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Introducción : Los linfomas son la tercera neoplasia maligna en los niños y, dentro de ellos, los linfomas no Hodgkin (LNH) representan tan solo el 7% del cáncer en menores de 15 años. La quimioterapia constituye actualmente el tratamiento de elección. El objetivo de este estudio es analizar la toxicidad secundaria al tratamiento en pacientes pediátricos diagnosticados de LNH. Material y métodos: Estudio retrospectivo de pacientes diagnosticados de LNH de células B maduras tratados según el protocolo LMB 2001, desde enero del 2007 hasta febrero del 2014. Se recogieron los datos referentes al diagnóstico, el tratamiento y las toxicidades que desarrollaron durante el mismo. Resultados: Se diagnosticaron 20 LNH de células B maduras: 16 linfomas Burkitt, 2 linfomas difusos de células grandes y 2 leucemias maduras. Un 65% de los pacientes se clasificó al diagnóstico en un estadio de alto grado (III-IV). Los procesos infecciosos graves, la mielosupresión severa, las alteraciones hepáticas y la mucositis fueron las toxicidades más frecuentes. La supervivencia global fue del 95% (19/20). Un paciente falleció por causas no relacionadas con su enfermedad. Conclusión: La mayoría de los pacientes diagnosticados de LNH de células B maduras experimentan toxicidades grado III y IV durante el tratamiento, a pesar de lo cual la supervivencia es excelente (AU)

Introduction: Lymphomas are the third malignancy in children, and within them non-Hodgkin lymphoma (NHL) accounts for just 7% of cancers in children under 15 years old. Chemotherapy is currently the treatment of choice. The objective of this study is to analyze the toxicity caused by the treatment in pediatric patients diagnosed with NHL. Material and methods: A retrospective study was conducted on patients diagnosed with mature B-cell NHL, treated according to the LMB protocol 2001, from January 2007 to February 2014. Data concerning the diagnosis, treatment and toxicities that developed in the patients during the same period were collected. Results: A total of 20 mature B-cell NHL cases were diagnosed: 16 Burkitt lymphomas, 2 diffuse large cell lymphomas and 2 mature leukemias. Almost two-thirds (65%) of patients were classified in a high grade stage (III-IV) at diagnosis. Serious infectious processes, severe myelosuppression, liver abnormalities, and mucositis were the most frequent toxicities. Overall survival was 95% (19/20). One patient died of causes unrelated to the illness. Conclusion: Despite the excellent survival rate, most patients diagnosed with NHL mature B cells experience grade III and IV toxicities during treatment (AU)

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Alternative methods are being developed to reduce, refine, and replace (3Rs) animals used in experiments, aimed at protecting animal welfare. The present study reports alternative tests which are based on the principles of the 3Rs and the efforts made to validate these tests. In Europe, several methodologies have already been implemented, such as tests of irritability, cell viability, and phototoxicity as well as in vitro mathematical models together with the use of in silico tools. This is a complex process that spans from development to regulatory approval and subsequent adoption by various official entities. Within this regulatory framework is REACH, the European Community Regulation for chemicals and their safe use. In Brazil, the BraCVAM (Brazilian Center for the Validation of Alternative Methods) was recently established to validate alternative methods and stimulate incorporation of new methodologies. A new vision of toxicology is emerging for the 21st century (Tox-21), and the subsequent changes are shaping a new paradigm.

Métodos alternativos estão sendo desenvolvidos para a redução, o refinamento e a substituição (3R) do número de animais utilizados em experimentos, visando ao seu bem-estar. Esses testes alternativos baseiam-se no princípio dos 3R e esforços têm sido empregados para que sejam validados. Na Europa, diversas metodologias já foram implantadas tais como: testes de irritabilidade, testes de viabilidade celular, testes de fototoxicidade e modelos matemáticos in vitro, além do uso de ferramentas in silico. Esse é um processo complexo, que abrange desde o seu desenvolvimento até a aceitação regulatória e posterior adoção por diversas organizações oficiais. No contexto regulatório está o REACH, o Regulamento da Comunidade Européia, para produtos químicos e sua utilização segura. No Brasil, o BraCVAM (Centro Brasileiro de Validação de Métodos Alternativos) foi recentemente estabelecido para validação de métodos alternativos e estímulo à incorporação de novas metodologias. Uma nova visão de toxicologia vem surgindo para o século XXI (Tox-21) e as mudanças ocasionadas promoverão um novo paradigma.

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Intoxications have become a relevant complaint in the emergency room since the second half of the last century. Toxidromes have been replaced by a more practical combined analysis of vital signs, directed physical examination and selected laboratory tests. Most of the mortality can be prevented by the correct and opportune implementation of general management strategies, including supportive care, prevention of absortion, enhancement of elimination and extracorporeal removal of toxins. Through the following pages we will review many of different diagnostic and therapeutic alternatives...

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INTRODUCTION: Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine, which is not life-threatening but could compromise capecitabine efficacy. MATERIALS AND METHODS: This phase II, multicenter, non-controlled study assessed the safety, particularly grade three HFS incidence, and efficacy of four capecitabine-based chemotherapy regimens [cisplatin/capecitabine (CX), epirubicin/cisplatin/capecitabine (ECX), epirubicin/oxaliplatin/capecitabine (EOX) and docetaxel/cisplatin/capecitabine (DCX)] as first-line treatment for advanced and/or metastatic gastric cancer. RESULTS: One hundred and eight patients were assigned to one of the four treatment groups, according to investigator's criteria, and grouped together for both safety and efficacy primary analyses. HFS was reported in 31 patients (19.6%) and its first presentation occurred at a median of 72 days (range 19-209 days). Grade 3 HFS developed in 6.3, 5.2, 3.7 and 2.4%, of patients receiving ECX, DCX, EOX or CX chemotherapy regimen, respectively. Capecitabine dose reduction/discontinuation due to HFS was required in 5.7% of patients (9/158). The most common (> 10%) grade 3-4 treatment-related AEs were neutropenia (15.2%), asthenia (12.0%) and diarrhoea (11.4%). CONCLUSIONS: A moderate incidence of HFS was reported in patients treated with capecitabine, which generally presented late and required dose reduction in < 1/3 of patients. The results suggest that capecitabine may be useful in combination with standard fluorouracil-based regimens in patients with advanced and/or metastatic gastric cancer with favourable safety profile (AU)

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Se discuten diversas interpretaciones del término tóxico y la necesidad de actualizar la definición adaptándola a los cambios producidos por los avances científicos. Tras analizar los factores que contribuyen a la relatividad del término y sus fronteras, se propone una definición clara y precisa, que pretende ajustarse al concepto más ampliamente extendido de su significado. La nueva definición dice: «tóxico es, para los seres humanos y su entorno biológico no patógeno o dañino, toda radiación electromagnética o corpuscular y todo agente químico no infeccioso, de tamaño no superior a una pequeña partícula o fibra, que, tras generarse internamente o entrar en contacto, penetrar y/o ser absorbido por un organismo vivo, en dosis suficientemente alta, puede producir o produce un efecto adverso directo o indirecto en el mismo no manifiestamente relacionado con su temperatura o con una diferencia mensurable de potencial eléctrico». El conocimiento científico precisa definiciones exactas que eviten ambigüedades (AU)

We discuss different interpretations of the term poison as well as the need of bringing up to date the changes in this matter according to the science progress. A clear and exact definition is proposed after analysing the factors that affect the relativity of the concept and its boundaries. The proposal for a definition is presented taking into account the most broadly extended concepts concerning its significance. That is to say: "a poison is, for human beings and their non-pathogenic and non-harmful biological environment, an electromagnetic or corpuscular radiation, or a non-infectious chemical agent, structured no larger in size than a small particle or fibre that, after being generated internally or after contact, penetration and/or absorption by a live organism, in sufficiently high dose, can produce or produces a direct or indirect adverse effect unrelated to its temperature or measurable electrical potential difference". The scientific knowledge needs accurate definitions to avoid ambiguities (AU)

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The centrally located a-helix 5 of Bacillus thuringiensis d-endotoxins is critical for insect toxicity through ion-channel formation. We analyzed the role of the highly conserved residue Histidine 168 (H168) using molecular biology, electrophysiology and biophysical techniques. Toxin H168R was ~3-fold more toxic than the wild type (wt) protein whereas H168Q was 3 times less toxic against Manduca sexta. Spectroscopic analysis revealed that the H168Q and H168R mutations did not produce gross structural alterations, and that H168R (Tm= 59 °C) was more stable than H168Q (Tm= 57.5 °C) or than the wt (Tm= 56 °C) toxins. These three toxins had similar binding affinities for larval midgut vesicles (Kcom) suggesting that the differences in toxicity did not result from changes in initial receptor binding. Dissociation binding assays and voltage clamping analysis suggest that the reduced toxicity of the H168Q toxin may result from reduced insertion and/or ion channel formation. In contrast, the H168R toxin had a greater inhibition of the short circuit current than the wt toxin and an increased rate of irreversible binding (kobs), consistent with its lower LC50 value. Molecular modeling analysis suggested that both the H168Q and H168R toxins could form additional hydrogen bonds that could account for their greater thermal stability. In addition to this, it is likely that H168R has an extra positive charge exposed to the surface which could increase its rate of insertion into susceptible membranes.

La a-Hélice 5 del domino I de las d-endotoxinas de Bacillus thuringiensis, es crítica para la toxicidad de las toxinas contra insectos al participar en la formación de canales iónicos. La participación en la función tóxica del residuo Histidina 168 (H168) –el cual es altamente conservado– fue estudiada mediante técnicas de biología molecular, electrofisiología y biofísica. La toxina mutante H168R fue ~ 3 veces más tóxica que la toxina silvestre (ts) en Manduca sexta, mientras que H168Q fue 3 veces menos tóxica. Los análisis espectroscópicos indicaron que las mutaciones no producen alteraciones estructurales significativas y que la toxina H168R (Tm= 59 °C) es más estable que las toxinas H168Q (Tm= 57.5 °C) y wt (Tm= 56 °C). Las tres toxinas exhibieron uniones de afinidad similares (Kcom) en vesículas de intestino de larvas de insecto, indicando que las diferencias en la toxicidad no se deben a cambios en la unión inicial al receptor. Los ensayos de unión/disociación y fijación de voltaje mostraron que la reducción de la toxicidad de la toxina H168Q se puede atribuir a una disminución en la inserción y/o en la formación de canales iónicos. De otro lado, H168R mostró una inhibición a la corriente de corto circuito mayor que la ts y un aumento en unión irreversible (kobs), lo cual es consistente con un menor valor de CL50. La modelación molecular sugiere que H168Q y H168R forman puentes de hidrógeno adicionales, lo que les confiere mayor estabilidad térmica. Adicionalmente, es probable que H168R tenga una carga positiva extra expuesta en la superficie, lo cual aumentaría su tasa de inserción en membranas susceptibles.

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