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Artykuły w czasopismach na temat "Doxorubicine – Toxicologie"
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V., Rakshitha B., Nalini G. K., Sahana G. N., Deepak P., Jayashree V. Nagaral, Mohith N. i Divyashree C. R. "Comparison of safety and toxicity of liposomal versus conventional Doxorubicin: an updated review". International Journal of Basic & Clinical Pharmacology 8, nr 6 (23.05.2019): 1453. http://dx.doi.org/10.18203/2319-2003.ijbcp20192220.
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Cancer persists to be a major cause of hospitalization and death every year. With the passage of time, new formulations of anticancer drugs are being introduced to the market and are drawing the concern of healthcare professionals in terms of the superiority, toxicology, and cost-effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, a highly potent chemotherapeutic agent, it comes with three formulations (pegylated liposomal, nonpegylated liposomal and non-liposomal conventional formulations). English-language literature of the three formulations of Doxorubicin has been reviewed to inform the healthcare professionals regarding the differences between these formulations. Liposomal Doxorubicin promotes better toxicology profile than non-liposomal conventional Doxorubicin with an increased cost. Due to very limited studies, the cost-effectiveness of liposomal Doxorubicin is not well defined. Apart from that, this review highlights the inter patient variability in regard to the clearance and volume of distribution following the administration of liposomal Doxorubicin. In conclusion, further studies regarding the superiority of liposomal formulation of Doxorubicin , efficacy and dose standardization of liposomal Doxorubicin should be sought in the near future in a more better way.
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Bressolle, Fran�oise, Jeanne-Marie Jacquet, Marc Galtier, Jacques Jourdan, Daniel Donadio i Jean-Fran�ois Rossi. "Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva". Cancer Chemotherapy and Pharmacology 30, nr 3 (1992): 215–18. http://dx.doi.org/10.1007/bf00686315.
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Jacquet, Jeanne-Marie, Fran�oise Bressolle, Marc Galtier, Magali Bourrier, Daniel Donadio, Jacques Jourdan i Jean-Fran�ois Rossi. "Doxorubicin and doxorubicinol: intra-and inter-individual variations of pharmacokinetic parameters". Cancer Chemotherapy and Pharmacology 27, nr 3 (1990): 219–25. http://dx.doi.org/10.1007/bf00685716.
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Cusack, Barry J., Stephan P. Young, Joni Driskell i Richard D. Olson. "Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit". Cancer Chemotherapy and Pharmacology 32, nr 1 (1993): 53–58. http://dx.doi.org/10.1007/bf00685876.
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Tan, Jun, Jingfen Ye, Meijun Song, Mi Zhou i Yaoren Hu. "Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced eIF4E activation". Journal of Biochemical and Molecular Toxicology 32, nr 1 (7.11.2017): e22007. http://dx.doi.org/10.1002/jbt.22007.
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Duncan, R., J. K. Coatsworth i S. Burtles. "Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymerdoxorubicin (PK1)". Human & Experimental Toxicology 17, nr 2 (luty 1998): 93–104. http://dx.doi.org/10.1177/096032719801700204.
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N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) is a novel polymeric anticancer agent containing doxorubicin (approximately 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptidyl linker. The approximate LD50 of PK1 in MF1 mice after a single i.v. injection was 63 mg/kg (doxorubicin-equivalent). Single doses of PK1 were administered to MF1 mice at 22.5 or 45 mg/kg and blood samples taken on days 3, 7 and 14 for haematological examination and clinical chemistry. At day 14 all animals were sacrificed for necropsy. In a multiple dose study, PK1 was administered i.v. to MF1 mice or Wistar rats (20 animals per group) weekly for five consecutive weeks at doses of 12.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg (rats). After 31 days 10 animals from each group were sacrificed for necropsy and the remainder were sacrificed after 59 days. Blood samples were taken 3 days after administration of each dose and at the end of the experiment, and urine samples were collectedonthe day prior to sacrifice.Mortality inthe single dose mouse and multiple dose rat studies was low. In the multiple dose mouse study 4/10 animals were killed in extremis before the scheduled day 31 and all animals died before day 37. PK1 induced a reduction in WBC and platelets in rats and mice shortly after treatment and RBC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage was seen only in rat tissue during histological examination. Other histological changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multiple dose study an increase in nuclear size in the proximal tubules of the kidney (although no changes in urine were seen). Recovery from these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m2 (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.
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Dewi, Ermi Girsang, Ali Nafiah Nasution i Liena. "The Effect of Salam Leaf Ethanol Extract on the Histopathology of Doxorubicin-Induced Rats and its Effectiveness in Protecting the Heart Compared with Positive Control (Vitamin E)". International Journal of Science and Environment (IJSE) 1, nr 1 (21.11.2021): 8–14. http://dx.doi.org/10.51601/ijse.v1i1.2.
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This study aims to determine the effect of bay leaf ethanol extract on the histopathological picture of the kidneys of rats induced by doxorubicin. To determine the administration of bay leaf ethanol extract is more effective in protecting the heart than the positive control (Vitamin E). The bay leaves used were obtained from the Harjosari II Medan Amplas area of Medan city. The independent variable in this study was Salam Leaf Ethanol Extract, while the dependent variable was kidney histopathology. This research was conducted at the Pharmacology and Toxicology Laboratory of the Faculty of Pharmacy, University of North Sumatra. The results showed that the administration of vitamin E together with doxorubicin showed a better renal histopathological picture. Vitamin E as a basic antioxidant is able to reduce the damage caused by doxorubicin which is seen in the absence of widening in the Bowman capsule.
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Rodrigues, Daniela, Luke Coyle, Barbara Füzi, Sofia Ferreira, Heeseung Jo, Bram Herpers, Seung-Wook Chung i in. "Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids". International Journal of Molecular Sciences 23, nr 3 (24.01.2022): 1286. http://dx.doi.org/10.3390/ijms23031286.
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Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.
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Candussio, Luigi, Giuliana Decorti, Enrico Crivellato, Marilena Granzotto, Anna Rosati, Tullio Giraldi i Fiora Bartoli. "Toxicologic and pharmacokinetic study of low doses of verapamil combined with doxorubicin". Life Sciences 71, nr 26 (listopad 2002): 3109–19. http://dx.doi.org/10.1016/s0024-3205(02)02175-6.
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Che, Feifei, Yu Liu i Caigang Xu. "Prevention and Treatment of Doxorubicin-Induced Cardiotoxicity by Dexrazoxane and Schisandrin B in Rabbits". International Journal of Toxicology 30, nr 6 (12.10.2011): 681–89. http://dx.doi.org/10.1177/1091581811415873.
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The cost of dexrazoxane, a drug used to provide protection from doxorubicin-induced cardiotoxicity, limits its use in low-income countries. We aimed to see whether schisandrin B, an inexpensive drug, could provide protection equivalent to that provided by dexrazoxane. New Zealand white rabbits were randomly divided into groups and treated with saline, doxorubicin, doxorubicin + dexrazoxane, or doxorubicin + schisandrin B. Doxorubicin-induced damage and the protective effects were studied by recording the echocardiographic parameters and serum levels of superoxide dismutase, malondialdehyde, cardiac troponin I, and brain natriuretic peptide and observing the histology and degree of apoptosis. Schisandrin B had dose-dependent effects in decreasing the magnitude of doxorubicin-induced indicators of cardiomyopathy to a degree that approximated the decrease produced by dexrazoxane treatment. Schisandrin B might be a useful, low-cost alternative drug for this application.
Rozprawy doktorskie na temat "Doxorubicine – Toxicologie"
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Bengaied, Dorsaf. "Nanoparticules de resveratrol/PLAGA pour réduire la toxicité notamment hépatique de la doxorubicine". Electronic Thesis or Diss., Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB012.
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La doxorubicine (DOX) a été utilisée dans le traitement de divers cancers, mais son administration est limitée par une toxicité dose-dépendante. Ses effets cytotoxiques sur les cellules ont montré des cardiotoxicités, d'hépatotoxicité, d'insufisance rénale. L'utilisation des antioxydants ont été explorés pour leurs propriétés de prévention du cancer et et de la toxicité induite par DOX. Le resvératrol (RSV) est un constituant polyphénolique de plusieurs aliments principalement de raisin et de vin. Récemment, son potentiel anticancéreux a été largement exploré, révélant son effet anti-prolifératif sur différentes lignées de cellules cancéreuses, in vitro et in vivo. Le RSV est également connu pour avoir des effets modulateurs sur l'apoptose, la migration et la croissance des cellules via diverses voies de signalisation. Bien que le RSV possède une grande valeur médicinale, ses applications en tant que médicament thérapeutique sont limitées. Des problèmes tels qu'une biodisponibilité orale faible et une solubilité aqueuse médiocre font du RSV un candidat peu fiable à des fins thérapeutiques. De plus, la digestion gastro-intestinale rapide du VRS constitue également un obstacle majeur à sa traduction clinique. Par conséquent, pour surmonter ces inconvénients, nous avons fabriqué des nanoparticules de PLGA/RSV, PLGA/DOX et PLGA/RSV/DOX. Les nanoparticules de RSV ont montré des résultats prometteurs dans son absorption par le système épithélial ainsi que la livraison améliorée au site cible et de réduire l'hépatotoxicité induite par la doxorubicineDoxorubicin (DOX) has been used in the treatment of variety of cancers but its administration is limited by a dose-dependent toxicity. Its cytotoxic effects on malignant cells, have shown an increase in the risk of cardiotoxicity, hepatoxicity, renal insufisance. Antioxydants have been explored for both their cancer preventive properties and chemodulatory of DOX toxicity. Resveratrol (RSV) is a polyphenolic constituent of several dietary mainly of grapes and wine origin recently its anti-cancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. RSV is also known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, RSV possesses great medicinal value, its applications as a therapeutic drug are limited. Problems like low oral bioavailability and poor aqueous solubility make RSV an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of RSV is also a major barrier for its clinical translation. Hence, to overcome these disadvantages RSV-based nanodelivery systems have been considered in recent times.we used nanodelivery systems of RSV, DOX and DOX/RSV have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site and reduce the hepatotoxicity induced by doxorubicin
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Cartot, Sylvaine. "Etude "in vitro" de la vectorisation de la doxorubicine, par différents types de nanoparticules, pour combattre la multirésistance aux anticancéreux". Paris 5, 1993. http://www.theses.fr/1993PA05P247.
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Cottin, Yves. "Cardiotoxicité des anthracyclines : incidences fonctionnelles et métaboliques chez le rat. Apport de l'angioscintigraphie". Dijon, 1998. http://www.theses.fr/1998DIJOMU06.
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Gasser, Adeline. "Découverte et mise en évidence des effets cardioprotecteurs du premier agoniste non-peptidique du récepteur-1 des prokinéticines". Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ078/document.
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Les prokinéticines sont des hormones angiogéniques qui exercent leurs fonctions biologiques par l’intermédiaire de deux récepteurs couplés aux protéines G : PKR1 et PKR2. PKR1 a été révélé comme crucial dans l’homéostasie cardiovasculaire. L’objectif de ce projet de thèse était de développer un nouvel agoniste non–peptidique à PKR1 pour la cardioprotection et la régénération cardiaque. Les premiers résultats ont permis de caractériser le premier ligand spécifique à PKR1 : IS20. L’étude in vivo a démontré qu’IS20 est capable de prévenir les lésions après induction d’un infarctus du myocarde chez la souris. Ce composé améliore les fonctions cardiaques en activant la prolifération de cellules progénitrices cardiaques et la néovascularisation (Gasser et al, PlosOne, 2015). Dans une deuxième étude, nous avons évalué le potentiel cardioprotecteur d’IS20 face à la toxicité induite par la doxorubicine (DOX), un anticancéreux de la famille des anthracyclines très efficace mais cardiotoxique. Les résultats montrent qu’IS20 atténue l’apoptose des cardiomyocytes H9c2 et des cellules progénitrices humaines de types EPDC, induite par la doxorubicine, sans affecter la cytotoxicité de la doxorubicine sur les cellules cancéreuses. In vivo, le traitement par IS20 atténue la diminution de la prolifération provoquée par la doxorubicine dans un modèle de cardiotoxicité juvénile. Dans un modèle de cardiotoxicité chronique, IS20 maintient l’intégrité cellulaire et tissulaire des vaisseaux et protège des défaillances produites par DOX. Par ses effets cytoprotecteurs des cardiomyocytes et des cellules progénitrices cardiaques, l’IS20 présente un potentiel thérapeutique prometteur pour protéger les patients cancéreux des effets cardiotoxiques des anthracyclinesProkineticins are angiogenic hormones that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. The aim of this thesis project was to develop a first non-peptide PKR1 agonist stimulates cardioprotection and cardiac regeneration in mouse model of myocardial infarction (MI) or anti-cancer drug mediated cardiotoxicity. Collaboration with chemist and biomodelization team, we characterized the first selective/specific PKR1 agonist, named IS20. In vivo study demonstrated IS20 prevented cardiac lesion formation and improved cardiac function after myocardial infarction in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis (Gasser et al., 2015). Since use of a very potent anthracycline chemotherapeutic, Doxorubicin (DOX) is limited by cardiotoxicity, we hypothesized that IS20 could protect heart against DOX-mediated cardiotoxicity. Indeed, IS20 attenuated apoptosis induced by DOX in H9c2 cardiomyocytes and human epicardial progenitors in vitro. However, IS20 did not affect antineoplastic or cytostatic effect of DOX in cancer cell lines. In vivo, in the juvenile model of cardiotoxicity, IS20 significantly attenuated DOX-induced decrease in viability and proliferation cardiac progenitor cells. In the chronic cardiotoxicity model by DOX, IS20 improves heart structure and function by the activation of cardiac progenitor cells, diminishing cardiac cell death, improving vascular stability. IS20 has translational potential for cardioprotection in patients with cancer receiving anthracyclines
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Ferreira, André. "Exercise and Doxorubicin effects on testes function". Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10414.
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Mestrado em Biomedicina MolecularA Doxorubicina (DOX) é um agente antineoplásico de grande eficácia utilizado no tratamento de vários tipos de tumores. No entanto, a sua utilização clínica é limitada devido à sua toxicidade em vários órgãos, com destaque para o coração. Outros órgãos afectados por este fármaco incluem fígado, cérebro, rins e testículos. Algumas estratégias farmacológicas e não farmacológicas têm sido desenvolvidas de forma a contrariar os seus efeitos secundários tóxicos, incluindo suplementação com antioxidantes e, mais recentemente, exercício físico. Assim, o objectivo do presente estudo é avaliar o efeito da actividade física na funcionalidade testicular, bem como no stress oxidativo e apoptose, sugeridos para a acção tóxica da DOX. Trinta e seis ratos macho Sprag-Dawley foram divididos em 6 grupos: salino sedentário (SAL+SED), sedentáros tratados com doses sub-crónicas de DOX – injecções de 2mg.Kg-1 durante sete semanas (DOX+SED), salinos treinados na passadeira durante 12 semanas (SAL+TM), treinados tratados com DOX (DOX+TM), salinos realizando exercício voluntário em roda livre (SAL+FW) e tratados realizando exercício voluntário em roda livre (DOX+FW). Vinte e quatro horas depois da última sessão de exercício, os animais foram sacrificados, os espermatozóides foram obtidos e tratados para estudos de contagem e de motilidade. Os testículos foram recolhidos para posterior análise de marcadores de stress oxidativo (actividade da aconitase, concentrações de substâncias reactivas de ácido tiobarbiturico, malondialdeido (MDA) e de grupos sulfidril (-SH) e sinalização apoptotica (actividades das caspases 3,8 e 9). O tratamento com DOX induziu uma diminuição significativa na contagem e motilidade dos espermatozóides, independentemente da actividade física. Apesar de existir uma tendência para um aumento de MDA e diminuição de –SH com o tratamento com DOX, não foi detectado qualquer efeito significativo nos marcadores de stress oxidativo e apoptose. Não foi observado qualquer efeito do exercício nestes parâmetros. Concluindo, o exercício físico não influenciou o impacto que a DOX teve na funcionalidade testicular. Surpreendentemente, nem a DOX nem o exercício modularam o ambiente redox e a sinalização apoptótica nos testículos, considerando os marcadores analisados.
The anthracycline Doxorubicin (DOX) is a widely used antineoplastic agent against several tumors with high efficacy. However, the clinical use of this drug is limited by its dose-related toxicity in several organs with particular emphasis on the heart. Other organs affected by DOX include liver, brain, kidney and testes. Several pharmacological and non-pharmacological strategies have been designed to antagonize the toxic side effects of DOX, including antioxidant supplementation and, recently, physical exercise. Therefore, the aim of the present study is to analyze the effect of physical exercise in testes function as well as oxidative damage and apoptosis, suggested mechanisms by which DOX exerts its toxic effects. Thirty-six Sprag Dawley male rats were randomly divided into 6 groups as follows: Saline Sedentary (SAL+SED), Sedentary sub-chronically treated with DOX – 2mg.Kg-1 injections for 7 weeks (DOX+SED), Saline endurance treadmill trained for 12 weeks (SAL+TM), trained receiving DOX (DOX+TM), saline voluntary exercised in a free-wheel (SAL+FW) and voluntary exercised receiving DOX (DOX+FW). Twenty-four hours after the last exercise bout, animals were sacrificed; sperm was obtained and treated for counting and motility studies. Testes were harvested for tissues analysis of markers of oxidative stress and damage (aconitase activity, thiobarbituric acid reactive substances, as MDA, and sulfhydryl –SH groups content) and apoptotic signaling (caspases 3,8 and 9 activities). DOX treatment induced significant decrease in sperm count and motility, irrespective of exercise training status. Despite a tendency for MDA increase and –SH decrease with DOX treatment, no significant effect was detected in either markers of oxidative damage or apoptosis. No exercise effect was observed as well. In summary, chronic physical exercise did not influence DOX-induced testes dysfunction. Surprisingly, neither DOX nor exercise modulated testes redox environment and apoptotic signaling, at least seen by the measured markers.
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Candido, Caroline Damico [UNESP]. "Avaliação de distribuição de doxorrubicina incorporada em microemulsão lipídica em tecido tumoral e cardíaco em Camundongos". Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/91616.
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000736475.pdf: 1129710 bytes, checksum: 6b6d2e9c66931f72bef30065b36cb94c (MD5)A doxorrubicina (DOX) é o antineoplásico mais utilizado na terapêutica no tratamento de tumores sólidos e leucemias, porém sua cardiotoxicidade limita, muitas vezes, a continuidade do tratamento. Neste contexto, Formariz (2008) desenvolveu uma microemulsão (ME) contendo DOX (DOX-ME) que apresentou cardiotoxicidade reduzida – avaliada através da atividade da enzima MB da creatinina quinase (CKMB) - em relação ao produto comercial (pó liofilizado na forma de cloridrato). A DOX incorporada nessa nova ME apresentou aumento da DL50 em ratos Wistar e camundongos com manutenção da DE50, com consequente aumento da sua margem de segurança. Em estudos de farmacocinética pré-clínica foi observado que a DOX incorporada a esta microemulsão lipídica teve seus parâmetros farmacocinéticos modificados, apresentando menor volume de distribuição e diminuição da cardiotoxicidade, fato que sugere menor captação do fármaco pelo miocárdio. Neste estudo investigou-se a distribuição da DOX em tecido cardíaco e tumoral em camundongos Swiss fêmeas, nas quais foi inoculado e desenvolvido o tumor de Ehrlich. Esses animais foram distribuidos em dois grupos (n=7 cada) que receberam, por via intraperitoneal e em dose única (10 mg/kg), a DOX veiculada por microemulsão (DOX-ME) ou na forma de cloridrato (DOX-Cl). Quinze minutos após a administração os animais foram sacrificados por deslocamento cervical e a massa tumoral total e o coração foram coletados. Após a coleta as amostras foram processadas e analisadas em um sistema UPLC Waters® com detecção por fluorescência (ƛ exc = 480 nm; ƛ em= 560 nm), utilizando coluna Acquity CSH C18 1,7 μm (2,1 x 100 mm), protegida por coluna de guarda Vanguard C18 1,7 μm (2,1 x 50 mm). A fase móvel foi constituída de acetonitrila : ácido fórmico 0,1% (40:60), em modo isocrático, em fluxo de 0,4 mL/min. O volume de injeção foi de 10 μL de amostra no sistema cromatográfico. O método...
Doxorubicin (DOX) is the most used antineoplastic in the therapy for the treatment of solid tumors and leukemias but its cardiotoxicity often limits the continuity of the treatment. In this context, Formariz (2008) developed a microemulsion (ME) containing DOX (DOX-ME) that showed reduced cardiotoxicity - assessed by the activity of the enzyme creatine kinase MB (CK-MB) - in relation to the commercial product (in the form of hydrochloride lyophilized powder). The DOX incorporated into the new ME showed an increase of LD50 in rats and mice with the maintaining of the ED50, consequently increasing its safety margin. In preclinical pharmacokinetic studies was observed that the DOX lipid microemulsion had its pharmacokinetic parameters modified, with smaller volume of distribution and reduced cardiotoxicity, which suggests less drug uptake by the myocardium. In this study was investigated the distribution of DOX in cardiac tissue and tumor in female Swiss mice, which were inoculated and developed Ehrlich tumor. These animals were divided in two groups (n = 7) that received intraperitoneal dose (10 mg / kg) of DOX microemulsion (ME DOX) or hydrochloride (DOX-Cl) . Fifteen minutes after the administration, the animals were sacrificed by cervical dislocation and the total tumor mass and heart were collected. After collecting, the samples were processed and analyzed on a Waters ® UPLC System with fluorescence detection (ƛ exc = 480 nm; ƛ em = 560 nm) using column Acquity CSH C18 1.7 micrometre (2.1 x 100 mm) protected by guard column C18 Vanguard 1.7 micrometre (2.1 x 50 mm). The mobile phase consisted of acetonitrile: 0.1% formic acid (40:60) in isocratic flow at 0.4 ml / min. The injection volume was 10 uL of sample into the chromatographic system. The bioanalytical method was validated in accordance with resolutions of ANVISA and the guidance of the FDA, and demonstrated confidence limits appropriate for their application in the ...
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Candido, Caroline Damico. "Avaliação de distribuição de doxorrubicina incorporada em microemulsão lipídica em tecido tumoral e cardíaco em Camundongos /". Araraquara, 2013. http://hdl.handle.net/11449/91616.
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Orientador: Rosângela Gonçalves PeccininiCoorientador: Iracilda Zeppone Carlos
Banca: Anselmo Gomes de Oliveira
Banca: Thalita Pedroni Formariz Pilon
Resumo: A doxorrubicina (DOX) é o antineoplásico mais utilizado na terapêutica no tratamento de tumores sólidos e leucemias, porém sua cardiotoxicidade limita, muitas vezes, a continuidade do tratamento. Neste contexto, Formariz (2008) desenvolveu uma microemulsão (ME) contendo DOX (DOX-ME) que apresentou cardiotoxicidade reduzida - avaliada através da atividade da enzima MB da creatinina quinase (CKMB) - em relação ao produto comercial (pó liofilizado na forma de cloridrato). A DOX incorporada nessa nova ME apresentou aumento da DL50 em ratos Wistar e camundongos com manutenção da DE50, com consequente aumento da sua margem de segurança. Em estudos de farmacocinética pré-clínica foi observado que a DOX incorporada a esta microemulsão lipídica teve seus parâmetros farmacocinéticos modificados, apresentando menor volume de distribuição e diminuição da cardiotoxicidade, fato que sugere menor captação do fármaco pelo miocárdio. Neste estudo investigou-se a distribuição da DOX em tecido cardíaco e tumoral em camundongos Swiss fêmeas, nas quais foi inoculado e desenvolvido o tumor de Ehrlich. Esses animais foram distribuidos em dois grupos (n=7 cada) que receberam, por via intraperitoneal e em dose única (10 mg/kg), a DOX veiculada por microemulsão (DOX-ME) ou na forma de cloridrato (DOX-Cl). Quinze minutos após a administração os animais foram sacrificados por deslocamento cervical e a massa tumoral total e o coração foram coletados. Após a coleta as amostras foram processadas e analisadas em um sistema UPLC Waters® com detecção por fluorescência (ƛ exc = 480 nm; ƛ em= 560 nm), utilizando coluna Acquity CSH C18 1,7 μm (2,1 x 100 mm), protegida por coluna de guarda Vanguard C18 1,7 μm (2,1 x 50 mm). A fase móvel foi constituída de acetonitrila : ácido fórmico 0,1% (40:60), em modo isocrático, em fluxo de 0,4 mL/min. O volume de injeção foi de 10 μL de amostra no sistema cromatográfico. O método ...
Abstract: Doxorubicin (DOX) is the most used antineoplastic in the therapy for the treatment of solid tumors and leukemias but its cardiotoxicity often limits the continuity of the treatment. In this context, Formariz (2008) developed a microemulsion (ME) containing DOX (DOX-ME) that showed reduced cardiotoxicity - assessed by the activity of the enzyme creatine kinase MB (CK-MB) - in relation to the commercial product (in the form of hydrochloride lyophilized powder). The DOX incorporated into the new ME showed an increase of LD50 in rats and mice with the maintaining of the ED50, consequently increasing its safety margin. In preclinical pharmacokinetic studies was observed that the DOX lipid microemulsion had its pharmacokinetic parameters modified, with smaller volume of distribution and reduced cardiotoxicity, which suggests less drug uptake by the myocardium. In this study was investigated the distribution of DOX in cardiac tissue and tumor in female Swiss mice, which were inoculated and developed Ehrlich tumor. These animals were divided in two groups (n = 7) that received intraperitoneal dose (10 mg / kg) of DOX microemulsion (ME DOX) or hydrochloride (DOX-Cl) . Fifteen minutes after the administration, the animals were sacrificed by cervical dislocation and the total tumor mass and heart were collected. After collecting, the samples were processed and analyzed on a Waters ® UPLC System with fluorescence detection (ƛ exc = 480 nm; ƛ em = 560 nm) using column Acquity CSH C18 1.7 micrometre (2.1 x 100 mm) protected by guard column C18 Vanguard 1.7 micrometre (2.1 x 50 mm). The mobile phase consisted of acetonitrile: 0.1% formic acid (40:60) in isocratic flow at 0.4 ml / min. The injection volume was 10 uL of sample into the chromatographic system. The bioanalytical method was validated in accordance with resolutions of ANVISA and the guidance of the FDA, and demonstrated confidence limits appropriate for their application in the ...
Mestre
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Zhang, Wei. "LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE". UKnowledge, 2015. http://uknowledge.uky.edu/toxicology_etds/12.
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Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown.
The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and their C57BL (WT) littermates. Chronic DOX caused body weight loss and hemotoxicity, and these adverse effects were significantly exacerbated in Mrp1-/- vs WT mice. Importantly, loss of Mrp1 potentiated DOX-induced cardiotoxicity, presenting as worsened cardiac function and more cellular apoptosis in DOX treated Mrp1-/- mice. Mrp1 also protected neonatal mouse cardiomyocytes (CM) and cardiac fibroblasts (CF) culture against DOX cytotoxicity in vitro. This was demonstrated by the decreased cell survival, more apoptosis and more DNA damage in DOX treated Mrp1-/- vs WT cells.
In addition, the effects of deletion of Mrp1 was studied on glutathione (GSH)/glutathione disulfide (GSSG) homeostasis, glutathione conjugate of 4-hydroxy-2-nonenal (GS-HNE) accumulation, protein oxidative damage and expression of antioxidant enzymes. Loss of Mrp1 led to significantly higher GSH and GSSG basal levels in heart. Following DOX treatment, Mrp1-/- CM and CF showed increased GSH and GSSG levels vs WT cells. Meanwhile, DOX increased expression of the GSH synthesis enzymes in Mrp1-/- but not WT cells. Thus, increased GSH synthesis may contribute to the further increase in the GSH pool in DOX-treated Mrp1-/- cells. DOX induced comparable increases of GS-HNE concentration in WT and Mrp1-/- mice hearts. Finally, expression of extracellular superoxide dismutase (ECSOD/SOD3) was significantly lower in Mrp1-/- vs. WT CM treated with either saline or DOX.
In summary, this study is the first to document a protective role of Mrp1 in DOX-induced cardiotoxicity. It gives critical information regarding the potential adverse sequelae of introduction of MRP1 inhibitors as adjuncts to clinical chemotherapy of multidrug resistant tumors.
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Ren, Xiaojia. "STUDIES OF OXIDATIVE DAMAGE, BRAIN PROTEOME, AND NEUROCHEMICAL METABOLITES IN COGNITIVE AND NEURODEGENERATIVE DISORDERS: (1) CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENT; (2) PARKINSON DISEASE RAT MODEL". UKnowledge, 2019. https://uknowledge.uky.edu/chemistry_etds/116.
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The rate of cancer patients is increasing as the development of science and technology. Twenty million cancer survivors are estimated living in the United States by 2025. However, many cancer survivors show cognitive dysfunction, negatively affecting the quality of life. These cognitive impairments are recognized as chemotherapy-induced cognitive impairment (CICI), also called "chemo brain" by cancer survivors, including the diminished ability of memory and learning, hard to concentrate and focus, as well as diminution of executive function and processing speed. The etiologies and pathologies of CICI are complicated, especially in most cases the anti-cancer drug cannot cross the blood-brain barrier (BBB).
One of the significant candidate mechanisms underlying CICI is chemotherapy-induced, oxidative damage-mediated tumor necrosis factor-alpha (TNF-a) elevation. One of the prototypes of reactive oxygen species (ROS)-generating chemotherapeutic agents is Doxorubicin, normally used as part of multi-drug chemotherapeutic regimens to treat solid tumors and lymphomas. In this dissertation, TNF-a null (TNFKO) mice were used to investigate the role of TNF-a in Dox-induced, oxidative damage-mediated alterations in brain. Dox-induced oxidative damage in brain is ameliorated and brain mitochondrial function is preserved in brains of TNFKO mice. Both Dox-decreased levels of hippocampal choline-containing compounds and activities of brain phospholipases are partially protected in the TNFKO group. It is shown in this dissertation that Dox-targeted mitochondrial damage and levels of brain choline-containing metabolites, as well as changes in the activity of phospholipases, including both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PLD), are decreased in the CNS and associated with oxidative damage mediated by TNF-a. The results are discussed with respect to identifying a potential therapeutic target to protect against cognitive problems after chemotherapy and thereby improve the quality of life of cancer survivors.
We also tested the effect of a chemotherapy drug adjuvant, 2-mercaptoethane sulfonate sodium (MESNA), on CICI in this dissertation research. MESNA ameliorated Dox-induced oxidative protein damage in plasma and led to decreased oxidative damage in brain. MESNA was demonstrated to rescue the memory deficits caused by Dox in the novel object recognition test. The activity of PC-PLC was preserved when MESNA was co-administered with Dox. This study is the first evidence for demonstrating the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.
Parkinson Disease (PD) is considered as the second most neurodegenerative disease, associated with aging and gender. Although the detailed mechanisms remain unknown, inflammation and oxidative damage are two main etiological factors of PD. Certain genetic factors have been discovered related to this disease. Thus, using rodent models with relative gene mutations are the main strategies to investigate PD. However, few rodent models showed same clinical and biochemical features of PD. PTEN-induced putative kinase -1 (PINK1) knockout (KO) rat is the rodent model used in this dissertation research. The oxidative damage in the brain of PINK1 KO rats, the ventricle sizes, and neurochemical metabolite profiles in these rats as a function of age and gender were measured. Distinct gender- and age-related alterations were found, many consistent with those in PD. The proteome of brain of PINK1 KO rat as a function of age and gender also was studied. Based on the collected data, the suitability of this unique rat as a faithful model of known characteristics of PD with our results is discussed.
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Yarana, Chontida. "ROLE OF OXIDIZED EXTRACELLULAR VESICLES AS EARLY BIOMARKERS AND INFLAMMATORY MEDIATORS IN CHEMOTHERAPY-INDUCED NORMAL TISSUE INJURY". UKnowledge, 2018. https://uknowledge.uky.edu/toxicology_etds/23.
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Significant advances in the efficacy of cancer therapy have been accompanied by an escalation of side effects that result from therapy-induced injury to normal tissues. Patients with high grade cancer or metastasis are often treated with chemotherapy, 50% of which are associated with reactive oxygen species generation and cellular oxidative stress. Heart is the normal tissue most susceptible to chemotherapy-induced oxidative stress and heart disease is the most common leading cause of death in cancer survivors. However, early and sensitive biomarkers to identify heart disease are still lacking. Extracellular vesicles (EVs) are released from cells during oxidative stress and send oxidized proteins into the circulation as a compensatory mechanism that prevents cellular proteotoxicity. Thus, the protein contents of EVs released during the pre-degeneration stage reveal that oxidative stress is occurring early in the damaged tissue. Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we demonstrated that EVs can be used as an early diagnostic tool for tissue injury as they are oxidatively modified with 4-hydroxynonenal and contain tissue specific proteins—glycogen phosphorylase brain/heart, muscle, and liver isoforms—that indicate their origins. These biomarkers increased early, before the changes of conventional biomarkers occurred.
EVs also mediate intercellular communication by transferring bioactive molecules between cells. In the cell culture system, EVs play an important role in oxidative stress response by inducing macrophage polarization. EVs from cardiomyocytes promoted both proinflammatory (M1) and anti-inflammatory (M2) macrophage polarization evidenced by higher pro- and anti-inflammatory cytokines and nitric oxide generation, as well as mitochondrial oxidative phosphorylation suppression and glycolysis enhancement. In contrast, EVs from the hepatocytes supported anti-inflammatory macrophage (M2) by enhancing oxidative phosphorylation and anti-oxidant proteins. DOX promoted the immunostimulatory effects of cardiomyocyte EVs but not hepatocyte EVs. The differential functions of EVs on macrophage phenotype switching are due to their different effects on Thioredoxin 1 redox state, which regulates activities of redox sensitive transcription factors NFκB and Nrf-2. Our findings shed light on the role of EVs as a redox active mediator of immune response during chemotherapy.
Części książek na temat "Doxorubicine – Toxicologie"
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Rossini, L., E. Monti, D. Cova i F. Piccinini. "Determination of Doxorubicin and Doxorubicin-3-ol in Rat Heart". W Archives of Toxicology, 474–78. Berlin, Heidelberg: Springer Berlin Heidelberg, 1986. http://dx.doi.org/10.1007/978-3-642-71248-7_102.
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Paulus, G., M. T. Masson i P. Mompon. "Cardiotoxicity of Doxorubicin: A Histochemical and Morphometric Approach". W Archives of Toxicology, 410–12. Berlin, Heidelberg: Springer Berlin Heidelberg, 1988. http://dx.doi.org/10.1007/978-3-642-73113-6_78.
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Yu, Li-Rong, i Varsha G. Desai. "Doxorubicin Cardiotoxicity: Preclinical and Clinical Circulating Protein Markers". W Biomarkers in Toxicology, 1–27. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-87225-0_44-1.
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Yu, Li-Rong, i Varsha G. Desai. "Doxorubicin Cardiotoxicity: Preclinical and Clinical Circulating Protein Markers". W Biomarkers in Toxicology, 677–703. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-07392-2_44.
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Cova, D., L. Rossini, E. Monti, L. Paracchini i F. Piccinini. "Detection of DNA Damage Induced by Doxorubicin and the Effect of Glutathione". W Archives of Toxicology, 330–33. Berlin, Heidelberg: Springer Berlin Heidelberg, 1988. http://dx.doi.org/10.1007/978-3-642-73113-6_58.
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Zbinden, G., D. DeCampeenere i R. Baurain. "Preclinical Assessment of the Cardiotoxic Potential of Anthracycline Antibiotics: N-L-Leucyl-Doxorubicin". W Archives of Toxicology, 107–17. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-74936-0_22.
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Amin, Mohamadreza, i Mahmoud Reza Jaafari. "Preparation, Characterization, and In Vitro and In Vivo Evaluation of PEGylated Liposomal Doxorubicin Modified with Different cRGD Peptides". W Methods in Pharmacology and Toxicology, 51–68. New York, NY: Springer New York, 2015. http://dx.doi.org/10.1007/7653_2015_57.
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"Doxorubicin Cardiotoxicity". W Principles of Cardiac Toxicology, 551–82. CRC Press, 1991. http://dx.doi.org/10.1201/9781439805367-21.
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