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Linagliptina: desenvolvimento de método indicativo de estabilidade por cromatografia líquida de alta eficiência e estudos de segurança biológicaFerreira, Raquel Balestri Heleno January 2016 (has links)
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Previous issue date: 2016 / A linagliptina (LGT) é um fármaco inibidor da DPP-4, da classe das gliptinas, utilizado para o controle glicêmico de diabetes mellitus tipo 2. Levando-se em conta que os fármacos utilizados no processo de produção das formulações farmacêuticas não são considerados totalmente puros, alguns Guias Regulatórios (ICH) descrevem a necessidade da quantificação do fármaco e suas impurezas de síntese. Diante disso, o objetivo do estudo é o desenvolvimento de um método por cromatografia líquida de alta eficiência (CLAE) para quantificação do fármaco e de suas três principais impurezas de síntese e o estudo de segurança biológica destas substâncias. O desenvolvimento e a validação do método para LGT e das três impurezas foram realizados por CLAE acoplada a um detector de arranjo de diodo (DAD), utilizando coluna C8 (5 μm - 4,6x100 mm), fase móvel eluída em modo gradiente, constituída de uma mistura de ácido fórmico 0,1% pH 3,5 e acetonitrila (ACN) eluída com uma rampa crescente de 10% na proporção de ACN de (0) zero ao 4 min (30% para 70%) e decrescente de 10% na proporção de ACN de 5 a 8 min (70% para 30%), vazão de 0,6 mL/min, volume de injeção de 20 μL e temperatura do forno de 30°C. Os comprimentos de onda de detecção utilizados foram 294, 278, 268 e 280 nm para LGT, impureza 1, 2 e 3, respectivamente. O método apresentou-se seletivo e específico para a LGT e as impurezas, pois não houve interferência dos produtos de degradação por Ultravioleta A, hidrólise básica (hidróxido de sódio 1,0 mol/L) e ácida (ácido clorídrico 1,0 mol/L), peróxido hidrogênio 30%, temperatura 60 °C e hidrólise básica e ácida em condições térmicas à 80 °C e dos excipientes na quantificação do fármaco. A resposta foi linear na faixa de 2,41-144,0 μg/mL (r = 0,9996) para a LGT e na faixa de 0,06-3,6 μg/mL para as impurezas testadas (r = 0,9963, 0,9994 e 0,9991 para impureza 1, 2 e 3, respectivamente). O método demonstrou exatidão, com teores de recuperação de 99,79, 93,12, 92,92 e 93,99% para a LGT e impureza 1, 2 e 3, respectivamente. A precisão intra e inter-dia foi satisfatória (RSD 1,36, 4,14, 3,50 e 4,08% para a LGT e impureza 1, 2 e 3, respectivamente) e a robustez não apresentou diferenças significativas com pequenas alterações nas condições analíticas (pH, fase móvel, temperatura, fluxo e detector). A cinética de degradação em condição alcalina associada a temperatura de (80 ºC), apresentou resultados de primeira ordem. A avaliação da segurança biológica foi realizada por meio da citotoxicidade, mutagenicidade e genotoxicidade através dos testes de viabilidade celular, micronúcleo e cometa, respectivamente. Nos testes de segurança biológica a LGT apresentou-se apenas citotóxica na concentração 10 vezes superior a concentração plasmática máxima, enquanto as impurezas 1 e 3 apresentaram-se citotóxica, mutagênica e genotóxica em uma concentração equivalente a 10% concentração plasmática máxima do fármaco e a impureza 2 evidenciou sua citotoxicidade e genotoxicidade na concentração equivalente a 10% da concentração plasmática máxima do fármaco. De acordo com os resultados obtidos, pode-se observar que o método proposto foi indicativo de estabilidade por CLAE para LGT e ainda demonstrou-se adequado para análise quantitativa das impurezas de síntese do fármaco. Além disso, evidenciou-se que a LGT e as impurezas de síntese estão em conformidade com os testes de segurança biológica empregados, desde que utilizadas nas concentrações adequadas. / Linagliptin (LGT) is an inhibitor of DPP4 used for glycemic control of type 2 mellitus diabetes. Since the drugs used in the production process of the pharmaceutical formulations are not considered totally pure, the Regulatory Guides describing the need of the drug quantification and impurities potentials. Therefore, the aim of this study was to develop a method by highperformance liquid chromatography to quantify the drug and three potential synthetic impurities and biological safety studies. The development and validation of the method for LGT and the three impurities were carried out by HPLC coupled to a photodiode array detector. The chromatographic separation was performed in a RP8 column (150 x 4.6 mm, 5 μm), at 30°C. The separation was performed by means of a linear gradient elution (eluent A: formic acid 0.1% pH 3.5; eluent B: acetonitrile). The gradient obeys the following sequence: 3070% of B (0 - 4 minutes) and 7030 of B (4,01 - 8 minutes) at a flowrate of 0.6 mL min1 and run time of 10 minutes. The injection volume was 20 μL and detection at 294, 278, 268 e 280 nm for LGT, impurity 1, 2 and 3, respectively. The method showed selectivity and specific for the LGT and synthetic impurities, therefore no interference of degradation products (UV-A, basic hydrolysis (sodium hydroxide 1.0 mol L1) and acid (hydrochloric acid 1.0 mol L1), peroxide (30%), temperature (60 ° C) and acidic and basic hydrolysis under thermal conditions (80° C)) and the excipients in the quantification of the drug. The response was linear from 2.41 to 144.0 μg mL1 (r = 0.9996) for the LGT and in the range of 0.06 to 3.6 μg mL1 (r = 0.9963, 0.9994 and 0.9991 for impurity 1, 2 and 3, respectively ). The method showed accuracy, with recovery levels of 99.79, 93.12, 92.92 and 93.99% for LGT and impurity 1, 2 and 3, respectively. The intra and inter-day precision was suitable (RSD 1.36, 4.14, 3.50 and 4.08% for LGT and impurity 1, 2 and 3, respectively) and the robustness showed no significant differences with small changes in the analytical conditions (pH of the mobile phase, temperature, flow-rate and detector). The kinetics of degradation in alkaline conditions associated with temperature (80° C), showed results of the first order. The evaluation of the biological was performed by cytotoxicity, mutagenicity and genotoxicity through the cell viability test, micronucleus and comet, respectively. In biological safety testing LGT had only cytotoxic activity at a concentration of 10 times the maximum plasma concentration, while the impurity 1 and 3 set out cytotoxic, mutagenic and genotoxic in a concentration equivalent to 10% maximum plasma concentration of the drug and impurity 2 showed cytotoxicity and genotoxicity in concentration equivalent to 10% of the maximum plasma concentration of the drug. According to the results, it can be seen that the proposed method by HPLC is stability-indicating and suitable for quantitative analysis of the drug and synthetic impurities. Furthermore, it was observed that the LGT and synthetic impurities are in accordance with biological safety studies, if they are used in appropriate concentration.
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Avalia??o do teste de micron?cleo em linf?citos para uso como biomarcador de risco de c?ncer em usu?rios de esteroides anabolizantes androg?nicosSouza, Leonardo da Cunha Menezes 30 September 2013 (has links)
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Previous issue date: 2013-09-30 / Funda??o de Amparo ? Pesquisa do Estado da Bahia - FAPEB / The use of anabolic androgenic steroids (AAS) has grown among practitioners of recreational bodybuilding, with significant contributions of "Designer Steroids" (DS), EAA designed aiming muscle hypertrophy in healthy subjects. The abusive use of AAS in general is associated with adverse effects, one of the most worrisome is cancer development. Given that cancer is a genetic disease resulting from changes in genes critical in maintaining genomic stability and in the control of proliferation and differentiation, biomarkers able to identify these changes can take predictive value and contribute to reducing the high rates of morbidity and mortality by this disease. The aim of this study was to evaluate the effectiveness of the Cytokinesis Block Micronucleus Test (CBMN) in human lymphocytes in identifying risk groups for cancer development in users of AAS. Was collected 5ml of blood from 15 AAS users bodybuilders (G1), 20 nonusers bodybuilders (G2) and 20 nonusers sedentary (G3). Lymphocytes were cultured with blocking of cytokinesis and subsequent processing for making slides. MN analysis was performed on a minimum of 1000 binucleated lymphocytes. The occurrence of MN was significantly higher (p <0.05) in individuals of G1 compared to G2 and G3. The results indicate the sensitivity of CBMN in human lymphocytes in the identification of chromosomal damage in consequence of AAS using, however, further studies are needed to determine their potential to predict the cancer risk in users of AAS. / O uso de esteroides anabolizantes androg?nicos (EAA) tem crescido entre praticantes recreativos de muscula??o, com contribui??es significativas dos Designer Steroids (DS), EAA projetados para fins de hipertrofia muscular em indiv?duos saud?veis. O uso abusivo de EAA em geral est? associado a efeitos adversos, sendo um dos mais preocupantes o desenvolvimento de c?ncer. Tendo em vista que o c?ncer ? uma doen?a gen?tica resultante de altera??es em genes cr?ticos na manuten??o da estabilidade gen?mica e do controle da prolifera??o e diferencia??o, biomarcadores capazes de identificar estas altera??es podem assumir valor preditivo e contribuir para diminui??o das altas taxas de morbidade e mortalidade por esta doen?a. O objetivo deste estudo foi avaliar a efic?cia do Teste de Micron?cleo com Bloqueio da Citocinese (MNCtB) em linf?citos humanos na identifica??o de grupos de risco para o desenvolvimento de c?ncer em usu?rios de EAA. Foram coletados 5ml de sangue de 15 usu?rios de EAA praticantes de muscula??o (Grupo I), 20 n?o usu?rios praticantes de muscula??o (Grupo II) e 20 n?o usu?rios sedent?rios (Grupo III). Foi realizada cultura de linf?citos com o bloqueio da citocinese e posterior processamento para confec??o de l?minas. A an?lise de MN foi realizada em um m?nimo de 1000 linf?citos binucleados. A ocorr?ncia de MN foi significativamente maior (p<0,05) nos indiv?duos do Grupo I comparados aos do Grupo II e Grupo III. Os resultados apontam para a sensibilidade do MNCtB na identifica??o de danos cromoss?micos decorrentes do uso de EAA. Estudos subsequentes para determinar seu potencial preditivo para o risco de c?ncer em usu?rios de EAA s?o necess?rios.
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Avalia??o da ocorr?ncia de danos cromoss?micos, apoptose e necrose em c?lulas esfoliadas da mucosa oral de usu?rios de ester?ides anabolizantes androg?nicosSouza, Jeanderson Pereira 25 March 2013 (has links)
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Previous issue date: 2013-03-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Exposure to genotoxic agents induces changes in the DNA molecule to commit that genes involved with the repair mechanisms and the control of cell proliferation and differentiation pathways or genes associated with apoptosis can lead to cancer development. Among the many chemicals that have been identified as mutagenic action, include the Androgenic Steroids (AAS), hormones widely used in the search for improved physical performance and increased muscle mass. Objective: In this context, the aim of the development of this study was to evaluate the potential of androgenic anabolic steroid nandrolone decanoate, testosterone propionate and testosterone cypionate to induce chromosome damage, apoptosis and necrosis, using the micronucleus test in exfoliated cells from the oral mucosa of users of AAS with a view to its application as a tool in cancer prevention. Method: The study sample consisted of 55 volunteers, male, divided into two (02) groups, matched for age: 25 subjects (G1) users of nandrolone decanoate, testosterone propionate and testosterone cypionate (alone or simultaneously ) and 30 subjects in the control group (G2). The collection methodology and cytological analysis followed the protocol of Tolbert et al. (1992) and Thomas et al. (2009), which includes, in addition to micronuclei, the computation of degenerative nuclear changes indicative of apoptosis (cariorr?xis, condensed chromatin and pyknosis) and necrosis (karyolysis, cariorr?xis, condensed chromatin and pyknosis). Statistical analysis of the endpoints analyzed (micronucleus, cariorr?xis, condensed chromatin, karyolysis, pyknosis and broken eggs) was performed using the conditional test to compare proportions in situations of rare events. Results: Statistical analysis revealed no significant difference in the occurrence of micronuclei, karyolysis and broken eggs between groups. The occurrence of apoptosis was significantly greater in cells from control individuals. Conclusion: The results show inhibition of apoptosis induced by EAA, suggesting that the described association between the use of these substances and the carcinogenic process can be permeated by this mechanism. / A exposi??o a agentes genot?xicos induz altera??es na mol?cula do DNA que ao comprometerem genes envolvidos com os mecanismos de reparo e com o controle da prolifera??o e diferencia??o celular ou genes associados ?s vias de apoptose, podem levar ao desenvolvimento de c?ncer. Entre os muitos agentes qu?micos que t?m sido identificados como de a??o mutag?nica, incluem-se os Ester?ides Anabolizantes Androg?nicos (EAA), horm?nios amplamente utilizados na busca da melhoria do desempenho f?sico e aumento da massa muscular. Objetivo: Neste contexto, objetivou-se com o desenvolvimento do presente estudo, avaliar o potencial dos ester?ides anabolizantes androg?nicos decanoato de nandrolona, propionato de testosterona e cipionato de testosterona em induzir danos cromoss?micos, apoptose e necrose, atrav?s do uso do Teste de Micron?cleo em c?lulas esfoliadas da mucosa oral de usu?rios de EAA com vista ? sua aplica??o como ferramenta na preven??o do c?ncer. M?todo: A amostra do estudo foi composta por 55 volunt?rios, do sexo masculino, distribu?dos em dois (02) grupos, pareados por idade: 25 indiv?duos (G1) usu?rios de decanoato de nandrolona, propionato de testosterona e cipionato de testosterona (isoladamente ou simultaneamente) e 30 indiv?duos no grupo controle (G2). A metodologia de coleta e an?lise citol?gica seguiu o protocolo de Tolbert et al. (1992) e Thomas et al. (2009), que inclui, al?m de micron?cleos, o computo de altera??es nucleares degenerativas indicadoras de apoptose (cariorr?xis, cromatina condensada e picnose) e necrose (cari?lise, cariorr?xis, cromatina condensada e picnose). A an?lise estat?stica dos endpoints analisados (micron?cleo, cariorr?xis, cromatina condensada, cari?lise, picnose e broken eggs) foi realizada com o uso do teste condicional para compara??o de propor??es em situa??es de eventos raros. Resultados: A an?lise estat?stica revelou que n?o houve diferen?a significativa na ocorr?ncia de micron?cleo, cari?lise e broken eggs entre os grupos. A ocorr?ncia de apoptose foi, significativamente, maior em c?lulas dos indiv?duos do grupo controle. Conclus?o: Os resultados obtidos mostram inibi??o da apoptose induzida pelo uso de EAA, sugerindo que a associa??o descrita entre uso destas subst?ncias e o processo carcinog?nico possa ser permeada por este mecanismo.
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Génotoxicité du glyphosate, de l'atrazine et de leurs produits de dégradation seuls et en mélanges : étude de l'effet protecteur d'un cocktail de plantes / Genotoxicity of glyphosate, atrazine and their degradation products alone and in mixtures : study of the protective effect of a plant cocktailRoustan, Audrey 14 December 2016 (has links)
Le glyphosate, l’atrazine, et leurs principaux produits de dégradation (la déséthyl-atrazine ou DEA, et l’amino methyl phosphoric acid ou AMPA) sont parmi les pesticides les plus utilisés dans le monde et en France. Ils sont retrouvés en grande quantité dans plusieurs matrices environnementales dans les denrées alimentaires et les eaux de boisson.L’objectif de notre travail a été d’évaluer le potentiel génotoxique et mutagène in vitro et in vivo de ces quatre pesticides seuls et en mélanges, puis d’étudier les effets protecteurs d’un mélange d’extrait de plantes anti-mutagènes (Berberis vulgaris, Arctium lappa et Taraxacum officinalis) (DIG) sur la génotoxicité du mélange des quatre pesticides.Les résultats de notre étude in vitro ont montré que le potentiel génotoxique des pesticides dépend de leur environnement physico-chimique, et que les mélanges de pesticides peuvent révéler des propriétés génotoxiques bien plus importantes que celles prévisibles lors de l’exposition aux molécules individuelles avec survenue d’un effet cocktail. Les résultats de notre étude in vivo ont établi la puissante activité génotoxique et mutagène du mélange composé de quatre pesticides. Ils ont mis en évidence les effets cocktails qui peuvent se produire dans les mélanges de pesticides soulignant les limites des stratégies toxicologiques habituelles. Nous avons montré que les cellules cérébrales sont la principale cible des pesticides, probablement en rapport avec une importante sensibilité au stress oxydatif. Dans une troisième partie, nous avons démontré les effets protecteurs de DIG sur la génotoxicité/mutagénicité du mélange des quatre pesticides. / Glyphosate, atrazine, and their main degradation products (desethyl-atrazine or DEA, and the amino methyl phosphoric acid or AMPA) are among the most widely used pesticides in the world and in France. They are found in large quantities in several environmental matrices but also in food and drinking water.The aim of our work was to evaluate the genotoxicity and mutagenicity in vitro and in vivo of these four pesticides, alone and in mixtures, and to study the protective effects of a mixture composed with extracts of anti-mutagenic plants (Berberis vulgaris, Arctium lappa and Taraxacum officinalis) (DIG) on the genotoxicity of the mixture of four pesticides.The results of our in vitro study showed that the genotoxic potential of pesticides depends on their physico-chemical environment, and that mixtures of pesticides can reveal genotoxic properties more important than those predictable during the exposure to individual molecules, with occurrence of a cocktail effect. The results of our in vivo study clearly established the powerful genotoxic and mutagenic activity of the mixture of four pesticides. They highlighted the cocktail effects that may occur in mixtures of pesticides, underlining the limits of conventional toxicological strategies based on an individual assessment of the molecules. We have shown that brain cells are the main target of pesticides, probably related to a significant sensitivity to oxidative stress. In the third part, we demonstrated the protective effects of DIG on the genotoxicity and mutagenicity of the mixture of four pesticides.
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Nouvelles approches en toxicologie prédictive pour l'étude de la toxicité des mélanges de contaminants présents dans l'alimentation française / New approaches in predictive toxicology for study the mixtures of contaminants present in the french foodKopp, Benjamin 12 October 2018 (has links)
A travers leur alimentation, les consommateurs sont exposés à plusieurs substances chimiques simultanément qui peuvent avoir des effets combinés délétères sur la santé. Six mélanges de contaminants alimentaires auxquels la population française est exposée ont été définis en couplant des données individuelles de consommation et de contamination des aliments. L'objectif de cette thèse était d'étudier in vitro les effets génotoxiques de ces mélanges en utilisant de nouvelles approches. L'étude a montré que deux mélanges étaient génotoxiques et mutagènes, à des concentrations où les composés pris individuellement n'ont aucun effet, suggérant un effet combiné non additif. Nous avons également observé que, pour ces mélange, les effets sont conduits par deux métaux lourds et que leurs effets sont synergiques. Enfin, nous avons achevé cette étude en fournissant des informations détaillées sur les mécanismes d'action des mélanges permettant de mieux comprendre les interactions observées. / Through diet, people are exposed simultaneously to a variety of contaminants that could have combined adverse effects on human health. Six food contaminant mixtures to which the French population is exposed were defined based on individual food consumption data and data on the concentration of chemicals in foodstuff. The purpose of this work was to investigate the genotoxic effects of mixtures in vitro using novel approaches. We demonstrated that two mixtures could be genotoxic and mutagenic, at concentrations for which each individual compound did not induce any DNA damage, suggesting that the combined effect was not additive. We also concluded that, for the two mixtures, the effects were driven by two heavy metals and displayed a great synergy. Finally, we achieved our work by providing detailed information on the mechanisms of action of mixtures to better understand interaction.
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The effect on chromosomal stability of some dietary constituentsDurling, Louise January 2008 (has links)
When food is heated, a vast number of compounds are formed. Some of these are known to be toxic. Among these are furan, HMF, PhIP, IQ, and MeIQx, the subjects of this thesis. All these compounds are known or suspected carcinogens but the detailed mechanisms behind their carcinogenicity have not yet been fully examined. The aim of this thesis was to study genotoxic properties of these compounds using both in vitro and in vivo methods. Clastogenic effects of all five compounds were assessed with the flow cytometer-based micronucleus assay in vivo and for furan also with the micronucleus assay in vitro. DNA-damaging effects of HMF were studied using the comet assay. No induction of micronuclei was obtained after exposure to IQ, MeIQx or furan. Hence, it can be argued that non-genotoxic mechanisms are partly responsible for the carcinogenic properties of these compounds. PhIP, on the other hand, generated a clear response in the in vivo test. Comparing these result with previous results on acrylamide indicates that PhIP is much more potent. However, acrylamide probably poses a higher risk for humans as the intake is considerably higher. For HMF no effects were seen using the in vivo setup. To further investigate the influence of bioactivation of HMF by sulfotransferases (SULTs) the comet assay was performed in cell lines expressing different levels of SULT. However, no correlation between SULT-expression and DNA-damage was observed. Thus, the DNA-damaging effects found in our experimental setup is probably due to other factors than SULT mediated effects. Furthermore, in this thesis the effects of folic acid on chromosomal stability in healthy people were studied. A negative correlation was found between micronucleus frequency and folate status. The results gained within this thesis will hopefully contribute to the risk assessment of compounds present in our diet.
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Assessing the cyto-genotoxic impacts of un-neutralised and pH-neutralised acid mine drainage on the human breast cancer cell line, MCF-7Botha, Shirmone 12 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: The use of toxicity tests to evaluate the quality of streams affected by mixtures such as acid mine drainage (AMD), adds value to assessments whereby site-specific toxicological data may identify toxicants that pose a threat to humans. To successfully evaluate the risk of combined mixtures, an improved understanding of the individual components, their uptake, metabolism, excretion and mode of action is required. This study aimed to identify the extent of AMD toxicity in a dose dependant manner on the MCF-7 cell line. The first study site associated with gold mining was chosen as the Tweelopies Stream situated in the Gauteng province of South Africa. The AMD effluent (un-neutralised) contaminating the Tweelopies Stream had undergone pH-neutralisation using a reactor-bed limestone technology incorporating the use of both calcium carbonate (CaCO3) powder and limestone beds. The second study site, the Kromdraai River, is situated in the eMalahleni region of South Africa where a predominance of coal mining exists. The pH -neutralisation of the AMD (un-neutralised) contaminated Kromdraai River was performed using a caustic soda (NaOH) precipitation technique. This study demonstrated the rapid and effective application of the comet assay as a screening tool for AMD-associated DNA breakages in the human cell line, MCF-7. Moreover, the study analysed parameters of cellular survival, DNA fragmentation and variations in morphologies indicative of cellular death. Collectively, the cyto-genetic aberrations observed in the MCF-7 cells as a result of exposure to gold and coal mining associated AMD, confirms the urgency of incorporating high-throughput screening in ecological toxicity assessment to evaluate cellular damage at genetic levels in low dose exposures where detection might be missed. / AFRIKAANSE OPSOMMING: Die gebruik van toksisiteitstoetse om die gehalte van strome te evalueer wat geraak word deur mengsels soos suur mynwater (SM), gee waarde aan spesifieke toksikologiese data van gifstowwe wat 'n bedreiging vir die mens kan identifiseer. Om die risiko van gekombineerde mengsels en hul individuele komponente beter te begrip en suksesvol evalueer, is hul opname, metabolisme, uitskeiding en modus van aksie nodig. Hierdie studie het gepoog om die omvang van SM-toksisiteit in 'n dosis afhanklike wyse op die MCF-7-sellyn te identifiseer. Die eerste studie-area wat gekies is, hou verband met goudmyn-ontginning, en is die Tweelopiesspruit, geleë in die Gauteng-provinsie van Suid-Afrika. Die SM-uitvloeisel (on-geneutraliseerde) wat die Tweelopiesspruit besoedel, het pH-neutralisasie ondergaan met behulp van die integrasie van 'n reaktor-bed kalksorpsietegnologie wat gebruik maak van beide kalsiumkarbonaat (CaCO3) poeier en kalksteenbeddens. Die tweede studie-area, is die Kromdraairivier geleë in die eMalahleni-streek van Suid-Afrika, waar steenkoolontginning die oorheersende aktiwiteit is. Die pH-neutralisasie van die SM (on-geneutraliseerde) in die geval van die Kromdraairivier word met behulp van 'n bytsoda (NaOH) neerslag tegniek, uitgevoer. Hierdie studie het die komeet-toets getoon as 'n vinnige en doeltreffende toepassing vir SM-geassosieerde DNA-breekskade in die menslike sel lyn, MCF-7. Verder het die studie parameters van sellulêre oorlewing, DNA-fragmentasie en variasies in sel morfologieë wat ‘n aanduiding van sellulêre dood is, ontleed. Gesamentlik dui die resultate daarop dat die sitogenetiese afwykings wat in die MCF-7-selle waargeneem is, as 'n gevolg van blootstelling aan goud- en steenkool-geassosieerde SM is. Die studie het verder die dringendheid van die integrasie van hoë-deurset tegnologieë in ekologiese toksisiteitstoetse in selle wat genetiese skade mag ondergaan, na 'n lae dosis blootstelling waar opsporing dalk gemis word, ondersteun.
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Estudo da caracterização inflamatória e genotóxica em indivíduos expostos a alisantes capilares contendo formaldeídoBarbosa, Luana Aparecida January 2018 (has links)
Orientador: Marjorie de Assis Golim / Resumo: O formaldeído (FA) é um composto químico produzido mundialmente e economicamente importante devido às suas diversas utilizações comerciais e industriais. A exposição ocupacional ao FA ocorre em uma variedade de profissões, incluindo cabelereiros. No Brasil, a utilização e/ou a adição de FA à alisantes capilares é proibido pela ANVISA, entretanto vem sendo uma prática comum, pois mesmo não apresentando FA em sua composição, esses produtos contêm outras substâncias que durante o procedimento de alisamento, promove a liberação de FA, em forma de vapor, expondo epiderme, mucosas e, principalmente vias respiratórias. O FA é tóxico para o homem, podendo levar a diversas manifestações sistêmicas em diferentes graus, tanto em indivíduos expostos esporadicamente, a exemplo dos usuários dos alisantes capilares, quanto para profissionais frequentemente expostos, sendo este risco proporcional à concentração do FA e frequência de exposição. Estudos prévios têm demonstrado diversas alterações em indivíduos expostos ao FA comparados àqueles não expostos como: elevação dos níveis de ácido fórmico na urina (produto final da metabolização do FA), dano de DNA (presença de micronúcleos e fragmentação de DNA), influência em células do sistema imunológico (natural killer, linfócitos T e B), diminuição nos níveis de glutationa (enzima envolvida na metabolização de FA), entre outros. O presente estudo objetivou avaliar se ocorre desequilíbrio no padrão de citocinas pró/anti-inflamatórias (IL-1β, IL-... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Formaldehyde (FA) is an economically relevant chemical compound worldwide due to its various commercial and industrial applications. Occupational exposure to FA occurs in a variety of professions, including hair slytlist. In Brazil, the use and / or addition of FA to capillary straighteners is prohibited by ANVISA; however, it has been a common practice, since even without FA in its composition, these products contain other substances that during the straigntening procedure, promote release of FA, in the form of vapor, exposing epidermis, mucous membranes and mainly respiratory airways. FA is toxic to humans and can lead to different systemic manifestations to different degrees, both in individuals exposed sporadically, as in the case of users of hair straighteners, and for professionals who are frequently exposed, being this risk proportional to the concentration of FA and frequency of exposure. Previous studies have demonstrated several alterations in individuals exposed to FA compared to those not exposed such as: elevation of formic acid levels in urine (end product of FA metabolism), DNA damage (presence of micronucleus and DNA fragmentation), influence on cells of the immune system (natural killer, T and B lymphocytes), decrease in glutathione levels (enzyme involved in the metabolism of FA), among others. The aim of this is study was evaluate the imbalance in the pattern of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α and IL-12p70), serum chemokines (ILP... (Complete abstract click electronic access below) / Mestre
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Estudo do lodo gerado em reator biológico, pelo tratamento da água de produção do petróleo, no terminal marítimo Almirante Barroso, município de São Sebastião, SP visando sua disposição finalGuerra, Ricardo Consigliero [UNESP] 28 April 2009 (has links) (PDF)
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guerra_rc_dr_rcla.pdf: 1730338 bytes, checksum: 82956154d1c3e1fd309e6b0db1ba5492 (MD5) / Agência Nacional do Petróleo, Gás Natural e Biocombustíveis (ANP) / A atividade de recuperação do petróleo tem como característica a extração de uma parcela de água misturada ao óleo. Esta água deve ser separada do petróleo antes do processamento pelas refinarias, assim, originando um resíduo conhecido como Água de Produção. Os sistemas projetados para o tratamento deste efluente empregam diferentes métodos, visando atingir maior eficiência na separação dos contaminantes da água. Entretanto, os processos de tratamento geram subprodutos que necessitam de posterior manuseio e descarte. O presente estudo tem como objetivo avaliar o lodo produzido pela etapa de tratamento biológico da água de produção em uma estação piloto de tratamento de efluentes, instalada no Terminal Marítimo Almirante Barroso, localizado no município de São Sebastião, SP, visando a disposição final deste resíduo. Os seguintes procedimentos foram realizados para tal: classificação do resíduo de acordo com os critérios da norma técnica NBR 10.004 “Resíduos Sólidos: classificação”; avaliação da toxicidade do extrato solubilizado do lodo frente à germinação, crescimento da raiz e hipocótilo das espécies Barbarea verna Mill., Brassica. oleracea L., Cucumis. sativus L. e Eruca. sativa Mill.; avaliação da toxicidade e genotoxicidade frente ao sistema teste de Allium cepa L.; determinação da biodegradação de proporções crescentes do lodo adicionado ao solo inoculado com chorume, gerado em aterro sanitário. Os resultados indicam a classificação do lodo, de acordo com os ensaios de Lixiviação e Solubilização, como resíduo não inerte; efeito tóxico sobre a germinação de sementes nas menores concentrações de aplicação do extrato solubizado; concentração de inibição CI50 para o crescimento da raiz e hipocótilo variando entre 10,49 e 25,06% do extrato solubilizado; indução de efeitos tóxicos às células meristemáticas... / Among the oil extracted from petroleum production fields a great water volume is coproduced. This water must be eliminated prior to oil processing, the resulting wastewater is known as Produced water. Looking for greater treatment efficiency, different methods are coupled for this waste stream treatment. However, all treatment methods have its own byproducts to deal for. The present work objective is to evaluate the ultimate sludge disposal conditions from a pilot oil produced water biological treatment at Terminal Marítimo Almirante Barroso, located at São Sebastião, São Paulo State, Brazil. The following procedures wore developed in achieving this intent: NBR 10.004 waste classification procedures; germination and root/hypocotyl elongation sludge solubilization extract toxicity to Barbarea verna Mill., Brassica. oleracea L., Cucumis. sativus L. and Eruca. sativa Mill. plant species; Allium cepa L. test system toxicity and genotoxicity; sludge biodegradation at different soil application rates. Results indicate sludge waste classification as not inert; sludge solubilization extract toxic effect to seed germination at the lowest tested concentrations; root and hypocotyl elongation IC50 between 10,49 and 20,06% of sludge solubilization extract concentration; toxicity to Allium cepa meristematic cells by mitotic index reduction and cell death induction and; continuous but slow sludge biodegradation rate after microorganisms to salinity adaptation at the highest evaluated sludge application rates. These results lead to ultimate disposal need of a specific industrial landfill, with adequate environmental protection measures to harmful solubilization byproducts from this solid waste and potential toxic effects to exposed organisms.
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Avaliação do potencial citotóxico das lectinas de Canavalia ensiformis, Canavalia brasiliensis e Cratylia floribunda / Evaluation of the cytotoxic potential of lectins Canavalia ensiformis, Canavalia brasiliensis e Cratylia floribunda.Martins, Gláucia Veríssimo Faheina 10 June 2009 (has links)
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Previous issue date: 2009-06-10 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Lectins constitute a class of glycoproteins which are capable of binding carbohydrates
selectively and reversibly, distinguishing small structural differences in complex
oligosaccharides. Some studies have shown that binding of lectins to carbohydrate surface of
normal and tumor cells leads to various biological effects such as, cell proliferation in normal
lymphocytes and apoptosis in tumor cells. This study investigated the assessment of cytotoxic
lectins of legumes Canavalia ensiformis (ConA), Canavalia brasiliensis (Conbr) and Cratylia
floribunda (CFL) in normal, mouse peritoneal macrophage, and tumor cells. Initially the
cytotoxic activity of the lectins was evaluated by reduction of tetrazolium (MTT) salt assay
and measured the content of nucleic acids (CAN). ConA, Conbr and CFL not decreased the
viability of peritoneal macrophages, but showed to be cytotoxic for J774, MCF-7, Molt-4 and
HL-60 lineages. The MTT assay was more sensitive to the effects of lectins on cell viability
and ConA was the most cytotoxic, followed by Conbr and CFL. The IC50 values ranged from
around 10, 20 and 45μg/mL at ConA, Conbr and CFL respectively. The genotoxic potential of
lectins was also evaluated using the comet assay, showing that proteins had a high rate of
lesions in DNA from MCF-7, Molt-4 and H-60 cells, reaching a damage frequency exceeding
70% in concentration of 50 μg/mL for all lectins. The lectins caused morphological changes
as assessed by differential staining with ethidium bromide and acridine orange, characteristic
of apoptosis, and necrosis can be observed in higher lectin concentrations in tumor cell lines.
In tests that evaluated the apoptosis, ConA, Conbr and CFL caused internucleossomal
fragmentation, loss of membrane integrity which is characteristic of late apoptosis or necrosis,
and mitochondrial depolarization. It was concluded that ConA, Conbr and CFL exhibited
cytotoxicity to tumor cells causing cell death by apoptosis, therefore these proteins can be
considered as a class of molecules with antitumor potential. / Lectinas constituem uma classe de glicoproteínas que ligam-se reversivelmente e
seletivamente à carboidratos, sendo capazes de distinguir pequenas diferenças estruturais em
oligossacarídeos complexos. Estudos têm mostrado que a ligação de lectinas a carboidratos de
superfície de células normais e tumorais provoca vários efeitos biológicos, tais como,
proliferação celular em linfócitos normais e apoptose em células tumorais. Neste trabalho, foi
investigado a citotoxicidade das lectinas de plantas Canavalia ensiformis (ConA), Canavalia
brasiliensis (Conbr) e Cratylia floribunda (CFL), sobre linhagens de células normais e
tumorais. Inicialmente, a atividade citotóxica das lectinas foi avaliada pelos ensaios de
redução do sal de tetrazólio (MTT) e medida do conteúdo de ácidos nucléicos (CAN). As
lectinas ConA, Conbr e CFL não diminuíram a viabilidade de células normais (macrófagos
peritoneais), no entanto, mostraram-se citotóxicas para as linhagens tumorais J774, MCF-7,
MOLT-4 e HL-60. O ensaio de MTT foi o mais sensível aos efeitos das lectinas sobre a
viabilidade celular do que o ensaio de CAN, sendo ConA a lectina mais citotóxica, seguida de
Conbr e CFL. Os valores de CI50 variaram em torno de 10, 20 e 45μg/mL, para ConA, Conbr
e CFL repectivamente. O potencial genotóxico das lectinas também foi avaliado usando o
teste do cometa, mostrando que essas proteínas produziram alto índice de lesões do DNA nas
células MCF-7, MOLT-4 e HL-60, atingindo uma freqüência de danos superior a 70% na
concentração de 50μg/mL para todas as lectinas. Nessas mesmas linhagens tumorais, as
lectinas também causaram alterações morfológicas, avaliadas por coloração diferencial com
brometo de etídeo e laranja de acridina, características de apoptose, sendo possível observar
necrose nas concentrações mais elevadas. Nos ensaios que avaliaram apoptose, as lectinas
ConA, Conbr e CFL causaram fragmentação internucleossomal e perda da integridade de
membrana, nas maiores concentrações testadas e despolarização mitocondrial. Concluiu-se
que as lectinas ConA, Conbr e CFL são citotóxicas para as células tumorais causando morte
celular por apoptose, podendo ser consideradas como uma classe de moléculas com elevado
potencial antitumoral.
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