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Item Estratégias computacionais como métodos alternativos para avaliação da sensibilização cutânea(Universidade Federal de Goiás, 2017-05-12) Alves, Vinícius de Medeiros; Tropsha, Alexander; Muratov, Eugene; http://lattes.cnpq.br/9372290911831306; Andrade, Carolina Horta; http://lattes.cnpq.br/2018317447324228; Andrade, Carolina Horta; Oliveira, Gisele Augusto Rodrigues de; Ferreira, Márcia Miguel Castro; Costa, Fernando Batista da; Nascimento, Paulo Gustavo Barboni DantasIntroduction: Skin sensitization is a major environmental and human health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. Skin sensitization is commonly evaluated using structural alerts. However, there has been a growing concern that alerts disproportionally flag too many chemicals as toxic, which questions their reliability as toxicity markers. The main goal of this thesis was to develop and apply new cheminformatics methods to predict skin sensitization of chemical compounds that lack experimental data. Methodology: It has been compiled, curated, analyzed, and compared the available human data and the murine (performed in mice) animal model data, named LLNA (local lymph node assay). Using these data, it was developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. It was developed a freely accessible web-based application for the identification of potential skin sensitizers. In addition, it was demonstrated that contrary to the common perception of QSAR models as “black boxes” they can be used to identify statistically significant chemical substructures (QSAR-based alerts) that influence toxicity. Results and discussion: The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance. We have succeeded to develop predictive QSAR models of all available human data with the external correct classification rate of 71%. A consensus model integrating concordant QSAR predictions and LLNA results afforded a higher correct classification rate of 82% but at the expense of the reduced external dataset coverage (52 %). We used the developed QSAR models for virtual screening of CosIng database and identified 1,061 putative skin sensitizers; for seventeen of these compounds, we found published evidence of their skin sensitization effects. The developed Pred-Skin web app (http://www.labmol.com.br/predskin/) is based on binary QSAR models of human (109 compounds) and LLNA (515 compounds) data with good external correct classification rate (70-81% and 72-84%, respectively). It is also included a multiclass potency model based on LLNA data (accuracy ranging between 73-76%). Conclusions: Models reported herein provide more accurate alternative to LLNA testing for human skin sensitization assessment across diverse chemical data. In addition, they can also be used to guide the structural optimization of toxic compounds to reduce their skin sensitization potential. The Pred-Skin web app is a fast, reliable, and user-friendly tool for early assessment of chemically-induced skin sensitization. A new approach that synergistically integrates structural alerts and rigorously validated QSAR models for a more transparent and accurate safety assessment of new chemicals was also proposed.Item Estratégia associando métodos substitutivos à experimentação animal para avaliação da toxicidade ocular, categorização e rotulagem de formulações agrotóxicas comercializadas no Brasil(Universidade Federal de Goiás, 2018-11-20) Andrade, Wanessa Machado; Valadares, Marize Campos; http://lattes.cnpq.br/615775524316701; Valadares, Marize Campos; Costa, Renata Mazaro; Paula, José Realino de; Gomes, Thaisângela Rodrigues Lopes e Silva; Gomes, Marcelo do NascimentoIntroduction: Different strategies for categorization and labeling (C & L) of ingredients and finished products have been considered by the Regulatory Agencies. Regarding agrochemical formulations, the lack of global harmonization for C & L is the main problem for the implementation of substitute methods. On the other hand, in vitro and ex vivo methods are successfully adopted to assess the potential toxicity of chemicals. The standard Bovine Cornea Opacity and Permeability (BCOP) test provides information on permeability and opacity, but histomorphometric analysis of the cornea has been recommended as an additional parameter to better categorize irritant products for the eyes. Objective: To suggest a platform, associating in vitro and ex vivo methods, based on mechanistic parameters of ocular toxicity evaluation for C & L of agrochemical formulations commercialized in Brazil. As well as measuring the depth of bovine corneal injury induced by eye irritants from all categories of the United Nations Globally Harmonized System for Classification and Labeling of Chemicals (UN GHS) and associating it with the severity of the damage. Material and Methods: For the platform, 86 agrochemical formulations of different categories of ocular toxicity were selected in the categorization system of the National Agency of Sanitary Surveillance (ANVISA). First, the potential for ocular toxicity was assessed through the cytotoxicity endpoint using the Short Time Exposure (STE) test. In the second step, the non-classified samples and those classified as non-irritating by the STE were evaluated for the opacity, permeability and histopathological changes of the cornea through the BCOP test. The third step was to evaluate the potential for induction of vascular damage through coagulation and hemorrhage outcomes using the Hen egg Chorion-allantoic Membrane test (HET-CAM). For proficiency, 12 substances belonging to the categories UN GHS (Category 1, 2A and 2B) were selected. The BCOP assay was performed to determine the in vitro irritation index (IVIS). After the fluorescein permeability assay, the corneas used were sectioned in a 5 μm thick cryostat, stained with Hoechst 33342 and analyzed by fluorescence microscopy. Five measurements of depth of permeation of fluorescein were obtained in relation to the total thickness of the epithelium. Results and Discussion: From the palataform, of the 86 formulations of agrochemicals, after the STE test, 68 were highly cytotoxic and were categorized as Category 1 by UN GHS; 13 not classified and 5 non-irritating. These 18 agrochemical formulations were evaluated at the second level of the platform by the BCOP test followed by histopathological analysis, and the irritation profile of these agrochemical formulations was confirmed by the HET-CAM assay. Thus, 7 presented opacity, damage to the cornea in the epithelial portion and in the stroma, coagulation and hemorrhage, and therefore were categorized in Category 2 A of the UN GHS. 11 caused only coagulation and hemorrhage and were categorized into Category 2 B of the UN GHS. In the proficiency, the results showed that the permeation depth of fluorescein was directly proportional to the degree of irritation of the substances tested. Conclusion: Since C&L of agrochemical formulations in Brazil is not based on the UN GHS, this tier platform could be useful to harmonize the categorization of agrochemical formulations in Brazil, providing regulatory subsidies for ANVISA. As well as, refinement of BCOP by analysis of lesion depth through epithelial permeation of fluorescein can be considered a useful quantitative parameter to better categorize eye irritants.Item Alternativas tecnológicas para aumentar a biodisponibilidade de anti-inflamatórios: gel mucoadesivo termorreversível e aplicação de sílica mesoporosa para amorfização(Universidade Federal de Goiás, 2020-03-20) Antonino, Rayane Santa Cruz Martins de Queiroz; Nascimento, Thais Leite; http://lattes.cnpq.br/4065607913504134; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; Alonso, Christian Gonçalves; Gil, Eric de Souza; Silva, Luís Antônio Dantas; Brito, Wesley de AlmeidaImproving the therapeutic response of drugs is one of the major goals of pharmaceutical technology. This large area of research and development uses multidisciplinary technologies and knowledge aimed at optimizing drug delivery systems. It seeks, for example, to reduce side effects with the application of nanoparticulate systems (Chung et al., 2019), to improve the reach of drugs in the central nervous system (CNS) through new delivery and administration systems (Qureshi et al., 2019), increase the delivery and therapeutic action of drugs by promoting longer drug contact time at the site of action, such as the development of mucoadhesive formulations for the treatment of inflamed mucous membranes (Léber et al., 2019). It also seeks to increase the bioavailability of drugs with low aqueous solubility by obtaining the amorphous form of the drug either through porous adsorbent systems, such as mesoporous silicas, but also to increase the stability of the amorphous form in relation to the storage time (Zůza et al., 2019). The search for better therapeutic efficacy of drugs was the main motivation for this research, using different technologies for the development of formulations with different therapeutic objectives and targets. The first part of this research aimed to develop a mucoadhesive in situ thermoreversible gel, capturing a corticosteroid for the treatment of mucous regions with inflammation. This first part produced three scientific publications that are organized as the first two chapters of this document and an annex. The second part of the research aimed to investigate the adsorbent role of mesoporous silica in two different drugs in terms of the tendency to crystallization, aiming beyond bioavailability to increase the physical stability of the systems and the impact of the drugs on the storage of the systems. Through the development of this study, a scientific article was produced presented in the third and last chapter of this document. In summary, the research developed during the PhD period is organized in two parts, in which: Chapter 01 - This chapter has mucoadhesion as its central theme, and constitutes a review of the literature published as a chapter in the book “Sciences applied to health products”, by the publisher of the State University of Goiás in 2019, ISBN 978-85-5582- 060-1 (annex 3). Strategies for the development of new mucoadhesive pharmaceutical forms, mucus and its function in the human body, the theories that analyze mucoadhesion, the mucoadhesive formulations already available and the techniques and assays used to quantify mucoadhesion were covered in this chapter. Chapter 02 - In this chapter we describe the development and characterization in vitro / in vivo of a mucoadhesive in situ gelling formulation using poloxamer 407 (Pluronic® F 127), a thermoreversible polymer, capturing budesonide (BUD), a potent corticosteroid used for treatment of a wide range of inflammatory diseases, including those that affect mucous membranes, such as in the gastrointestinal tract. This chapter was published in 2019 as an original article in the Journal of Controlled Release, entitled Thermoreversible mucoadhesive polymer-drug dispersion for sustained local delivery of budesonide to treat inflammatory disorders of the GI tract (appendix 4). The term with the approval by the ethics committee for the use of animals is attached (annex 1). Another publication, referring to oral pharmaceutical compositions of corticosteroids that gel in situ, was the production of a patent (annex 2). Patent filed and published at the United States Patent and Trademark Office, with international application under Patent Cooperation Treaty (PCT), WO 2018/193423 A1, 2018. This patent is the result of a partnership between the University and a pharmaceutical industry, Ferring Pharmaceuticals, established for the development of mucoadhesive pharmaceutical formulations. In turn, depending on the second part, which deals with technologies aimed at optimizing bioavailability and promoting greater stability using porous adsorbent systems, we have chapter 3. Chapter 03 - In this chapter, a method has been described to determine the monolayer loading capacity (MLC) of naproxen, a weak drug to amorphize, in mesoporous silica (MS). MS can be used as a carrier to stabilize the amorphous form of a drug. In addition, the impact of monolayer, pore filling and excess, on the physical stability of this system was studied and compared to ibuprofen, a strong drug to amorphize. Finally, we investigated the impact of drug loading on storage below and above the glass transition temperature (Tg), in particular with a focus on the amorphous (in) stability of the confined drug, for both drugs. Using Theoretical Functional Density Theory (DFT) and Molecular Dynamics ab initio (AIMD), the binding energies for the monolayer suggest that the monolayer is thermodynamically more favorable than the crystalline form, while the confined amorphous form is thermodynamically less favorable. This chapter was published as an original article in the International Journal of Pharmaceutics: X, in 2019 (Annex 5).Item Desenvolvimento de métodos eletroanalíticos para avaliação da capacidade antioxidante(Universidade Federal de Goiás, 2016-03-28) Benjamin, Stephen Rathinaraj; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Gil, Eric de Souza; Marreto, Ricardo Neves; Ghedini, Paulo César; Colmati Junior, Flavio; Oliveira, Severino Carlos Bezerra deThis study investigated the antioxidant activity using biosensors based on carbon paste electrode (CPE) modified with crude extract of laccase (Pycnoporus sanguineus, activity 2019 U L-1) in different compositions. The biosensor consists of carbon nanotubes activated with DNA (CPEL-DNA: CN) showed the best sensitivity level, 0.0549 μA / μM and 1.2 uM detection limit (LOD) in the concentration range of 20-140 μM of rutin. This biosensor showed excellent stability over 10 days and reproducibility (RSD <5%). This biosensor was used to determine the total amount of phenol in coffee samples (expressed by the equivalent rutin) using electroanalytical technique. For the evaluation of its detection capability, the results were compared with other electroanalytical techniques using analytical basis as samples of commercial coffee from different countries. The CPL-DNA: CN was used to determine the total amount of phenol in coffee samples (expressed by the equivalent rutin). Thus, it was possible to propose the CPL as an analytical tool for the detection of phenols. In this research, we developed several studies using different CPE to investigate the antioxidant natural product profile such as coffee samples, dry extracts of acerola, obtained by cyclic voltammetry (CV),) differential pulse voltammetry (DPV) and square wave voltammetry (SWV), which allowed to conclude classes of antioxidants present in the samples. The quantitative determination of these compounds was performed using the standard addition method by differential pulse voltammetry and electrochemical index (EI) has been proposed for estimating the oxidizing potential between different samples. Carbon paste electrode was also investigated using the different quality control samples commercialized produced from acerola employing DPV for the quantification of ascorbic acid (AA) in all samples, where the limit of detection (LOD) and limit of quantification (LOQ) was 0.31 and 0.96 μM and with excellent recovery between 97.4 to 102.2% The DPPH tests were used to compare the antioxidant activity in coffee and acerola samples. The Folin-Ciocalteu method was used to estimate the antioxidant activity of rutin from coffee samples. These methods proposed had advantages such as simplicity of sample preparation and the speed of the analysis of antioxidant capacity.Item Estudo da porosidade de comprimidos de Cloridrato de Propranolol a partir do processamento de imagens de microscopia eletrônica de varredura por elétrons retroespalhados(Universidade Federal de Goiás, 2021-12-07) Camargo, Henrique Santiago de; Gonçalves, Cristhiane; http://lattes.cnpq.br/3935775322457150; Conceição, Edemilson Cardoso da; http://lattes.cnpq.br/7193007113950510; Conceição, Edemilson Cardoso da; Silva Júnior, Arnóbio Antônio da; Marreto, Ricardo Neves; Soares, Luiz Alberto Lira; Costa, Roseane Maria RibeiroThe porosity of solid pharmaceutical forms plays a fundamental role in the drug's disintegration the dosage form and consequently in the bioavailability of the active, ensuring its therapeutic action in the desired time, in addition, the porosity influences other aspects such as the mechanical strength of the tablet. Understanding and having methods to study and manipulate the porosity of pills is a crucial factor to have a quality pharmaceutical form. Objectives: Thus, the objective of this work was to study the porosity of Propranolol Hydrochloride tablets from 5 (five) laboratories by processing images obtained in a scanning electron microscope and to correlate these results with dissolution studies and the composition of each tablet. Methodology: The tablets were characterized by thermal techniques, Scanning Differential Calorimetry (DSC) and Thermogravimetry (TGA), and were submitted to hardness, friability and dissolution tests. Electron backscatter SEM images were obtained and processed in order to obtain an estimate of the surface and fracture porosity. Results and discussion: The tablets showed variations in their internal porosity and fracture, all had friability and hardness data that meet current regulatory standards, for the dissolution study, all laboratories presented data within the acceptance criteria of regulatory standards. Conclusions: Through the processing of scanning electron microscopy images obtained from propranolol hydrochloride tablets, it was possible to estimate the surface and fracture porosity of these tablets, thus, this technique is shown as an alternative for the study of the porosity of solid dosage forms (tablets) , being possible to observe the morphology and characteristics of the pores.Item Eletroanálise aplicada a ensaios de compatibilidade e estabilidade de fármacos(Universidade Federal de Goiás, 2020-08-31) Carvalho, Murilo Ferreira de; Garcia, Luane Ferreira; http://lattes.cnpq.br/6624146379323596; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Garcia, Luane Ferreira; Leite, Karla Carneiro de Siqueira; Alecrim, Morgana Fernandes; Marreto, Ricardo Neves; Oliveira, Thiago Levi SilvaIntroduction: The pharmaceutical industry faces a major challenge to improve the solubility of some active ingredients. Carvedilol (CRV) is the drug of therapeutic choice in cardiovascular diseases. CRV presents low water solubility and low bioavaliability. Several researches were performed in order to increase the oral bioavailability, where selfemulsifying appeared as viable alternatives. Objective: The objective of this work was to evaluate interactions between CRV and its excipients, detecting the oxidative potential of these substances, thus, providing predictive data for the oxidation that may affect the stability and bioavailability of the drug system. Methodology: In the carbon pastes preparation were used 70 mg (graphite) and 30 mg (oil). Six excipients, oleic acid, canola, capmul, safflower, sesame and Plurol isoestearique. The following proportions were used in the making of the paste: 30:0, 20:10, 15:15, 10:20 and 0:30 of liquid excipient (sample): mineral oil (mg:mg) and 1.5:68.5, 3:67 and 7:63 of solid excipient (sample): graphite (mg:mg). CRV was incorporated in the oil moiety for solubilization and after used in solidstate analysis in the carbon paste. The techniques used were cyclic voltammetry, differential pulse voltammetry and electrochemical impedance spectroscopy. Results and Discussions: The Isostearique Plurol® was found to be electro-active in the studied potential, however, this oil oxidizes in different potentials from CRV. The results show that Isostearique Plurol®, liquid excipient, isoestearique acid and the solid excipient presented the greatest variations of anodic potential and were considered the best excipients for the CRV formulation. CRV presented higher stability at room temperature (25 ºC), whereas, it presented higher stability at 50 ºC when mixed with 7% estearique acid. Conclusions: Evidences of incompatibility were not found, relative to the increase of oxidation vulnerability, when in the presence of these excipients. The employment of electroanalysis for CRV compatibility studies show promising viability.Item Liberação controlada por magnetohipertermia de doxorrubicina em magnetolipossomas direcionados ao receptor de superfície celular folato(Universidade Federal de Goiás, 2018-10-08) Cintra, Emilio Ramos; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; Senna, Elenara Mara Teixeira Lemos; Bakuzis, Andris Figueiroa; Mendanha Neto, Sebastião Antônio; Souza, Ana Luiza Ribeiro deDoxorubicin is one of the most commonly used antineoplastic agents in the treatment of solid tumors, such as soft tissue tumors and osteosarcomas. However, the high occurrence of cardiotoxic side effects due to its prolonged use causes damages to adherence and therapeutic efficacy. In order to diminish the side effects, during the present research magnetoliposomes with magnetic nanoparticles coencapsulating doxorubicin were developed in their aqueous interior vectors for the folate receptor aiming controlled release by magnetohypertermia. This work was divided in four stages: optimization and validation of analytical methodology to quantify doxorubicin; synthesis of magnetic fluids with different layers of coverage; development of magnetoliposomes coencapsulating doxorubicin with and without vectorization in order to compare if the effectiveness of the vectorization and in vitro studies for the chemotherapy effectiveness of the liposomal formulation against the B16F10 cell was verified. The magnetoliposomes were prepared by the lipid film hydration method followed by extrusion and the physical-chemical and morphological results showed that the liposomal formulations have an average size close to 150 nm. The magnetic particles have an average size of 13 nm, high saturation magnetization, superparamagnetic behavior and are composed by manganese ferrite with different layers of coverings. The magnetoliposomes were able to generate heat through magnetohyperthermia with alternating magnetic field. The liposomal formulation of magnetoliposome with vectorized doxorubicin to the folate receptor showed higher antitumor activity when compared to formulation without vectorization. When compared to hyperthermia test, it showed that the increase in temperature is linked to a better effect with the drug for a greater cytotoxic effect. These results suggest, therefore, that the obtaining of a liposomal formulation towards the antitumor activity represents a promising alternative associated to the codelivery chemotherapeutic and magnetic nanoparticles directed at the tumor tissue.Item Estudo clínico de segurança não controlado do uso de drogas vegetais em pacientes atendidos em um ambulatório público de fitoterapia(Universidade Federal de Goiás, 2020-03-02) Cirilo, Hérica Núbia Cardoso; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Bara, Maria Teresa Freitas; http://lattes.cnpq.br/3914164125498267; Bara, Maria Teresa Freitas; Santos, Thalyta Renata Araújo; Alves, Suzana Ferreira; Paula, José Realino de; Soares, Amanda QueirozIntroduction: The use of medicinal plants has been increasing worldwide, so as the reports of adverse events (AE) related to them. The World Health Organization Toxicity Grading Scale for Determining the Severity of Adverse Events (WHO-TGS) establishes the toxicity criteria for laboratory tests in clinical trials with humans, allowing to evaluate the safety of a treatment. Additionally, the Naranjo Algorithm establishes the causal relationship between the observed AE and the product under investigation. Main objective: To verify the safety of the use of 12 medicinal plants in subjects attended at a phytotherapy outpatient clinic of the Unified Health System, using the WHO-TGS and the Naranjo Algorithm. Methodology: This is an open and prospective uncontrolled "before and after" clinical study. The selected participants were submitted to laboratory tests before and after 30 days of use of the prescribed medicinal plants. The results were analyzed according to WHO-TGS. The medicinal plants were suspended for 30 days in those who presented laboratory alterations indicative of toxicity, the exams were repeated, and the results analyzed. The observed AE had their causality established through the Naranjo Algorithm. Results and discussion: There was a higher prevalence of female individuals, mean age of 46 years, graduated level, who sought the health service to treat depression and anxiety. The majority of them are non-users of tobacco and illicit drugs, while half regularly consume alcoholic beverages, and are characterized mainly by the daily use of medicinal plants, plant drugs and herbal medicines for therapeutic purposes. 42 subjects were selected to use the medicinal plants prescribed for 30 days, of which 17 (40.5%) did not present AE, whereas 25 (59.5%) presented Grade 1 toxicity (GT1) AE, mainly the increase in amylase concentration (n=9). After the suspension of the medicinal plants use, 14 participants continued to present GT1 AE, mainly hypomagnesemia and hematuria. The Naranjo Algorithm established a possible causal relationship between hyperamylasemia; hypomagnesemia; hematuria; AST, ALT and GGT increase; hyperglycemia; hypocalcemia; hypercalcemia; thrombocytopenia; prothrombin time elevation; proteinuria and the medicinal plants used. Conclusions: The results obtained revealed the socio-demographic, clinical, life habits and pharmacotherapeutic profile of the participants. They demonstrated the occurrence of AE after the use of Bauhinia forficata, Curcuma longa, Cynara scolymus, Equisetum arvense, Erythrina mulungu, Matricaria chamomilla, Melissa officinalis, Passiflora edulis, Phyllanthus niruri e Zingiber officinale, evidencing a possible causal relationship to the use of these medicinal plants. Such relationship corresponds to a low level of probability of occurrence of an AE by the products under investigation, that is, it demonstrates safety in the use of these medicinal plants, in the experimental conditions employed.Item Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos(Universidade Federal de Goiás, 2019-01-11) Cordeiro, Kelly Carolina Frauzino Araújo; Oliveira, Valéria de; http://lattes.cnpq.br/6300240031300604; Oliveira, Valéria de; Silva, Lorena Maione; Silva, Maria do Rosário Rodrigues; Cunha, Carla Rosane Mendanha da; Terezan, Ana PaulaHesperetin belongs to the flavanone class of flavonoids, its human metabolites (i.e. hesperetin-3’-sulfate, hesperetin-7-sulfate, hesperetin-3’-glucoronide and hesperetin -7-glucoronide), and its glycosylated derivative has potential pharmacological properties. The use of microorganisms, such as filamentous fungi, is an alternative in derivatives production and a useful tool in scale up process. Therefore, the goal of the work was to apply and evaluate different bioprocesses for the production of active metabolites of hesperetin by fungal biotransformation. Application of microbioreactors, use of different carbon sources, substrate concentration, fungal immobilization and monitored reactions by liquid chromatography coupled to high resolution mass spectrometry were some of evaluated bioprocesses. From 15 tested fungi, 12 strains were able to biotransform hesperetin. In silico metabolite prediction modeling with MetaPrint 2D software, indicated positions 7 e 3’ as energetically favored for glycosylation, glucuronidation and sulfation reactions. Mortierella isabellina NRRL 1757 and Beauveria bassiana ATCC 7159 produced only sulfate and glucuronide hesperitins, respectively. Cunninghamella echinulata ATCC 9244 strain produced the glycosylated metabolite. A morphological difference was observed in C. echinulata ATCC 9245 growth using different microbioreactors. Square microwell plates resulted in an amorphous growth whereas round bottom microwell plates favored pellets growth. The latest, with volume well of 2.2 ml led to a higher content of fungi and 48 hours was found to be the ideal time to substract addition. All four strands of Cunninghamella tested for biotransformation in a microscale were able to produce the glycosylated metabolite. Analyzes of the biotransformation kinetics by HPLC-HRMS showed that Cunninghamella echinulata ATCC 9244 produced four microplate derivatives: eriodictiol, sulfated hesperetin, glycosylated hesperetin and glucuronidated hesperetin. Such analyzes have also shown that high concentrations of hesperetin inhibit these derivatives formation. Stainless steel sponge proved to be efficient for Cunninghamella echinulata and Cunninghamella elegans strains immobilization. The immobilization process achieved biofilm in 48 hours. ESI-IT-MS and ESI-IT-MS/MS analysis indicated production of a glycosylated and a hydroxylated-sulfonated derivative. Thus, studies demonstrated that different bioprocesses can be applied to optimize scale up reactions and produce hesperetin derivatives using filamentous fungiItem Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele(Universidade Federal de Goiás, 2018-04-11) Dias, Marina França; Silva Júnior, Armando da Cunha; http://lattes.cnpq.br/8278273904187275; Lima, Eliana Martins; Serakides, Rogéria; Barros, André Luís Branco de; Pereira, Bruno GonçalvesSkin cancer has the highest incidence among all types of neoplasms and the tendency is the increasing number of new cases in next decades, wich makes necessary new modalities and treatment options. Chemotherapeutic agent imiquimod is used in treatment of disease, but the high occurrence of local and systemic adverse effects associated with its use as well as its low skin permeation impair adherence and therapeutical effectiveness, respectively. The aim of the present work was evaluate the antitumor activity of nanocapsules imiquimod-loaded compared to its commercial product in murine model of skin cancer. Polymeric nanocapsules containing imiquimod, in the absence and presence of chitosan coating, were obtained by the precipitation of preformed polymer technique and characterized by encapsulation efficiency, size, zeta potential, pH, morphology (transmission electron microscopy and scanning), optical scanning spectrophotometry and in vitro release through dialysis membrane in pH 5.6 buffer. Presence of chemical interactions between formulation components was evaluated by thermogravimetric analysis and infrared spectroscopy. Detection of crystalline structures was performed by X-ray diffractometry. The nanocapsules and commercial imiquimod formulation antiagiogenic activity was determined in a chicken embryo chorioallantoic membrane model. Cutaneous permeation of nanocapsules imiquimod-loaded and commercial imiquimod was determined in Swiss albino mice. The chemopreventive activity of colloidal dispersions and the commercial imiquimod was evaluated through the tumoral inhibition promoted by these treatments in a multi- stage model of chemical carcinogenesis in Swiss mice. Encapsulation efficiency, mean diameter, zeta potential and pH of uncoated nanocapsules imiquimod-loaded were 92.5% ± 0.4; 249 ± 22.4 nm; -40.1 mV ± 3.7 and 5.4 ± 0.01 respectively, whereas for nanocapsules with cationic coating the parameters found were: 88.6 ± 2.3%; 287.0 ± 12.6 nm; + 11.3 ± 0.5 mV and 3.7 ± 0.0, respectively. The formulations morphology obtained by scanning and transmission electron microscopy images confirmed the presence of nanocapsules. In the stability analysis by optical scanning spectrophotometry (Turbiscan), all dispersions obtained a backscattering variation less than 2% over 5 weeks and were considered stable. In the in vitro release assay, imiquimod-loaded nanoparticles obtained slower release of the drug compared to free and commercial imiquimod. There were chemical interactions between chitosan and other formulation components evaluated by thermogravimetric and infrared studies. No crystalline structure was detected by the X-ray diffraction technique for the coated and uncoated imiquimod formulation. The dispersion of nanocapsules containing imiquimod presented antiangiogenic activity superior than commercial formulation in chicken embryo chorioallantoic membrane model. Nanocapsules containing imiquimod both uncoated and coated with chitosan presented cutaneous permeation in deep layers of the skin and inhibition in the chemically induced carcinogenicity process superior than tumor control group and groups treated with placebo nanoparticles while the commercial formulation presented retention of the drug in superficial layers of the skin and did not obtain a statistically significant reduction in the number of papillomas formed compared to the carcinogenic control. These results allow to conclude, therefore, that stable nanocarreadores were obtained and the chemopreventive activity and the antiangiogenic effect of these systems represent a promising alternative for the treatment of cutaneous neoplasias.Item Estudo ecotoxicológico de corante têxtil e remediação por Fenton e Fenton-like(Universidade Federal de Goiás, 2018-06-18) Fernandes, Neemias Cintra; Marreto, Ricardo Neves; http://lattes.cnpq.br/6127043775208484; Marreto, Ricardo Neves; Costa, Orlene Silva da; Oliveira, Gisele Augusto Rodrigues de; Cunha Filho, Marcílio Sérgio Soares da; Brito, Núbia Natália deAzo dyes represent the most important class of textile dyes, being widely used in the pharmaceutical and food industry. These molecules are present in domestic and industrial wastewater, and are resistant to conventional effluent treatment eventually producing more toxic products than the original dyes. Advanced oxidative processes (AOPs) have been implemented in order to decompose or mineralize substances that are difficult to treat, reducing their toxicity and the inherent risks of releasing pollutants into the environment. Objective: To study the ecotoxicity and optimize the operational conditions in the decomposition of textile azo dye DR343 using Fenton and Fenton-like reactions. Method: Oxidative processes were studied using the factorial design Box-Behnken Design (BBD), and the optimization of the reaction conditions was performed by applying the desirability function. The pH of the medium, the reaction time, the concentrations of iron [Fe 2+ ] (Fenton) and [Fe 3+ ] (Fenton-like) as well as the oxidizing agent [H 2 O 2 ] were used as independent variables in the planning. The responses studied were the removal of DR343, the concentration of residual hydrogen peroxide [H 2 O 2residual ] and the mortality of Artemia salina. The toxicity of the untreated dye was evaluated in different organisms (lettuce seeds, Artemia salina and zebrafish embryos). Samples treated under optimal conditions were submitted to the same protocols. Results: The dye removal was in the range of 5.8% to 100%, being affected only by the concentration of catalyst [Fe 2+ /Fe 3+ ] in both processes. On the other hand, the process time had a significant effect on the mortality of A. salina in samples submitted to the Fenton process, which suggests formation of toxic oxidation byproducts at the beginning of the process, followed by the mineralization of the samples. Optimum conditions for the Fenton reaction included [Fe 2+ ] of 0.33 mmol.L -1 and [H 2 O 2 ] of 4.50 mmol.L -1 . Under these conditions, 100% of the dye decomposition was observed in 16.1 minutes. On the other hand, the optimal conditions of the Fenton-like process included [Fe 3 + ] of 0.25 mmol.L -1 and [H 2 O 2 ] of 0.54 mmol.L -1 . Under these conditions total dye decomposition was observed in only 9.2 minutes. No [H 2 O 2residual ] was detected in both optimized processes. No significant phytotoxic effects were observed on the untreated dye dispersions, nor after treatment in both procedures. In the case of the A. salina assays, differences between the two processes were observed. Samples treated by Fenton-like did not show significant toxicity, whereas the Fenton process induced significant mortality for this organism. Samples treated under optimal conditions, from both methods, did not induce lethal or sublethal effects on zebrafish embryos. Total organic carbon reduction of 52.0% and 34.8% was observed for Fenton and Fenton-like, respectively. Conclusion: Both the studied processes can be successfully used to decompose the DR343 dye in water, however, the Fenton reaction, despite obtaining better mineralization rates, produced more toxic by-products when compared to the Fenton-like process. The untreated dye did not show phytotoxicity, nor did it generate significant effects on zebrafish embryos.Item Biossorção de micropoluentes em fibra de sabugo de milho e detecção analítica usando fluorescência de raio x, espectroscopia Raman e análise quimiométrica(Universidade Federal de Goiás, 2021-04-07) Golveia, Jhéssica Cavalcante de Souza; Schimidt, Fernando; http://lattes.cnpq.br/1884442831412446; Santiago, Mariângela Fontes; http://lattes.cnpq.br/7143224488081563; Col, José Augusto da; Zang, Warde Antonieta da Fonseca; Morais, Mariana Cristina de; Sanches, Renato; Schimidt, FernandoThe presence of micro-pollutants in the waters has led to growing concern due to the impact on human health. Among the most important molecules is Bisphenol-A (BPA), pesticides, hormones and dyes. On the other hand, micro-pollutant removal processes that make use of agro-industrial waste have aroused the interest of researchers. This is because the accumulation of lignocellulosic materials is also an environmental problem. The adsorption capacity was tested using the molecules BPA, diuron, cyproterone acetate, caffeine, erythrosine red and tartrazine yellow. The detection of these pollutants requires the use of sensitive and easy-to-handle techniques. In this context, the X-ray Fluorescence (FRX) and Raman spectroscopic methods are highlighted.The objective of this work is to use corncob agroindustrial residue (CC) as an adsorbent in the removal of micropollutants of aqueous matrix and detect them using FRX and Raman Spectroscopy. The values was treated using Chemoface Software and PLS (Partial Least Square) Model of calibration. The adsorption studies were carried out in reaction media containing the ground vegetable fiber and different concentrations of molecules, as well as at different pHs. Isotherms models and kinetic models were evaluated. The results showed that CC is a potent adsorbent in aqueous solution, leading to about 90% of removal for BPA. The adsorption kinetics followed the pseudo-second order model and isotherm that best suited the Lagmuir model, and the maximum adsorption capacity was 51.25 mg per gram of adsorbent fiber, after 20 minutes of contact. The chemometric analyze showed hat PLS model allows to determine a calibration model capable to reach high values of R2 and low values of error. The thermogravimetric analysis allowed to conclude that it is a material resistant to high temperatures, due to the presence of considerable amount of lignin. Finally, the best results of BPA removal efficiency by CC compared to activated carbon corroborate its high biosorption capacity.Item Planejamento, síntese guiada por QSAR, avaliação biológica e modelagem molecular de chalconas com atividade antituberculose(Universidade Federal de Goiás, 2017-04-06) Gomes, Marcelo do Nascimento; Oliveira, Guilherme Roberto de; http://lattes.cnpq.br/8239498431579015; Andrade, Carolina Horta; http://lattes.cnpq.br/2018317447324228; Andrade, Carolina Horta; Emery, Flávio da Silva; Lião, Luciano Morais; Romeiro, Luiz Antônio Soares; Oliveira, Valéria deIn view of the current panorama of tuberculosis (TB) pandemic in the world, aggravated by co-infection with the HIV virus and the emergence of resistant strains of Mycobacterium tuberculosis (M. tb.), The research and discovery of new Anti-TB drugs. The present work aimed at the planning, synthesis and biological evaluation of new compounds with anti-TB activity, candidates for TB drugs. Structure and activity relationship (SAR) studies were developed using Matched Pair Molecular Analysis (MMPA) and binary models of quantitative relations between structure and activity (QSAR) using a combination of molecular fingerprints and machine learning methods. Bioisosteric replacement were proposed to plan new aryl and heteroaryl chalcones using the information obtained from SAR and QSAR analyses. Thirty-three compounds were selected by the consensus QSAR model for the synthesis. These compounds were synthesized and their structures confirmed by infrared (IR), hydrogen nuclear magnetic resonance (1H NMR) and carbon (13C NMR) spectroscopic methods and mass spectrometry (MS). Compounds which showed high purity (≥95% in HPLC) were tested against strains of M. tb. H37Rv (sensitive) and resistant to rifampicin (RMP) or isoniazid (INH). In addition, they were also tested in mammalian cell cytotoxicity assays and activity spectrum. We identified 22 hits with anti-TB activity, with minimum inhibitory concentration (MIC) in M. tb. H37Rv in aerobic conditions (MABA) <10 μM. Of these, 12 compounds exhibited potent M. tb. replication activity on nanomolar scale, with MIC values in MABA <1 μM and in micromolar under anaerobic conditions (LORA) with MIC <10 μM. In addition, these compounds also showed potent inhibitory activity against monoresistant strains at RMP or INH (MIC <1 μM and MIC <10 μM, respectively). Hits also demonstrated low cytotoxicity in mammalian cells (Vero cells) and selectivity index between 11 and 545 for M. tb. The same selectivity was verified in the activity spectrum assay against four commensal strains and six strains of non-tuberculosis mycobacteria (NTMs), in which the compounds presented broad spectrum against the NTMs strains. These results demonstrated that the combination of in silico strategies for the design of aryl and heteroaryl chalcones was efficient in identifying new compounds that proved to be potent, selective and promising candidates for prototypes of anti-TB drugs.Item Dispositivo de liberação intravítrea para tratamento de degeneração macular relacionada à idade(Universidade Federal de Goiás, 2023-04-04) Guerra, Maria Carolina Andrade; Fialho, Sílvia Ligório; http://lattes.cnpq.br/6277013725246341; Cunha Júnior, Armando da Silva; http://lattes.cnpq.br/8278273904187275; Cunha Júnior, Armando da Silva; Lima, Eliana Martins; Dias, Marina França; Dourado, Lays Fernanda Nunes; Fialho, Silvia LigórioAge-related macular degeneration, AMD, is a chronic eye disease which damages the macular area. It is the main cause of adult blindness worldwide. The pharmacological treatment of choice for the neovascular form of AMD consists of intravitreal injections of anti-VEGF agents that, occasionally, might be combined with corticosteroids. Intravitreal injections are the preferred route for drug delivery to the posterior segment of the eye but have limited therapeutic success due to the quick elimination of substances, requiring frequent injections that bring complications to the patient and low adherence to treatment. Intravitreal implants are capable to maintain therapeutic levels of drugs for a long period. Biodegradable nanofibers can modulate drug release in addition to allowing the incorporation of fragile bioactive substances. The present work aimed the development of biodegradable intravitreal implants containing dexamethasone coated with polymeric nanofibers containing bevacizumab as a therapeutic proposal for the treatment of AMD. Nanocoated implants were successfully developed. The characterization of the system, the study of degradation and efficiency of the coating process were evaluated by scanning electron microscopy. The drug release profile was determined by high performance liquid cromatography and the Bradford method. The antiangiogenic activity was determined by the chicken embryo chorioallantoic membrane model. The safety of the formulation was evaluated in rabbit eyes. So far, the system was successfully developed. The study degradation study confirmed the presence of nanofibers on the implant surface for up to 35 days. The degradation study demonstrated the presence of nanofibers on the surface of the implant for up to 35 days. The release profile showed that 68% of dexamethasone was released within 35 days and 90% of bevacizumab within 48 hours. The formulation presented activity in reducing vessels and was safe for the rabbits’ retina. No clinical or histopathological changes were observed, neither alteration in retinal thickness by optical coherence tomography during the 28 days. The developed implants, therefore, may be considered as a new alternative for the treatment of AMD.Item Preparação e uso de eletrodos de frafite nanoestruturados de vanadato de bismuto na degradação fotoeletrocatalítica de radamina B isotiacianato(Universidade Federal de Goiás, 2023-02-10) Isecke, Bruna Guimarães; Teixeira, Guilhermina Ferreira; http://lattes.cnpq.br/5992362464264556; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Gil, Eric de Souza; Oliveira, Sérgio Botelho de; Colmati Júnior, Flávio; Oliveira, Mayk Teles de; Prado, Lara Barroso BritoPhotoelectrocatalysis is a promising way to treat water contaminated by negative organic compounds. The use of BiVO4 nanoparticles supported on a conductive substrate allows the degradation of pollutants to be carried out under less energetic conditions. In this work, we report the degradation of Rhodamine B Isothiocyanto dye in a BiVO4/graphite (BVO@C) electrode performed under visible light irradiation through a photoelectrocatalytic process. The BiVO4 particles passed through ultrasonic irradiation by coprecipitation and then deposited on the surface of a graphite by the impregnation method. The 23 factorial design was used to optimize electrode fabrication. The electrode was characterized using SEM/EDS, XRD and DLS techniques. For the electrochemical characterization of the electrode, cyclic voltammetry (VC) and electronic impedance spectroscopy (EIS) were performed. The evaluation of the degradation of RhB isothionate was carried out in the processes of electrooxidation and photoelectrocatalysis, controlling or not controlling the temperature using the unmodified electrode and the BVO@C electrode. The characterization of the electrode confirmed the impregnation of the graphite with a BiVO4 particle through SEM/EDS, revealing specific peaks referring to vanadium (V), bismuth (Bi) and oxygen (O). The XRD analysis bought peaks related to the monoclinic phase of BiVO4, this fact being important due to the smaller band gap value, which implies activation of the semiconductor through light in the visible range. DLS and zeta potential analysis revealed negative charges on the surface of BVO@C, PDI values that indicated that the solution used for impregnation had monodispersive characteristics, which corroborated to a less regular impregnation, since this factor does not contribute to a deposition independent. Electrochemical analyzes confirm a considerable improvement of the modified electrode through a decrease in resistivity that may be associated with the presence of BiVO4, in addition to a decrease in hysteresis in relation to the emission/reduction pair. After 30 minutes, the degradation results in the electrocatalysis (EC) and photoelectrocatalysis (PEC) system, the results were considered relevant, reaching almost 100% of the dye being degraded, with a higher degradation rate for the photoelectrocatalysis experiments in relation to electroxidation, and higher values in experiments in which temperature was not controlled. To analyze the electrode reuse cycles, several reuse cycles were performed and the electrode efficiency (BVO@C) was observed. After nine cycles of reuse of the BVO@C electrode, it was observed that it presented more than 80% of RhB efficiency. and photoelectrocatalysis of dyes from industrial effluents.Item Avaliação do potencial antioxidante e atividade vasorrelaxante de Cinnamomum sp.(Universidade Federal de Goiás, 2023-05-16) Moreno, Emily Kussmaul Gonçalves; Macêdo, Isaac Yves Lopes de; http://lattes.cnpq.br/7801802836007488; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Macêdo, Isaac Yves Lopes de; Garcia, Telma Alves; Rocha, Matheus Lavorenti; Carvalho, Murilo Ferreira de; Machado, Fabio BahlsThe great interest in the study of antioxidants is mainly the prevention of physiological damage caused by oxidative processes. Cinnamon (Cinnamomum sp.), is a spice used worldwide in cooking and has gained prominence for its pharmacological properties, such as anti-inflamatory, antibacterial, antifungal, cardiovascular, among others. Given the importance of determining the antioxidant capacity in relation to therapeutic methods, this study aims to evaluate the antioxidant profile of commercial cinnamon samples by spectrophotometric, electrochemical and vasorelaxant methods. The spectrophotometric methods performed were 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azinobis (3- ethylbenzothiazoline-6-sulfonic acid) (ABTS) and Folin-Ciocalteu. For the electrochemical experiments, a three-electrode system was used, consisting of carbon paste electrode, platinum wire, and Ag/AgCl/KClsat, representing the working, auxiliary, and reference electrodes, respectively. The electroanalytical methods used were differential pulse, square wave, and cyclic voltammetries. Vascular reactivity was evaluated in aortic artery rings from male Wistar rats, using arteries with intact vascular endothelium and without endothelium. The endothelial nitric oxide synthase (eNOS) pathway and the inhibitor N-nitro-L-arginine-methylester (L-NAME) were used in this analysis. The correlation between the electrochemical approach and total phenols by the ABTS, DPPH, and Folin- Ciocalceu methods were 0.63, 0.70, and 0.73, respectively, with 1 being an ideal correlation. The correlation between spectrophotometric methods was 0.83. For the electrochemical results, a similar profile was observed, with anodic peak a.c Epa1= 0.1 V, indicative of polyphenolic compounds with high antioxidant power. In addition, a biosensor on a carbon paste electrode was applied to the selected extracts using laccase enzyme, obtained by the fungus Marasmiellus sp. and a signal improvement of up to 4 times in the antioxidant profile was observed when compared to the electrode without modification. The samples were analyzed by mass spectrometer, and the main chemical markers found were coumarin, cinnamaldehyde, and eugenol. Pharmacological assays showed that these samples also promoted a significant vasorelaxant effect associated to the antioxidant potential. Thus, cinnamon showed a high antioxidant capacity, in agreement with the results obtained in other studies, emphasizing its importance as a functional food.Item Produção de lacases por Pleurotus ostreatus e o uso da biorremediação e adsorção para tratamento de poluentes via biomassa residual(Universidade Federal de Goiás, 2022-02-24) Nunes, Elaine Sousa; Santiago, Mariângela Fontes; http://lattes.cnpq.br/7143224488081563; Santiago, Mariângela Fontes; Paula, José Realino de; Morais, Mariana Cristina de; Zang, Warde Antonieta da Fonseca; Faria, Fabrícia Paula deThe contaminants of effluents with domestic and industrial releases have been proven in several regions of the planet. In the face of outbreaks caused by flaviviruses the use of repellents has grown significantly, as well as synthetic dyes, because they are widely used in the textile industry and bisphenol A, because it is found in different commercial polymers, are commonly found in pollutants keeping present in waters generating possible harmful effects. Conventional effluent treatment processes have low chemical removal efficiency and are expensive. In view of this, the objective of this study was the development and evaluation of methodologies for the treatment of effluents contaminated with the active ingredient of repellents, icairidina, red textile dye Drimaren CL-5B and bisphenol A (BPA) by using açaí residue as adsorbent material and/or bioremediation with the lacase produced from the white decomposition fungus Pleurotus ostreatus using as enzymatic inducer the solid residues of acai, pineapple, mexerica and pequi. The enzymatic production with the residues of açaí and pineapple obtained an activity of 1139 UmL-1 and 1031 UmL-1 respectively. Remediation was efficient for BPA, being able to bioremediate up to 100 % of the compound, but it was ineffective for icariride. However, açaí revealed high adsorptive capacity, reaching to fully adsorb bisfinel A, more than 50 % of iridin and more than 70 % of the dye when in a synthetic sample and 40 % in an industrial sample, demonstrating a promising methodology.Item Potencial antioxidante e atividade vasodilatadora de cervejas comerciais(Universidade Federal de Goiás, 2017-05-05) Oliveira Neto, Jerônimo Raimundo de; Vaz, Boniek Gontijo; http://lattes.cnpq.br/7814534710550639; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Gil, Eric de Souza; Paula, José Realino de; Guedini, Paulo César; Cunha, Luiz Carlos da; Ferreira, Rafael de QueirozBeer is one of the oldest and most popular beverages consumed by mankind, the main classification of beers is the type of fermentation, divided into ale or lager, high and low fermentation, respectively. In this study, beer samples were divided into two portions, the first one for the spectrophotometric and electrochemical tests, which was used in natura form. And the second part was lyophilized, aiming at the concentration use standardization, alcohol withdrawal and guaranteeing an increase of durability, and then used in the pharmacological and chromatographic tests. The aim of this study was to investigate the antioxidant potential and vasodilator activity and correlate them with the phenolic profiles of twenty-two commercial beers. In addition, the antioxidant activity and the phenolic profile of hops and malts from different origins were also verified. From the raw materials, hops samples showed better antioxidant activity when compared to malt samples (p <0.05). The correlation between electrochemical index (EI) and total phenols (TPC), and radical scavenging methods, 1,1-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzthiazoline -6-sulphonic acid) (ABTS) was 0.86, 0.77 and 0.85 respectively for the hop samples. From the beers, ale group showed better antioxidant activity and TPC values when compared to the lager group. However, according to the Pearson correlation matrix, the correlation between IE with TPC, DPPH and ABTS was 0.86, 0.89 and 0.96 respectively for the lager group. While for the ale group, the correlations were not statistically significant (p> 0.05), mainly due to the turbidity interference of the samples during spectrophotometric assays. This fact reiterates the use of electrochemical methods, which minimize this type of problem besides being more sensitive and quick. Following the proposed electrochemical methodology, using the IE calculation, LB10 and AB1 samples obtained the highest indices. In the results of the principal components analysis (PCA) three groups were observed, where group III confirms LB10 and AB1 as the best antioxidants potential. LB10, AB1 and AB6 showed a maximal vasodilator effect of 92 ± 4, 88 ± 3 and 79 ± 3%, respectively. Both the vasodilator effect and the lipid peroxidation inhibition capacity may be associated with the presence of phenolic compounds in the beer samples, identified by mass spectrometry. This study, therefore, verified that the proposed IE methodology is an important tool to evaluate antioxidant properties and showed a good correlation with radical scavenging assays. Moreover, the study showed that beers may have a beneficial effect on the cardiovascular system, showing a good correlation of the vasodilator effect and antioxidant potential, which may be useful for future research on health, sensorial properties and quality parameters. Still from the standpoint of the quality of the beers, hop extracts as well as malt exhibited statistically results, corroborating to the applicability of these tools in the choice of these major ingredients improve the quality of the final product.Item Desenvolvimento de lipossomas vetorizados ao receptor folato contendo paclitaxel e imatinibe coencapsulados: avaliação da atividade antiproliferativa e da expressão gênica do VEGF em células tumorais(Universidade Federal de Goiás, 2014-04-30) Peres Filho, Marco Júnio; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Oliveira, Anselmo Gomes; Magalhães, Nereide Stela Santos; Batista, Aline Carvalho; Rocha, Matheus lavorentiThe impact of Nanotechnology is constantly raising in different areas of science, with the development of new products that bring benefits in comparison with the alternatives available in the market. When encapsulated in nanoparticles, anticancer drugs can achieve several advantages, most importantly the possibility of reducing the amount of drug administered through targeting strategies, which are not accomplished by conventional medication. Passive targeting is related to leaky vasculature in pathological sites, and active targeting comprehends the attachment of specific ligands, anchored in nanoparticles surface, to recognize and bind receptors overexpressed in cancer cells. Coencapsulation of anticancer drugs in the same pharmaceutical carrier can coordinate pharmacokinetics of encapsulated drugs. In the present work, liposomal formulations targeted to folate receptor with paclitaxel (PTX) and imatinib (IB) coencapsulated were obtained, aiming to combine cytotoxic and antiangiogenic effects of the drugs, respectively. New analytical method was developed and validated for simultaneous quantification of IB and PTX. Soy phosphatidylcholine liposomes were prepared, with cholesterol and DSPEmPEG( 2000), to obtain long circulation particles. DSPE-PEG(2000)-FA was obtained by an unpublished method of synthesis, and this product was further used in the formulation by post-insertion technique. Cytotoxic effect and VEGF gene suppression were studied in vitro in two different cell lines, MCF7 (breast adenocarcnioma) and PC3 (prostatic adenocarcinoma), after treatment with liposomal vesicles. Analytical procedures were developed with isocratic elution, 6,5 minutes runs, with linearity, specificity, precision and accuracy. Quantification limit was 750 Ng/mL and 1000 Ng/mL for IB and PTX, respectively. After extrusion, liposomes had mean diameter close to 100 nm and low polidispersion index. Post-insertion of folic acid attached to lipid anchor procedure increased polidispersion, because the procedure lasted 24h. Drug to lipid ratios were 1:26 and 1:27 (IB and PTX respectively). Lyophilized formulations containing trehalose remained stable after 60 days of storage in terms of %EE. Synthesis of DSPE-PEG(2000)-FA was confirmed by RMN, FT-IR and ESIMS techniques. Liposomal PTX was more cytotoxic (p<0,05) than free drug in MCF7 cell line, after both 24h and 48h of exposion, for all tested concentrations. Targeted formulation containing folic acid ligand, had more impact on cell viability reduction (p<0,05) than non targeted liposomes (LPIP), also after 24h. On PC3 cell line cell viability reduction was greater (p<0,01) when the cells were exposed to targeted vesicles loaded with 1 and 10 Ng/mL of IB and PTX, after 24 and 48h. VEGF gene expression was reduced in MCF7 and PC3 (p<0,05), and once more targeted vesicles showed better results than non-targeted liposomes. It is, thus, plausible to conclude, through in vitro experiments results, that the attachment of folic acid to liposomal formulations, resulting in multi-functional liposomes, is an interesting strategy to achieve enhanced internalization and accumulation of drugs in targeted cells. This was observed by the enhancement of cytotoxic and antiangiogenic effects in breast and prostate cell lines.Item Os estágios iniciais do desenvolvimento do zebrafish como modelo alternativo para predizer a toxicidade oral aguda in vivo(Universidade Federal de Goiás, 2021-02-11) Prado, Lara Barroso Brito; Valadares, Marize Campos; http://lattes.cnpq.br/6157755243167018; Oliveira, Gisele Augusto Rodrigues de; http://lattes.cnpq.br/6221735418479539; Oliveira, Danielle Palma de; Rocha, Matheus Lavorenti; Ferreira, Monica Valdyrce dos Anjos Lopes; Alves, Vinícius de Medeiros; Valadares, Marize CamposZebrafish (Danio rerio) early-life stages offer a complex and multicellular system integrating various tissues and differentiation processes. In addition, the zebrafish embryos are structurally and functionally similar to vertebrates, including humans. The acute toxicity test with zebrafish embryos and larvae is already worldwide recognized as an alternative model for ecotoxicological assessment, but it is not include in normative of the Council fot the Control of Animal Experimentation (CONCEA), wich recognize the use of alternative methods validated in research activities in Brazil. This organism model can filling the gap between conventional in vitro and in vivo tests for extrapolation of data for humans, the present study aimed to assess the acute toxicity of substances with different Global Harmonization System (GHS) categories using zebrafish early-life stage to determine LC50 values and compared with in vivo (LD50) acute oral toxicity data from literature, in order to generate a model to prediction acute oral toxicity. This prediction model was evaluated by the application of a drug candidate (LQFM 021). Fifteen substances were evaluated by Fish Embryo Acute Toxicity (FET) test (OECD 236). Parameter evaluated was lethal and sublethal effects after 96 h of exposure. A linear regression- model using the log-transformed of the LC50 values and LD50 was generated for the estimated of LD50 from LC50 values. This model resulted in the following equation Log LD50 (mg/kg) = 0.5749 x log LC50 (mg/L) + 1.284. The method domain of application was 53.33% and the R2 was 0,66. Sublethal effects indicate that substances more toxic presented more abnormalities. The DL50 predicted with FET testing LQFM 021, which classified as category 4 in GHS acute oral systemic toxicity assessment, was of 408.52 mg/kg, which also classified as Category 4. In this work, Quantitative Activity-Activity Relationship (QAAR) models were also developed, based on the data obtained in the FET test with zebrafish. This model using seven toxicological descriptors generated statistically predictive models with R2 values ranging from 0.80 to 0.95 and in combination with the Random Forest method it presented the best performance in the prediction of acute oral toxicity in vivo. Therefore, our results suggest that early-life stages of zebrafish could be at least a refinement in the sense of the principles of the 3R’s to predict acute oral toxicity in vivo, being as an intermediary in the preclinical evaluation between in vitro and in vitro.