Ephedra Herb extract ameliorates adriamycin-induced nephrotic syndrome in rats via the CAMKK2/AMPK/mTOR signaling pathway / 中国天然药物

This study aimed to investigate the effect and mechanisms of Ephedra Herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidn injury molecule-1 were used to evaluate the activities of EH extract on renal function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR and p-mTOR in the kidneys were detected by Western blot. The effective material basis of EH extract was screened by MTT assay. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent material basis on adriamycin-induced cell injury. EH extract significantly improved renal injury and relieve inflammation, oxidative stress, and apoptosis in rats. Network pharmacology and Western blot results showed that the effect of EH extract on NS may be associated with the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, which were blocked by CC. In sum, EH extract may ameliorate renal injury via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.

Protective effects of psoralen polymer lipid nanoparticles on doxorubicin - induced myocardial toxicity

Abstract Doxorubicin (DOX) induced myocardial toxicity may limit its therapeutic use in clinic. Psoralen (PSO), a major active tricyclic furocoumarin extracted from Psoralea corylifolia, is widely used as an antineoplastic agent in treatment of leukemia and other cancers. This study is aim to find the protective effect of psoralen polymer lipid nanoparticles (PSO-PLN) on doxorubicin-induced myocardial toxicity in mice. The model of myocardial toxicity induced by DOX was established. The experiment was divided into 6 groups: normal saline group, DOX + Sulfotanshinone Sodium, DOX + PSO-PLN (3 mg/kg), DOX + PSO-PLN (6 mg/kg), DOX + PSO-PLN (9 mg/ kg), DOX group. DOX alone treated mice lead to a significant decrease in the body weight, heart weight, and increase in the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) markers of cardiotoxicity. However, DOX reduced glutathione (GSH) content and activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX), were recovered by PSO-PLN. And PSO-PLN also decreased markers of cardiotoxicity in the serum. Western blotting data showed that the protective effects of PSO-PLN might be mediated via regulation of protein kinase A (PKA) and p38. Our study suggest that PSO-PLN possesses antioxidant activities, inactivating PKA and p38 effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

Chloroquine ameliorates adriamycin-induced testicular damage by suppressing the inflammation and apoptosis in rats: a histological, immunohistochemical and biochemical study / La cloroquina mejora el daño testicular inducido por la adriamicina al suprimir la inflamación y la apoptosis en ratas: un estudio histológico, inmunohistoquímico y bioquímico

SUMMARY: Adriamycin (ADR) is an anthracycline antibiotic used for treatment of many types of cancer. However, its applications may damage to healthy tissues. Chloroquine (CLQ) is an anti-inflammatory agent used in treatment of many inflammation associated diseases such as malaria and rheumatoid arthritis. Moreover, it is used in the treatment of pneumonia caused by COVID-19. The aim of this study is to determine possible therapeutic effects of Chloroquine on Adriamycin-induced testicular toxicity in rats. We investigated the effect of CLQ on testicular injury caused by ADR. Rats were divided into four groups: Control, ADR, CLQ, ADR+CLQ. After administrations, animals were sacrificed, and testis tissues were extracted from the animals for the further examinations. Histopathological changes in testis tissues were evaluated and TNF-α and IL-6 immunostaining were performed to determine the expression levels of these cytokines. TUNEL method were used for evaluation of apoptotic index. Moreover, serum testosterone levels were measured by ELISA assay. We observed that ADR group showed histopathological deterioration when compared to the Control group and CLQ treatment ameliorated this damage induced by Adriamycin.An increase in TNF-α and IL-6 immunoreactivities and in the number of apoptotic cells and a decrease in serum testosterone levels were determined in the ADR group compared to the Control and CLQ group. Furthermore, our examinations showed an improvement in testicular tissue in ADR+CLQ group in terms of these parameters when compared to the ADR group. We suggest that CLQ can be used as a protective agent to reduce the toxic effects of Adriamycin as a result of its anti-inflammatory and anti-apoptotic properties.

RESUMEN: La adriamicina (ADR) es un antibiótico de antraciclina que se usa para el tratamiento de muchos tipos de cáncer. Sin embargo, sus aplicaciones pueden dañar los tejidos sanos. La cloroquina (CLQ) es un agente antiinflamatorio que se utiliza en el tratamiento de enfermedades asociadas a la inflamación, tal como la malaria y la artritis reumatoide. También se utiliza en el tratamiento de la neumonía causada por COVID-19. El objetivo de este estudio fue determinar los posibles efectos terapéuticos de la cloroquina sobre la toxicidad testicular inducida por adriamicina en ratas. Investigamos el efecto de CLQ sobre la lesión testicular causada por ADR. Las ratas se dividieron en cuatro grupos: Control, ADR, CLQ, ADR + CLQ. Después de las administraciones, se sacrificaron los animales y se extrajeron los testículos de los animales para los exámenes adicionales. Se evaluaron los cambios histopatológicos en los tejidos testiculares y se realizó la inmunotinción de TNF-α e IL-6 para determinar los niveles de expresión de estas citocinas. Se utilizó el método TUNEL para la evaluación del índice apoptótico. Además, los niveles de testosterona en suero se midieron mediante un ensayo ELISA. El grupo ADR mostró un deterioro histopatológico en comparación con el grupo Control y observamos que el tratamiento con CLQ mejoró el daño inducido por Adriamicina. Un aumento en las inmunorreactividades de TNF-α e IL-6 y en el número de células apoptóticas además de una disminución en los niveles séricos de testosterona se determinaron en el grupo de ADR en comparación con el grupo de control y CLQ. Además, nuestros exámenes mostraron una mejora en el tejido testicular en el grupo ADR + CLQ en términos de estos parámetros en comparación con el grupo ADR. Sugerimos que CLQ se puede utilizar como agente protector para reducir los efectos tóxicos de la Adriamicina, gracias a sus propiedades antiinflamatorias y antiapoptóticas.

Exercício Aeróbio e Função Cardíaca de Murinos Expostos à Doxorrubicina: uma Metanálise / Aerobic Exercise and Cardiac Function of Murines Exposed to Doxorubicin: a Meta-Analysis

Resumo Fundamento: A cardiotoxicidade pode ser uma consequência do tratamento com doxorrubicina (DOX). Objetivos: Verificar o efeito do exercício aeróbio na prevenção da disfunção cardíaca de murinos expostos à DOX. Método: Uma busca abrangente foi realizada em nove bases de dados, em dezembro de 2017. Estudos que avaliaram a função cardíaca de murinos expostos à DOX foram incluídos. O nível de significância adotado foi de 5%. Resultados: Na comparação entre 230 murinos submetidos a exercício aeróbio mais DOX e 222 controles (tratados somente com DOX), a fração de encurtamento mostrou uma melhora de 5,33% a favor do grupo experimental (p = 0,0001). A pressão desenvolvida no ventrículo esquerdo também mostrou um aumento de 24,84 mmHg a favor do grupo de 153 murinos que realizaram exercício em comparação com o grupo controle de 166 murinos (p = 0,00001). Conclusão: Estudos pré-clínicos incluídos nesta metanálise indicaram que o exercício é uma boa estratégia não farmacológica para preservar a função cardíaca pós-DOX.

Abstract Background: Cardiotoxicity may be a consequence of treatments with doxorubicin (DOX). Objectives: To investigate the effect of aerobic exercise on the prevention of cardiac dysfunction in murines exposed to DOX. Method: A comprehensive search was conducted in 9 databases in December 2017. Studies that evaluated the cardiac function of murines exposed to DOX were included. The significance level adopted was 5%. Results: In a comparison between 230 murines that underwent aerobic exercise plus DOX treatment and 222 control murines (DOX treatment only), fractional shortening showed an improvement of 5.33% in favor of the experimental group (p = 0.00001). Left ventricle developed pressure also showed an increase of 24.84 mm Hg in favor of the group of 153 murines that performed exercise in comparison to the control group of 166 murines (p = 0.00001). Conclusion: Preclinical studies included in this meta-analysis indicated that exercise is a good nonpharmacological strategy for preserving post-DOX cardiac function.

Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy / Alteração Contrátil Segmentar Ventricular Esquerda é Preditor Independente de Cardiotoxicidade em Pacientes com Câncer de Mama em Tratamento Quimioterápico

Abstract Background: Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied. Objective: To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy. Methods: Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time. Results: Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity. Conclusion: In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Resumo Fundamento: Os agentes quimioterápicos da classe das antraciclinas e dos anticorpos monoclonais humanizados são tratamentos eficazes para o câncer de mama, entretanto, apresentam alto risco de cardiotoxicidade. Diversos parâmetros têm sido reconhecidos como preditores no desenvolvimento de toxicidade cardíaca, sendo que a avaliação da alteração contrátil segmentar ventricular esquerda (ACSVE) ainda não foi estudada. Objetivo: Analisar a associação entre o surgimento de ACSVE e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia. Métodos: Coorte prospectiva de pacientes diagnosticados com câncer de mama e em tratamento quimioterápico com doxorrubicina e/ou trastuzumab. Foram realizados ecocardiogramas transtorácicos antes, durante e depois do tratamento para avaliar a presença ou não de cardiotoxicidade. A cardiotoxicidade foi definida por um decréscimo de 10% na fração de ejeção do ventrículo esquerdo, em pelo menos um ecocardiograma. Modelos de regressão logística multivariada foram utilizados para verificar os fatores preditores na ocorrência de cardiotoxicidade ao longo do tempo. Resultados: Dos 112 pacientes selecionados (idade média = 51,3 ± 12,9 anos), 18 (16,1%) apresentaram cardiotoxicidade. Na análise multivariada os pacientes com ACSVE (OR = 6,25 [IC 95%: 1,03; 37,95], p < 0,05), diâmetro sistólico do VE (OR = 1,34 [IC 95%:1,01; 1,79], p < 0,05) e strain longitudinal global pela técnica de speckle tracking (OR = 1,48 [IC 95%: 1,02; 2,12], p < 0,05) foram preditores significativos e independentes na predição de cardiotoxidade. Conclusão: Mostramos que ACSVE, bem como a redução do strain longitudinal global foram preditores independentes para cardiotoxicidade, podendo ser úteis na estratificação de risco destes pacientes.

Cardiotoxicidade nas Terapias Neoadjuvante e Adjuvante do Câncer de Mama / Cardiotoxicity in Adjuvant and Neoadjuvant Therapy for Breast Cancer / Cardiotoxicidad en Terapias de Cáncer de Mama Neoadyuvante y Adyuvante

Introdução: O câncer de mama é o mais comum entre as mulheres em todo o mundo, representando quase 25% de todos os casos de câncer. Alguns fármacos possuem características peculiares relacionadas à cardiotoxicidade. Objetivo: Analisar a incidência, as características clínicas e os fatores de risco associados à ocorrência de cardiotoxicidade em pacientes submetidas ao protocolo doxorrubicina e ciclofosfamida seguido ou não de taxanos e naquelas que realizaram o mesmo protocolo associado ao trastuzumabe. Método: Trata-se de um estudo de coorte realizado em um hospital público do Rio de Janeiro. Foram incluídas 153 pacientes que iniciaram tratamento entre os meses de setembro e novembro de 2012. A cardiotoxicidade foi definida com base nos critérios do Cardiac Review and Evaluation Committee e da Sociedade Brasileira de Cardiologia. Foi calculado o risco relativo (RR), utilizando-se um intervalo de confiança (IC) de 95%. Resultados: A incidência de cardiotoxicidade foi de 17%. Observou-se queda da fração de ejeção do ventrículo esquerdo em 31,3% e 52,2% das pacientes nos grupos human epidermal growth factor receptor-type 2 (HER-2) negativo e positivo, respectivamente. Foram identificados três casos de insuficiência cardíaca, sendo dois em pacientes HER-2 positivas. As pacientes que utilizaram trastuzumabe apresentaram maior risco de desenvolver cardiotoxicidade (RR=3,53; IC 95%: 1,84-6,79) em comparação com as mulheres do grupo HER-2 negativo. Conclusão:Foi possível verificar a ocorrência de casos de cardiotoxicidade em ambos os grupos com maior incidência para o grupo HER-2 positivo.

Introduction: Breast cancer is the most common among women worldwide, accounting for almost 25% of all cancer cases. Some drugs have a peculiar characteristic related to cardiotoxicity. Objective: Analyze the incidence, clinical characteristics and risk factors associated with cardiotoxicity in patients undergoing protocol doxorubicin and cyclophosphamide followed or not by taxanes and in those who underwent the same protocol associated with trastuzumab. Method: Cohort study conducted in a public hospital in Rio de Janeiro. 153 patients were included between September and November 2012. Cardiotoxicity was defined based on the criteria of the Cardiac Review and Evaluation Committee and the Brazilian Society of Cardiology. The relative risk (RR) was calculated using a 95% confidence interval (CI). Results: The incidence of cardiotoxicity was 17%. Left ventricular ejection fraction decreased in 31.3% and 52.2% of the patients in the negative and positive human epidermal growth factor receptor-type 2 (HER-2) groups, respectively. Three cases of heart failure were identified, two in HER-2 positive patients. Patients using trastuzumab had a higher risk of developing cardiotoxicity (RR=3.53; CI 95%: 1.84-6.79) compared to women in the HER-2 negative group. Conclusion: It was possible to verify the occurrence of cases of cardiotoxicity in both groups with higher incidence for the HER-2 positive group.

Introducción: El cáncer de mama es el más común entre las mujeres en todo el mundo, y representa casi el 25% de todos los casos de cáncer. Algunos medicamentos tienen característica peculiar relacionada con la cardiotoxicidad. Objetivo: Analizar la incidencia, las características clínicas y los factores de riesgo asociados con la cardiotoxicidad en pacientes sometidos al protocolo doxorrubicina y ciclofosfamida seguidos o no por taxanos y en aquellos que se sometieron al mismo protocolo asociado con trastuzumab. Método: Este es un estudio de cohorte realizado en un hospital público en Río de Janeiro. Se incluyeron 153 pacientes que comenzaron el tratamiento entre septiembre y noviembre de 2012. La cardiotoxicidad se definió según los criterios del Comité de Revisión y Evaluación Cardíaca y la Sociedad Brasileña de Cardiología. El riesgo relativo (RR) se calculó utilizando un intervalo de confianza (IC) del 95%. Resultados: La incidencia de cardiotoxicidad fue del 17%. La fracción de eyección del ventrículo izquierdo disminuyó en el 31,3% y el 52,2% de los pacientes en los grupos human epidermal growth factor receptor-type 2 (HER-2) negativo y positivo, respectivamente. Se identificaron tres casos de insuficiencia cardíaca, dos en pacientes con HER-2 positivo. Los pacientes que usaban trastuzumab tenían un mayor riesgo de desarrollar cardiotoxicidad (RR=3,53; IC 95%: 1,84-6,79) en comparación con las mujeres en el grupo negativo HER-2. Conclusión: Fue posible verificar la aparición de casos de cardiotoxicidad en ambos grupos con mayor incidencia para el grupo HER-2 positivo.

Aconselhamento telefônico: identificação de sintomas em pacientes com linfoma em quimioterapia antineoplásica / Consulta telefónica: identificación de síntomas en pacientes con linfoma en quimioterapia antineoplásica / Telephone counseling: identification of symptoms in patients with lymphoma undergoing antineoplastic chemotherapy

Resumo Objetivo Identificar os sinais e sintomas apresentados por pacientes com Linfoma de Hodgkin submetidos ao protocolo quimioterápico composto por Doxorrubicina, Bleomicina, Vimblastina e Dacarbazina (ABVD) por meio de aconselhamento telefônico e comparar os escores de gradação dos sinais e sintomas apresentados nos ciclos do protocolo. Métodos Descritivo, prospectivo, quantitativo. Sete pacientes receberam aconselhamento telefônico, em 24 tempos de chamadas programadas e não programadas, correspondentes a 6 ciclos de quimioterapia com protocolo ABVD. Utilizou-se o Inventário de Sintomas do M.D Anderson e o Critério Comum de Terminologia para Eventos Adversos, para a gradação dos sintomas e um protocolo de condutas. Realizou-se análise descritiva e analítica. Resultados Duzentas e oitenta e seis chamadas telefônicas geraram1.870 queixas sintomáticas. Nas chamadas programadas, as queixas com maior prevalência foram fadiga, preocupações, falta de apetite, vômitos e náuseas. Quanto a interferência nas atividades de vida diária, os itens relacionados a atividades em geral, no trabalho e dificuldade para caminhar, além de alterações no humor foram relatados em maior frequência. Nas chamadas não programadas, a falta de apetite e desregulação menstrual foram as queixas mais recorrentes. Na análise da progressão dos sintomas, observou-se aumento de náuseas e vômitos (p=0,02), diminuição da fadiga e falta de ar (p≤0,03), melhora do sono (p=0,02) e diminuição do estresse (p=0,02). Conclusão A fadiga, náusea, vômito e alteração nas atividades de trabalho foram relatados frequentemente. Houve progressão de náuseas e vômitos, mas regressão da fadiga e do estresse. O aconselhamento telefônico permitiu a comunicação e o manejo rápido de um número expressivo de sintomas.

Resumen Objetivo Identificar los signos y síntomas presentados por pacientes con linfoma de Hodgkin sometidos al protocolo quimioterápico compuesto por doxorrubicina, bleomicina, vinblastina y dacarbazina (ABVD) mediante consulta telefónica, y comparar los puntajes de graduación de los signos y síntomas presentados en los ciclos del protocolo. Métodos Descriptivo, prospectivo, cuantitativo. Siete pacientes recibieron asesoramiento telefónico en 24 momentos de llamadas programadas y no programadas, correspondientes a 6 ciclos de quimioterapia con protocolo ABVD. Se utilizó el Inventario de Síntomas de M. D. Anderson y el Criterio de Terminología Común para Efectos Adversos, para la puntuación de lis síntomas, y un protocolo de conductas. Se realizó análisis descriptivo y analítico. Resultados Doscientas ochenta y seis llamadas telefónicas determinaron 1.870 quejas sintomáticas. En las llamadas programadas, las quejas más prevalentes fueron: fatiga, preocupaciones, falta de apetito, vómitos y náuseas. Respecto a interferencia en actividades cotidianas, los ítems relacionados con actividad en general, laboral y dificultad para caminar, además de cambios del humor, fueron informados con mayor frecuencia. En llamadas no programadas, la falta de apetito y la irregularidad menstrual resultaron las quejas más habituales. En el análisis de progresión de los síntomas se observó aumento de náuseas y vómitos (p=0,02), disminución de fatiga y falta de aire (p≤0,03), mejora del sueño (p=0,02) y disminución del estrés (p=0,02). Conclusión Hubo informe frecuente de fatiga, náuseas, vómitos y cambios en actividades laborales. Existió progresión de náuseas y vómitos, y regresión de fatiga y estrés. La consulta telefónica permitió comunicación y rápido manejo de una expresiva cantidad de síntomas.

Abstract Objective To identify through telephone counselling the signs and symptoms presented by patients with Hodgkin's Lymphoma undergoing chemotherapy with the protocol composed by doxorubicin, bleomycin, vinblastine and dacarbazine and to compare severity scores of the signs and symptoms presented in the cycles of the protocol. Methods Descriptive, prospective, quantitative study. Seven patients received telephone counselling in 24 scheduled and unscheduled calls, corresponding to 6 ABVD chemotherapy cycle. The MD Anderson Symptom Inventory and the Common Terminology Criteria for Adverse Events were used for scoring the symptoms, along with a conduct protocol. A descriptive and analytical analysis was conducted. Results Two hundred and eighty-six telephone calls generated 1,870 symptomatic complaints. In scheduled calls, the most prevalent complaints were fatigue, distress, lack of appetite, vomiting and nausea. As for the interference in daily life activities, the items related to general activities, work, difficulty walking, and mood changes were reported more frequently. In unscheduled calls, lack of appetite and irregular menstruation were the most recurring complaints. The analysis of the progression of symptoms showed an increase in nausea and vomiting (p=0.02), decrease in fatigue and shortness of breath (p≤0.03), improvement in sleep (p=0.02) and decrease of stress (p=0.02). Conclusion Fatigue, nausea, vomiting and alterations in work activities were frequently reported. There was progression of nausea and vomiting but regression of fatigue and stress. Telephone consultation allowed a rapid communication and management of an expressive number of symptoms.

Arterial Stiffness Use for Early Monitoring of Cardiovascular Adverse Events due to Anthracycline Chemotherapy in Breast Cancer Patients. A Pilot Study / Uso da Rigidez Arterial para Monitoramento Precoce de Eventos Adversos Cardiovasculares por Antracíclicos em Pacientes com Câncer de Mama. Um Estudo Piloto

Abstract Background: Chemotherapy with doxorubicin and cyclophosphamide, although efficient for treating breast cancer, is associated with cardiovascular complications. Recent studies seek to identify methods that can early detect cardiological and vascular changes as a strategy to decrease the incidence of cardiovascular comorbidities. Objective: To evaluate the role of arterial stiffness measurement in the monitoring of doxorubicin and cyclophosphamide-induced cardiotoxicity in breast cancer patients. Methods: Prospective longitudinal study in 24 breast cancer patients undergoing treatment with doxorubicin and cyclophosphamide. Patients underwent an indirect evaluation of arterial stiffness through non-invasive measurement of hemodynamic parameters such as pulse wave velocity with the Mobil-O-Graph® 24H PWA device at three different times of the chemotherapy treatment (pre-chemotherapy, after the first and the fourth cycle). The left ventricular ejection fraction was also evaluated by Doppler echocardiography (pre-chemotherapy and after the fourth chemotherapy cycle). Data were considered significant when p ≤ 0.05. Results: Patients had a mean age of 52.33 ± 8.85 years and body mass index of 31 ± 5.87 kg/m2. There was no significant difference between the hemodynamic parameters evaluated by the oscillometric method or in the left ventricular ejection fraction in the different evaluated periods. Conclusion: Evaluations of arterial stiffness by oscillometry and measurement of left ventricular ejection fraction by Doppler echocardiography showed equivalence in the values found, suggesting that the evaluation method of arterial stiffness studied could be used as a marker for cardiovascular adverse events associated with doxorrubicin-based chemotherapy drugs.

Resumo Fundamento: O tratamento quimioterápico com doxorrubicina e ciclofosfamida, apesar de eficiente no combate ao câncer de mama, está associado a complicações cardiovasculares. Trabalhos recentes identificam métodos que possam detectar alterações cardiológicas e vasculares precocemente, visando a uma estratégia para diminuição na incidência de comorbidades cardiovasculares. Objetivo: Avaliar o papel da medida da rigidez arterial no acompanhamento da ocorrência de eventos adversos cardiovasculares induzidos por doxorrubicina e ciclofosfamida em pacientes com câncer de mama. Métodos: Estudo longitudinal prospectivo realizado com 24 pacientes com câncer de mama em tratamento com doxorrubicina e ciclofosfamida. As pacientes foram submetidas à avaliação indireta da rigidez arterial, por mensuração não invasiva de parâmetros hemodinâmicos, como a velocidade de onda de pulso, pelo equipamento Mobil-O-Graph® 24H PWA em três diferentes momentos do tratamento quimioterápico (pré-quimioterapia, após o primeiro e após o quarto ciclos). Foi avaliada também a fração de ejeção do ventrículo esquerdo pelo ecoDopplercardiograma (pré-quimioterapia e após o quarto ciclo quimioterápico). Os valores de p ≤ 0,05 foram considerados significativos. Resultados: As pacientes apresentaram média de idade de 52,33 ± 8,85 anos e índice de massa corporal de 31 ± 5,87 kg/m2. Não houve diferença significativa entre os parâmetros hemodinâmicos avaliados pelo método oscilométrico ou na fração de ejeção do ventrículo esquerdo, nos diferentes períodos avaliados. Conclusão: As avaliações de rigidez arterial por oscilometria e medida da fração de ejeção do ventrículo esquerdo por ecoDopplercardiograma mostraram equivalência nos valores encontrados, sugerindo que o método de avaliação da rigidez arterial estudado possa ser utilizado como mais um marcador para eventos adversos cardiovasculares associados aos medicamentos quimioterápicos baseados em doxorrubicina.

Cardiotoxicidade Decorrente do Tratamento com Doxorrubicina e Exercício Físico: Revisão Sistemática / Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review

O presente estudo investigou se a prática de exercícios possui um efeito protetor contra a toxicidade cardíaca decorrente do tratamento com doxorrubicina. Para tal, foi realizada uma revisão sistemática da literatura, de ensaios clínicos randomizados que verificam o exercício como meio de controle ou prevenção da cardiotoxicidade induzida pela utilização de DOX. Foram realizadas buscas nas bases de dados MEDLINE e LILACS. Foram utilizados os descritores: exercício, condicionamento físico, antraciclinas, doxorrubicina, adriamicina, agentes cardiotóxicos. Para seleção dos trabalhos que se incluíam nos critérios estabelecidos, foram avaliados os resumos de todos os artigos. Foram excluídos estudos que não abordaram o tema central da pesquisa, não se referiram ao exercício físico ou a DOX, abordaram exclusivamente outros tipos de toxicidade por antraciclinas (muscular, hepática e renal), ou verificaram outros efeitos do exercício sobre toxicidade da DOX (fadiga). O presente estudo observou, com relação às variáveis relacionadas à prescrição de exercício, que a frequência não apresentou relação direta com os resultados dos referidos estudos. A intensidade também não foi definitiva para a preservação da função cardíaca, porém o treinamento mais intenso esteve relacionado com melhoras no sistema antioxidante que não esteve presente em alguns estudos com intensidades mais baixas. Não houve diferença significativa nos efeitos dos exercícios quando realizados antes, durante ou depois do tratamento. Portanto, exercício aeróbio parece exercer um efeito protetor das funções cardíacas se realizado antes, durante ou depois do tratamento com DOX. Porém, os mecanismos associados a esse efeito ainda são desconhecidos

Atrial Function in Patients with Breast Cancer After Treatment with Anthracyclines / Função Atrial em Pacientes com Câncer de Mama Após tratamento com Antraciclinas

Abstract Background: Atrial electromechanical delay (EMD) is used to predict atrial fibrillation, measured by echocardiography. Objectives: The aim of this study was to assess atrial EMD and mechanical function after anthracycline-containing chemotherapy. Methods: Fifty-three patients with breast cancer (48 ± 8 years old) who received 240 mg/m2of Adriamycin, 2400 mg/m2 of cyclophosphamide, and 960 mg/m2 of paclitaxel were included in this retrospective study, as were 42 healthy subjects (47 ± 9 years old). Echocardiographic measurements were performed 11 ± 7 months (median 9 months) after treatment with anthracyclines. Results: Left intra-atrial EMD (11.4 ± 6.0 vs. 8.1 ± 4.9, p=0.008) and inter-atrial EMD (19.7 ± 7.4 vs. 14.7 ± 6.5, p=0.001) were prolonged; LA passive emptying volume and fraction were decreased (p=0.0001 and p=0.0001); LA active emptying volume and fraction were increased (p=0.0001 and p=0.0001); Mitral A velocity (0.8 ± 0.2 vs. 0.6 ± 0.2, p=0.0001) and mitral E-wave deceleration time (201.2 ± 35.6 vs. 163.7 ± 21.8, p=0.0001) were increased; Mitral E/A ratio (1.0 ± 0.3 vs. 1.3 ± 0.3, p=0.0001) and mitral Em (0.09 ± 0.03 vs. 0.11 ± 0.03, p=0.001) were decreased; Mitral Am (0.11 ± 0.02 vs. 0.09 ± 0.02, p=0.0001) and mitral E/Em ratio (8.8 ± 3.2 vs. 7.6 ± 2.6, p=0.017) were increased in the patients. Conclusions: In patients with breast cancer after anthracycline therapy: Left intra-atrial, inter-atrial electromechanical intervals were prolonged. Diastolic function was impaired. Impaired left ventricular relaxation and left atrial electrical conduction could be contributing to the development of atrial arrhythmias.

Resumo Fundamento: Atraso eletromecânico atrial (AEA) é utilizado para prever fibrilação atrial, medido pela ecocardiografia. Objetivos: O propósito deste estudo era verificar o AEA e a função mecânica após quimioterapia com antraciclinas. Métodos: Cinquenta e três pacientes com câncer de mama (48 ± 8 anos) que receberam 240 mg/m2 de adriamicina, 2400 mg/m2 de ciclofosfamida, e 960 mg/m2 de paclitaxel foram incluídas neste estudo retrospectivo, além de 42 indivíduos saudáveis (47 ± 9 anos). Medidas ecocardiográficas foram realizadas por aproximadamente 11 ± 7 meses (média de 9 meses) após tratamento com antraciclinas. Resultados: AEA esquerdo intra-atrial (11,4 ± 6,0 vs. 8,1 ± 4,9, p=0,008) e AEA interarterial (19,7 ± 7,4 vs. 14,7 ± 6,5, p=0,001) foram prolongados; Volume de esvaziamento passivo e fracionamento de AE diminuíram (p=0,0001 e p=0,0001); Volume de esvaziamento ativo e fracionamento de AE (p=0,0001 e p=0,0001); Tempo de aceleração mitral A (0,8 ± 0,2 vs. 0,6 ± 0,2, p=0,0001) e de desaceleração de onda-E mitral (201,2 ± 35,6 vs. 163,7 ± 21,8, p=0,0001) aumentarão; Razão mitral E/A (1,0 ± 0,3 vs. 1,3 ± 0,3, p=0,0001) e mitral Em (0,09 ± 0,03 vs. 0,11 ± 0,03, p=0,001) diminuíram; Razão mitral Am (0,11 ± 0,02 vs. 0,09 ± 0,02, p=0,0001) e mitral E/Em (8,8 ± 3,2 vs. 7,6 ± 2,6, p=0,017) aumentaram nos pacientes. Conclusões: Em pacientes com câncer de mama após terapia com antraciclina: intervalos eletromecânicos intra-atriais esquerdos, intra-atriais foram prolongados. A função diastólica foi prejudicada. O relaxamento ventricular esquerdo foi prejudicado, e a condução elétrica atrial esquerda pode estar contribuindo para o desenvolvimento de arritmias atriais.

Serious stomatitis and esophagitis: a peculiar mucous reaction induced by pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin is an important antineoplastic agent with activity in a variety of solid tumors. It has a totally different profile of pharmacokinetics and toxicity compared with doxorubicin. It rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in many kinds of mucocutaneous reactions, including palmar-plantar erythrodysesthesia, diffuse follicular rash, intertrigo-like eruption, new formation of melanotic macules, stomatitis and radiation recall dermatitis. We present a rare case of multiple myeloma who immediately developed serious stomatitis and esophatitis associated with minor palmar-plantar erythrodysesthesia after a single course of pegylated liposomal doxorubicin.

The efficacy of 2-nitrovinylfuran derivatives against Leishmania in vitro and in vivo

Despite recent advances in the treatment of some forms of leishmaniasis, the available drugs are still far from ideal due to inefficacy, parasite resistance, toxicity and cost. The wide-spectrum antimicrobial activity of 2-nitrovinylfuran compounds has been described, as has their activity against Trichomonas vaginalis and other protozoa. Thus, the aim of this study was to test the antileishmanial activities of six 2-nitrovinylfurans in vitro and in a murine model of leishmaniasis. Minimum parasiticide concentration (MPC) and 50% inhibitory concentration (IC50) values for these compounds against the promastigotes of Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis were determined, as were the efficacies of two selected compounds in an experimental model of cutaneous leishmaniasis (CL) caused by L. amazonensis in BALB/c mice. All of the compounds were active against the promastigotes of the three Leishmania species tested. IC50 and MPC values were in the ranges of 0.8-4.7 µM and 1.7-32 µM, respectively. The compounds 2-bromo-5-(2-bromo-2-nitrovinyl)-furan (furvina) and 2-bromo-5-(2-methyl-2-nitrovinyl)-furan (UC245) also reduced lesion growth in vivo at a magnitude comparable to or higher than that achieved by amphotericin B treatment. The results demonstrate the potential of this class of compounds as antileishmanial agents and support the clinical testing of Dermofural(r) (a furvina-containing antifungal ointment) for the treatment of CL.

Subclinical Ventricular Dysfunction Detected by Speckle Tracking Two Years after Use of Anthracycline / Disfunção Ventricular Subclínica Detectada por Speckle Tracking Dois Anos após Uso de Antraciclina

Background: Heart failure is a severe complication associated with doxorubicin (DOX) use. Strain, assessed by two-dimensional speckle tracking (2D-STE), has been shown to be useful in identifying subclinical ventricular dysfunction. Objectives: a) To investigate the role of strain in the identification of subclinical ventricular dysfunction in patients who used DOX; b) to investigate determinants of strain response in these patients. Methods: Cross-sectional study with 81 participants: 40 patients who used DOX ±2 years before the study and 41 controls. All participants had left ventricular ejection fraction (LVEF) ≥55%. Total dose of DOX was 396mg (242mg/ms2). The systolic function of the LV was evaluated by LVEF (Simpson), as well as by longitudinal (εLL), circumferential (εCC), and radial (εRR) strains. Multivariate linear regression (MLR) analysis was performed using εLL (model 1) and εCC (model 2) as dependent variables. Results: Systolic and diastolic blood pressure values were higher in the control group (p < 0.05). εLL was lower in the DOX group (-12.4 ±2.6%) versus controls (-13.4 ± 1.7%; p = 0.044). The same occurred with εCC: -12.1 ± 2.7% (DOX) versus -16.7 ± 3.6% (controls; p < 0.001). The S’ wave was shorter in the DOX group (p = 0.035). On MLR, DOX was an independent predictor of reduced εCC (B = -4.429, p < 0.001). DOX (B = -1.289, p = 0.012) and age (B = -0.057, p = 0.029) were independent markers of reduced εLL. Conclusion: a) εLL, εCC and the S’ wave are reduced in patients who used DOX ±2 years prior to the study despite normal LVEF, suggesting the presence of subclinical ventricular dysfunction; b) DOX was an independent predictor of reduced εCC; c) prior use of DOX and age were independent markers of reduced εLL. .

Fundamento: A insuficiência cardíaca é uma complicação grave associada ao uso da doxorrubicina (DOX). O strain, avaliado por speckle tracking bidimensional (2D-STE), tem se mostrado útil na identificação de disfunção ventricular subclínica. Objetivos: a) Investigar o comportamento do strain na identificação de disfunção ventricular subclínica em pacientes que usaram DOX; b) investigar determinantes do comportamento do strain nestes pacientes. Métodos: Estudo transversal com 81 participantes: 40 pacientes que usaram DOX ± 2 anos antes do estudo e 41 controles. Todos tinham fração de ejeção do ventrículo esquerdo (FEVE) ≥ 55%. A dose total de DOX foi de 396 mg (242 mg/m2). A função sistólica do VE foi avaliada pela FEVE (Simpson), assim como pelo strain longitudinal (εLL), circunferencial (εCC) e radial (εRR). Realizamos análise de regressão linear multivariada (RLM) usando como variáveis dependentes o εLL (modelo 1) e o εCC (modelo 2). Resultados: Os valores da pressão arterial sistólica e diastólica foram maiores no grupo controle (p < 0,05). O εLL foi menor no grupo DOX (-12,4 ± 2,6%) versus controle (-13,4 ± 1,7%; p = 0,044). O mesmo ocorreu em relação ao εCC: -12,1 ± 2,7% (DOX) versus -16,7 ± 3,6% (controles; p < 0,001). A onda S' foi menor no grupo DOX (p = 0,035). Na RLM, a DOX foi preditora independente de redução do εCC (B = -4,429, p < 0,001). DOX (B = -1,289, p = 0,012) e idade (B = -0,057, p = 0,029) foram marcadores independentes de redução do εLL. Conclusões: a) O εLL, o εCC e a onda S' estão reduzidos nos pacientes que usaram DOX ±2 anos antes do estudo, apesar da FEVE ser normal, sugerindo presença de disfunção ventricular subclínica; b) a DOX foi preditora independente de redução do εCC; c) o uso prévio da DOX e a idade foram marcadores independentes de redução do εLL. .

Single Nodular Opacity of Granulomatous Pneumocystis Jirovecii Pneumonia in an Asymptomatic Lymphoma Patient

The radiologic findings of a single nodule from Pneumocystis jirovecii pneumonia (PJP) have been rarely reported. We described a case of granulomatous PJP manifesting as a solitary pulmonary nodule with a halo sign in a 69-year-old woman with diffuse large B cell lymphoma during chemotherapy. The radiologic appearance of the patient suggested an infectious lesion such as angioinvasive pulmonary aspergillosis or lymphoma involvement of the lung; however, clinical manifestations were not compatible with the diseases. The nodule was confirmed as granulomatous PJP by video-assisted thoracoscopic surgery biopsy.

Increased cardiac endothelin-1 and nitric oxide in adriamycin-induced acute cardiotoxicity: Protective effect of Ginkgo biloba extract.

Cardiotoxicity and congestive heart failure are the major factors that limit the use of anti-neoplastic drug adriamycin (ADR). There is increasing experimental evidence that endothelin-1 (ET-1) and nitric oxide (NO) are vasoactive mediators that regulate cardiac performance. The present study was undertaken to investigate the role of ET-1 and NO in ADR-induced acute cardiotoxicity and to evaluate the protective effect of Ginkgo biloba extract (EGb761) in rats. A single dose of ADR (20 mg/kg i.p.) caused a significant increase in the cardiac enzyme activities of aspartate transaminases (AST), lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in the serum of animals. This was accompanied by significant increase in cardiac malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor-alpha (TNF-α), ET-1 and nitrite/nitrate (NOx) levels. On the other hand, reduced glutathione (GSH) was significantly depressed. Histopathological examination of heart tissues showed hyalinization of the myocardium, with interstitial edema and inflammatory exudates. Pre-treatment of the animals with EGb761 (100 mg/kg, orally) 10 days before and 5 days after ADR treatment reversed the cardiac enzyme levels to normal value, decreased cardiac MDA, TAC, TNF-α, ET-1 and NOx, increased GSH and reversed the histopathological damage induced by ADR. In conclusion, the cardioprotective effects of EGb761 on markers of ADR-induced acute cardiotoxicity appeared to have been mediated by the regulation of inflammatory and vasoactive mediators, as well as the inhibition of membrane lipid peroxidation. Thus, EGb761 may find use as promising adjuvant therapy to ameliorate cardiotoxicity of ADR.

Histopathologic changes following neoadjuvant chemotherapy in locally advanced breast cancer.

Aims: To compare the clinical and pathologic assessment of response to neoadjuvant chemotherapy and describe the various histopathologic changes observed. Materials and Methods: We studied a group of 40 patients with locally advanced breast cancer who had their initial workup in the form of clinico-imaging assessment of the size and pretreatment biopsy from the lesion. All the patients received two to six cycles of neoadjuvant chemotherapy, either cyclophosphamide 50 to 60 mg/m 2 IV, doxorubicin 40 to 50 mg/m 2 IV and 5-fluorouracil 500 to 800 mg/m 2 IV (CAF) or cyclophosphamide, epirubicin, and 5-fluorouracil (CEF). Clinical and pathologic assessment of response to chemotherapy was done based on the UICC guidelines. Result: Complete clinical response (cCR) was seen in 10% cases (4/40), thirty percent patients had (12/40) partial response and 60% (24/40) had stable disease after neoadjuvant chemotherapy. Pathologic complete response (pCR) with no evidence of viable tumor was observed in 20% patients (8/40). Fifteen patients (37.5%) showed partial response and 42.5% patients (17/40) had a stable disease. No patient progressed during the course of chemotherapy. Changes in the tumor type were observed following chemotherapy, most common being the mucinous change. Histologic changes like dyscohesion, shrinkage of tumor cells, elastosis, collagenization, necrosis, lymphocytic reaction, giant cell response are some of the common observations seen following treatment with neoadjuvant chemotherapy. Conclusion: Pathologic assessment of response to neoadjuvant chemotherapy is a better predictor than the clinical response. The chemotherapy drugs can be modified based on the response observed after 1-2 cycles of neoadjuvant, the response being based on both tumor and patient's responsiveness.

In vitro and in vivo studies of pirarubicin-loaded SWNT for the treatment of bladder cancer

Intravesical chemotherapy is an important part of the treatment for superficial bladder cancer. However, the response to it is limited and its side effects are extensive. Functional single-walled carbon nanotubes (SWNT) have shown promise for tumor-targeted accumulation and low toxicity. In the present study, we performed in vivo and in vitro investigations to determine whether SWNT-based drug delivery could induce high tumor depression in rat bladder cancer and could decrease the side effects of pirarubicin (tetrahydropyranyl-adriamycin, THP). We modified SWNT with phospholipid-branched polyethylene glycol and constructed an SWNT-THP conjugate via a cleavable ester bond. The cytotoxicity of SWNT-THP against the human bladder cancer cell line BIU-87 was evaluated in vitro. Rat bladder cancer in situ models constructed by N-methyl-N-nitrosourea intravesical installation (1 g/L, 2 mg/rat once every 2 weeks for 8 weeks) were used for in vivo evaluation of the cytotoxicity of SWNT and SWNT-THP. Specific side effects in the THP group including urinary frequency (N = 12), macroscopic hematuria (N = 1), and vomiting (N = 7) were identified; however, no side effects were observed with SWNT-THP treatment. Flow cytometry was used to assess the cytotoxicity in vitro and in vivo. Results showed that SWNT alone did not yield significant tumor depression compared to saline (1.74 ± 0.56 and 1.23 ± 0.42%) in vitro. SWNT-THP exhibited higher tumor depression than THP-saline in vitro (74.35 ± 2.56 and 51.24 ± 1.45%) and in vivo (52.46 ± 2.41 and 96.85 ± 0.85%). The present findings indicate that SWNT delivery of THP for the treatment of bladder cancer leads to minimal side effects without loss of therapeutic efficacy. Therefore, this nanotechnology may play a crucial role in the improvement of intravesical treatment of bladder cancer.

Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: A Phase II study.

Aim: The aim of this Phase II study was to evaluate the activity and safety of biweekly pegylated liposomal doxorubicin (PLD) and oxaliplatin (L-OHP) in patients with platinum-taxane resistant ovarian cancer. Materials and Methods : Treatment consisted of PLD (20 mg/m 2 ) on Day 1; and L-OHP (50 mg/m 2 ) administered on Days 1 and 2, every two weeks. Response to therapy was assessed using the Response Evaluation Criteria in Solid Tumors RECIST ; toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria. Results: Forty patients pretreated with platinum/taxane chemotherapy, with a median age of 61 years, were recruited for the study. Thirty-eight patients were available for response evaluation: three complete responses and nine partial responses were registered; resulting in an overall response rate of 31.5%. Twenty-eight patients gained clinical benefit (73.7%) from this chemotherapy regimen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 10 months respectively. The hematological and non-hematological toxicity profile was favorable. No Grade 4 toxicity was observed. Major toxicities included Grade 3 neutropenia (13.2%), Grade 2 palmar-plantar erythrodysesthesia (7.9%), and Grade 1-2 neuropathy in 15.8% of patients. Conclusion: Biweekly PLD and L-OHP combination has high activity, with less than anticipated adverse toxicity, for treatment of platinum-resistant ovarian cancer. A comparison of the doublet PLD/L-OHP with single-agent treatment is warranted.