Recomendaciones para el manejo de la cardiotoxicidad relacionada con el tratamiento del cáncer. Segunda parte / Recommendations for the management of cardiotoxicity related to cancer treatment. Part two / Recomendações para a gestão de cardiotoxicidade relacionada com o tratamento do câncer. Primeira [i.e. Segunda] parte

Las nuevas terapias oncológicas han logrado aumentar la sobrevida del paciente con cáncer, observando, sin embargo, un incremento de la morbilidad y mortalidad vinculadas a sus efectos secundarios. El desarrollo de eventos cardiovasculares adversos impacta negativamente en el pronóstico durante el tratamiento del cáncer, pero también en los supervivientes al cáncer, donde las enfermedades cardiovasculares (ECV) y las segundas neoplasias son la principal causa de muerte1-5. La cardiotoxicidad inducida por el tratamiento del cáncer se define como el conjunto de ECV derivadas de los tratamientos oncológicos. Su manifestación es variada e incluye el desarrollo de disfunción ventricular, insuficiencia cardíaca (IC), isquemia miocárdica, hipertensión arterial (HTA) y arritmias, entre otras. Puede ser consecuencia tanto del efecto directo del tratamiento sobre la estructura y función cardíacas, como del desarrollo acelerado de enfermedad cardiovascular6-9. Con frecuencia, se utiliza el término cardiotoxicidad como sinónimo de disfunción ventricular por quimioterapia (DV-QT). Dado que la cardiotoxicidad abarca un espectro más amplio de afectación cardiovascular, creemos conveniente hablar de DV-QT para referirnos a la afectación de la función sistólica del ventrículo izquierdo. La DV-QT y el desarrollo de IC representan una de las complicaciones más temidas por su impacto pronóstico en la esfera cardiovascular y oncológica, dado que limitan el arsenal terapéutico para el tratamiento del cáncer5,10. Han sido creadas diversas sociedades de cardio-onco-hematología con el fin de generar recomendaciones de práctica clínica y formar profesionales capacitados para el manejo de las complicaciones CV del tratamiento del cáncer11. La cardio-oncología es una disciplina en creciente y continuo desarrollo. Creemos que es fundamental realizar tareas de formación médica continua, así como también estimular el trabajo conjunto de diversas especialidades para brindar una mejor asistencia. Este texto es el resultado del trabajo de un equipo multidisciplinario que incluye cardiólogos, hematólogos y oncólogos, y pretende brindar información a los integrantes del equipo de salud involucrados en la asistencia de pacientes oncológicos. Debido a la extensión del presente texto, hemos decidido fraccionar el contenido en tres partes para facilitar su difusión.

New oncological therapies have been successful in increasing cancer patient survival, but they have also led to an increase in morbidity and mortality linked to their side effects. During cancer treatment, the development of cardiovascular side effects has a negative impact in prognosis, but also in cancer survivors, in whom cardiovascular diseases and secondary malignancies are the main cause of death. Cancer related cardiotoxicity is defined as the development of cardiovascular diseases related to cancer treatment. Clinical presentation is broad involving ventricular dysfunction, heart failure, myocardial ischemia, arterial hypertension and arrhythmias among others. This may result from the direct cardiovascular effect of a cancer treatment or accelerated development of cardiovascular diseases. Frequently, in the literature cardiotoxicity and chemotherapy related ventricular dysfunction are used as synonyms. However, cardiotoxicity includes a broad spectrum of cardiovascular manifestations, thus in this text we refer to chemotherapy related ventricular dysfunction as the presence of left ventricular systolic impairment. Chemotherapy related ventricular dysfunction and heart failure are two of the most feared complications of cancer treatment due to its impact on cardiovascular and oncological prognosis, affecting treatment options. Numerous worldwide cardio-onco-hematology societies have emerged to generate clinical practice guidelines and improve the diagnosis and evaluation of cardiovascular cancer treatment side effects. Cardio-Oncology is a discipline in continuous growth and development. We strongly believe that continuum medical education and a multidisciplinary approach is necessary to provide a quality health care. This text is the result of a multidisciplinary work involving cardiologists, hematologists and oncologists. It is our goal to provide information to the health care team involved in the assistance of cancer patients. Due to its extension, it will be divided in three parts.

O desenvolvimento de novas terapias oncológicas levou a um aumento na sobrevida dos pacientes, mas ao mesmo tempo traz consigo morbidades relacionadas aos tratamentos. O desenvolvimento de efeitos cardiovasculares adversos tem um impacto negativo no prognóstico dos pacientes em tratamento, bem como nos pacientes considerados curados, nos quais doença cardiovascular e malignidades secundárias são as principais causas de morte. Cardiotoxicidade relacionada ao câncer é definida como o desenvolvimento de doença cardiovascular secundária ao tratamento. A gama de apresentações clínicas é ampla, podendo se manifestar como disfunção ventricular, insuficiência cardíaca, isquemia miocárdica, hipertensão arterial, arritmias, entre outras. Isto pode ser resultante de desenvolvimento e progressão acelerados de doença cardiovascular ou por efeito direto das terapias. Frequentemente é dito na literatura que cardiotoxicidade e disfunção ventricular relacionada à quimioterapia são sinônimos. Entretanto, cardiotoxicidade engloba um amplo espectro de manifestações cardiovasculares. Neste texto, portanto, nos referimos à disfunção ventricular causada por quimioterápicos exclusivamente como a presença de disfunção sistólica ventricular esquerda. Disfunção ventricular relacionada à quimioterapia e insuficiência cardíaca são duas das mais temidas complicações do tratamento oncológico devido ao seu impacto no prognóstico cardiovascular e oncológico, podendo afetar ainda a escolha e manutenção das opções terapêuticas. Diversas sociedades cardio-onco-hematológicas surgiram ao redor do mundo com o objetivo de gerar diretriz clínicas práticas e melhorar o diagnóstico e tratamento das complicações cardiovasculares resultantes das terapias oncológicas. A cardio-oncologia é uma disciplina em contínuo crescimento e desenvolvimento. Nós acreditamos fortemente que educação médica continuada e uma abordagem multidisciplinar são necessárias para um cuidado médico de qualidade. Este texto é o resultado de um trabalho multidisciplinar envolvendo cardiologistas, hematologistas e oncologistas. Nosso objetivo é de oferecer informação à equipe de cuidados em saúde envolvido na assistência destes pacientes. Devido à sua extensão, este texto será dividido em três partes.

Productos intermedios de la cocaína: la pasta base o "paco" / Intermediate products of cocaine: the base paste or "paco"

El uso indebido de drogas se ha convertido en un grave problema a nivel mundial. En los últimos años, en nuestro país se ha incrementado en más del 200% el consumo de pasta base de cocaína (paco). A pesar de que el paco es un producto intermedio en la obtención de cocaína, y que muchos de sus efectos son atribuibles al contenido de esa droga, su consumo produce un cuadro clínico claramente distinto al observado en los consumidores de clorhidrato de cocaína, lo cual puede estar relacionado con su impureza. Sin perjuicio del gran impacto social producido por el consumo de paco, poco se sabe sobre su composición química y menos aún sobre sus efectos crónicos en los distintos órganos ni sobre su fisiopatología. Si bien existe material de autopsia de adictos al paco, los hallazgos están contaminados por la coexistencia en un mismo paciente de múltiples tóxicos. Urge la formación de grupos multidisciplinarios, con moderna tecnología para enfrentar este gravísimo flagelo. (AU)

Drug abuse has become a serious problem worldwide. In recent years, in our country the consumption of cocaine base paste (Paco) has increased by more than 200%. Despite of the fact that Paco is an intermediate product in the manufacture of cocaine, and that many of its effects are attributable to its content, its consumption produces a clearly different clinical picture than that observed in cocaine hydrochloride users, which It may be related to the impurity of this drug. Without prejudice to the great social impact produced by the consumption of this drug, little is known about its chemical composition and even less about its chronic effects on the different organs or its pathophysiology. Although there is an autopsy material for drug addicts, the findings are contaminated by the coexistence of multiple toxins in the same patient. The formation of multidisciplinary groups is urgent, with modern technology to face this very serious scourge. (AU)

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

Abstract Purpose To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury. Methods Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination. Results Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). Conclusions Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.

Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers

SUMMARY OBJECTIVES This study aimed at assessing the role of beta-blockers on preventing anthracycline-induced cardiotoxicity in adults. METHODS A systematic review was performed on electronic databases, including relevant studies that analysed beta-blockers as cardioprotective agents before the use of anthracyclines by adult oncologic patients. RESULTS After application of eligibility and selection criteria, eight articles were considered as high quality, complying with the proposed theme; all eight clinical trials, four of them placebo-controlled, with a total number of 655 patients included. From this sample, 281 (42.9%) used beta-blocker as intervention, and carvedilol was the most frequent (167 patients - 25.5%). Six studies were considered positive regarding the cardioprotection role played by beta-blockers, although only four demonstrated significant difference on left ventricle ejection fraction after chemotherapy on groups that used beta-blockers compared to control groups. Carvedilol and nebivolol, but not metoprolol, had positive results regarding cardioprotection. Other beta-blockers were not analysed in the selected studies. CONCLUSIONS Despite the potential cardioprotective effect of beta-blockers, as demonstrated in small and unicentric clinical trials, its routine use on prevention of anthracycline-associated cardiotoxicity demands greater scientific evidence.

RESUMO OBJETIVO Este estudo teve como objetivo analisar o papel dos betabloqueadores na prevenção da cardiotoxicidade induzida pelas antraciclinas em adultos. MÉTODOS Foi realizada uma revisão sistemática em bases de dados eletrônicos, incluindo os estudos relevantes que analisaram fármacos betabloqueadores como agentes cardioprotetores antes do início do uso de antraciclinas por pacientes oncológicos adultos. RESULTADOS Após aplicação dos critérios de elegibilidade e seleção, foram obtidos oito artigos considerados de boa qualidade, que se adequavam à temática proposta, sendo todos ensaios clínicos, quatro placebo-controlados, totalizando 655 pacientes incluídos. Destes, 281 (42,9%) fizeram uso de algum betabloqueador como intervenção, sendo o carvedilol o mais utilizado (167 pacientes - 25,5%). Seis estudos foram considerados positivos quanto à cardioproteção exercida pelos betabloqueadores, porém apenas quatro demonstraram diferença na fração de ejeção do ventrículo esquerdo após a quimioterapia nos grupos que usaram betabloqueadores em relação aos grupos controle. O carvedilol e o nebivolol, mas não o metoprolol, tiveram resultados positivos quanto à cardioproteção. Outros betabloqueadores não foram avaliados nos estudos incluídos. CONCLUSÕES Apesar de haver um potencial efeito cardioprotetor dos betabloqueadores, conforme demonstrado em ensaios clínicos pequenos e unicêntricos, sua utilização rotineira na prevenção da cardiotoxicidade associada às antraciclinas requer maiores comprovações científicas.

Global Longitudinal Strain Accuracy for Cardiotoxicity Prediction in a Cohort of Breast Cancer Patients During Anthracycline and/or Trastuzumab Treatment / Acurácia do Strain Longitudinal Global na Predição de Cardiotoxicidade em uma Coorte de Pacientes com Câncer de Mama em Tratamento com Antracíclicos e/ou Trastuzumab

Abstract Background: The high cardiotoxicity morbidity and mortality rates associated with the antineoplastic therapy for breast cancer could be reduced with the early use of cardioprotective drugs. However, the low sensitivity of left ventricular ejection fraction limits its use in that preventive strategy. New parameters, such as global longitudinal strain, are being used in the early detection of contractile function changes. Objectives: To assess the incidence of cardiotoxicity in patients treated for breast cancer, the independent factors associated with that event, and the ability of strain to identify it early. Methods: Prospective observational study of consecutive outpatients diagnosed with breast cancer, with no previous antineoplastic treatment and no ventricular dysfunction, who underwent anthracycline and/or trastuzumab therapy. The patients were quarterly evaluated on a 6- to 12-month follow-up by an observer blind to therapy. Cox regression was used to evaluate the association of cardiotoxicity with clinical, therapeutic and echocardiographic variables. A ROC curve was built to identify the strain cutoff point on the third month that could predict the ejection fraction reduction on the sixth month. For all tests, the statistical significance level adopted was p ≤ 0.05. Results: Of 49 women (mean age, 49.7 ± 12.2 years), cardiotoxicity was identified in 5 (10%) on the third (n = 2) and sixth (n = 3) months of follow-up. Strain was independently associated with the event (p = 0.004; HR = 2.77; 95%CI: 1.39-5.54), with a cutoff point for absolute value of -16.6 (AUC = 0.95; 95%CI: 0.87-1.0) or a cutoff point for percentage reduction of 14% (AUC = 0.97; 95%CI: 0.9-1.0). Conclusion: The 14% reduction in strain (absolute value of -16.6) allowed the early identification of patients who could develop anthracycline and/or trastuzumab-induced cardiotoxicity.

Resumo Fundamentos: A elevada morbimortalidade da cardiotoxicidade associada à terapia antineoplásica para o câncer de mama poderia ser reduzida com uso precoce de drogas cardioprotetoras. No entanto, a baixa sensibilidade da fração de ejeção limita sua utilização nessa estratégia preventiva. Novos parâmetros, como o strain longitudinal global, estão sendo utilizados na detecção precoce das alterações da função contrátil. Objetivos: Avaliar a incidência de cardiotoxicidade entre pacientes tratados para câncer de mama, os fatores independentes associados a esse evento e a capacidade do strain em identificá-la precocemente. Métodos: Estudo prospectivo observacional de pacientes ambulatoriais consecutivos com diagnóstico de câncer de mama, sem tratamento antineoplásico prévio, sem disfunção ventricular, submetidos ao uso de antracíclicos e/ou trastuzumab, avaliados trimestralmente de forma cega em relação à terapia, seguidos por 6 a 12 meses. Regressão de Cox foi utilizada para avaliar a associação de variáveis clínicas, terapêuticas e ecocardiográficas com cardiotoxicidade. Curva ROC foi construída para identificar o ponto de corte do strain capaz de prever redução da fração de ejeção. Para todos os testes, o nível de significância estatística foi definido com p ≤ 0,05. Resultados: Dentre 49 mulheres com idade média de 49,7 ± 12,2 anos, identificamos 5 casos de cardiotoxicidade (10%), aos 3 (n = 2) e 6 (n = 3) meses de seguimento. Strain foi associado de forma independente ao evento (p = 0,004; HR = 2,77; IC95%: 1,39-5,54), tendo como ponto de corte o valor absoluto de -16,6 (ASC = 0,95; IC95%: 0,87-1,0) ou redução de 14% (ASC = 0,97; IC95%: 0,9-1,0). Conclusão: A redução de 14% do strain (ou valor absoluto de -16,6) foi capaz de identificar precocemente pacientes que podem evoluir com cardiotoxicidade associada ao antracíclico e/ou trastuzumab.

Cardiac Sympathetic Hyperactivity after Chemotherapy: Early Sign of Cardiotoxicity? / Hiperatividade Simpática Cardíaca Após Quimioterapia: Sinal Precoce de Cardiotoxicidade?

Background:Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 (123I-mIBG) seems to precede the drop in left ventricular ejection fraction.Objective:To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline.Methods:Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of 123I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2).Results:Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of 123I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of 123I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of 123I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of 123I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02).Conclusion:In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with 123I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.

Fundamento:A quimioterapia com antracíclicos e trastuzumabe pode causar cardiotoxicidade. A alteração da função adrenérgica cardíaca, avaliada pela metaiodobenzilguanidina marcada com iodo-123 (123I-mIBG), parece preceder a queda da fração de ejeção do ventrículo esquerdo.Objetivo:Avaliar e comparar a presença de alterações cardiovasculares entre pacientes com câncer de mama submetidas à quimioterapia com antracíclicos e trastuzumabe e apenas a antracíclico.Métodos:Foram analisadas variáveis clínicas, laboratoriais, eletro e ecocardiográficas, além de atividade simpática cardíaca. Nas imagens cintilográficas, foram calculadas a relação da captação do 123I-mIBG entre o coração e o mediastino, e a taxa de clareamento. As variáveis foram comparadas entre os pacientes que receberam antracíclicos e trastuzumabe (Grupo 1) e apenas antracíclicos (Grupo 2).Resultados:Vinte pacientes, com idade média 57 ± 14 anos, participaram deste estudo. A fração de ejeção do ventrículo esquerdo média pelo ecocardiograma foi 67,8 ± 4,0%. A taxa de clareamento média foi 28,39 ± 9,23%, e a relação da captação do 123I-mIBG entre o coração e o mediastino foi de 2,07 ± 0,28. Dentre as pacientes, 82% mostraram taxa de clareamento aumentada e 25%, uma relação da captação do 123I-mIBG entre o coração e o mediastino diminuída. Em relação aos grupos, a média da taxa de clareamento no Grupo 1 foi de 32,68 ± 9,30% e, no Grupo 2, de 24,56 ± 7,72% (p = 0,06). A relação da captação do 123I-mIBG entre o coração e o mediastino foi normal em todas as pacientes do Grupo 2, entretanto, no Grupo 1, 50% mostraram relação da captação do 123I-mIBG entre o coração e o mediastino ≤ 1,8 (p = 0,02).Conclusão:Em mulheres com câncer de mama submetidas à quimioterapia, a avaliação da atividade simpática cardíaca com 123I-mIBG pode ser um marcador precoce de cardiotoxicidade. A associação de quimioterápicos proporcionou maior risco de hiperatividade adrenérgica cardíaca.

Cardiac toxicity in breast cancer patients

To asses cardiac toxicity post radiotherapy in left cancer breast patients with different fractionations. This is a prospective randomized study conducted at Kasr El-Ainy Center of Clinical Oncology and Nuclear Medicine [NEMROCK]. Cardiological assessment using RTOG toxicity criteria was done for left sided breast cancer patients after at least five years of conformal radiation therapy. There were two arms of radiation, conventional [50Gy/25sttt/5 Ws] and hypofractionation [42.5 Gy 716 fractions /3 1/5 weeks]. Thirty patients were included in each arm. After a median follow up of 62 months [range 60 to 72], cardiac dysfunction developed more in the conventional arm but was insignificant [P value =0.36]. Grade I and II toxicity was 83.3 vs 70% and grade III was 3.3% in the hypofractionated arm only. The rate of local-regional tumor relapse at 5 years was similar [3.3%]. Hypofractionated radiotherapy decreased cardiac toxicity though not statistically significant, however it is more cost effective and time consuming

Comparative cardiac toxicity in two treatment schedules of 5-FU/LV for colorectal carcinoma

The purpose of the study is evaluation and assessment of parameters of cardiac toxicity in patients subjected to 5-FU based chemotherapy. Cardiac morbidity is a reported outcome in different 5FU/LV regimens; however none of them are definite or proximate. The bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective as compared to the monthly regimen of low dose leucovorin. We report the detailed assessment of few cardiac parameter of toxicity in patients of advanced colorectal carcinoma subjected to two Schedules of high and low dose Folinic Acid, 5-Fluorouracil, bolus and continuous infusion. The correlation of elevated cardiac biomarkers, angina and hypertension is comparatively assessed in patients with normal general status, hyperglycemia and known cardiac disorders subjected to two different 5FU based chemotherapeutic regimen

Experimental induction of steatosis in different tissues after the ingestion of a carbohydrate-rich diet: effect on the liver, on the heart and on indicators of oxidation / Esteatose experimental em diferentes tecidos induzida pela ingestão de dieta rica em carboidratos: efeito sobre o fígado, coração e indicadores do estresse oxidativo

CONTEXT: The western dietary pattern is characterized by a high calorie intake with a high proportion of simple sugars. This diet is associated with comorbidities such as hepatic fat deposition and is possibly related to non-alcoholic fatty liver disease. OBJECTIVE: To evaluate the capacity of a hyperglucidic diet to induce steatosis in adult male Wistar rats. After the administration of a carbohydrate-rich diet, we also evaluated the presence of hepatic and cardiac steatosis and the levels of intrinsic antioxidants in the liver. METHODS: Forty-six eutrophic adult male Wistar rats were used and 10 of them were chosen, at random, to serve as controls, while the remaining ones formed the experimental group. Control animals received the standard ration offered by the animal house and the experimental group received the hyperglucidic diet. The diets were offered for 21 days and, at the end of this period, tissue samples were collected for analysis of indicators of oxidative stress (malondialdehyde, and reduced glutathione) and of vitamin E. The animals were then sacrificed by decapitation and their viscera were removed for analysis of liver and heart fat. RESULTS: The hyperglucidic diet used induced hepatic fat deposition, with lipid vacuoles being detected in 83 percent of the livers analyzed by histology. No lipid vacuoles were observed in the heart. Malondialdehyde and reduced glutathione levels remained unchanged when the animals were submitted to the hyperglucidic diet, probably because there was no liver development of fibrosis or inflammation. In contrast, the levels of vitamin E (antioxidant) were reduced, as confirmed in the literature for steatotic animals. CONCLUSION: The hyperglucidic diet induced hepatic steatosis. In the heart there was an increase in fat content, although no histological changes were observed. These alterations cannot be explained by the presence of malondialdehyde or reduced glutathione (indicators of oxidation), since the values were similar in the groups studied. However, a significant reduction of vitamin E was observed in the experimental group.

CONTEXTO: O padrão alimentar ocidental é caracterizado pela ingestão de dieta rica em açúcares simples. Esta alimentação é associada com comorbidades como, por exemplo, deposição de gordura no fígado e possivelmente relacionada com a esteatose hepática não-alcoólica. OBJETIVO: Avaliar a capacidade de uma alimentação hiperglicídica induzir esteatose em ratos Wistar adultos. Após administração de uma dieta rica em hidratos de carbono, foi avaliada a presença de esteatose hepática cardíaca e a presença de antioxidantes no fígado. MÉTODOS: Quarenta e seis ratos Wistar adultos eutróficos foram utilizados no experimento. Destes, 10 animais escolhidos por meio de sorteio simples (ao acaso) foram considerados controles e os demais pertencentes ao grupo experimental. Os animais controles receberam, durante todo experimento dieta usual do biotério. Os animais do grupo experimental, durante 21 dias, receberam dieta com 70 por cento de sacarose. Ao final os animais foram sacrificados por decapitação e suas vísceras (fígado e coração) analisada quanto ao teor de gordura. As amostras de tecido hepático foram também analisadas quanto ao teor de antioxidantes (malondialdehido e glutationa reduzida) e vitamina E. RESULTADOS: A dieta hiperglicídica induziu a deposição de gordura no fígado, sendo os vacúolos lipídicos detectados em 83 por cento das amostras no fígado (histologia). No coração foi detectado bioquimicamente aumento do percentual de gordura, sem a detecção de vacúolos lipídico por histologia. Os teores de malondialdehido e glutationa reduzida não foram diferentes entre os animais dos grupos controle e experimental. Por outro lado, os valores de vitamina E, no grupo experimental, foram significativamente inferiores ao do grupo controle. CONCLUSÃO: A dieta hiperglicídica induziu ao esteatose hepática. No coração houve maior deposição de lípides, embora a histologia não tenha mostrado alterações. Esta deposição, tanto no coração como no fígado, não pode ser explicada pelos indicadores de oxidação utilizados. No entanto, foram observados baixos níveis de vitamina E, que pode estar associada a esta indução de esteatose, principalmente, hepática.

A cardiolipina é o alvo da cardiotoxicidade dos anestésicos locais?: [revisão] / Is cardiolipin the target of local anesthetic cardiotoxicity?: [review]

JUSTIFICATIVA E OBJETIVOS: Os anestésicos locais são amplamente utilizados na prevenção ou na reversão de dor aguda e no tratamento de dor crônica. A reação de cardiotoxicidade induzida pelos anestésicos locais é um evento acidental sem terapia farmacológica, exceto a infusão de intralípides relatados recentemente cujo mecanismo de ação ainda não é bem compreendido. CONTEÚDO: A cardiolipina, um fosfolipídio aniônico, desempenha papel relevante na determinação de reação respiratória mitocondrial, metabolismo de ácidos graxos e apoptose celular. A disfunção do metabolismo energético mitocondrial é sugerida em associação com a cardiotoxicidade dos anestésicos locais, a partir de um estudo in vitro de que ela talvez se deva a fortes ligações eletrostáticas entre os anestésicos locais e a cardiolipina na membrana mitocondrial. Não há, contudo, evidência experimental. Portanto, levantamos a hipótese de que as interações anestésico-cardiolipina sejam o principal determinante associado à reação de cardiotoxicidade, o que pode ser estabelecido com a adoção de métodos teóricos e biológicos estruturais. Esse modelo de interação nos daria uma pista sobre o mecanismo da cardiotoxicidade dos anestésicos locais, visando a futuras pesquisas na área de desenvolvimento de fármacos de prevenção a esse evento na prática clínica. CONCLUSÕES: A interação entre a cardiolipina mitocondrial e os anestésicos locais pode ser a principal fonte de sua cardiotoxicidade, em função de seus efeitos sobre o metabolismo energético e o estado eletrostático.

BACKGROUND AND OBJECTIVES: Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. Local anesthetic-induced cardiotoxic reaction has been considered the accidental event without currently effective therapeutic drugs except for recently reported intralipid infusion whose possible mechanism of action is not well known. CONTENTS: Cardiolipin, an anionic phospholipid, plays a key role in determining mitochondrial respiratory reaction, fatty acid metabolism and cellular apoptosis. Mitochondrial energy metabolism dysfunction is suggested as associated with local anesthetic cardiotoxicity, from an in vitro study report that the local anesthetic cardiotoxicity may be due to the strong electrostatic interaction of local anesthetics and cardiolipin in the mitochondria membrane, although there is a lack for experimental evidence. Herein we hypothesized that local anesthetic-cardiolipin interactions were the major determinant of local anesthetic-associated cardiotoxic reaction, established by means of theoretic and structural biological methods. This interacting model would give an insight on the underlying mechanism of local anesthetic cardiotoxicity and provide clues for further in depth research on designing preventive drugs for such inadvertent accidence in routine clinical practice. CONCLUSIONS: The interaction between local anesthetic and mitochondrial cardiolipin may be the underlying mechanism for cardiotoxicity affecting its energy metabolism and electrostatic status.

Número de áreas anatômicas envolvidas como preditor de risco no linfoma de Hodgkin em crianças: um estudo retrospectivo / Number of involved anatomic areas as a risk predictor in pediatric Hodgkin's lymphoma: a retrospective study

OBJETIVO: Determinar se o número de áreas anatômicas envolvidas pode modificar os grupos de risco padrão no linfoma de Hodgkin pediátrico, identificando as crianças que poderiam se beneficiar de uma redução da intensidade do tratamento. MÉTODOS: Estudo retrospectivo com avaliação de idade, sexo, histologia, classificação de Ann-Arbor, presença de sintomas B, número de áreas anatômicas envolvidas, grupos de risco (favorável versus desfavorável) e exames laboratoriais. Todos os pacientes receberam quimioterapia com doxorrubicina. Os pacientes em remissão completa por 5 anos ou mais foram avaliados para a detecção de efeitos tardios. RESULTADOS: Sessenta e nove pacientes (2-18 anos) foram incluídos, sendo que 68 por cento pertenciam ao grupo de risco desfavorável. A sobrevida global e a sobrevida livre de eventos foram de 94 e 87 por cento, respectivamente. Os efeitos tardios foram detectados em 46 casos. Estágio avançado e > quatro áreas anatômicas envolvidas tiveram impacto negativo sobre a sobrevida livre de eventos, enquanto que o número de áreas anatômicas envolvidas apresentou significância estatística de acordo com a análise de Cox (razão de risco = 6,4; IC95 por cento = 1,08-38,33; p = 0,04). Os grupos de risco foram ajustados por número de áreas anatômicas envolvidas (< quatro/> quatro áreas anatômicas envolvidas), com uma significativa realocação de pacientes (p = 0,008). Dos 30 pacientes com efeitos tardios, 21 estavam no grupo de risco desfavorável original, e 14 poderiam ter sido realocados para o grupo de risco favorável com base no número de áreas anatômicas envolvidas. CONCLUSÃO: Se uma reestratificação tivesse sido aplicada, um número considerável de crianças teria recebido tratamento de menor intensidade e, consequentemente, poderia ter tido menores chances de apresentar efeitos tardios. Um estudo prospectivo poderia definir se o ajuste de grupos de risco pelo número de áreas anatômicas envolvidas teria algum impacto sobre ...

OBJECTIVE: To determine if the number of involved anatomic areas can modify the standard risk groups in pediatric Hodgkin's lymphoma, identifying children who would benefit from a reduction in treatment intensity. METHODS: Retrospective study evaluating age, sex, histology, Ann-Arbor stage, presence of B symptoms, number of involved anatomic areas, risk grouping (favorable vs. unfavorable), and laboratory exams. All patients received doxorubicin-containing chemotherapy. Patients in complete remission for 5 years or longer were evaluated as for late effects. RESULTS: Sixty-nine patients (2-18 years) were included, 68 percent belonged to the unfavorable risk group. Overall survival and event-free survival were 94 and 87 percent, respectively. Late effects were screened in 46 cases. Advanced stage and > four involved anatomic areas had negative impact on event-free survival, while only the number of involved anatomic areas retained statistical significance when using Cox analysis (hazard ratio = 6.4, 95 percentCI = 1.08-38.33; p = 0.04). Risk groups were adjusted by number of involved anatomic areas (< four/> four involved anatomic areas), with a significant reallocation of patients (p = 0.008). Of the 30 patients with late effects, 21 were in the original unfavorable risk group and 14 (66.6 percent) could have been reallocated to the favorable risk group based on the number of involved anatomic areas. CONCLUSION: If re-stratification had been applied, a considerable number of children would have received less intensive treatment and, consequently, could have had lower chances of late effects. A prospective study could define if adjustment of risk group by number of involved anatomic areas would have any impact on survival rates.

Hemodynamic effects of local anesthetics intoxication: experimental study in swine with levobupivacaine and bupivacaine

PURPOSE: To compare the hemodynamic repercussions following a toxic dose of levobupivacaine and bupivacaine intravascularly injected in swines. Methods: Large White pigs were anesthetized with thiopental, tracheal intubation was performed and mechanical ventilation was instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, the animals were randomly divided into two groups in a double-blinded fashion and received a bolus injection of 4 mg/kg of either agent for intoxication. Hemodynamic results were then evaluated at 1, 5, 10, 15, 20 and 30 minutes. RESULTS: Levobupivacaine had greater hemodynamic repercussions than racemic bupivacaine. These results disagree with those found when the levorotatory isomer of bupivacaine was used in humans, but are in agreement with recently reported findings in animals. CONCLUSION: Levobupivacaine was shown to be more toxic in pigs than racemic bupivacaine when large doses are injected intravenously.

OBJETIVO: Comparar as repercussões hemodinâmicas da levobupivacaína e bupivacaína após uma dose tóxica intravascular em suínos. MÉTODOS: Porcos Large-White foram anestesiados com tiopental, entubados e mantidos em ventilação controlada mecânica. Parâmetros hemodinâmicos foram registrados através de pressão invasiva e cateterização da artéria pulmonar (cateter de Swan-Ganz). Após 30 minutos de repouso, os animais foram divididos aleatoriamente em dois grupos e receberam injeção endovenosa em duplo-cego de 4 mg/kg de um ou outro agente anestésico simulando uma intoxicação. Foram avaliados resultados hemodinâmicos aos 1, 5, 10, 15, 20 e 30 minutos. RESULTADOS: Levobupivacaína teve maiores repercussões hemodinâmicas que a bupivacaína racêmica. Estes resultados discordam daqueles encontrados com o isômero levógiro em humanos, mas estão de acordo com resultados recentemente informados em animais. CONCLUSÃO: Levobupivacaína mostrou ser agente mais tóxico em suínos do que a bupivacaína racêmica quando grandes doses são injetadas por via intravascular.

New antihistamines: a critical view

OBJETIVO: Avaliar criticamente os mais novos anti-histamínicos anti-H1 e os diferentes termos utilizados para denominá-los, com base na revisão de evidências sobre o papel dos anti-H1 no tratamento das doenças alérgicas. FONTES DOS DADOS: Artigos originais, revisões e consensos indexados nos bancos de dados MEDLINE e PUBMED de 1998 a 2006. Palavra chave: anti-histamínicos. SíNTESE DOS DADOS: Os anti-histamínicos de segunda geração diferenciam-se dos de primeira geração por sua elevada especificidade e afinidade pelos receptores H1 periféricos e pela menor penetração no sistema nervoso central (SNC), com conseqüente redução dos efeitos sedativos. Embora os anti-histamínicos de segunda geração sejam, geralmente, melhor tolerados do que seus predecessores, alguns efeitos adversos, principalmente cardiotoxicidade, surgiram com alguns deles. Nos últimos 20 anos, novos compostos, com diferentes farmacocinéticas, foram sintetizados. A maioria deles manifesta propriedades antiinflamatórias que independem de sua atividade no receptor H1. Aprimoramentos mais recentes, geralmente na forma de metabólitos ativos, levaram ao uso do termo anti-histamínico de terceira geração. Esse termo surgiu espontaneamente, sem uma descrição clara de seu significado e implicações clínicas, criando grande confusão entre os profissionais da saúde. CONCLUSÕES: Com base nas evidências sobre anti-histamínicos anti-H1, nenhum deles pode ser considerado como "anti-histamínico de terceira geração". Para tanto, seria preciso comprovar que a nova classe de anti-histamínicos possui vantagens clínicas distintas sobre os compostos existentes e preenche pelo menos três pré-requisitos: ausência de cardiotoxicidade, de interações medicamentosas e de efeitos sobre o SNC.

OBJECTIVE: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSIONS: On the basis of the evidence on H1 antihistamines, none of them deserve the title"third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS.

Benefit of electrocardiography during front-line combination paclitaxel and carboplatin chemotherapy for epithelial ovarian cancer.

OBJECTIVE: To evaluate the patterns of electrocardiography (ECG), cardiac risk factors and its clinical consequence in women with epithelial ovarian cancer (EOC) who received paclitaxel and carboplatin (PC) as front line chemotherapy. MATERIAL AND METHOD: The medical records and electrocardiographic data of women with EOC who received paclitaxel (175 mg/min2) and carboplatin (AUC=5) every 3 weeks at Chiang Mai University Hospital between January 2000 and December 2004 were reviewed for cardiac risk factors and clinical consequence. RESULTS: Among 79 women receiving PC for EOC, 43 (54.4%) had cardiac risk factors. Seventy (88.6%) women had normal ECG, the remaining nine had sinus tachycardia (5), bundle branch block (2), mild T inversion (1), and Wolff-Parkinson-White syndrome (1) before the first course of chemotherapy. Among 70 women with normal initial ECG 8 (11.4%) had sinus tachycardia, one (1.4%) had early depolarization, two (2.9%) had sinus bradycardia and three (4.3%) had sinus arrhythmia in subsequent ECG All these cardiac disturbances were asymptomatic and needed no intervention, indicating grade I toxicity. The odds ratio of developing abnormal ECG in women with cardiac risk factor was 1.24 (95% CI = 0.33 to 4.64, p = 0.77). Among nine patients with abnormal ECG before the first course of PC, six (66.7%) had subsequent abnormal ECG but all were asymptomatic and no worsening of abnormal ECG pattern was noted. CONCLUSION: Although paclitaxel and carboplatin chemotherapy could induce abnormal ECG in women with either normal or abnormal prior ECG, its consequence was of no clinical significance. Therefore, the benefit of ECG before each treatment course was theoretically limited.

Mechanistic pathways of antioxidant cytoprotection by a novel IH636 grape seed proanthocyanidin extract.

To understand the bioavailability and mechanistic pathways of cytoprotection by IH636 grape seed proanthocyanidin extract (GSPE, commercially known as ActiVin) a series of in vitro and in vivo studies were conducted. Comparative protective abilities of GSPE, and vitamins C and E, singly and in combination, were assessed against smokeless tobacco extract (STE)-induced oxidative stress, DNA fragmentation and apoptotic cell death in a primary culture of normal human oral keratinocytes. GSPE protected against STE-induced oxidative stress, DNA damage and apoptotic cell death, and provided better protection as compared to vitamins C and E, singly and in combination. The bioavailability and protective ability of GSPE were examined against acetaminophen (AP)-induced hepato- and nephrotoxicity, amiodarone (AM)-induced lung toxicity, doxorubicin (DX)-induced cardiotoxicity and dimethylnitrosamine (DM)-induced spleenotoxicity in mice. GSPE-fed animals were compared with GSPE-untreated mice to evaluate the protective ability of GSPE against these structurally diverse drugs/chemicals. Serum chemistry changes, histopathology and DNA damage were evaluated. Results indicate that GSPE preexposure prior to the drugs/chemicals such as AP, AM, DX or DM treatment, provided near complete protection in terms of serum chemistry changes and inhibition of both forms of cell death, e.g., apoptosis and necrosis. DNA damage in various tissues triggered by these agents was significantly reduced in GSPE-fed animals. Histopathological examination of multiple target organs provided similar data. The results suggest that GSPE exposure is bioavailable and provides significant multiorgan protection against structurally diverse drug- and chemical-induced toxic assaults. Further, these studies exhibited a series of mechanistic information including free radical scavenging ability, anti-endonucleolytic activity, cytochrome P450 2E1 inhibitory activity, anti-necrotic, anti-apoptotic and anti-carcinogenic activities, modulatory effects on antioxidative and apoptotic regulatory genes such as Bcl2, c-myc and p53, which may be responsible for the novel chemoprotective properties exhibited by GSPE.