Programa de Pós-Graduação em Ciências Farmacêuticas
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Master Thesis Estabilidade da Anfotericina B em um carreador nanotecnológico(Universidade Federal do Rio Grande do Norte, 2016-04-29) Santos, Sarah Rafaelly Araújo; Egito, Eryvaldo Sócrates Tabosa do; Azeredo, Francine Johansson; http://lattes.cnpq.br/6907806915889763; http://lattes.cnpq.br/1287626190706313; Lima, Adley Antonini Neves de; https://orcid.org/0000-0002-3798-3915; http://lattes.cnpq.br/4061809277935577; Ramaldes, Gilson AndradeAmphotericin B is a water-insoluble compound widely used to effectively treat systemic fungal infections. The use of more effective therapies with higher doses of AmB directed to invasive systemic mycoses, together with a real need to reduce AmB intrinsic toxicity, has trigged the development of alternative carriers for AmB administration. Lipid microemulsions have been very important in the pharmaceutical field, once they are pharmacologically more efficient and present reduced side effects. Thus, this work aimed to evaluate the stability and the pharmacological and the toxic profile of AmB incorporated in a microemulsion system (AmB-ME), and to compare its performance with free and conventional AmB. To assess AmB stability, the formulations were subjected to a stress study (thermal stress and UV luminous radiation) and accelerated stability studies for 90 days, in which the formulations were stored at 25ºC and 45ºC. Then, at pre-determined times, the AmB content, followed by activity and toxicity assays, was evaluated. The results showed that AmB has higher susceptibility to UV luminous radiation rather than high temperatures. For all formulations, AmB presented a first order kinetic degradation profile. However, AmB-ME revealed the shortest degradation profile for a shelf-life of almost 30 days. Regarding the antifungal activity, the AmB-ME formulation was able to inhibit C.parapsilosis growth during 90 days of the experiment. Nevertheless, AmB-ME showed higher toxicity levels, as revealed by potassium and hemoglobin release assays. Thus, the microemulsion can be considered a very interesting strategy to stabilize AmB under the stress conditions, but it is necessary to optimize the product formulation to minimize possible cellular damage.Master Thesis Plasmídeos formulados com nanopartículas catiônicas: análise da estabilidade físico química e biológica(Universidade Federal do Rio Grande do Norte, 2019-03-28) Cardoso, Anna Clara de Araújo; Silva, Marcelo de Sousa da; https://orcid.org/0000-0002-1000-0149; http://lattes.cnpq.br/1295430560645312; http://lattes.cnpq.br/3358002467400398; Silva Júnior, Arnobio Antônio da; https://orcid.org/0000-0002-7516-1787; http://lattes.cnpq.br/2593509584288129; Lacerda, Ariane Ferreira; Santos, Elizabeth Cristina Gomes dosThe plasmids (pDNAs) have been standing out regarding to its application at biotechnology, mostly in DNA vaccination and genic therapy. pDNAs are DNA molecules with extra chromosomal double bands, presenting circular shape and have different isoforms. The Food and Drug Administration recommends that during pDNAs utilization on immunization protocols, they must be at least 80% on its super-curled isoform, once the studies assign that super-curled isoforms have a larger access to the interior of cells. Super curled isoform may be altered by chemical, physical and biological factors. Owing to its importance at pDNAs structure stability at biological function, this study aims to evaluate the pDNAs stability used at biotechnology, ands tests a nanoformulation with polyethyleneimine (PEI) associated to pDNAs, in order to promote a stability and bioavailability increasing of pDNAs. We evaluate the temperature effect at incubation, plasmid size and nucleases concentrations under super-curled isoform conservation. Also, it was evaluated pDNAs stability using functionalized nanoparticles with PEI through time variables, nucleases concentration and comparing to non functionalized nanoparticles formulated pDNAs. On 37°C and 42°C temperatures, there was higher degradation on plasmids, as well as higher serum concentration, presenting super-curly isoforms only at 1:64 dilution. The smaller sized plasmid presented lower degradation in all the tests. The preparation of functionalized nanoparticles with PEI associated to pDNA showed to be a promising alternative of protection against enzymatic degradation, with 100% efficiency of plasmid association. However, it requires more in vitro and in vivo studies to verify security factors and genic transference rate.Master Thesis Avaliação das atividades anti-inflamatória, cicatrizante e antiofídica de um gel contendo extrato hidroetanólico das folhas de Jatropha mollissima (Pohl) Baill(Universidade Federal do Rio Grande do Norte, 2019-03-29) Passos, Júlia Gabriela Ramos; Pedrosa, Matheus de Freitas Fernandes; Silva, Juliana Félix da; https://orcid.org/0000-0003-3131-9025; http://lattes.cnpq.br/7927574480239375; http://lattes.cnpq.br/2929963416385218; http://lattes.cnpq.br/1969453327313987; Guerra, Gerlane Coelho Bernardo; http://lattes.cnpq.br/5677318431530876; Luna, Karla Patrícia de OliveiraAccidents caused by snakes are considered a major public health problem in several regions of the world. Bothrops are responsible for the vast majority of ophidic accidents in Brazil. It is known that, currently, the only specific treatment available for the bite of these snakes is the bothropic antivenom, but it has some limitations, such as not combat local effects effectively, difficult access in some regions, and high cost. Plants of the genus Jatropha (Euphorbiaceae) are often indicated by traditional medicine, in some regions of Brazil, to reverse the damage caused by snake bites and also with anti-inflammatory function. In this view, the objective of this work was to evaluate the anti-inflammatory, healing and antiophidic potential against the venom of the snake Bothrops jararaca of the hydroethanolic extract of the leaves of Jatropha mollissima (Pohl) Baill. incorporated into a formulation developed for topical application. Tests were performed to evaluate the topical anti-inflammatory activity of this species in carrageenan-induced paw edema and ear edema induced by single application (acute inflammation) or multiple applications (chronic inflammation) of chroton oil. Tests were also performed to evaluate the healing activity of the formulation, while the skin irritation test was conducted to analyze safety during topical use of the formulations developed. It was possible to observe that the gel had anti-inflammatory action in acute inflammation models induced by carrageenan, and in acute and chronic inflammation models by chroton oil. chroton oil. It was also observed that the gel has cicatrizant activity, since it significantly decreased the size of the wound in relation to the placebo group. The gel did not cause skin irritation in mice, proving to be safe for topical use. The efficacy of the gel containing the hydroethanolic extract of the leaves of J. mollissima alone and in association with the commercial polyvalent antibothropic-crotalic commercial antivenom in relation to its antiophidic potential against the local effects of B. jararaca envenoming were evaluated in the paw edema and muscle hemorrhagic models and it was seen that the venom-induced edematogenic and hemorrhagic activities were inhibited, both by the gel alone and by the association with the antiophidic antivenom, since these treatments reduced edema (the gel treatment containing the extract in association with the antiophidic antivenom had an inhibition of approximately 90% after four hours of the envenoming), in addition to significantly reducing the concentration of hemoglobin in the evaluated tissues, consequently having a significant anti-hemorrhagic potential. In conclusion, the results show that the gel containing the hydroethanolic extract of the leaves of J. mollissima shows potential anti-inflammatory, healing and antiophidic activity, acting on the local effects of the bite, suggesting that this formulation of topical use has an important antiophidic potential as a complementary alternative to the treatment of local effects caused by bothropic envenoming, besides acting as healing potential and topical antiinflammatory for the treatment of various skin diseases.Master Thesis Estudo das atividades antiinflamatória e antinociceptiva do extrato seco padronizado de Phyllanthus niruri L(Universidade Federal do Rio Grande do Norte, 2013) Porto, Cínthia Raquel da Costa; Soares, Luiz Alberto Lira; Guerra, Gerlane Coelho Bernardo; http://lattes.cnpq.br/5677318431530876; http://lattes.cnpq.br/4290808161139329; http://lattes.cnpq.br/5130924482564483; Almeida, Maria das Graças; http://lattes.cnpq.br/8644617307948221; Maia, Maria Bernadete de Sousa; http://lattes.cnpq.br/0046739385454383; Leite, Edda Lisboa; http://lattes.cnpq.br/7712988818433906As atividades antiinflamatória e antinociceptiva foram estudadas para o extrato seco padronizado de Phyllanthus niruri L., (PnSDE) em modelos experimentais de inflamação e dor. A atividade antiinflamatória do PnSDE foi avaliada por meio dos modelos de edema de pata induzido por carragenina, migração leucocitária induzida por tioglicolato e artrite induzida por zymosan. A atividade antinociceptiva foi avaliada utilizando os testes de Randall e Selitto, retirada da calda e placa quente. Este estudo mostrou que o extrato seco padronizado de Phyllanthus niruri L (PnSDE) apresentou importante atividade antiinflamatória frente aos modelos experimentais de edema de pata, migração leucocitária e artrite induzida por zymosan. Assim, o PnSDE, nas doses utilizadas reduziu de forma significativa a resposta vascular no processo inflamatório induzido por carragenina e inibiu a migração leucocitária para o local da inflamação induzida por tioglicolato. Em relação ao modelo de artrite, o PnSDE conseguiu reduzir de maneira significativa os níveis da enzima mieloperoxidase e provocar uma elevação dos níveis de glutationa total. Neste modelo, a análise histopatológica das sinóvias revelou uma significativa redução dos eventos inflamatórios avaliados no tecido inflamado. Na avaliação imunohistoquímica das sinóvias, os resultados sugerem que o extrato pode ter contribuído com a redução da expressão para RANKL, RANK, OPG, COX-2, MMP-2 e MMP-9. Na avaliação da atividade antinociceptiva, os ensaios realizados evidenciaram que o PnSDE exibiu uma marcante atividade antinociceptiva periférica e central. Em conclusão, este estudo sugere que o extrato seco padronizado de Phyllanthus niruri L. possui potentes atividades antiinflamatória e antinociceptiva. Este estudo contribui para uma possível obtenção de uma preparação fitoterápica, utilizando o extrato seco padronizado de Phyllanthus niruri (PnSDE), validando o seu uso para o tratamento da dor e distúrbios inflamatórios.Master Thesis Avaliação da estabilidade da associação de isoniazida e rifampicina(Universidade Federal do Rio Grande do Norte, 2010) Barbosa, Manuela Bernardo Câmara; Raffin, Fernanda Nervo; Oliveira, Eduardo de Jesus; http://lattes.cnpq.br/1293090609428232; Aragão, Cícero Flávio Soares; http://lattes.cnpq.br/9657118649043311; http://lattes.cnpq.br/1052562183676637; http://lattes.cnpq.br/7501998432159911; Moura, Túlio FIávio Accioly de Lima eTuberculosis is a disease of older, known in the worid. The main treatment for this disease is achieved with the fixed-dose combination formulations, involving the main drugs. This study aims to determine the quality and conduct the first evaluation of stability of capsules of isoniazid and rifampicin formulations nationals with respect to physical, Chemical properties and dissolution after storage in accelerated conditions (40 ° C temperature and 75% RH) and under conditions of long duration (30 ° C temperature and 75% relative humidity). USP methods were used previously validated, based on visible spectrophotometry for the dissolution of rifampicin and high performance liquid chromatography for the content of rifampicin and isoniazid and disbandment. Four samples were submitted to six months of accelerated stability study and 12 months of stability study of long duration. The drugs were subjected to stressful conditions, performing hydrolysis at different pH values and temperatures. All formulations tested showed satisfactory for pharmacopoeial testing. In degradation studies, there were products resulting from the conditions imposed on drugs. But a more careful analysis, using methods more sensitive and specific instruments is needed to separate and quantify these degradation products. The formulations tested are nationals of good quality and monitoring the appearance of degradation products is needed throughout the stability study.Master Thesis Commiphora leptophloeos (Mart.) J.B. Gillett (Burseraceae): estudo fitoquímico, toxicidade e avaliação do potencial antiinflamatório e antimicrobiano(Universidade Federal do Rio Grande do Norte, 2019-03-28) Medeiros, Renato Dantas de; Langassner, Silvana Maria Zucolotto; Silva, Juliana Félix da; Ferreira, Leandro de SantisThe specie Commiphora leptophloeos (Burseraceae) is a native plant from Brazil, belongs to caatinga biome and is known popularly as “imburana-de-espinho” and “imburana-decambão”. The ethnopharmacology studies mention the use of this specie in the treatment of inflammations and infections. In this context, the present study aimed to evaluate the toxicity, anti-inflammatory and antimicrobial activity in non-clinical in vitro and in vivo assays of leaf and stem bark extracts, and to isolate, identify and quantify chemical markers. In the phytochemical study, the hydroethanolic extract was prepared by maceration and the fractionation was performaded by liquid-liquid partition (dichloromethane, ethyl acetateAcOEt and n-buthanol-BuOH fractions). Isolation, structural elucidation and characterization of the extracts were performed by CPC, LC-MS, FIA-ESI-IT-MS/MS and 1H NMR and quantification of the content of markers in the extracts was made by HPLC-DAD and HPLCELSD. The toxicity of both extracts was evaluated by MTT and flow cytometry assays and in vivo by the acute toxicity test. The in vitro anti-inflammatory activity was evaluated using LPS-induced nitric oxide assay and in viv by carrageenan-induced paw edema and oral zymosan induced air pocket models. The antimicrobial activity was measured by the determination of minimum inhibitory concentration (MIC) and virtual screening of the isolated compounds was performed by in silico studies. From leaves extract, 2 flavonoids were isolated by CPC and 16 compounds were characterized by Mass spectrometry such as phenolic acids, glycosylated flavonoids derivatives of quercetin, luteolin and apigenin, and condensed tannins derivatives of catechin. From the stem bark extract, 2 tannins were isolated by CPC and 8 compounds were characterized as phenolic acids and procyanidins. The leaves extract at 200 µg/mL and stem bark extract at concentrations of 1, 10, 100 and 200 µg/mL demonstrated in vitro anti-inflammatory effect in the LPS-induced nitric oxide assay. In the carrageenan-induced paw edema of model, the extracts of leaves and stem bark at the doses of 100, 200 and 400 mg/kg, by oral route, significantly reduced the edema followed by reduction of myeloperoxidase (MPO) and in the zymosan-induced model of pouch-air, at doses tested, significantly reducing (p < 0.001), cell migration, total protein concentration, myeloperoxidase (MPO), and malondialdehyde (MDA) and the proinflammatory cytokine TNF-α and increased the production of the anti-inflammatory cytokine IL-10. In the evaluation of the antimicrobial activity, the extracts of the barks and the AcOET and BuOH fractions at concentrations of 20 to 100 μg/mL demonstrated a fungistatic and bactericidal effect. The in silico study indicated possible ligands of type B dimeric procyanidin and isovitexin related to anti-inflammatory and antimicrobial activity. The results obtained are unprecedent for the specie, justify its use in folk medicine and reveals that extracts of leaves and stem bark have a therapeutic potential for the development of herbal products with antiinflammatory and antimicrobial properties.Doctoral Thesis Nanopartículas biodegradáveis e biocompatíveis para liberação modificada de benznidazol(2019-06-27) Silva, Alaine Maria dos Santos; Silva Júnior, Arnóbio Antonio da; ; ; Silva, Marcelo de Sousa da; ; Damasceno, Bolivar Ponciano Goulart de Lima; ; Porto, Carlos Alberto Robello; ; Soares Sobrinho, José Lamartine;Benznidazole (BNZ) is the drug of choice for the treatment of patients with infection by Trypanosoma cruzi. Despite its wide use, this molecule presents efficacy problems due to high toxicity, in addition to low solubility in aqueous medium. The nanoparticles have proven ability to traverse most biological barriers and intracellular targeting of drugs, especially when surface binders are inserted to increase the efficacy of the drug in cells infected. The aim of this work was to make a structural design and monitoring of functionalized and fluorescent nanoparticles of poly (lactic-co-glycolic acid) (PLGA) for modified release of benznidazole. The particles were produced by the emulsification solvent evaporation method. The development of the formulation and parameters of obtaining were optimized by measurements of particle size, polydispersity index, zeta potential, atomic force microscopy (MFA), scanning electron microscopy (SEM), confocal microscopy (MC), fourier transform infrared absorption spectroscopy (FTIRATR), encapsulation efficiency, in vitro and in vivo studies. Spherical and stables polymeric nanoparticles below 250 nm were obtained, with encapsulation efficiency greater than 95%. The in vitro release kinetics of the drug showed a slow release of the drug and the improvement of the biological activity of nanoparticles containing BNZ. In vitro assays in normal cells (Hek 293), tumor cells (Hep G2 and HT-29), amastigotes (strains H9c2 and Dm28c) and with epimastigotes (strains Y, CL-Brenner and Dm28c) showed an increase in the potency of the nanoparticles containing BNZ over the free BNZ. The confocal microscopy analysis showed that the nanoparticles come in the parasite with high efficiency, especially those functionalized with sialic acid and cholesterol. In vivo tests revealed that the nanoparticles containing BNZ had similar effect to the free BNZ, even used in 20-fold inferior concentration. Thus, the present work systematically discusses the development of a nanotechnological system with innovative potential to increase the efficacy of benznidazole in cells infected with Trypanosoma cruzi.Master Thesis Quantificação de células T gama delta em pacientes com neoplasias cervicais intra-epiteliais (NIC) e cancer cervical: contribuição do papilomavírus humano (HPV) e das citocinas próinflamatórias(2016-07-31) Rocha, Rhadamés Menezes da Costa; Freitas, Janaina Cristiana de Oliveira Crispim; Langassner, Silvana Maria Zucolotto; ; ; ; Silbiger, Vivian Nogueira; ; Simões, Renata Toscano;Invasive squamous cell carcinoma is resulting from progression of precursor pre-invasive lesions known as cervical intraepithelial neoplasia (CIN).In the United States (US), it is estimated that 12,990 new cases were diagnosed and 4,120 women will be cervical cancer victims in 2016.Estimates from the National Cancer Institute (INCA) for the year 2016 in Brazil indicate that cervical carcinoma being in 3rd place among 10 types of more incidents cancer, excluding the nonmelanoma skin. Evidence has implicated the Human Papillomavirus (HPV) as the primary etiologic agent of cervical cancer. The host's immune system in most cases (80- 90%) can eradicate the virus HPV, leaving only a smaller portion (10-20%) of women who will present a persistent infection framework, which may progress to cancer cervical. It is known that the evolution and emergence of cervical cancer are influenced by several endogenous and exogenous factors, among which: the host immune system, HPV oncogenicity, nutritional status, age, education, number of pregnancies, use of condoms, first sexual intercourse, number of sexual partners over a lifetime, among others, are determining factors. Regarding the host immune response, recently, has been discussed the role of Tγδ cells, a subpopulation of cells of the innate immune system in different studies. It is known that your presence in the tumor microenvironment may play a role in the progression or inhibition of tumor. The role of Tγδ cells and their participation in the tumor microenvironment is not yet well established. The aim of this study was to quantify the percentage in peripheral blood Tγδ lymphocytes and correlate the groups of women with cervical intraepithelial neoplasia (CIN) and cervical cancer. In addition, it is intended to correlate these variables with the presence of HPV, cytokines, demographic, clinical, laboratory and histopathological and evaluate the impact in the pathogenesis of cervical cancer. At first study moment it was observed that lymphocytes gamma delta T are in larger amount in the group of patients without cervical intraepithelial neoplasia compared with the other groups, but this difference was not statistically significant. However, still need to include in this study to quantify the Tγδ cells in patients with cervical cancer, HPV typing, the quantification of cytokines and assess whether there is a correlation with the cervical cancer patients in order to understand the role of these cells to the progression of cervical cancers.Master Thesis Desenvolvimento de método indicativo de estabilidade de monocrotalina por CL/EM, análise térmica e técnicas complementares(2017-06-29) Germano, Gessiane Ferreira; Aragão, Cícero Flávio Soares; Nogueira, Fernando Henrique Andrade; ; ; ; Pontes, Daniel de Lima; ; Conceição, Marta Maria da;The monocrotaline is a pyrrolizidine alkaloids isolad from the Crotalaria retusa with activity against Trichomonas vaginalis, when used topically. This study has the aim of characterize this isolad used thermal and non-thermal techniques and and identification and quantification of monocrotaline through of the liquid chromatography-mass spectrometry (LC/MS). The thermal and complementary techniques using were: Thermal (Thermogravimetry – TG; differential scanning calorimetry – DSC and differential termal analysis – DTA), complementary (Fourier-transform infrared spectroscopy – FTIR; optical microscopy – OM; Capturing images of the decomposition process and X-ray diffraction – XRD). In the thermal techniques were employed five heating rate (2.5; 5; 10; 20 and 40 °C.min-1), from room temperature to 900 ºC in TG and DTA, and from room temperature to 500 ºC in DSC, both under nitrogen atmosphere flowing at 100 mL.min-1. In the TG and DSC curves were observed five events in both techniques, exception in DSC curve in the heating rate 2.5 °C.min-1, was observed four events. In the heating rate of 10 °C.min-1, thelargest decomposition occurs in the third event, between the temperatures 204 and 286 °C, with mass loss of 65% and with an initial decomposition temperature of about 100 °C. In the DSC, this same heating rate, the first event when compared with the images of the decomposition process, there is a sample contraction between the temperatures of 124 and 152° C. And with the images of the decomposition process demonstrated that the monocrotaline melts around 202 °C followed by decomposition of the sample. Futhermore observed that the results of the DTA curve were similar with the DSC curves. The results of the DRX, FTIR e MO techniques revealed that the monocrotaline has a crystalline character and with the heat the molecule has significant changes in your structure in 150 °C. Besides, the monocrotaline was identified by LC/MS, in a retention time of 1.7 min, flow 0.2 mL.min-1, with a column of 50mm x 3.0 mm and 2.2 μm particles and quantified in extract of Crotalaria retusa, using the analytical curve.Doctoral Thesis Farmacocinética populacional e toxicidade do sulfato de magnésio na pré-eclampsia(2019-12-12) Costa, Tatiana Xavier da; Martins, Rand Randall; ; ; ; Silva Filho, Miguel Adelino da; ; Cobucci, Ricardo Ney Oliveira; ; Langassner, Silvana Maria Zucolotto; ; Silbiger, Vivian Nogueira;Background: Magnesium sulfate (MgSO4) is the drug of choice to treat seizures in preeclampsia (PE) Despite the wide use, the therapeutic range ranges from 2.0-3.5 mmol/L. Objectives: To develop a population pharmacokinetic (PK) model of MgSO4 in preeclampsia, evaluating the impact of covariates in its pharmacokinetics,and to estimate the incidence of adverse drug reactions (ADR) in high-risk pregnancy and risk factors of RAM. Methods: Prospective cohort of patients with PE enrolled from June 2016 to February 2018 in use of MgSO4. Serum magnesium concentrations were obtained from 109 patients who received 4 g intravenously of MgSO4 and subsequent infusion of 1 g/h for 24 hours. Blood samples were obtained before administration and after 2, 6, 12 and 18 hours of the initial dose. Population pharmacokinetic parameters of MgSO4 (clearance, volume of distribution, time of half life) were estimated using the Monolix software ® 2018 Suite (Lixoft ®, Antony, France). A pharmacokinetic model including demographic, clinical and laboratory covariates of patients was developed. For the identification of ADR, 607 patients hospitalized in the ICU were evaluated daily through active search by pharmaceutical anamnesis, medical chart review and interviews with the healthcare team. Suspected ADR were classified about causality with Naranjo’s algorithm. Univariate and multivariate logistic regression was used to identify risk factors of ADR. Written informed consent was obtained from all patients. Results: The PK model that best adjusted the data was the one compartment with linear elimination. The population clearance was 1.38 L/h, the volume of distribution was 13,3 L and the baseline magnesium concentration was 0,77 mmol/L (1,87 mg/dL). The covariates body weight and serum creatinine have shown a statistically significant association with magnesium clearance and volume of distribution, respectively. Regarding ADR in high-risk pregnancy, one or more ADR were observed in 27.2%, the most implicated drug was MgSO4 (25.2%) with 44.5% of patients administered MgSO4experiencing ADR, most often somnolence (68.6%), absent patellar reflex (21.6%) and hypotension (9.8%). Risk factors of ADR were blood pressure (adjusted odds-ratio (aOR) 1.02), haemoglobin level (aOR 1.21) and body temperature (aOR 0.71). Conclusion: The pharmacokinetics of MgSO4 in pregnant women with PE are significantly affected by serum creatinine and body weight. Pregnant women with PE and higher body weight have a higher volume of distribution and, consequently, a lower elimination rate of MgSO4. Pregnant women with PE and higher serum creatinine value show lower clearance and, therefore, lower magnesium sulfate elimination rate. ADR affect about one fourth of high-risk pregnancies, mainly due to MgSO4administrations. High blood pressure, lower body temperature, and high haemoglobin concentration on admission were associated with increased risk of ADR.