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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Farmacocinética pré-clínica e cardiotoxicidade da doxorrubicina veiculada por sistema microemulsionado /

Assumpção, Juliana Uruguay Corrêa Vidigal. January 2011 (has links)
Orientador: Rosângela Gonçalves Peccinini / Banca: Hérida Regina Nunes Salgado / Banca: Regina Helena Costa Queiroz / Resumo: Neste estudo investigou-se o perfil farmacocinético da DOX administrada na forma de microemulsão lipídica, em dose única i.v (6 mg/kg), a ratos Wistar (n=12; 250 g) e comparou-se ao perfil farmacocinético da doxorrubicina administrada na forma de cloridrato em solução aquosa. Ainda, avaliou-se a atividade da CKMb nos dois grupos de animais antes e após a administração das formulações com o objetivo de evidenciar a cardiotoxicidade do produto. Para a avaliação do perfil farmacocinético foram colhidas amostras seriadas de sangue (0 - 16 h) através de cânulas previamente implantadas na veia femoral, e para a avaliação da atividade de CKMb foram colhidas amostras de sangue nos tempos zero, 1 h e 12 h após a administração das formulações. Para a determinação da doxorrubicina em amostras de sangue e nas formulações, desenvolveu- se e validou-se um método analítico por HPLC com detecção por fluorescência (exc= 480 nm; em= 560 nm), empregando-se coluna Xterra (C18, 5 µm, 3,9 x 150 mm) e fase móvel composta por 25% de acetonitrila e 75% de água na presença de ácido fórmico (0,1%) e de solução de amônia 25% (0,1%), pH 3,0 , com fluxo de 0,8 mL/min, em modo gradiente. Para as determinações da atividade da CKMb utilizou-se o kit labtest. O método analítico desenvolvido demonstrou limites de confiança adequados para a sua aplicação na determinação da DOX em formulações e em amostras de plasma para a avaliação do seu perfil farmacocinético. Os parâmetros farmacocinéticos que apresentaram diferenças estatisticamente significativas (p<0,05, Mann-Whitney) entre a microemulsão e solução aquosa, apresentados como média (IC 95), foram respectivamente: Vd (L/kg) = 38,23 (24,94 - 51,50) vs 68,85 (55,69 - 82,00); tss (h) = 45,33 ( 39,45 - 58,20) vs 33,23 ( 27,7 - 38,75); β(h-1 )= 0,0014 (0,00072 - 0,00208) vs 0,00078 ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The present study investigated the DOX pharmacokinetic profile when administered as a lipid microemulsion in a single dose (6 mg/kg, IV) to Wistar rats (n=12; 250g) and compared it to the pharmacokinetic profile of doxorubicin administered as hydrochloride in aqueous solution. With the purpose of demonstrating the cardiotoxicity of the product it also evaluated the CKMB activity in both animal groups before and after administration of the formulations. Serial blood samples were obtained (0 - 16h) through cannulas previously implanted into the femoral vein to evaluate the pharmacokinetic profile. To evaluate the CKMB activity, blood samples were collected after the formulation was administered at times zero, 1h and 12h. An analytical method by HPLC with fluorescence detection (exc= 480 nm; em= 560 nm) was developed and validated for the determination of doxorubicin in blood samples and in the formulations. The column used as stationary phase was Xterra  (C18, 5 µm, 3.9 x 150 mm) and the mobile phase was composed of 25% of acetonitrile and 75% of water in presence of formic acid (0.1%) and ammonia solution 25% (0.1%), pH 3.0 at a flow rate of 0.8 mL/min, gradient mode. The developed method demonstrated appropriate safety limits to its use in determining doxorubicin in formulations and in plasma samples, and therefore to evaluate the DOX pharmacokinetic profile. For the determination of CKMB activity it was used the Labtest. The pharmacokinetic parameters that showed statistically significant differences (p<0.05, Mann-Whitney) between the microemulsion and the aqueous solution, presented as medians (IC 95), were respectively: Vd (L/kg) = 38.23 (24.94 - 51.50) vs 68.85 (55.69 - 82.00); tss (h) = 45.33 (39.45 - 58.20) vs 33.23 ( 27.70 - 38.75); β(h-1 )= 0.0014 (0.00072 - 0.00208) vs 0.00078 ( 0.0004386 - 0.001076) and t1/2 (h) = 9.24 (5.31 - 13.17) vs 16.51 ... (Complete abstract click electronic access below) / Mestre
12

Nanomaterials as a platform for the doxorubicin transport - Fluorescence imaging

Blažková, Iva January 2015 (has links)
Doxorubicin (DOX) is an important anthracycline antineoplastic drug used to treat a variety of cancers. As well as other antineoplastic agents, DOX has negative side effects; the most serious one is cardiotoxicity. Conjugation of DOX with nanomaterials could help to reduce its adverse effects. The presented thesis entitled ,,Nanomaterials as a platform for the DOX transport -- Fluorescence imaging" is primarily focused on the study of DOX interaction with biomolecules such as amino acids and albumin. The interaction was analysed by fluorescence spectrometry and by other analytical methods and significant interaction with amino acids as well as with protein albumin was detected. Next work was focused on the utilization of nanoparticles in DOX transport. DOX was conjugated with fullerenes or encapsulated in liposomes and properties of these nanoconstructs, in vitro and in vivo, were analysed. Both of these nanomaterials seemed to be good nanotransporters for DOX targeted delivery.
13

Mecanismos envolvidos na cardiotoxidade aguda induzida pela doxorrubicina em ratos

Polegato, Bertha Furlan [UNESP] 07 November 2011 (has links) (PDF)
Made available in DSpace on 2014-06-11T19:31:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-07Bitstream added on 2014-06-13T20:41:30Z : No. of bitstreams: 1 polegato_bf_dr_botfm.pdf: 3262960 bytes, checksum: 5e228e55d5391695f03d5175bdcfb7ef (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A doxorrubicina, ou adriamicina, é uma droga utilizada como agente antineoplásico no tratamento de tumores sólidos e neoplasias hematológicas, principalmente. Apesar de seu amplo uso, apresenta como efeito colateral mais importante a cardiotoxicidade. A toxicidade crônica é bastante conhecida e estudada e cursa com miocardiopatia dilatada e quadro clínico clássico de insuficiência cardíaca. A toxicidade aguda, por cursar com quadro clínico pouco exuberante e manifestar-se através de alterações eletrocardiográficas, é muito pouco diagnosticada e seu mecanismo fisiopatológico não é totalmente conhecido. Os mecanismos envolvidos na toxicidade cardíaca são distintos dos mecanismos de ação da droga e são múltiplos: aumento do estresse oxidativo, aumento da apoptose e alteração na dinâmica intracelular do cálcio. Nossa hipótese é que ocorra lesão estrutural e funcional cardíaca, precocemente, após infusão da doxorrubicina. O objetivo do presente estudo foi avaliar a função ventricular esquerda agudamente após administração de doxorrubicina, a expressão gênica das proteínas reguladoras do trânsito de cálcio, a atividade de metaloproteinases 2 e 9 no miocárdio e alterações das citocinas inflamatórias no miocárdio de ratos tratados com a droga. Para isso, foram utilizados ratos Wistar machos adultos (n=35), que foram submetidos à infusão intraperitoneal de dose única de doxorrubicina de 20 mg/Kg ou volume equivalente de salina (grupo controle). Os animais foram eutanasiados 48 horas após injeção da droga. Todos os ratos foram submetidos ao ecocardiograma antes e 48 horas após a injeção da doxorrubicina. Além da avaliação da função cardíaca in vivo pelo ecocardiograma, a função ventricular esquerda foi avaliada in vitro através de estudo do coração isolado, segundo preparação... / Doxorubicin, or adriamycin, is a drug used as an antineoplastic agent in the treatment of solid tumors and hematologic malignancies. Despite of its use, there are several side effects, and the most important is cardiotoxicity. Chronic toxicity is well known and studied. It presented with dilated cardiomyopathy and clinical features of heart failure. The acute toxicity has mild clinical signs manifesting usually as electrocardiographic changes. Probably, this acute effect is underdiagnosed and the pathophysiological mechanism is not fully understood. The mechanisms involved in cardiac toxicity are multiple, and include increased oxidative stress, increased apoptosis and alteration in intracellular calcium dynamics. Our hypothesis is that structural and functional damage occurs in the heart early after infusion of doxorubicin. The purpose of this study was to evaluate left ventricular function acutely after doxorubicin administration. In addition, gene expression of calcium regulatory proteins, activity of metalloproteinases 2 and 9, and inflammatory cytokines in the myocardium of rats treated with this drug will also be evaluated. Thus, we used adult male Wistar rats (n = 35) who received a single-dose, by intraperitoneal infusion, of doxorubicin (20 mg / kg) or equivalent volume of saline (control group). After 48 hours of drug injection the rats were euthanized. All animals were submitted to echocardiography before drug infusion and immediately before euthanasia. Besides in vivo cardiac function evaluation by echocardiography. In vitro left ventricular function was assessed by isolated perfusion heart study, according to Langendorff preparation. We evaluated interstitial collagen and myocyte hypertrophy by light microscopy, and cardiac tissue metalloproteinases 2 and 9 activity was assessed by zymography. In addition... (Complete abstract click electronic access below)
14

Overexpression of Vascular Endothelial Growth Factor 165 (VEGF<sub>165</sub>) Protects Cardiomyocytes Against Doxorubicin-Induced Apoptosis

Chen, Tingting, Zhou, Gengyin, Zhu, Quan, Liu, Xian, Ha, Tuanzhu, Kelley, J. L., Kao, R. L., Williams, D. L., Li, Chuanfu 01 January 2010 (has links)
Doxorubicin (Dox) has been employed in cancer chemotherapy for a few decades. However its clinical application became restricted because of dose-dependent cardiomyopathy. Recent studies suggest that Dox-induced cardiomyocyte apoptosis is a primary cause of cardiac damage. Vascular endothelial growth factor (VEGF) is a major factor for endothelial cell survival and angiogenesis. We have previously shown that VEGF16S significantly attenuates oxidative stress-induced cardiomyocytes apoptosis. We hypothesized that VEGF165 will protect the cardiomyocytes from Dox-induced apoptosis. To evaluate our hypothesis, we transfected cardiomyocytes H9c2 with adenovirus expressing VEGF16S 24 hours before the cells were challenged with Dox at a concentration of 2 uM. Cardiomyocyte apoptosis was evaluated by Annexin V-FITC staining and by Western blot detection of cleaved caspase-3. The hypothesis was confirmed, and the protective mechanisms involve the inhibition of death receptor-mediated apoptosis and up-regulation of the prosurvival Akt/NF-κB/BcI-2 signaling pathway.
15

Pathologic characterization and chemoresponsiveness to adriamycin of moloney sarcoma virus-induced osteosarcoma in the rat /

Olson, Harry Marshall January 1977 (has links)
No description available.
16

Part I: A synthesis of 3-acetyl-6-bromo-3-hydroxy-1,5,8-trimethoxy-1,2,3,4-tetrahydronaphthalene. Part II: Synthesis of monothioacetals, ketones, and vinyl sulfides /

Narasimhan, S. Lakshmi January 1979 (has links)
No description available.
17

Effect of co-treatment of flavonoids with doxorubicin in chemotherapy.

January 2001 (has links)
Chan Ching-Man Loren. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 126-144). / Abstracts in English and Chinese. / Acknowledgement --- p.ii / Abstract --- p.iii / Table of Content --- p.vii / List of Figure --- p.ix / List of Abbreviations --- p.xii / Chapter Chapter One --- General Introduction / Chapter 1.1 --- Doxorubicin --- p.1 / Chapter 1.2 --- Antioxidants --- p.11 / Chapter 1.3 --- Flavonoids --- p.17 / Chapter 1.4 --- Protection against doxorubicin-induced cardiotoxicity by antioxidant --- p.25 / Chapter 1.5 --- Aim of research --- p.25 / Chapter Chapter Two --- Study of Cardioprotection Effect of Flavonoids Against Doxorubicin-induced Toxicity in Sprague-Dawley Rats / Chapter 2.1 --- Introduction --- p.27 / Chapter 2.2 --- Materials and Methods --- p.29 / Chapter 2.3 --- Results --- p.37 / Chapter 2.4 --- Discussion --- p.51 / Chapter ChapterThree --- Study of Effect of Flavonoids in Chemotherapy of Doxorubicinin Tumor-bearing Mice / Chapter 3.1 --- Introduction --- p.54 / Chapter 3.2 --- Materials and Methods --- p.56 / Chapter 3.3 --- Results --- p.63 / Chapter 3.4 --- Discussion --- p.80 / Chapter ChapterFour --- Study of the Effect of Flavonoids on Doxorubicin-induced Cytotoxicity on Human Tumor Cell Line and Doxorubicin-resistant Human Tumor Cell Line / Chapter 4.1 --- Introduction --- p.83 / Chapter 4.2 --- Materials and Methods --- p.86 / Chapter 4.3 --- Results --- p.94 / Chapter 4.4 --- Discussion --- p.120 / Chapter Chapter five --- Conclusion --- p.122 / References --- p.126
18

A study of human topoisomerase II#alpha# and #beta# as targets for anticancer agents

Meczes, Emma Louise January 1998 (has links)
No description available.
19

Διερεύνηση της σχέσης απόπτωσης και γενετικών αλλαγών που επάγονται από την αντικαρκινική ένωση δοξορουβικίνη στην κυτταρική σειρά ποντικού C2C12

Τροχούτσου, Αικατερίνη 11 November 2008 (has links)
Η δοξορουβικίνη αποτελεί μια ευρέως χρησιμοποιούμενη αντικαρκινική ένωση σε διάφορους τύπους νεοπλασιών και ανήκει στην οικογένεια των ανθρακυκλινών. Για την κυτταροστατική της δράση έχουν προταθεί διάφοροι μηχανισμοί, μεταξύ των οποίων επαγωγή απόπτωσης και γενετικές αλλαγές. Η απόπτωση αποτελεί μια φυσιολογική διαδικασία, η οποία ελέγχει τον αριθμό των κυττάρων σ’ έναν οργανισμό. Λειτουργεί ως αμυντικός μηχανισμός σε περιπτώσεις κυττάρων που έχουν υποστεί βλάβη και παρεμποδίζει την εξάπλωση μεταλλάξεων συμπεριλαμβανομένων και εκείνων που οδηγούν σε καρκινογένεση. Η απόπτωση μπορεί να ενεργοποιηθεί κυρίως μέσω της εξωγενούς και της ενδογενούς οδούς. Στην παρούσα ερευνητική εργασία μελετήθηκε η σχέση επαγωγής απόπτωσης και γενετικών βλαβών που προκαλούνται από τη δοξορουβικίνη σε κυτταρική σειρά ποντικού C2C12. Για τη διερεύνηση των γενετικών βλαβών μελετήθηκε η συχνότητα των μικροπυρήνων (ΜΝ) με χρώση DAPI. H επαγωγή απόπτωσης εξετάστηκε με τη μέθοδο διπλής χρώσης αννεξίνη V/ιωδιούχο προπίδιο. Η μελέτη του μηχανισμού προέλευσης των μικροπυρήνων πραγματοποιήθηκε με σήμανση πρωτεϊνών του κινητοχώρου, την ανοσοχημική μέθοδο CREST σε συνδυασμό με ανοσοσήμανση της α-τουμπουλίνης για την εμφάνιση του κυτταροπλάσματος. Παρατηρήθηκε ότι η δοξορουβικίνη στις μελετηθείσες συγκεντρώσεις (0.05 μg/ml, 0.10 μg/ml, 0.20 μg/ml, 1.00 μg/ml, 2.50 μg/ml και 5.00 μg/ml,) προκαλεί αυξημένες συχνότητες αποπτωτικών κυττάρων και κυττάρων που περιέχουν μικροπυρήνες. Διαπιστώθηκε ότι η αύξηση της απόπτωσης σχετίζεται με μείωση της συχνότητας των μικροπυρήνων, υποδεικνύοντας πιθανή συμμετοχή της απόπτωσης στον περιορισμό των κυττάρων που φέρουν γενετική βλάβη. Η μελέτη του μηχανισμού προέλευσης των μικροπυρήνων έδειξε ότι η δοξορουβικίνη επάγει τη χρωμοσωματική θραύση και σε μικρότερο βαθμό τη χρωμοσωματική καθυστέρηση. Η τελευταία παρατήρηση μας οδήγησε στη μελέτη της οργάνωσης της μιτωτικής συσκευής μετά την επίδραση με δοξορουβικίνη. Η μιτωτική συσκευή αποτελεί στόχο χημικών ενώσεων που επηρεάζουν το χρωμοσωματικό αποχωρισμό και η μελέτη της πραγματοποιήθηκε με διπλή ανοσοσήμανση για τους μικροσωληνίσκους (β-τουμπουλίνη) και το κεντρόσωμα (γ-τουμπουλίνη). Παρατηρήθηκαν επίσης, ανώμαλες μεταφάσεις και τροποποιημένος αριθμός κεντροσωμάτων, φαινόμενα που σχετίζονται με λανθασμένο χρωμοσωματικό αποχωρισμό. Τέλος σε προκαταρκτικά πειράματα κατά τα οποία πραγματοποιήθηκε αναστολή της απόπτωσης που προκαλείται από τη δοξορουβικίνη με το γενικό αναστολέα Z-VAD-fmk, παρατηρήθηκε αύξηση της συχνότητας των κυττάρων με μικροπυρήνες που προκαλούνται από την ίδια ένωση. Η παρατήρηση αυτή αποτελεί μια ακόμη ένδειξη για την πιθανή συμμετοχή της απόπτωσης στον περιορισμό των κυττάρων με γενετικές αλλαγές. Επίσης παρατηρήθηκε ότι η αναστολή της απόπτωσης τροποποιεί τη συχνότητα των κυττάρων με ανώμαλο αριθμό κεντροσωμάτων που επάγονται από τη δράση της δοξορουβικίνης, αυξάνοντας τα κύτταρα με ένα κεντρόσωμα και μειώνοντας τα κύτταρα με πολλαπλά κεντροσώματα, υποδεικνύοντας πιθανή εμπλοκή της απόπτωσης στο σχηματισμό ασύμμετρων κυτταρικών διαιρέσεων. Οι τελευταίες παρατηρήσεις χρειάζονται περαιτέρω διερεύνηση. / Doxorubicin is one of the most widely used anticancer drugs due to its broad spectrum of antitumor activity and belongs to the family of anthracyclines. Various mechanisms have been proposed for its cytostatic activity, including induction of apoptosis and genetic alterations. Apoptosis is a normal procedure which provides a cell control mechanism. It is a defense mechanism for the elimination of mutated cells including those that might cause carcinogenesis. Apoptosis is carried out by intrinsic as well as extrinsic pathways. In the present thesis we investigated the relationship between apoptosis and genetic damage induced by doxorubicin in C2C12 mouse cell line. Genetic damage was evaluated by studying the micronucleus (MN) frequency by DAPI staining.The induction of apoptosis was examined by double fluorescence staining of ANNEXIN V/PI. The analysis of the mechanism by which the micronuclei are induced was further investigated by kinetochore labeling using the immunocytochemical method CREST with simultaneous labeling of α- tubulin, for the detection of cytoplasm. It was observed that doxorubicin at the studied concentrations (0.05 μg/ml, 0.10 μg/ml, 0.20 μg/ml, 1.00 μg/ml, 2.50 μg/ml and 5.00 μg/ml) increased frequencies of apoptotic and micronucleated cells. It was shown that the induction of apoptosis was related with decreased micronucleus frequency, indicating a possible involvement of apoptosis in the elimination of the micronucleated cells. The analysis of the mechanism of micronucleus formation showed that doxorubicin induced chromosome breakage and in a lesser extent chromosome loss. The latter ability was further investigated by analyzing the integrity of mitotic apparatus after exposure to doxorubicin. The mitotic apparatus consists one of the main targets of chemical compounds which induce chromosome missegregation. The analysis was achieved by double immunofluorescence staining for microtubules (β-tubulin) and for centrosome (γ- tubulin). It was shown that doxorubicin provoked high abnormal metaphase figures and abnormal centrosome numbers, phenomena that are related with abnormal chromosome segregation. Finally, preliminary experiments, where doxorubicin-induced apoptosis was inhibited by the pancaspase inhibitor Z-VAD-fmk, resulted to an increase of the frequency of micronucleated cells generated by doxorubicin. This observation is an additional evidence for the involvement of apoptosis in the elimination of cells with genetic damage. Moreover, it was observed that inhibition of apoptosis altered the frequency of cells with abnormal centrosome number, which are formed after doxorubicin treatment, by increasing cells with only one centrosome and decreasing cells with multiple centrosomes, indicating a possible participation of apoptosis in the formation of asymmetric divisions. Further investigation is warranted to clarify the last observations.
20

Development and pharmacology of mitomycin C albumin microspheres

Allan, Lucy Jane January 1994 (has links)
No description available.

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