Ação citotóxica e antimicrobiana do extrato glicólico de Zingiber officinale sobre micro-organismos de interesse para odontologia / Cytotoxic action and antimicrobial of Zingiber officinale glycolic extract of microorganisms of interest for dentistryeng

O número de espécies bacterianas resistentes aos antimicrobianos tem atingido níveis elevados. Com isso, torna-se necessária a realização de pesquisas que avaliem os efeitos de métodos terapêuticos alternativos. Os objetivos desse trabalho foram avaliar a citotoxicidade do extrato glicólico de Zingiber officinale em macrófagos de camundongos e queranócitos humanos, atividade antimicrobiana sobre biofilmes monotípicos (micro-organismos aeróbios: Candida albicans, Staphylococcus aureus, Streptococcus mutans, Pseudomonas aeruginosa, e anaeróbios: Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia) e biofilmes heterotípicos (associação: C. albicans e bactérias aeróbias). Para ação citotóxica, as células foram cultivadas em meio DMEM, semeadas (2 x 104 células/poço) na placa de 96 poços. Após aderência inicial, foi adicionado o extrato em diluição seriada (5 min e 24 h), e realizado o teste de MTT. Para avaliar a ação antimicrobiana, a Concentração Inibitória Mínina (CIM) e Concentração Microbicida Mínima (CMM) foram determinadas segundo as normas do CLSI. Para biofilmes, foram adicionados 100 µL meio de cultura e 100 µL suspensão microbiana (107 UFC/mL) em placas de 96 poços, nos heterotípicos foram utilizados 50 µL de cada microorganismo. As placas foram incubadas (37ºC), por 48 h (aeróbios) ou por 7 dias (anaeróbios). Aplicou-se o extrato (5 min e 24 h), nas concentrações efetivas pré-determinadas (CMM) e duas superiores, depois os biofilmes foram desagregados e semeados para a contagem de UFC. Os dados foram analisados estatisticamente (ANOVA e Tukey, ou Kruskall-Wallis e Dunn, 5%). O extrato glicólico de Z. officinale apresentou viabilidade celular superior a 50% a partir de 50 (5 min) e 6,25 mg/mL (24 h) aos macrófagos, 25 (5 min) e 12,5 mg/mL (24 h) aos queratinócitos. Nos biofilmes monotípicos apresentou resultados mais significantes sobre C. albicans, P. endodontalis e P. intermedia. Mostrou-se mais efetivo sobre os biofilmes heterotípicos, como na associação entre C. albicans e S. aureus (24 h) onde apresentou redução de 90% e 100%, respectivamente. Conclui-se que o extrato glicólico de Z. officinale apresentou viabilidade celular superior a 50% na cultura de macrófagos e queratinócitos, apresentou atividade antimicrobiana sobre os biofilmes monotípicos de C. albicans, S. aureus, S. mutans, P. gingivalis, P. endodontalis, P. intermedia e sobre os biofilmes heterotípicos(AU)

The number of bacterial species resistant to antimicrobials has reached high levels. Thus, it is necessary to perform research that evaluates the alternative therapeutic methods, such as ginger. The present study was to evaluate the cytotoxicity of the Zingiber officinale glycolic extract in human and mouse macrophages, antimicrobial activity on monotypic biofilms (aerobic microorganisms: Candida albicans, Staphylococcus aureus, Streptococcus mutans, Pseudomonas aeruginosa, and anaerobes: Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia) and heterotypic biofilms (association: C. albicans and aerobic bacteria). To cytotoxic action, the cells have been cultivated in DMEM medium, seeded (2x104 cells/well) in the 96-well plate. After initial adhesion, the extract has been added to serial dilution (5 min and 24 h), and the MTT tests were performed. In order to assess the antimicrobial action, Minimal Inhibitory Concentration (MIC) and Minimum Microbicidal Concentration (MMC) were determined in according to CLSI standards. In the biofilms case, 100 µL culture medium and 100 µL microbial suspension (107 CFU / mL) were added to 96-well plates, 50 µL of each microorganism was used in the heterotypics. The plates were incubated (37°C) for 48 h period (aerobic) or for 7 days (anaerobic). The extract (5 min and 24 h) was applied at the pre-determined effective concentrations (MMC) and two higher concentrations, after which the biofilms were disaggregated and seeded for the CFU count. Data were analyzed statistically (ANOVA and Tukey, or Kruskall-Wallis and Dunn, 5%). The glycolic extract of Z. officinale presented cell viability greater than 50% from 50 (5 min) and 6.25 mg/mL (24 h) to macrophages, 25 (5 min) and 12.5 mg/mL (24 h) to keratinocytes. In the monotypic biofilms presented significant results on C. albicans, P. endodontalis and P. intermedia. It was shown to be more effective on heterotypic biofilms, as well as in the association between C. albicans and S. aureus (24 h), where it is presented a reduction of 90% and 100%, respectively. It concluded that Z. officinale glycolic extract presented cell viability greater than 50% in the macrophages and keratinocytes culture, in which presented antimicrobial activity on the monotypic biofilms of C. albicans, S. aureus, S. mutans, P. gingivalis, P. endodontalis, P. intermedia and on heterotypic biofilms(AU)

Fragilidad y vulnerabilidad como predictores de radiotoxicidad en adultos mayores: un estudio longitudinal en Perú / Frailty and vulnerability as predictors of radiotoxicity in older adults: A longitudinal study in Peru

Fundamento y objetivo: Evaluar la asociación entre fragilidad/vulnerabilidad y el desarrollo de radiotoxicidad en adultos mayores en un hospital de Perú. Material y métodos: Cohorte que incluyó pacientes con diagnóstico de cáncer e indicación de radioterapia que acudieron al servicio ambulatorio de Geriatría del Centro Médico Naval (Lima, Perú) entre 2013 y 2015. Antes de recibir radioterapia se evaluó la fragilidad usando el fenotipo de Fried, y se evaluó la vulnerabilidad usando las escalas VES-13 y G-8. Durante la radioterapia, se determinó el desarrollo de radiotoxicidad. Se elaboraron curvas ROC y modelos de regresión de Cox crudos y ajustados para evaluar la asociación entre las escalas de fragilidad/vulnerabilidad y el desarrollo de radiotoxicidad. Resultados: De un total de 181 pacientes (edad media: 78,1 años, todos del sexo masculino), 33 (18,2%) presentaron algún tipo de radiotoxicidad. La aparición de radiotoxicidad fue mayor en los pacientes con fragilidad o vulnerabilidad en comparación con aquellos sin estas condiciones, según los puntos de corte usuales del fenotipo de Fried (10,9% versus 41,9%), del VES-13 (5,0% versus 63,4%) y del G-8 (5,6% versus 67,6%). El área bajo la curva fue 0,61 (0,55-0,65) para el fenotipo de Fried, 0,79 (0,69-0,86) para el VES-13, y 0,86 (0,58-0,89) para el G-8. Conclusiones: Se encontró una asociación entre fragilidad/vulnerabilidad y el desarrollo de radiotoxicidad. El G-8 y el VES-13 tuvieron mayor área bajo la curva que el fenotipo de Fried, lo que sugiere que podrían ser herramientas útiles al momento de decidir la dosis de radioterapia en pacientes geriátricos (AU)

Background and objective: To assess the association between frailty/vulnerability and the development of radiotoxicity in older adults at a hospital in Peru. Material and methods: Cohort study that included patients with cancer with medical recommendation of radiotherapy, who attended the outpatient department of geriatrics at Naval Medical Center (Lima, Peru) between 2013 and 2015. Before receiving radiation therapy sessions, we measured frailty using Fried phenotype, and vulnerability using VES-13 and G-8 scales. During radiotherapy, we determined the development of radiotoxicity. ROC curves and crude/adjusted Cox regression models were prepared to evaluate the association between the frailty/vulnerability scales and the development of radiotoxicity respectively. Results: From a total of 181 patients (mean age: 78.1 years, all males), 33 (18.2%) developed some type of radiotoxicity. The appearance of radiotoxicity was higher in patients with frailty or vulnerability compared with those without these conditions, according to the usual cutoff points of Fried phenotype (10.9% versus 41.9%), VES-13 (5.0% versus 63.4%) and G-8 (5.6% versus 67.6%). The area under the curve was 0.61 (0.55-0.65) for the Fried phenotype, 0.79 (0.69-0.86) for the VES-13, and 0.86 (0.58-0.89) for the G-8. Conclusions: We found an association between frailty/vulnerability and the development of radiotoxicity. The G-8 and the VES-13 scales had a better area under the curve than Fried phenotype, suggesting that those could be useful tools when deciding the dose of radiotherapy in geriatric patients (AU)

Síndrome de eritema tenar periarticular y onicolisis: una manifestación de toxicidad cutánea por taxanos / Periarticular Thenar Erythema and Onycholysis Syndrome: A Manifestation of Taxane-Induced Cutaneous Toxicity

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Utilidad del cribado toxicológico en pediatría / Toxicology screening in paediatrics

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Exposoma. Un nuevo concepto en Salud Laboral y Salud Pública / Exposome. A new concept in Occupational and Public Health

El avance del conocimiento científico incorpora nuevas tecnologías y también nuevos conceptos. En toxicología medioambiental y laboral se ha acuñado en los últimos años un nuevo término, exposoma, que agrupa todas las exposiciones ambientales a las que el ser humano está sometido desde la concepción en adelante. Surge como una nueva estrategia para evidenciar los factores de riesgo de enfermedades generadas por el medio ambiente. Supone un reto al investigador en muchos aspectos, especialmente en cuanto a la evaluación del riesgo por exposición, puesto que han de ser considerados varios cientos de exposiciones variables en el tiempo y también desafíos estadísticos, ya que los métodos existentes actualmente no pueden separar de una forma clara las exposiciones que verdaderamente afectan a la salud y las exposiciones correlacionadas. Se revisan aquí algunas de las principales publicaciones en torno a este tema de los últimos años, su enfoque en Salud Ocupacional y repercusión en Salud Pública (AU)

Advancement of scientific knowledge incorporates new technologies and new concepts as well. In Environmental and Occupational Toxicology has been incorporated in the last years a new term, exposome, encompassing all environmental exposures from conception onwards. It arises as a new strategy to evidence environmental disease risk factors and supposes a research challenge on many related aspects, especially with regard to the evaluation of the risk from exposure, that several hundreds of time-varying exposures need to be considered and Statistical Challenges, as currently existing statistical methods cannot efficiently untangle the exposures truly affecting the health outcome from correlated exposures. We review here some of the major publications on this topic in recent years, its focus on Occupational Health and impact on Public Health (AU)

Toxicity in food flavorings at the cellular level associated with each other at different doses / Toxicidade em nível celular de aromatizantes alimentares associados entre si em diferentes doses

This study aimed to examine the cytotoxicity and genotoxicity of synthetic flavorings, nature identical, Chocolate, Strawberry and Condensed Milk. This evaluation was performed in root meristem cells of Allium cepa L., in exposure times of 24 and 48 hours and using doses of 0.2; 0.4 and 0.6 mL, in combination, in which one of the three doses of a flavoring was combined with a different dose of one of the two other flavor additives studied. Roots were fixed in Carnoys solution, hydrolyzed in hydrochloric acid, stained with acetic orcein and then analyzed, under light microscopy, 5,000 cells for each treatment. For data analysis, it was used Chi-square test at 5%. All the treatments with combinations between the flavorings Chocolate/Strawberry and Strawberry/Condensed Milk reduced, in both exposure times considered, cell division of A. cepa roots, proving to be cytotoxic. In turn, the treatments with the association of Chocolate/Condensed Milk did not change significantly the mitotic index of the cells analyzed. The Strawberry flavoring was the most cytotoxic among the additives tested. None of the evaluated associations was genotoxic under the study conditions.

Objetivou-se nesta pesquisa avaliar a citoxicidade e genotoxicidade de aromatizantes alimentares sintéticos de chocolate, morango e leite condensado. Esta avaliação ocorreu por meio das células meristemáticas de raízes de A. cepa L., nos tempos de exposição de 24 e 48h e nas doses de 0,2; 0,4 e 0,6 mL, em associação, em que para uma das três doses de um dos aromatizantes associou-se uma dose diferente de um dos outros dois aditivos de aroma em estudo. Em seguida, as raízes foram fixadas em solução de Carnoy, hidrolisadas em ácido clorídrico e coradas com orceína acética. Analisaram-se, em microscópio óptico, 5.000 células para cada grupo tratamento, e utilizou-se o teste estatístico Qui-quadrado a 5% para análise dos dados. A partir dos resultados, verificou-se que todos os tratamentos decorrentes das associações entre chocolate/morango e morango/leite condensado reduziram, nos dois tempos de exposição considerados, a divisão celular das raízes A. cepa, mostrando-se citotóxicos. Já os tratamentos provenientes da associação chocolate/leite condensado não alteraram de forma significativa os índices mitóticos das células do tecido em análise. Foi possível inferir que o aditivo de morango foi o mais citotóxico dos aditivos em estudo. Nenhuma das associações avaliadas foi genotóxica nestas condições de estudo.

On frogs, toxins and true friendship: an atypical case report

The authors report a series of events including the scientific interest for poisonous dendrobates of French Guiana, the human confrontation with the immensity of the evergreen rainforest, the fragility of the best-prepared individuals to a rough life, and the unique and very special manifestation of a solid friendship between two experts and enthusiasts of outdoor life. In the evergreen forest of South America, as in many other scientific field expeditions, everything may suddenly go wrong, and nothing can prepare researchers to accidents that may occur in a succession of uncontrollable errors once the first mistake is done. This is what happened during an expedition in search for dendrobates by an experienced forest guide and naturalist. The authors decided to report the story, considering that it deserved to be brought to the attention of those interested in venomous animals and toxins, in order to illustrate the potential danger of dealing with these organisms.

Antinociceptive and anti-inflammatory effects of Lantana camara L. extract in mice / Efeitos antinociceptivos do extrato de Lantana camara L. em camundongos

ABSTRACT: he Lantana camara L. belongs to the family Verbenaceae, which contains several active compounds in leaves and roots and which are reported to have medicinal and insecticidal properties. Studies of plants within the same family show the existence of anti-inflammatory activity in paw edema induced by carrageenan, serotonin and histamine and analgesic activity in the acetic acid writhing and tail-flick tests. The present study investigated whether the L. camara extract (ACE) also exerts these effects. The ACE toxicity was studied in male mice, and the percentage of mortality recorded 7 days after treatment was assessed. The ACE was evaluated as an antinociceptive agent in the hot plate, tail-flick and acetic acid writhing tests at a nontoxic dose of 1.0 g/Kg. The results showed that 1.5 g/Kg of ACE was not able to cause death, and doses of 3.0 and 4.0 g/Kg caused 50% and 60% death, respectively, in male mice. In all of the antinociceptive tests, 1 g/Kg of ACE markedly reduced responses to pain. Our findings suggest that ACE may have active anti-inflammatory and antinociceptive properties in much smaller doses than toxic.

RESUMO: Lantana camara L. pertence à família Verbenaceae, a qual contem muitos princípios ativos em suas folhas e raízes com propriedade medicinais e inseticidas. Estudos com plantas da mesma família mostram a existência de propriedades antinflamatórias no modelo de edema de pata induzido pela carragenina, serotonina e histamina, além da atividade analgésica nos testes de contorção induzida pelo ácido acético e da retirada da cauda por estímulo térmico. O presente trabalho investigou os efeitos tóxicos e antinociceptivos do extrato de L. camara (ACE) em camundongos. Para tanto, investigou-se a porcentagem de mortes em 7 dias após a administração de diferentes doses do extrato. Avaliou-se também os efeitos antinociceptivos do ACE pelos testes da placa quente, estimulação térmica da cauda e contorções abdominais induzidas pelo ácido acético com a dose não-tóxica [1,0 g/Kg]. Os resultados mostraram que 1,5 g/Kg do ACE não causou mortalidade, enquanto que 3,0 e 4,0 g/Kg promoveram 50 e 60% de mortalidade, respectivamente. Em todos os testes antinociceptivos, a dose de 1,0 g/Kg do ACE reduziu a resposta à dor. Os presentes resultados indicam que o ACE apresenta propriedades antinflamatórias e analgésicas em doses muito menores que a tóxica.

Efeito do extrato etanólico bruto e das frações da Hyptidendron canum (Pohl ex Benth. ) Harley em brânquias de Oreochromis niloticus L / Effect of the crude ethanol extract and fractions of Hyptidendron canum (Pohl ex Benth. ) Harley on the gills of Oreochromis niloticus L

Alguns problemas relacionados à criação intensiva de peixes estão mais evidentes devido ao aumento da aquicultura em todo o mundo, destacando-se os distúrbios nutricionais e o aumento de doenças nos sistemas de produção. Com isso as pesquisas envolvendo produtos derivados de plantas vem ganhando espaço nessa área. A Hyptidendron canum é uma planta utilizada na medicina popular como antimalárica, anti-inflamatória, antiulcerativa e anti-hepatotóxica. Objetivou-se, neste trabalho, avaliar os efeitos celulares e teciduais do extrato etanólico bruto e das frações hexano, clorofórmio e acetato de etila da H. canum nas brânquias de Oreochromis niloticus L. Para isso, o extrato etanólico e as frações foram administrados no peixe através da ração. Após 24 horas da ingestão da ração, os peixes foram sacrificados e o segundo arco branquial de cada um foi processado histologicamente e corado com tricômico de Masson e Hematoxilina e Eosina (HE). Pela análise qualitativa das brânquias ao microscópio de luz, observou-se que o extrato bruto e as três frações promoveram, em diferentes intensidades nas lamelas, descamação e destacamento do epitélio respiratório, alteração da curvatura, desorganização do eixo, hiperplasia celular do tecido epitelial interlamelar e vasodilatação nas lamelas e no vaso central do filamento. Os resultados deste experimento mostraram que o extrato etanólico bruto e as três frações de H. canum promoveram processos inflamatórios e/ou lesões sistêmicas, dose dependente para O. niloticus.

Some problems related to intensive fish farming are more evident because of the increased aquaculture worldwide, and we highlight the nutritional disorders and the increase of diseases in the production systems. Thus, research involving plant-derived products has been increasing in this area. The Hyptidendron canum is a plant used in folk medicine as an antimalarial, anti-inflammatory, anti-ulcer and antihepatotoxic agent. This study proposes to evaluate the cellular and tissue effects of the crude ethanol extract and the hexane, chloroform and ethyl acetate fractions of H. canum on the gills of Oreochromis niloticus L. The ethanol extract and fractions were administered through the feed of the fish. Twenty-four hours later, the fish were sacrificed and their second gill arch dissected. Histological analyses were performed using Masson's trichrome and Haematoxylin and Eosin (H&E). The qualitative analysis of the material showed that the crude extract and the three fractions caused varying degrees of peeling and detachment of the lamellar respiratory epithelium, alterations in the curvature and axis of the gill, cell hyperplasia in the interlamellar epithelium and lamellar vasodilation, as well as vasodilation in the central vessel of the filament. The results of this experiment showed that the crude ethanol extract and the three fractions of H. canum promoted inflammation and/or systemic lesions, dose dependent, for O. niloticus.

Toxicidade reprodutiva do extrato hidroalcóolico de Samanea tubulosa Benth em ratas wistar / Reproductive toxicity study in Wistar rats treated with hydroalcoholic extract of the pods of bordão-de-velho (Samanea tubulosa Benth)

RESUMOO objetivo deste trabalho foi avaliar possíveis efeitos do extrato das vargens de bordão-de-velho (Samanea tubulosa benth) sobre a reprodução em ratas Wistar. O extrato foi preparado a partir da secagem e trituração das vagens, seguida por maceração com etanol e, posteriormente, concentrado em rotavapor. Ratas Wistar gestantes foram tratadas com 75 mg.100 g-1 de peso corporal de extrato de S. tubulosa e o grupo controle recebeu 1ml/100 g-1 de peso corporal de solução salina por gavagem durante 19 dias. Após eutanásia no 20º dia, as seguintes variáveis foram analisadas: peso corporal fetal, peso dos fetos e placentas, número de corpos lúteos e de reabsorções, implantação, fetos vivos e mortos. O extrato de vagens de S. tubulosa apresenta toxicidade para o feto causando malformações, reabsorções fetais e diminuição pronunciada do peso ao nascer. Contudo, o extrato de vagens de S. tubulosanão influencia no número de corpos lúteos e número de implantações.

ABSTRACTThe aim of this study was to evaluate possible effects of pods from bordão-de-velho (Samanea tubulosa benth) extract on the reproduction of female rats.The extract was prepared by maceration wtith ethanol of dried and crushed pods, then it was concentrated in rotary evaporator. The pregnant Wistar rats were treated with a dose of 75 mg.100 g-1of body weight of Samanea tubulosa extract, by gavage , whereas the control group received 1ml.100g-1of saline by the same route for 19 days. After the euthanasia of the animals at day 20th,the following variables were analyzed: fetal body weight, weight of fetuses and placentas, number of corpora lutea, resorption points, live and dead fetuses and number of embryonic implantations. The extract from S. tubulosa pods, at the dose studied, showed toxicity causing fetal abnormalities, fetal resorption and pronounced decrease in the weight of offspring at birth. On the other hand, , the treatment with extract of S.tubulosa pods had no influence over corpora lutea and implantation numbers.

Resumen ejecutivo del documento de consenso sobre el manejo de la patología renal en pacientes con infección por el virus de la inmunodeficiencia humana / Executive summary of the recommendations on the evaluation and management of renal disease in human immunodeficiency virus-infected patients

El objetivo de este documento es actualizar las recomendaciones sobre la evaluación y el manejo de la afectación renal en pacientes con infección por el virus de la inmunodeficiencia humana (VIH) del año 2010. La función renal debe monitorizarse en todos los pacientes y debe incluir la medida de la concentración sérica de creatinina, la estimación del filtrado glomerular (ecuación CKD-EPI), la medida del cociente proteína/creatinina en orina, y un sedimento urinario. El estudio básico de la función tubular debe incluir la concentración sérica de fosfato y la tira reactiva de orina (glucosuria). En ausencia de alteraciones, el cribado será anual. En pacientes tratados con tenofovir o con factores de riesgo para el desarrollo de enfermedad renal crónica (ERC) se recomienda una evaluación más frecuente. Se debe evitar el uso de antirretrovirales potencialmente nefrotóxicos en pacientes con ERC o factores de riesgo para evitar su progresión. También se revisan las indicaciones de la biopsia renal, cuándo enviar el paciente al nefrólogo, y las indicaciones, la evaluación y el manejo del paciente en diálisis o del trasplante renal

The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (HIV)-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glycosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir, or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed

Validación de polimorfismos genéticos asociados a toxicidad al tratamiento quimioterápico en pacientes de cancer colorrectal / Validation of genetic polymorphisms associated to the toxicity of chemotherapy in colorectal cancer patients

Objetivo: Validar las asociaciones, encontradas previamente entres cohortes de pacientes del Hospital General Universitario Gregorio Marañón, entre los polimorfismos rs1128503, rs2032582 y rs1045642 del gen ABCB1 con síndrome mano-pie y diarrea en pacientes de cáncer color rectal tratados con regímenes que contenían capecitabina y 5-Fluorouracilo, respectivamente, y entre los polimorfismos rs2297595 del gen DPYD con nauseas/vómitos, rs11615 ERCC1 y neutropenia, yrs28399433 CYP2A6 y neutropenia en pacientes de cáncer colorrectal tratados con FOLFOX o XELOX en adyuvancia. Método: Se incorporaron al estudio pacientes de cáncer colorrectal tratados con regímenes quimioterápicos que contenían capecitabina (n = 157), 5-fluorouracilo (n = 99) y pacientes tratados en adyuvancia con XELOX o FOLFOX (n = 83). Los pacientes participantes fueron reclutados en el Hospital Universitario Doce de Octubre y en el Hospital General Universitario Gregorio Marañón tras firmar consentimiento informado. Se extrajo ADN a partir de muestras de sangre. Los genotipados se realizaron mediante SNaP shot. Se realizaron tablas de contingencia para analizar las asociaciones entre genotipos y reacciones adversas. Resultados: Ninguna de las asociaciones previamente identificadas fue replicada en la cohorte de validación. Conclusiones: Los estudios fármaco genéticos con un tamaño muestral limitado deben ser validados en cohortes más numerosas, a ser posible en estudios multicéntricos, reduciendo al máximo las variables y nunca deben ser utilizados en clínica sin validar (AU)

Objective: To validate the associations previously found in three cohorts of patients from the General University Hospital Gregorio Marañón, between the polymorphisms rs1128503, rs2032582 and rs1045642 of the ABCB1 gene and the hand-foot syndrome and diarrhea in colorectal cancer patients treated with chemotherapy regimens containing Capecitabine and 5-Fluorouracil, respectively, and between the polymorphisms rs2297595 of the DPYD gene and nausea/vomiting, rs11615 of ERCC1 and neutropenia, and rs28399433 CYP2A6 and neutropenia, in colorectal cancer patients treated with FOLFOX or XELOX as adjuvant therapy. Method: Colorectal cancer patients treated with chemotherapy regimes, containing Capecitabine (n = 157), 5-Fluorouracil (n =99) were included in the study, as well as patients treated with XELOX or FOLFOX (n = 83) as adjuvant therapy. The patients included were recruited from the Doce de Octubre University Hospital and from the Gregorio Marañón General University Hospital, and signed the informed consent form. DNA was obtained from blood samples. Genotyping was carried out with SNaP shot. Contingency tables were created for analyzing the associations between the genotypes and the adverse reactions. Results: None of the associations previously identified was replicated in the validation cohort. Conclusions: Pharmacogenetic studies with a limited sample size must be validated with bigger cohorts, if possible by means of multicentre studies, reducing the variables to the maximum and should never be used in clinical practice without validation (AU)

Atividade antioxidante e toxicidade preliminar do extrato e frações obtidas das folhas e cascas do caule de Dasyphyllum tomentosum (Spreng. ) Cabrera / Antioxidant activity and preliminary toxicity of the extracts and fractions obtained from the leaves and stem bark of Dasyphyllum tomentosum (Spreng. ) Cabrera

Dasyphyllum tomentosum (Spreng.) Cabrera, açucará ou espinho-de-agulha, pertence à família Asteraceae, a qual compreende muitas espécies com propriedades terapêuticas. O objetivo deste trabalho foi avaliar extratos e frações de folhas e de cascas do caule de D. tomentosum, com relação as atividade antioxidante, citotóxica e hemolítica em testes in vitro. Todas as amostras apresentaram atividade antioxidante pelo método de inibição de DPPH, com destaque para a fração acetato de etila obtida das folhas cuja atividade foi comparável à dos padrões ácido ascórbico e rutina. Com relação à redução do complexo fosfomolibdênio, observou-se que esta mesma fração foi semelhante somente a rutina enquanto a fração obtida das cascas do caule apresentou resultado superior. Não foi observada atividade citotóxica e hemolítica frente aos modelos utilizados com os extratos e frações. Os resultados obtidos demonstram o potencial antioxidante da espécie sem apresentar toxicidade.

Dasyphyllum tomentosum (Spreng.) Cabrera, which belongs to the Asteraceae family, is well known for having many species with therapeutic properties. The aim of this study was to evaluate the extracts and fractions from the leaves and stem bark of D. tomentosum with respect to the antioxidant, cytotoxic and hemolytic activity in in vitro tests. All samples showed antioxidant activity by the DPPH inhibition method, especially the ethyl acetate fraction obtained from the leaves, whose activity was comparable to that of standard ascorbic acid and rutin. Regarding the reduction of the phosphomolybdenum complex, we noted that this same fraction was only similar to rutin and the fraction obtained from the stem bark showed superior results. There was no cytotoxicity and hemolytic activity compared to the models used in the extracts and fractions. The results demonstrate the antioxidant potential of the species without showing toxicity.

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate / Pseudoalergia relacionada à ativação do complemento em cães após administração intravenosa de uma formulação lipossomal de antimoniato de meglumina

The increasing use of nanotechnologies in advanced therapies has allowed the observation of specific adverse reactions related to nanostructures. The toxicity of a novel liposome formulation of meglumine antimoniate in dogs with visceral leishmaniasis after single dose has been investigated. Groups of 12 animals received by the intravenous route a single dose of liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg), empty liposomes (GII) or isotonic saline (GIII). Evaluation of hematological and biochemical parameters showed no significant changes 4 days after administration. No undesired effects were registered in the GIII. However, adverse reactions were observed in 67.7% of dogs from both groups that received liposomal formulations. The side effects began moments after bolus administration and disappeared during the first 15 minutes after treatment. Prostation, sialorrhea and defecation were the most frequent clinical signs, registered in 33.3% and 41.6 % of animals from the groups GI and GII, respectively. Tachypnea, mydriasis, miosis, vomiting and cyanosis were also registered in both groups. The adverse reactions observed in this study were attributed to the activation of the complement system by lipid vesicles in a phenomenon known as Complement Activation-Related Pseudoallergy (CARPA). The influence of the physical-chemical characteristics of liposomal formulation in the triggering of CARPA is discussed.

O crescente uso das nanotecnologias nas terapias avançadas tem permitido a observação de reações adversas específicas relacionadas às nanoestruturas. A toxicidade de uma nova formulação lipossomal de antimoniato de meglumina após dose única foi avaliada em cães com leishmaniose visceral. Grupos de 12 animais receberam por via intravenosa uma dose única de antimoniato de meglumina lipossomal (grupo I [GI], 6,5 mg Sb/kg), lipossomas vazios (GII) ou solução salina isotônica (GIII). A avaliação de parâmetros hematológicos e bioquímicos não revelou alterações significativas quatro dias após a administração. Nenhum efeito indesejável foi registrado no GIII. No entanto, reações adversas foram observadas em 67,7% dos cães de ambos os grupos que receberam formulações lipossomais. Os efeitos colaterais iniciaram momentos após a administração em "bolus" e desapareceram no decurso dos primeiros 15 minutos após o tratamento. Prostração, sialorréia e defecação foram os sinais clínicos mais frequentes, registrados em 33,3% e 41,6% dos animais dos grupos GI e GII, respectivamente. Taquipnéia, midríase, miose, vômitos e cianose também foram registrados em ambos os grupos. As reações adversas observadas neste trabalho foram atribuídas à ativação do sistema complemento pelas vesículas lipídicas em fenômeno conhecido como Pseudoalergia Relacionada à Ativação do Complemento (PARAC). A influência das características físico-químicas da formulação lipossomal no desencadeamento de PARAC é abordada.

Toxicological evaluation of vegetable oils and biodiesel in soil during the biodegradation process

Vegetable oils and their derivatives, like biodiesel, are used extensively throughout the world, thus posing an environmental risk when disposed. Toxicity testing using test organisms shows how these residues affect ecosystems. Toxicity tests using earthworms (Eisenia foetida. are widespread because they are a practical resource for analyzing terrestrial organisms. For phytotoxicological analysis, we used seeds of arugula (Eruca sativa and lettuce (Lactuca sativa. to analyze the germination of seeds in contaminated soil samples. The toxicological experiment was conducted with four different periods of biodegradation in soil: zero days, 60 days, 120 days and 180 days. The studied contaminants were soybean oil (new and used) and biodiesel (B100). An evaluation of the germination of both seeds showed an increased toxicity for all contaminants as the biodegradation occurred, biodiesel being the most toxic among the contaminants. On the other hand, for the tests using earthworms, the biodiesel was the only contaminant that proved to be toxic. Therefore, the higher toxicity of the sample containing these hydrocarbons over time can be attributed to the secondary compounds formed by microbial action. Thus, we conclude that the biodegradation in soil of the studied compounds requires longer periods for the sample toxicity to be decreased with the action of microorganisms.

Incidence of hand-foot syndrome with capecitabine in combination with chemotherapy as first-linetreatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen

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)

Eficácia e toxicidade do pó comercial de Hoodia gordonii (Masson) swet ex decne utilizado no tratamento da obesidade / Efficacy and toxicity of Hoodia gordonii commercial powder used to combat obesity

A obesidade é atualmente o principal problema de saúde em países desenvolvidos e em desenvolvimento. Diversos recursos terapêuticos têm sido empregados para o tratamento da obesidade destacando-se os fitoterápicos, consagrados pelo conhecimento popular. Nesse contexto, a planta Hoodia gordonii tem despertado atualmente grande interesse mundial, principalmente pelas recentes descobertas e comprovações científicas da inibição do apetite e da sede pelo glicosídeo ativo P57 isolado de espécies da planta. Apesar disso, tais efeitos ainda não foram avaliados e comprovados em amostras comerciais do pó de H. gordonii (PHG), não existindo evidências científicas que garantam a sua eficácia e segurança. Portanto, o objetivo deste trabalho foi realizar ensaios biológicos com ratos para avaliar a atividade farmacológica e a toxicidade de amostras comerciais do pó de H. gordonii. As amostras foram administradas por gavagem em doses equivalentes a 20 vezes as recomendadas para humanos em ratas Wistar durante 4 semanas sendo avaliados os parâmetros indicadores do efeito terapêutico. Após as 4 semanas, os animais foram sacrificados, e amostras de sangue e órgãos foram coletados e submetidos à avaliação dos indicadores metabólicos, endócrinos, hematológicos e histopatológicos. Os resultados demonstraram que para todos os parâmetros avaliados não houve diferenças significativas entre o grupo controle que recebeu somente solução salina estéril e os grupos tratados com PHG indicando que os mesmos, apesar de não apresentarem quaisquer indícios de toxicidade, são incapazes de produzir os supostos efeitos de inibição de apetite e consequente tratamento da obesidade.

Obesity is currently the main health problem in developed and developing countries. Several therapeutic methods have been employed for the treatment of obesity, especially herbal medicines, highlighted by popular knowledge. In this context, the plant Hoodia gordonii has currently aroused great interest worldwide, especially for recent discoveries and scientific proof of inhibition of appetite and thirst by the active glycoside P57 isolated from plant species. Nevertheless, such effects have not been evaluated and proven for commercial samples of H. gordonii powder (PHG), with no scientific evidence to ensure its effectiveness and safety. Therefore, the aim of this study was to conduct biological tests with rats to evaluate the pharmacological activity and toxicity of commercial samples of H. gordonii powder. The samples were administered through gavage, at doses equivalent to 20 times those recommended for humans, in female Wistar rats during 4 weeks for evaluation of the parameters indicative of therapeutic efficacy. After 4 weeks, the animals were sacrificed and blood and organ samples were collected and subjected to the evaluation of metabolic, endocrine, hematological and histopathological indicators. Results showed that for all evaluated parameters, there were no significant differences between the control group that only received sterile saline solution and the groups treated with PHG, indicating that the latter, although presenting no evidence of toxicity, are unable to produce the alleged effects of appetite inhibition and subsequent obesity treatment.

Problemas associados ao uso de plantas medicinais comercializadas no Mercadão de Madureira, município do Rio de Janeiro, Brasil / Problems associated with the use of medicinal plants commercialized in "Mercadão de Madureira", Rio de Janeiro City, Brazil

O uso de plantas medicinais pela população brasileira é prática tradicional, sendo muitas vezes o único recurso utilizado na atenção básica de saúde. O uso terapêutico dessas plantas envolve várias etapas da cadeia produtiva, sendo a procedência, coleta, secagem, armazenamento, comércio, modo de preparo pelo usuário e uso. O objetivo desse trabalho documental, de caráter exploratório, foi levantar a produção científica existente sobre os problemas associados a cada uma dessas etapas e discutir as questões relacionadas à carência de estudos para comprovar a eficácia farmacológica e a ausência de riscos toxicológicos, bem como a prática de autodiagnóstico. As vinte plantas mais comercializadas em grande mercado do município do Rio de Janeiro em agosto de 2007 serviram de base para o levantamento documental do presente estudo. Dessas, seis apresentaram propriedades tóxicas comprovadas dependendo do preparo e uso, a arnica (Solidago chilensis Meyen), aroeira (Shinus terebinthifolius Raddi.), arruda (Ruta graveolens L.), babosa (Aloe vera L.), confrei (Symphytum officinale L.) e poejo (Mentha pulegium Lam. & DC.). A Agência Nacional de Vigilância Sanitária aponta contra indicações para boldo-do-Chile (Peumus boldus Molina), chapéu-de-couro (Echinodorus macrophyllus Micheli), erva-cidreira (Lippia alba N.E.Br.), erva-de-bicho (Polygonum spp.), espinheira-santa (Maytenus spp.), picão (Bidens pilosa L.), poejo (Mentha pulegium Lam.) e tanchagem (Plantago major L.). O abajerú, arnica, boldo-do-Chile, confrei, erva-de-bicho e espinheira-santa tiveram relato de problemas de identificação na coleta e comercialização frente a outras morfologicamente semelhantes. Plantas cultivadas e silvestres apresentam variabilidade de princípios ativos influenciados por fatores ambientais e genéticos, como chapéu-de-couro (Echinodorus macrophyllus Micheli), erva-cidreira (Lippia alba N.E.Br.) e erva-de-bicho (Polygonum spp.). A contaminação e o comprometimento da preservação dos princípios ativos pela secagem e armazenamento inadequados foram relatados para o guaco (Mikania glomerata Sprengel), camomila (Chamomilla recutita L.), erva-cidreira, chapéu-de-couro e boldo-do-Chile (Peumus boldus Molina). Pode-se constatar que todas as etapas da cadeia produtiva das plantas medicinais apresentam desafios para que se possa garantir identificação da espécie, disponibilidade, qualidade, segurança e eficácia de uso.

The use of medicinal plants by the Brazilian population is a traditional practice and is often the main resource used in primary healthcare. The therapeutic use of these plants involves several steps in the supply chain: origin, harvest, drying, storage, form of preparation by the user and use. The aim of this documental study of exploratory nature was to survey the scientific literature about the problems associated with each of those steps and discuss the issues related to the lack of studies to prove the pharmacological efficacy and the absence of toxicological risks, as well as the autodiagnosis practice. The 20 plants most commercialized in a large market of Rio de Janeiro City in August 2007 were the basis for the documental survey of the present study. Of these, six had proven toxic properties depending on their preparation and use: arnica (Solidago chilensis Meyen), aroeira (Shinus terebinthifolius Raddi.), rue (Ruta graveolens L.), "babosa" (Aloe vera L.), comfrey (Symphytum officinale L.) and pennyroyal (Mentha pulegium Lam. & DC.). The National Agency for Sanitary Surveillance shows contraindications for: "boldo-do-Chile" (Peumus boldus Molina), "chapéu-de-couro" (Echinodorus macrophyllus Micheli), lemon balm (Lippia alba N.E.Br.), "erva-de-bicho" (Polygonum spp.), "espinheira-santa" (Maytenus spp.), "picão" (Bidens pilosa L.), pennyroyal (Mentha pulegium Lam.) and plantain (Plantago major L.). "Abajerú", arnica, "boldo-do-Chile", comfrey, "erva-de-bicho" and "espinheira-santa" were reported to show identification problems in the harvest and in the commercialization compared to morphologically similar plants. Cultivated and wild plants showed variability in active principles influenced by environmental and genetic factors: "chapéu-de-couro" (Echinodorus macrophyllus Micheli), lemon balm (Lippia alba N.E.Br.) and "erva-de-bicho" (Polygonum spp.). Contamination and compromising of the preservation of active principles due to inadequate drying and storage was reported for guaco (Mikania glomerata Sprengel), camomile (Chamomilla recutita L.), lemon balm, "chapéu-de-couro" and "boldo-do-Chile" (Peumus boldus Molina). All stages of the supply chain of medicinal plants constitute challenges to ensure the proper species identification, availability, quality, safety, and efficacy of their use.

Characterization of a Mutant Bacillus thuringiensis d-endotoxin with enhanced stability and toxicity / Caracterización de una delta endotoxina mutante de Bacillus thuringiensis con estabilidad y toxicidad aumentadas

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.