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1.
Biomed Pharmacother ; 116: 108964, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102935

RESUMO

AIM: Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration. METHODS: The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations. RESULTS: Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration.


Assuntos
Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Metaboloma , Animais , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Concentração Inibidora 50 , Masculino , Ratos Sprague-Dawley
2.
PLoS One ; 14(4): e0214984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947243

RESUMO

Type 2 diabetes (T2D) is characterised by ß-cell damage and hyperglycaemia. The lipophilic drug, probucol, has shown significant ß-cell protective and potential antidiabetic effects, which were enhanced by hydrophilic bile acid incorporation using taurocholic acid and chenodeoxycholic acid. However, probucol has severe cardiotoxicity and a variable absorption profile, which limit its potential applications in T2D. Accordingly, this study aimed to design multiple formulations to optimise probucol oral delivery in T2D and test their effects on probucol absorption and accumulation in the heart. Adult male mice were given a high fat diet (HFD), and a week later, injected with a single dose of alloxan to accelerate T2D development, and once diabetes confirmed, divided into three groups (six to seven mice each). The groups were gavaged a daily dose of probucol powder, probucol microcapsules, or probucol-bile acid microcapsules for three months, and euthanized; and blood, tissues, and feces collected for blood glucose and probucol concentration analyses. Probucol concentrations in plasma were similar among all the groups. Groups given probucol microcapsules and probucol-bile acid microcapsules showed significant reduction in probucol accumulation in the heart compared with the group given probucol powder (p<0.05). Probucol microencapsulation with or without bile acids reduced its accumulation in heart tissues, without changing plasma concentrations, which may be beneficial in reducing its cardiotoxicity and optimise its potential applications in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Probucol , Administração Oral , Animais , Cápsulas , Cardiotoxicidade/sangue , Cardiotoxicidade/prevenção & controle , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Probucol/farmacocinética , Probucol/farmacologia
3.
J Cancer Res Clin Oncol ; 145(6): 1635-1643, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923943

RESUMO

PURPOSE: Radiation-induced cardiac toxicity (RICT) is an increasingly well-appreciated source of morbidity and mortality in patients receiving thoracic radiotherapy (RT). Currently available methods to predict RICT are suboptimal. We investigated circulating microRNAs (c-miRNAs) as potential biomarkers of RICT in patients undergoing definitive RT for non-small-cell lung cancer (NSCLC). METHODS: Data from 63 patients treated on institutional trials were analyzed. Prognostic models of grade 3 or greater (G3 +) RICT based on pre-treatment c-miRNA levels ('c-miRNA'), mean heart dose (MHD) and pre-existing cardiac disease (PCD) ('clinical'), and a combination of these ('c-miRNA + clinical') were developed. Elastic net Cox regression and full cross validation were used for variable selection, model building, and model evaluation. Concordance statistic (c-index) and integrated Brier score (IBS) were used to evaluate model performance. RESULTS: MHD, PCD, and serum levels of 14 c-miRNA species were identified as jointly prognostic for G3 + RICT. The 'c-miRNA and 'clinical' models yielded similar cross-validated c-indices (0.70 and 0.72, respectively) and IBSs (0.26 and 0.28, respectively). However, prognostication was not improved by combining c-miRNA and clinical factors (c-index 0.70, IBS 0.28). The 'c-miRNA' and 'clinical' models were able to significantly stratify patients into high- and low-risk groups of developing G3 + RICT. Chi-square testing demonstrated a marginally significantly higher prevalence of PCD in patients with high- compared to low-risk c-miRNA profile (p = 0.09), suggesting an association between some c-miRNAs and PCD. CONCLUSIONS: We identified a pre-treatment c-miRNA signature prognostic for G3 + RICT. With further development, pre- and mid-treatment c-miRNA profiling could contribute to patient-specific dose selection and treatment adaptation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cardiotoxicidade/sangue , Cardiotoxicidade/etiologia , MicroRNA Circulante/sangue , Neoplasias Pulmonares/radioterapia , Lesões por Radiação/sangue , Lesões por Radiação/etiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cardiotoxicidade/genética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Lesões por Radiação/genética
4.
Hum Exp Toxicol ; 38(1): 45-55, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29774748

RESUMO

Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.


Assuntos
Antidepressivos de Segunda Geração/toxicidade , Cardiotoxicidade , Trazodona/toxicidade , Administração Oral , Animais , Aspartato Aminotransferases/sangue , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Cardiotoxicidade/fisiopatologia , Dano ao DNA , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Troponina T/sangue
5.
Toxicol Appl Pharmacol ; 363: 164-173, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30517846

RESUMO

Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant ≥1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/sangue , Doxorrubicina/toxicidade , Administração Intravenosa , Animais , Biomarcadores/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Dexrazoxano/administração & dosagem , Doxorrubicina/administração & dosagem , Coração/efeitos dos fármacos , Masculino , Camundongos , Miocárdio/patologia , Substâncias Protetoras/administração & dosagem , Proteoma/análise , Proteoma/efeitos dos fármacos , Proteômica , Receptor Notch1/sangue , Medição de Risco/métodos , Fator de von Willebrand/análise
6.
Biomed Pharmacother ; 110: 1-8, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30453253

RESUMO

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo. METHODS: Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX-regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 µM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs. RESULTS: Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug. CONCLUSIONS: This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , MicroRNAs/biossíntese , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/patologia
7.
Int J Mol Sci ; 19(11)2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405071

RESUMO

To investigate the toxicity of water and ethanol "Fuzi" (FZ) extracts and to explore the toxicity mechanism in rats. Water and ethanol extracts were prepared. Three groups of rats received the water extract, ethanol extract, or water by oral gavage for seven days. Pathological section staining of heart tissue. Colorimetric analysis was used to determine serum lactate dehydrogenase. The metabolic expression of small molecules in rats was measured by a metabolomics method. Western blotting was used to detect the expression of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), transforming growth factor-ß1 (TGF-ß1), and caspase-3. Immunohistochemistry was used to detect the expression of CTnI, mTOR, and TGF-ß1. The water and ethanol FZ extracts exert cardiotoxic effects via activating the PI3K/Akt/mTOR signaling pathway to induce cardiomyocyte apoptosis.


Assuntos
Cardiotoxicidade/metabolismo , Metabolômica , Extratos Vegetais/toxicidade , Animais , Apoptose , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Caspase 3/metabolismo , Etanol , Masculino , Metaboloma , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Troponina I/metabolismo , Água
8.
Cancer Biomark ; 23(4): 473-484, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30452398

RESUMO

OBJECTIVE: This study aimed to evaluate predictive value of 14 pro-angiogenic miRNAs for cardiotoxicity induced by epirubicin/cyclophosphamide follow by docetaxel (EC-D) in breast cancer (BC) patients. METHODS: Three hundred and sixty-three BC patients receiving EC-D neoadjuvant chemotherapy were consecutively enrolled in this prospective cohort study. Peripheral blood sample was obtained from each patient, and plasma was separated. The expressions of 14 pro-angiogenic miRNAs, cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Left ventricular ejection fraction (LVEF) level at C0, the end of 4 cycles of EC chemotherapy (C4), the end of 4 cycles of docetaxel treatment (C8), 3rd months (M3), 6th months (M6), 9th months (M9) and 12th months (M12) after surgery were assessed. RESULTS: LVEF decreased at C4, C8, M3, M6, M9 and M12 compared with C0, and the total cardiotoxicity incidence was 5.2%. Additionally, the levels of let-7f, miR-17-5p, miR-20a, miR-126, miR-210 and miR-378 were reduced in cardiotoxicity patients. Multivariate logistic regression revealed that miR-17-5p and miR-20a were independently predictive factors for less cardiotoxicity. Receiver operating characteristics (ROC) curve displayed a satisfactory predictive value for lower cardiotoxicity risk with area under curve (AUC) of 0.842 of the combination of the miR-17-5p and miR-20a expressions. In addition, let-7f,miR-126, miR-210 and miR-378 levels negatively correlated with cTnI expression, and let-7f and miR-130a expressions reversely correlated with NT-proBNP level.CONLUSIONS: miR-17-5p and miR-20a could be served as biomarkers for lower cardiotoxicity induced by EC-D neoadjuvant chemotherapy in BC patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácidos Nucleicos Livres/sangue , MicroRNAs/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Cardiotoxicidade/sangue , Cardiotoxicidade/genética , Ciclofosfamida/efeitos adversos , Docetaxel/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Troponina I/sangue
9.
J Pharmacol Toxicol Methods ; 94(Pt 2): 54-63, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30195582

RESUMO

The isolated rat heart (Langendorff) assay combined with NMR spectroscopy and histology were used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Doxorubicin blood concentrations and pharmacokinetic parameters were assessed following a clinically relevant dose of 2 mg/kg in order to select concentrations for isolated heart perfusions. Isolated rat hearts were exposed to 1 or 10 µM of doxorubicin or 0.3 µM dox-ol for at least 60 min using the Langendorff perfusion method. Effects on heart function were monitored using ECGs, left ventricular contraction parameters, and microscopic histology. Cardiac energetics (PCr, ATP, and Pi) were evaluated before, during, and after exposure to doxorubicin/dox-ol in perfused hearts using NMR spectroscopy. Cardiac effects were evident following clinically relevant concentrations of doxorubicin and dox-ol in isolated rat hearts demonstrated by altered heart function, energetic reserve, and microscopic lesions. A cardiac stress test utilizing isoproterenol resulted in enhanced functional response and reductions in PCr in doxorubicin versus vehicle treated hearts indicating possible alterations in the isoproterenol mediated pathway. Dox-ol treated hearts were similar to control with regard to function, but exhibited histologic findings. The use of combined Langendorff/NMR/histology methodologies allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters. SHORT ABSTRACT: The isolated rat heart assay combined with NMR spectroscopy and histology was used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Heart function was altered and microscopic signs of toxicity were evident with dox and dox-ol exposures. The use of combined Langendorff/NMR/histology assays allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters.


Assuntos
Doxorrubicina/farmacocinética , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Coração/fisiologia , Animais , Cardiotoxicidade/sangue , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/análogos & derivados , Doxorrubicina/sangue , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/patologia , Preparação de Coração Isolado , Espectroscopia de Ressonância Magnética , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Perfusão , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
10.
Medicine (Baltimore) ; 97(38): e12447, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235730

RESUMO

The current study was to evaluate soluble ST-2 level and left ventricular ejection fraction (LVEF) in patients with breast cancer receiving doxorubicin or trastuzumab treatment for 6 months and determine whether soluble ST-2 level can be used to predictive left ventricular function impairment.Patients who were diagnosed as having breast cancer receiving doxorubicin or trastuzumab or combined therapy were enrolled. Demographic data, prior medical history and related medical therapy, and site and stage of breast cancer information were collected from electronic health record. Fasting blood was used to detect soluble ST-2 and brain natriuretic peptide (BNP) levels before and after 6 months doxorubicin or trastuzumab therapy. Echocardiography was performed before and after 6 months of doxorubicin or trastuzumab therapy.Participants were divided into 3 groups based on tertiary soluble ST-2 level. Compared with 1st tertiary group, patients in the 3rd tertiary group had higher proportion receiving combined therapy (14.3% vs 4.7%, P < .05). Baseline soluble ST-2 level was similar across groups. After 6 months' therapy, soluble ST-2 level was significantly higher in the 3rd tertiary group. Pearson correlation analysis showed that soluble ST-2 level was positively correlated with left ventricular volume and E/e' ratio while negatively correlated with LVEF. Doxorubicin, trastuzumab, combined therapy, soluble ST-2 level, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment were all independently associated with LVEF change.In breast cancer patients receiving doxorubicin or trastuzumab therapy, soluble ST-2 level can be used to predict cardiac function and structure changes.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/sangue , Ventrículos do Coração/efeitos dos fármacos , Peptídeo Natriurético Encefálico/sangue , Valor Preditivo dos Testes , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Ecocardiografia/métodos , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Volume Sistólico/efeitos dos fármacos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia
11.
Mol Med Rep ; 18(3): 3229-3241, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066944

RESUMO

Cordyceps sinensis (CS) is a prominent medicinal herb in traditional Chinese medicine, and fermented CS is frequently used as a substitute for natural CS. Doxorubicin (DOX), an antitumor drug used in chemotherapy, is limited by its poor cardiotoxicity. The aim of the present study was to evaluate the protective effect of fermented CS against DOX­induced cardiotoxicity and the potential underlying mechanisms. Male Sprague­Dawley rats (180­200 g) were randomly assigned to seven different treatment groups: Normal control, DOX control, DOX+captopril (0.05 g/kg), 0.75, 1.5 and 3 g/kg DOX+CS, and the CS (1.5 g/kg) control. Histopathological changes, cardiac energy metabolism, cyclic adenosine monophosphate (cAMP) signaling and the associated mRNA expression of AMP­activated protein kinase (AMPK) were then evaluated. Fermented CS decreased the left ventricular weight index, heart weight index and mortality; however, it increased diastolic blood pressure and mean arterial pressure. In addition, it shortened the duration of the QRS complex and Sα­T segment, decreased serum creatine kinase (CK) and aspartate aminotransferase activity, inhibited histopathological changes and reduced brain natriuretic peptide content. Treatment with fermented CS also increased the activities of superoxide dismutase and glutathione peroxidase, reduced malondialdehyde content, increased the mitochondrial activities of Na+K+­adenosine 5'­triphosphate (ATP) ase, Ca2+Mg2+­ATPase and CK, and increased the creatine phosphate/ATP ratio and AMP/ATP ratio. Furthermore, it decreased the ATP/adenosine 5'­diphosphate (ADP) ratio, upregulated AMPKα2 expression, reduced the activity of serum phosphodiesterases (PDEs) and increased myocardial cAMP content. The results of the present study demonstrated that fermented CS attenuated DOX­induced cardiotoxicity by inhibiting myocardial hypertrophy and myocardial damage, ameliorating systolic function and the antioxidant enzyme system, improving cardiac energy metabolism, depressing the activities of PDEs, and by upregulating the cAMP and AMPK signaling pathways. Thus, fermented CS may be a candidate for the prevention of DOX­induced cardiotoxicity, cardiac energy impairment and against a number of cardiac diseases.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cordyceps , Doxorrubicina/efeitos adversos , Fermentação , Coração/efeitos dos fármacos , Animais , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/fisiopatologia , Cordyceps/metabolismo , Coração/fisiopatologia , Masculino , Medicina Tradicional Chinesa , Miocárdio/patologia , Distribuição Aleatória , Ratos Sprague-Dawley
12.
Int J Nanomedicine ; 13: 4549-4561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127606

RESUMO

Background: Dose-dependent irreversible cardiac toxicity of doxorubicin (DOX) becomes a major obstacle for the clinical use. Nowadays much attention is being paid to combination therapy with DOX and antioxidant agents, which would improve the clinical efficacy by protecting from cardiotoxicity along with the maintained performance as an antitumor drug. With the assistance of nanoscience and polymer engineering, herein a complex polymeric micellar system was developed for co-loading DOX and a premium natural antioxidant curcumin (CUR), and we investigated whether this new formulation for DOX delivery could achieve such a goal. Methods: The dually loaded micelles co-encapsulating DOX and CUR (CPMDC) were prepared through thin-film rehydration by using the amphiphilic diblock copolymer monomethoxy poly(ethylene glycol) (mPEG)-poly(ε-caprolactone) (PCL)-N-t-butoxycarbonyl-phenylalanine (BP) synthesized by end-group modification of mPEG-PCL with BP. Quantitative analysis was conducted by HPLC methods for drugs in micelles or biosamples. Molecular dynamics simulation was performed using HyperChem software to illustrate interactions among copolymer and active pharmaceutical ingredients. The safety and antitumor efficacy were evaluated by in vitro viability of H9C2 cells, and tumor growth inhibition in tumor-bearing mice respectively. The protection effects against DOX-induced cardiotoxicity were investigated according to several physiological, histopathological and biochemical markers concerning systemic and cardiac toxicity. Results: CPMDC were obtained with favorable physicochemical properties meeting the clinical demand, including uniform particle size, fairly high encapsulation efficiency and drug loadings, as well as good drug release profiles and colloidal stability. The result from molecular dynamics simulation indicated a great impact of the interactions among copolymer and small molecules on the ratiometrical co-encapsulation of both drugs. MTT assay of in vitro H9C2 cells viability demonstrated good safety of the CPMDC formulation, which also showed definite signs of decrease in xenograft tumor growth. The studies on pharmacokinetics and tissue distribution further revealed that DOX delivered by CPMDC could result in prolonged systemic circulation and increased DOX accumulation in tumor but decreased level of the toxic metabolite doxorubicinol in heart tissue compared to free DOX alone or the cocktail combination. Conclusion: The findings from present study substantiated that such a complex micellar system codelivering DOX with CUR does produce the effect of killing two birds with one stone via distinctive nanocarrier-modified drug-drug interactions.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Micelas , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Cardiotoxicidade/sangue , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacocinética , Curcumina/farmacologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Ratos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Georgian Med News ; (278): 87-93, 2018 May.
Artigo em Russo | MEDLINE | ID: mdl-29905551

RESUMO

This review is devoted to the urgent problem of cardiology and oncology - the cardiotoxicity of chemotherapy drugs - anthracyclines, which are considered to be one of the most cardiotoxic and cause a variety of cardiotoxic effects. The review also examines the diagnosis, treatment or preventive treatment of this pathology. The urgency of the problem is associated with the possibility of early or late manifestations of cardiotoxicity, manifestations of cardiotoxicity against the background of cross treatment, manifestations of cardiotoxicity against the background of various concomitant diseases. The review identified 9 main categories of cardiovascular complications during chemotherapeutic treatment and presents the types of cardiotoxicity caused by the use of anthracyclines. The issue of heart failure as a manifestation of anthracycline cardiotoxicity and the approaches to early diagnosis of cardiac insufficiency were examined in detail. The recommendations of the European Society of Medical Oncology (ESMO) (2012), the recommendations the European Society of Cardiology (ESC) in 2016 regarding the diagnosis and treatment of these patients are reviewed. An overview of the literature on the treatment and diagnosis of this category of patients is presented, especially with concomitant diseases. Examination of the patients, the timing of the initiation of therapy, preventive treatment, medication correction of heart failure, the doses, the combinations of chemotherapeutic drugs are issues that are recommended for the multidisciplinary team to successfully manage these patients.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Biomarcadores/sangue , Cardiomiopatias/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Ecocardiografia , Venenos Elapídicos/sangue , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Humanos , Ivabradina/uso terapêutico , Peptídeo Natriurético Tipo C/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Análise de Sobrevida , Trastuzumab/efeitos adversos , Trimetazidina/uso terapêutico , Troponina I/sangue
14.
Biomed Pharmacother ; 102: 1052-1063, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710522

RESUMO

This research focuses on screening and evaluation of bioactive constituents in plants through pharmacological assays. In present study, we evaluated phytochemicals, cytotoxic activity, in vivo effect of M. monantha against CCl4 induced toxicity in cardiac and renal tissues and its aphrodisiac potential in rats. Shade dried plant was extracted with methanol. The phytochemical screening indicates the presence of flavonoids and alkaloids. Aphrodisiac study showed improved sexual desire; may be attributed to the presence of saponins that boosts the androgen level. Cytotoxicity of the plant was assessed through brine shrimp lethality assay and nearly all the fractions showed promising results. The in vivo study focused on the protective ability of extract against CCl4-induced oxidative damage in renal and cardiac tissues of rats. Serum analysis revealed that CCl4 intoxication increased the levels of bilirubin and blood urea nitrogen (BUN). Antioxidant enzyme analysis showed that catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione activity and protein levels declined due to CCl4 induced renal and cardiac toxicity. Moreover, the histopathological studies of both low & high dose plant treated group's revealed glomerular hypertrophy and glomerular congestion in kidney, cardiac degeneration and vacuolization of germinal epithelium induced by CCl4 intoxication. DNA also shows damage showed the toxic nature of the plant.


Assuntos
Medicago/química , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Afrodisíacos/farmacologia , Artemia/efeitos dos fármacos , Bilirrubina/metabolismo , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , Nitrogênio da Ureia Sanguínea , Cardiotoxicidade/sangue , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/patologia , Morte Celular/efeitos dos fármacos , Ensaio Cometa , Creatinina/metabolismo , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Nitritos/metabolismo , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
16.
Pediatr Hematol Oncol ; 35(2): 111-120, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29648903

RESUMO

OBJECTIVE: To investigate the cardiotoxicity indexes in children with malignant tumors after the administration of anthracycline (ANT) chemotherapy. MATERIALS AND METHODS: Data from 131 children with malignant tumors who were treated using ANT chemotherapy at our hospital from January 2011 to December 2015 were collected to analyze the serologic indexes (such as N-terminal pro-brain natriuretic peptide [NT-proBNP] and isoenzyme of creatine kinase [CK-MB]) and changes in corrected QT interval(QT-c) and left ventricular ejection fraction (LVEF) before and after treatment with different ANT cumulative doses. RESULTS: General clinical data revealed that 2 of the 131 children developed clinical cardiotoxicity. The ANT cumulative dose range was 12-697 mg/m2. All patients were divided into three groups according to the ANT cumulative dose: group 1 (<100 mg/m2), 2 (≥100 and <200 mg/m2), and 3 (≥200 mg/m2). Although NT-proBNP and LVEF among the three groups differed significantly after chemotherapy (p = 0.022 and 0.035, respectively), no significance was noted for CK-MB and QT-c among the three groups after chemotherapy (p = 0.190 and p = 0.084, respectively). Multiple linear regression analysis revealed that the ANT cumulative dose had the most significant impact on NT-proBNP (standardized coefficient 0.423, p = 0). Pearson correlation analysis revealed that ANT cumulative dose was positively correlated with NT-proBNP post-treatment (correlation coefficient 0.423), but LVEF was negatively correlated with NT-proBNP after chemotherapy (correlation coefficient -0.542). CONCLUSIONS: NT-proBNP showed significant changes when the ANT dose was >200 mg/m2. Post-treatment serum NT-proBNP was linearly correlated with ANT cumulative dose, hence strictly controlling the ANT cumulative dose and monitoring serum NT-proBNP may have certain clinical significance in predicting cardiotoxicity.


Assuntos
Antraciclinas/efeitos adversos , Creatina Quinase/sangue , Peptídeo Natriurético Encefálico/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/sangue , Volume Sistólico , Antraciclinas/administração & dosagem , Cardiotoxicidade/sangue , Cardiotoxicidade/epidemiologia , Cardiotoxicidade/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias/epidemiologia
17.
Eur J Cancer ; 94: 126-137, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29567630

RESUMO

BACKGROUND: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. METHODS: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. FINDINGS: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. INTERPRETATION: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antineoplásicos/efeitos adversos , Enalapril/uso terapêutico , Troponina C/sangue , Disfunção Ventricular Esquerda/prevenção & controle , Adulto , Idoso , Antraciclinas/efeitos adversos , Cardiotoxicidade/sangue , Cardiotoxicidade/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/induzido quimicamente
18.
Microrna ; 7(2): 115-119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29564990

RESUMO

BACKGROUND: Circulating cell-free miRNAs hold great promise as a new class of biomarkers due to their high stability in body fluids and association with disease stages. However, even using sensitive and specific methods, technical challenges are associated with miRNA analysis in body fluids. A major source of variation in plasma and serum is the potential cell-derived miRNA contamination from hemolysis. OBJECTIVES: The study aimed to evaluate the effect of the delayed whole blood processing time on the concentrations of miR-1 and -423-5p. METHODS: Ten blood samples were incubated for 0, 3 and 24 hours at room temperature prior to processing into plasma. For each time point, hemolysis was assessed in plasma by UV spectrophotometry at 414nm wavelength (λ414). Circulating levels of miR-1 and -423-5p were measured by RT-qPCR; miR-23a and -451 were also analyzed as controls. RESULTS: A significant hemolysis was observed only after 24h (λ414 0.3 ± 0.02, p < 0.001). However, only small changes in miR-1 and -423-5p levels were observed up to 24h of storage at room temperature (Ct 31.5 ± 0.5 to 31.8 ± 0.6for miR-1, p = 0.989; and 29.01 ± 0.3 to 29.04 ± 0.3, p = 0.614 for - 423-5p). No correlation was observed between hemolysis and the levels of miR-1 and -423-5p. CONCLUSION: Our data indicate that the storage of whole blood samples at room temperature for up to 24h prior to their processing into plasma does not appear to have a significant impact on miR-1 and - 423-5p concentrations.


Assuntos
Análise Química do Sangue , Cardiotoxicidade/sangue , MicroRNAs/sangue , Manejo de Espécimes/métodos , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Hemólise , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Estabilidade de RNA , Fatores de Tempo
19.
J Oncol Pharm Pract ; 24(4): 264-271, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29284360

RESUMO

Background Anthracycline-based chemotherapy is used in many malignancies. Current recommendations by several groups suggest cardiac monitoring prior to and during anthracycline therapy. We aim to review the usefulness of baseline cardiac screening for left ventricular ejection fraction to assess if it had any impact on chemotherapy decisions in patients to be treated with anthracycline-based regimens or any beneficial effect upon outcomes. Methods We conducted a retrospective three-year audit of cancer patients who underwent GBPS prior to anthracycline (doxorubicin) chemotherapy. Subjects were identified via records from the Department of Nuclear Medicine. Pharmacy dispensing records identified those who received doxorubicin. Patient demographics, cancer type, cardiac risk factors, GBPS ejection fraction (EF), and cumulative anthracycline dose were collected. Results From 1 August 2009 to 31 July 2012, 179 patients underwent GBPS pre-doxorubicin chemotherapy. The mean age was 59 years (range 21-89 years), with 51% being males. Only two patients (1.1%) had an abnormal EF < 50%, while 33 patients (18%) had an EF 51-59% and 144 patients (80%) had EF ≥ 60%. The two patients with reduced baseline EF still received anthracycline-based chemotherapy. All 135 patients without any known cardiovascular risk factors had normal EFs. The total number of patients who received anthracycline chemotherapy during the same period was 207. Thus 28 patients (13%) commenced anthracycline without a prior GBPS. Conclusion Only 1.1% of the screened patients had EF < 50%. These two patients still received doxorubicin chemotherapy despite a compromised EF, as their treating clinicians believed that the benefits of chemotherapy outweighed the risk of potential cardiac toxicity. Our audit questions the practice of routine cardiac evaluation pre-anthracycline screening with GBPS. We propose that routine screening only be requested if cardiac risk factors are present.


Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/sangue , Cardiotoxicidade/prevenção & controle , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Cardiopatias/sangue , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Adulto Jovem
20.
Breast Cancer Res Treat ; 168(3): 631-638, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29280043

RESUMO

BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.


Assuntos
Biomarcadores/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/sangue , Anormalidades Cardiovasculares/sangue , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Cardiotoxicidade/patologia , Anormalidades Cardiovasculares/induzido quimicamente , Anormalidades Cardiovasculares/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lapatinib/administração & dosagem , Lapatinib/efeitos adversos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor ErbB-2/genética , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Troponina T/sangue
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