento predominante. Em 5 anos, o lipegfilgrastim gerou uma economia de R$ 61.532.403 em custos médicos gerais. Houve 17.141 menos eventos neutropênicos e as mortes relacionadas à neutropenia febril reduziram em 239. Conclusão: Devido a melhores resultados e menores custos, lipegfilgrastim, comparado ao filgrastim e ao pegfilgrastim, foi uma estratégia econômica no sistema brasileiro. A análise de IO estimou uma redução nos custos médicos e melhorou os resultados em 5 anos após a introdução do lipegfilgrastim.

Granulocyte colony-stimulating factor combined with Methylprednisolone improves functional outcomes in rats with experimental acute spinal cord injury

OBJECTIVES: To evaluate the effects of combined treatment with granulocyte colony-stimulating factor (G-CSF) and methylprednisolone in rats subjected to experimental spinal cord injury. METHODS: Forty Wistar rats received a moderate spinal cord injury and were divided into four groups: control (no treatment); G-CSF (G-CSF at the time of injury and daily over the next five days); methylprednisolone (methylprednisolone for 24 h); and G-CSF/Methylprednisolone (methylprednisolone for 24 h and G-CSF at the time of injury and daily over the next five days). Functional evaluation was performed using the Basso, Beattie and Bresnahan score on days 2, 7, 14, 21, 28, 35 and 42 following injury. Motor-evoked potentials were evaluated. Histological examination of the spinal cord lesion was performed immediately after euthanasia on day 42. RESULTS: Eight animals were excluded (2 from each group) due to infection, a normal Basso, Beattie and Bresnahan score at their first evaluation, or autophagy, and 32 were evaluated. The combination of methylprednisolone and G-CSF promoted greater functional improvement than methylprednisolone or G-CSF alone (p<0.001). This combination also exhibited a synergistic effect, with improvements in hyperemia and cellular infiltration at the injury site (p<0.001). The groups displayed no neurophysiological differences (latency p=0.85; amplitude p=0.75). CONCLUSION: Methylprednisolone plus G-CSF promotes functional and histological improvements superior to those achieved by either of these drugs alone when treating spinal cord contusion injuries in rats. Combining the two drugs did have a synergistic effect.

The safety and clinical efficacy of recombinant human granulocyte colony stimulating factor injection for colon cancer patients undergoing chemotherapy

Summary Objective: The present study was designed to evaluate safety and efficacy of recombinant human granulocyte colony stimulating factor (G-CSF) injection and whether this regimen could reduce the incidence of adverse events caused by chemotherapy. Method: A total of 100 patients with colon cancer who were treated with chemotherapy in our hospital from January 2011 to December 2014 were randomly divided into two groups, with 50 patients in each group. The patients in the treatment group received G-CSF 24 hours after chemotherapy for consecutive three days; the patients in the control group received the same dose of normal saline. Routine blood tests were performed 7 days and 14 days after chemotherapy. Results: Compared with the control group, the incidences of febrile neutropenia and leukocytopenia in the treatment group were significantly lower (p<0.05). In addition, the incidence of liver dysfunction in the treatment group was lower than that of the control group, without statistical significance. The incidence of myalgia in the treatment was higher than that of the control group without statistical significance. Conclusion: The present study indicated that G-CSF injection after chemotherapy is safe and effective for preventing adverse events in colon cancer patients with chemotherapy.

Revisão sistemática e análise de custo- minimização de lipegfilgrastim na profilaxia da neutropenia e da neutropenia febril relacionadas à quimioterapia citotóxica / Systematic review and cost-minimization analysis of lipegfilgrastim in the prophylaxis of neutropenia and febrile neutropenia related to cytotoxic chemotherapy

Objetivo: Realizar avaliação econômica de lipegfilgrastim, fator de crescimento de longa duração (G-CSF), com os demais medicamentos da classe terapêutica disponíveis para a diminuição da duração da neutropenia grave (NG) e da incidência de neutropenia febril (NF), em pacientes adultos tratados com quimioterapia citotóxica para neoplasias malignas. Métodos: Revisão sistemática da literatura de evidências científicas sobre a eficácia e a segurança de lipegfilgrastim e análise de custo-minimização em comparação com pegfilgrastim ou filgrastim sob a perspectiva do Sistema Suplementar no Brasil. A análise incluiu tempo de tratamento de estudos clínicos, custo de infusão/ honorários médicos e custo com aquisição de medicamentos, distribuídos em três perspectivas: cenário 1 (conservador), cenário 2 (moderado) e cenário 3 (mundo real). Resultados: Seis estudos foram incluídos na análise, sendo três estudos randomizados e três revisões sistemáticas. O lipegfilgrastim resultou numa duração média de NG significativamente menor ao placebo e não inferior ao pegfilgrastim. Um estudo que comparou indiretamente lipegfilgrastim com filgrastim não encontrou diferenças estatisticamente significativas em redução de duração de NG e incidência de NF. O lipegfilgrastim apresentou redução de custos diretos de -R$ 3.673,50/paciente comparado com pegfilgrastim em todos os cenários avaliados e, na comparação com filgrastim, observou-se redução de -R$ 57.403,40; -R$ 19.183,67 e de -R$ 42,50/paciente nos cenários 1, 2 e 3, respectivamente. Conclusões: Lipegfilgrastim apresentou perfil de custo-minimização favorável em comparação com pegfilgrastim ou filgrastim, e surge como uma importante alternativa para o tratamento da redução da duração da neutropenia e da incidência da neutropenia febril durante a realização de tratamento quimioterápico, que pode representar economia de recursos para o Sistema de Saúde Suplementar.

jective: To develop an economic evaluation of lipegfilgrastin, long acting G-CSF, compared to other available G-CSF to reduce the duration of severe neutropenia (SN) and the incidence of febrile neutropenia (FN) in adult patients treated with cytotoxic chemotherapy for cancer in the Brazilian private Health System. Methods: Systematic literature review of scientific evidence evaluating the efficacy and safety of lipegfilgrastin and cost-minimization analysis comparing to pegfilgrastin or filgrastin in the Brazilian private Health System. The analysis includes time of treatment with filgrastin from clinical trials (scenario 1) or real world data (scenario 2 and 3) and considers direct medical costs. Results: Six studies were included in the analysis: three randomized controlled trials and three systematic reviews. Lipegfilgrastin resulted in a statistically significant reduction of median SN duration compared to placebo and non-inferior compared to pegfilgrastin. A study that performed an indirect comparison of lipegfilgrastin and filgrastin did not find any difference statistically significant reduction of SN duration and FN incidence. Lipefilgrastin resulted in a cost-difference of -R$ 3.673,50/patient compared to pegfilgrastin in all scenarios and -R$ 57.403,40; -R$ 19.183,67 and -R$ 42,50/patient compared to filgrastin in scenario 1, 2 and 3 respectively. Conclusions: Lipegfilgrastim showed a favorable cost-minimization profile compared to pegfilgrastin or filgrastin and is an important alternative treatment in reducing the duration of neutropenia and the incidence of febrile neutropenia during the course of chemotherapy, and may result in resource savings for the Brazilian Private Health System.

Is it feasible to use granulocyte-colony stimulating factor alone to mobilize progenitor cells in multiple myeloma patients induced with a cyclophosphamide, thalidomide and dexamethasone regimen?

ABSTRACT Background: Cyclophosphamide plus thalidomide as induction for multiple myeloma patients eligible for autologous stem cell transplantation may be a limiting factor for cell mobilization. The minimum acceptable mobilized peripheral blood stem cell count to prevent deleterious effects during transplantation is 2.0 × 106 CD34+ cells/kg. Combining other treatments to granulocyte-colony stimulating factor, such as cyclophosphamide, could overcome the mobilization limitation. The objective of this study was to assess the number of CD34+ cells mobilized using granulocyte-colony stimulating factor with and without cyclophosphamide after induction with cyclophosphamide, thalidomide and dexamethasone. Methods: A retrospective study was performed of a cohort of multiple myeloma patients submitted to autologous stem cell transplantations at two Brazilian centers between May 2009 and July 2013. The oral cyclophosphamide and thalidomide induction doses used were 1500 mg/month and 100-200 mg/day, respectively. Mobilization doses were 10-15 mcg/kg granulocyte-colony stimulating factor with 2-4 g/m2 cyclophosphamide, or 15-20 mcg/kg granulocyte-colony stimulating factor alone for 5 days. Collection of >2.0 × 106 CD34+ cells/kg was considered sufficient. Results: Eighty-eight patients were analyzed; only 18 received cyclophosphamide. The median age was 58 years old (range: 51-62) for the granulocyte-colony stimulating factor group and 56.5 years old (range: 54-60) for granulocyte-colony stimulating factor plus cyclophosphamide group. Fifty-two patients were male. Eighty cases (90.9%) were Durie-Salmon Staging System III-A/B and 38 (44.7%) and 20 cases (23.5%) were International Staging System 2 and 3, respectively. The group that received cyclophosphamide collected a higher median number of progenitor cells [3.8 (range: 3.1-4.4) vs. 3.2 (range: 2.3-3.8)] (p-value = 0.008). No correlation was observed between better responses or number of induction cycles and the number of cells collected. Conclusion: The number of cells mobilized with granulocyte-colony stimulating factor plus cyclophosphamide was higher. However, in both groups, the median number of CD34+ cells was sufficient to perform a single autologous stem cell transplantation; no deleterious effects were reported during harvesting.

Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations / Mobilização de células progenitoras hematopoéticas para transplante autólogo: recomendações de consenso

SUMMARY Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources.

RESUMO Pacientes selecionados com certas neoplasias hematológicas e tumores sólidos têm o potencial de alcançar sobrevida de longo prazo com o transplante autólogo de células progenitoras hematopoéticas. A coleta dessas células no sangue periférico evita múltiplas aspirações de medula óssea, resulta em enxertia mais rápida, e permite o tratamento de pacientes com infiltração, fibrose ou hipocelularidade medular. Contudo, para o sucesso desse procedimento, é essencial mobilizar um número suficiente de células progenitoras da medula óssea para a circulação sanguínea. Por isso, um painel de especialistas brasileiros se reuniu com o objetivo de desenvolver recomendações para estratégias de mobilização adaptadas à realidade do sistema de saúde nacional, que pudessem contribuir para minimizar os riscos de falha, reduzir a toxicidade e melhorar a alocação de recursos financeiros.

A intervenção educativa do enfermeiro no uso domiciliar do fator estimulador de colônias granulocítica (G-CSF): relato de experiência / The educational intervention of nurses in home use of granulocyte colony stimulating factor (G - CSF): experience report

Relatar a experiência oriunda da vivência de uma enfermeira assistencial, desenvolvidas no setor de quimioterapia infantil com os familiares de crianças em tratamento quimioterápico no âmbito ambulatorial e que fazem uso do G-CSF em domicilio. MÉTODO: estudo descritivo, tipo relato de experiência, realizado no serviço de quimioterapia infantil de um hospital público de referência no atendimento oncológico e de ensino e pesquisa do RJ Alicerçou-se na vivência de acompanhar os familiares de criança em tratamento quimioterápico que cursam com neutropenia pós-quimioterapia e necessitam do G-CSF, e busca promover o acolhimento deste familiar através da educação a partir da compreensão do sofrimento vivenciado pelo familiar da criança com câncer no processo do cuidado em domicilio. CONCLUSÃO: o enfermeiro que assiste á criança em tratamento oncológico deve ser capacitado, ter sensibilidade e compreender que a sua assistência é estendida a este familiar mediante as suas necessidades de acolhimento durante as diversas fases do tratamento da criança...

To report the experience comes from the experience of an assistant nurse, developed in the sector of chemotherapy playground with family members of children in chemotherapeutic treatment under ambulatory and who make use of the G-CSF in their formative years. Method: Descriptive study experience report, accomplished in the service of chemotherapy playground of a public hospital of reference in Oncological care and of teaching and research of RJ. Supported in the experience of accompany family of a child in chemotherapeutic treatment coursing with neutropenia post-chemotherapy and need of G-CSF, and seeks to promote the acceptance of this family through education from the understanding of the suffering experienced by the family of the child with cancer in the process of care in the home. Conclusion: the nurse who assists will be child in oncologic treatment must be trained, have sensitivity and understand that its assistance is extended to this family through their host needs during the various stages of the treatment of the child...

Presentar la experiencia derivada de una enfermera clínica, desarrollada en el sector de la quimioterapia infancia con las familias de los niños que reciben quimioterapia en forma ambulatoria y hacer uso de G-CSF en domicilio. Métodos: Estudio descriptivo, informe de la experiencia, que se celebró en el servicio de la quimioterapia de los nines de un hospital público de referencia en el tratamiento del cáncer y de la ensenanza y la investigación de RJ Sus fundamentos en la experiencia de acompanar a la familia del niño en concomitante quimioterapia, con neutropenia después de la quimioterapia y la necesidad de que el G-CSF, y busca promover la acogida de esta família a través de la educación a partir de la comprensión del sufrimiento experimentado por la familia del niño con proceso de atención del cáncer en el hogar. CONCLUSION: La enfermera que ayude aios nines en el tratamiento del cáncer debe ser calificado, ser sensibles y entienden que su asistencia se extiende a esta familia a través de sus necesidades de alojamiento durante las diversas etapas del tratamiento del niño...

Ação educativa do enfermeiro no cuidado domiciliar de adolescentes e crianças: uso do fator estimulador de crescimento de colônia granulocítica (G-CSF) ­ uma perspectiva fenomenológica / Nursing education in the home care of adolescents and children: use of granulocytic colony growth stimulating factor (G-CSF) - a phenomenological perspective

Problema: Atualmente o câncer infantil representa a segunda causa de morte na faixa etária de 5 a 19 anos, ultrapassado apenas pelos óbitos provocados por causas externas. E, a partir do diagnóstico, traça-se uma das propostas de tratamento, a terapêutica com os agentes antineoplásicos, conhecidos como quimioterápicos, os quais são responsáveis pelo longo período de internação, tendo em vista que um dos efeitos adversos desta terapêutica com maior incidência é a neutropenia pós-quimioterapia. Tal condição representada pela contagem de neutrófilos inferior a 1500/m3 torna necessário o uso de moduladores de resposta muitas vezes em domicílio. Objetivo: Este estudo tem como objetivo construir uma ação educativa durante a utilização em domicílio do fator estimulador de colônias granulocíticas (G-CSF), pelo paciente e/ou familiar, buscando conhecer o significado desta ação educativa a ser construída em conjunto com os familiares, considerando e respeitando o conhecimento e saber emanado por eles, em todo o processo holístico de saúde onde o indivíduo apresenta necessidades interligadas ao meio que o cerca. Método: É um estudo de natureza qualitativa, tipo descritivo com apropriação do método fenomenológico na percepção de Maurice Merleau Ponty, e a teoria transpessoal de Jean Watson e teve como cenário o centro de quimioterapia infantil do Instituto Nacional de Câncer, que é uma Instituição Pública Federal de referência na área oncológica, e obteve aprovação no CEP em 22/12/2015n° do CAAE-51715515.500005243 e no CEP da instituição coparticipante em 07/01/2016 n0 do CAAE-51715515.5.3001.5274. O estudo foi desenvolvido em conformidade com os princípios éticos estabelecidos na Resolução do Conselho Nacional de Saúde (CNS) 466/12. Resultado: A coleta de dados ocorreu no serviço de quimioterapia infantil por meio de entrevista com participação de dezoito familiares. As entrevistas foram transcritas na integra com apropriação do método de Giorgi e após analise a luz da fenomenologia da Percepção de Maurice Merleau-Ponty originou-se a formação de quatro categorias: Categoria 1-O impacto do diagnóstico de câncer na perspectiva do familiar; Categoria 2-O significado do câncer e tratamento na percepção do familiar; Categoria 3-A importância da espiritualidade na percepção do familiar da criança com câncer; 4-O significado do cuidado domiciliar na perspectiva do familiar. Considerações finais: Durante o decorrer deste estudo percorreu-se um caminho direcionado ao cuidado, tanto ao cuidador quanto do ser a ser cuidado com o objetivo de compreender e auxiliar os familiares no processo do cuidar a partir da percepção da experiência vivenciada por estes em um contexto familiar. Tais propósitos incluíram o respeito e valorização do conhecimento e das experiências desses familiares, incluindo suas crenças, cultura, e hábitos sociais. E, neste contexto é de extrema importância que o enfermeiro vivencie a experiência a partir da percepção do sujeito deste estudo, considerando os conceitos humanísticos, visando almejar uma assistência cada vez mais qualificada e de excelência, o que propiciou a construção de uma tecnologia educacional (cartilha educativa), no que se refere ao uso em domicilio do fator estimulador de crescimento de colônias de granulócitos

Problem: Currently, childhood cancer represents the second cause of death in the age group of 5 to 19 years, surpassed only by deaths caused by external causes. From the diagnosis, one of the treatment proposals is the treatment with antineoplastic agents, known as chemotherapeutic agents, which are responsible for the long period of hospitalization, considering that neutropenia is one of the adverse effects of this therapy with a higher incidence after chemotherapy. That condition, represented by the neutrophil count below 1500 / m3 makes it necessary to use response modulators often at home. Objective: This study aimed to construct an educational action during the use of the granulocytic colony-stimulating factor (G-CSF), by the patient and / or family member at home. It seeks to know the meaning of this educational action built together with the family, considering and respecting the knowledge and knowledge emanated by them, throughout the holistic process of health where the individual present needs interconnected to the environment that surrounds him. Method: It is a descriptive qualitative study, based on the phenomenological method from the perspective of Maurice Merleau Ponty, and the transpersonal theory of Jean Watson. It had as setting the child chemotherapy center of the National Cancer Institute, which is a public federal hospital, specialized in oncology area, and obtained approval in the CEP on 12/22/2015 under protocol number CAAE51715515.500005243 and in the CEP of the participating Institution on 07/01/2016 under protocol number CAAE-51715515.5.3001.5274. The study was developed in conformity with the ethical principles set out in National Health Council (CNS) Resolution No.466/12. Results: Data collection took place in the infant chemotherapy service through an interview with the participation of eighteen relatives. We transcribed the interviews in full, with appropriation of the Giorgi method, followed by analysis under the perspective of the phenomenology of Perception by Maurice Merleau Ponty. Then, four categories originated category 1. The impact of the cancer diagnosis from the family perspective; category; 2. The meaning of the cancer and treatment under the perception of the family member; category 3. The importance of the spirituality under the perception of the family member of the child with cancer; -the meaning of home care from the perspective of the family member. Final Considerations. During the development of this study, we went through a path directed to care that reached both the caregiver and the being to be cared for with the objective of understanding and helping the family in the care process from the perception of experiences lived by them in a family context. Such purposes included the respect and valorization of the knowledge and experiences of these relatives, including their beliefs, culture, and social habits. And in this context, it is extremely important that nurses live the experience from the perception of the subject of this study, considering the humanistic concepts, aiming for an increasingly qualified and excellent assistance, which has enabled the construction process of an educational technology (educational leaflet) as regards the use at home of granulocytes colony stimulating factor

Problema: En la actualidad el cáncer infantil es la segunda causa de muerte en el grupo de edad de 5-19 años sólo superada por las muertes provocadas por causas externas. Y, desde el diagnóstico, se expone una de las propuestas de tratamiento, la terapéutica con agentes antineoplásicos, conocidos como la quimioterapia, los cuales son responsables por el largo período de hospitalización, dado que algunos de los efectos adversos de este tratamiento con mayor incidencia es la neutropenia pos quimioterapia. Tal condición representada por un conteo de neutrófilos inferior a 1.500 / m3 hace que sea necesario el uso de moduladores de la respuesta muchas veces en el domicilio. Objetivo: Este estudio tiene como objetivo construir una actividad educativa durante el uso del estimulador de colonias de factor de granulocitos (G-CSF), el paciente y / o familia en uso en el familiar, buscando conocer el significado de esta actividad educativa que se construirá en conjunto con el familia, teniendo en cuenta y respetando los conocimientos y experiencia que emana de ellos durante todo el proceso holístico de salud donde el individuo presenta necesidades interrelacionadas con el medio que lo rodea. Método: Se trata de un estudio cualitativo, descriptivo, con la apropiación del método fenomenológico en la percepción de Maurice Merleau-Ponty, y la teoría transpersonal Jean Watson y se realizó en el centro de la quimioterapia de los niños del Instituto Nacional del Cáncer, que es una institución pública Federal referencia en oncología, con la aprobación en el CEP Coordinador 22/12/2015 Nº de CAAE-51715515.500005243 y CEP de la institución copartícipe en el CAAE 01/07/2016 N.51715515.5.3001.5274. Se realizó a partir de los principios éticos que implican la investigación en seres humanos. Resultados: Los datos fueron recolectados en el servicio de quimioterapia infantil a través de entrevistas con la participación de dieciocho familiares. Las entrevistas se transcribieron enteras con apropiación del método de Giorgi y después del análisis a la luz de la fenomenología de Maurice Merleau-Ponty se originó la formación de cuatro categorías: Categoría 1-El impacto del diagnóstico de cáncer en la perspectiva de la familia; Categoría 2-El significado del cáncer y el tratamiento en la percepción de la familia; Categoría 3-La importancia de la espiritualidad en la percepción de la familia de los niños con cáncer; 4-El significado de la atención domiciliaria en perspectiva familiar. Consideraciones finales: En el transcurso del estudio se ha recorrido un camino dirigido a la atención, para llegar tanto al cuidador como al ser humano que debe ser cuidado con el fin de comprender y ayudar a la familia en el proceso de atención a de la percepción de la experiencia vivida por ellos en un contexto familiar, respetando y valorando los conocimientos y experiencias de vida de estas familias, con sus creencias, la cultura y los hábitos sociales y, en este contexto, es extremadamente importante que las enfermeras experimentan la experiencia a partir de la percepción del sujeto de este estudio, teniendo en cuenta los conceptos humanísticos, buscando una asistencia cada vez más cualificada y de excelencia, que propició la construcción de una tecnología educativa (cartilla educativa) en lo que respecta al uso en domicilio del factor de crecimiento de colonias de granulocitos

Assessment of Autonomic Function by Phase Rectification of RRInterval Histogram Analysis in Chagas Disease / Avaliação da Função Autonômica na Doença de Chagas Através da Análise de Histogramas de Intervalos RR com Retificação de Fase

Background: In chronic Chagas disease (ChD), impairment of cardiac autonomic function bears prognostic implications. Phase‑rectification of RR-interval series isolates the sympathetic, acceleration phase (AC) and parasympathetic, deceleration phase (DC) influences on cardiac autonomic modulation. Objective: This study investigated heart rate variability (HRV) as a function of RR-interval to assess autonomic function in healthy and ChD subjects. Methods: Control (n = 20) and ChD (n = 20) groups were studied. All underwent 60-min head-up tilt table test under ECG recording. Histogram of RR-interval series was calculated, with 100 ms class, ranging from 600–1100 ms. In each class, mean RR-intervals (MNN) and root-mean-squared difference (RMSNN) of consecutive normal RR-intervals that suited a particular class were calculated. Average of all RMSNN values in each class was analyzed as function of MNN, in the whole series (RMSNNT), and in AC (RMSNNAC) and DC (RMSNNDC) phases. Slopes of linear regression lines were compared between groups using Student t-test. Correlation coefficients were tested before comparisons. RMSNN was log-transformed. (α < 0.05). Results: Correlation coefficient was significant in all regressions (p < 0.05). In the control group, RMSNNT, RMSNNAC, and RMSNNDC significantly increased linearly with MNN (p < 0.05). In ChD, only RMSNNAC showed significant increase as a function of MNN, whereas RMSNNT and RMSNNDC did not. Conclusion: HRV increases in proportion with the RR-interval in healthy subjects. This behavior is lost in ChD, particularly in the DC phase, indicating cardiac vagal incompetence. .

Fundamento: Na doença de Chagas (DCh) crônica, a função autonômica cardíaca está frequentemente comprometida e traz implicações quanto ao prognóstico. A retificação de fase da série de intervalos RR isola as influências simpática (fase de aceleração – AC) e parassimpática (fase de desaceleração – DC) na modulação autonômica cardíaca. Objetivo: Este estudo investigou a variabilidade da frequência cardíaca (VRR) como função dos intervalos RR, para avaliar a função autonômica em indivíduos saudáveis e com DCh. Métodos: Os grupos controle (n = 20) e com DCh (n = 20) foram estudados. Todos fizeram o teste de inclinação ortostática de 60 minutos, com o registro do ECG. O histograma da série de intervalos RR dividido em classes de 100 ms, variando de 600 a 1100 ms foi calculado. Para cada classe, foram calculados os intervalos RR médios (MNN) e a diferença média quadrática (RMS) entre os intervalos RR normais que se encaixavam naquela classe. A média de todos os valores de RMS foi analisada como uma função dos MNN na série inteira (RMST) e nas fases de aceleração (RMSAC) e desaceleração (RMSDC). A inclinação das linhas de regressão linear foi comparada entre grupos através do teste t de Student. Os coeficientes de correlação foram testados antes das comparações. A RMS sofreu transformação logarítmica (α < 0,05). Resultados: O coeficiente de correlação foi significativo em todas as regressões (p < 0,05). No grupo controle, a RMST, a RMSAC e a RMSDC aumentaram de forma significativa proporcionalmente ao MNN (p < 0,05). No grupo com DCh, apenas a RMSAC mostrou um aumento significativo como função do MNN, enquanto a RMST e a RMSDC não aumentaram significativamente. Conclusão: A VRR aumenta proporcionalmente ao intervalo RR em indivíduos saudáveis. Este comportamento é perdido na DCh, especialmente na DC, indicando incompetência vagal cardíaca. .

Mobilization and collection of CD34+ cells for autologous transplantation of peripheral blood hematopoietic progenitor cells in children: analysis of two different granulocyte-colony stimulating factor doses

The use of peripheral hematopoietic progenitor cells (HPCs) is the cell choice in autologous transplantation. The classic dose of granulocyte-colony stimulating factor (G- CSF) for mobilization is a single daily dose of 10 µg/kg of patient body weight. There is a theory that higher doses of granulocyte-colony stimulating factor applied twice daily could increase the number of CD34+ cells collected in fewer leukapheresis procedures. Objective: The aim of this study was to compare a fractionated dose of 15 µg G-CSF/kg of body weight and the conventional dose of granulocyte-colony stimulating factor in respect to the number of leukapheresis procedures required to achieve a minimum collection of 3 × 106 CD34+ cells/kg body weight. Methods: Patients were divided into two groups: Group 10 - patients who received a single daily dose of 10 µg G-CSF/kg body weight and Group 15 - patients who received a fractioned dose of 15 µg G-CSF/kg body weight daily. The leukapheresis procedure was carried out in an automated cell separator. The autologous transplantation was carried out when a minimum number of 3 × 106 CD34+ cells/kg body weight was achieved. Results: Group 10 comprised 39 patients and Group 15 comprised 26 patients. A total of 146 apheresis procedures were performed: 110 (75.3%) for Group 10 and 36 (24.7%) for Group 15. For Group 10, a median of three (range: 1-7) leukapheresis procedures and a mean of 8.89 × 106 CD34+ cells/kg body weight (±9.59) were collected whereas for Group 15 the corresponding values were one (range: 1-3) and 5.29 × 106 cells/kg body weight (±4.95). A statistically significant difference was found in relation to the number of apheresis procedures (p-value <0.0001). Conclusions: To collect a minimum target of 3 × 106 CD34+ cells/kg body weight, the administration of a fractionated dose of 15 µg G-CSF/kg body weight significantly decreased the number of leukapheresis procedures performed.

Sangramiento digestivo asociado al tratamiento con filgrastim: efecto secundario infrecuente / Digestive bleeding associated to treatment with filgrastin: infrequent adverse side effect

El factor estimulante de colonias granulocíticas (FEC-G), Filgrastim, es utilizado cada día con mayor frecuencia como agente movilizador para la obtención de concentrado de células progenitoras de sangre periférica. Generalmente, la movilización con FEC-G es bien tolerada aunque se ha reportado un amplio espectro de reacciones adversas asociadas a su uso, que incluyen: cefalea, poliartralgia y mialgia entre las más comunes. Ocasionalmente se han comunicado epistaxis y hemorragia retiniana. Los fenómenos tromboembólicos, el distrés respiratorio, la ruptura esplénica, la hemorragia intracraneal son algunos de los efectos secundarios rara vez comunicados. Las manifestaciones digestivas como náuseas y vómitos son frecuentes, no así los sangramientos del tracto digestivo...