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Item Avaliação do perfil metabólico da estavudina através do emprego da bioconversão e da modelagem molecular do citocromo P-450 CYP3A4(Universidade Federal de Goiás, 2009-06-26) FREITAS, Lênis Medeiros de; SABINO, José Ricardo; http://lattes.cnpq.br/9101677399031185; OLIVEIRA, Valeria de; http://lattes.cnpq.br/6300240031300604Before the approval of an active compound, metabolism studies are necessary to ensure its safety, once active metabolites could be synthesized during human biotransformation. The use of eukaryotic microorganisms for the study of drug metabolism has been widely explored, due to its capability of producing metabolites similar to the mammalians, and in silico studies consist in a fast strategy when compared with traditional metabolism studies. In this context, molecular modeling, using docking of molecules of interest in the active site of enzymes involved in drug metabolism, is a useful tool to evaluate the interactions between drug and receptor, because it could predict favorable orientations that could be biotransformated. In this work, sixteen filamentous fungi strains, obtained from collections and isolated from soil in the central Brazil, were evaluated for their capability of the antiretroviral stavudine biotransformation, also complemented by animal metabolism studies and molecular modeling of the most relevant cytochrome P450 isoform of human metabolism: CYP3A4. From the bioconversion experiments, the fungus Cunninghamella elegans ATCC 26169 was capable of metabolize stavudine, forming mammalian metabolites, producing the thymine derivative. Dynamic molecular studies demonstrated that the most probable reactions for stavudine, catalyzed by CYP3A4, involves hydroxylation of methyl group (position C-7) and the double bond epoxidation of the furanic ring, showing the importance of some residues of the active site in this process, like Arg212Item Bioconversão do derivado N-Fenilpiperazínico LASSBio 579, um potencial candidato a protótipo de fármacos(Universidade Federal de Goiás, 2007-09-12) GOMES, Tatiana Caixeta Ferreira; OLIVEIRA, Valeria de; http://lattes.cnpq.br/6300240031300604Bioconversion reactions using filamentous fungi have been extensively exploited and the results obtained are interesting for metabolism studies. The microbial models of animal metabolism, based on the similarity between mammalian metabolism and enzymatic microbial, became a promising alternative for the elucidation of metabolic routes of drugs. In this context, the aim of this work was to promote bioconversion studies with the N-phenylpiperazine derivative LASSBio 579, (1-[1-(4-Chlorophenyl)-1H-pyrazol-4-methyl]-4-phenyl-piperazine), a potencial lead of drugs prototypes. For that HPLC and TLC analytical methodologies were developed and tested for monitoring the bioconversion reactions for this compound. Beneath the documented catalytic activity for different microorganism, fiftteen of filamentous fungi were employed in this study: Absídia blakesleana ATCC 26617; Absídia blakesleana ATCC 10148b; Aspergillus candidus ATCC 2023; Aspergillus ochraceus ATCC 1009; Beauveria bassiana ATCC 7149; Chaetonium indicum LCP 984200; Cunninghamella echinulata ATCC 9244; Cunninghamella echinulata ATCC 9245; Cunninghamella elegans ATCC 36112; Cunninghamella elegans ATCC 26169; Curvularia lunata NRRL 2380; Fusarium roseum ATCC 14717; Mortierella isabelina NRRL 1757; Mucor griseocyanus ATCC 1207a; Rhizopus arrhizus ATCC 11145. Cunninghamella echinulata ATCC 9244 and Aspergillus candidus ATCC 2023 were chosen for studies in semi-preparative scales due to their capacity of producing a bigger variety of metabolites and one of them in greater amount, respectively. Five different derivatives were detected of which three were characterized by NMR and MS (LaBioCon 23, 24 and 25) as hidroxylated, glycosylated and methylpiperazine derivatives respectively, being this last comparative one and identified as being the mammalian derivate of LASSBio 579.Item Avaliação da toxicidade oral aguda e atividade diurética de Celtis iguanaea (Jacq.) Sargent(Universidade Federal de Goiás, 2011-08-30) GONÇALVES, Nádyla Zanon; CUNHA, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679Celtis iguanaea (Jacq.) Sargent is a species commonly known as cock-spur, in the Ulmaceae family and characterized as a shrub or small tree with branches long and very flexible. Is used for the treatment of urinary tract infections, kidney (kidney stones and pyelonephritis) and as a diuretic. Popular reports in the State of Goiás indicate the use of the spur cockscomb in the form of tea leaves. The aqueous extract of Celtis iguananea was tested in Wistar rats to assess single dose diuretic activity in observing the effect of same on urinary volume and products of metabolism (urea and creatinine) and assess the multiple-dose diuretic activity by observing the effect on the urinary volume and urinary excretion of electrolytes sodium (Na +) and potassium (K +), and also in Wistar rats and mice Swiss to test its acute oral toxicity following the Guide 423 (OECD), in which the animals were observed for 14 days after single administration of 2000mg/kg of extract, including this test the histopathological study of heart, lung, kidneys, liver, spleen, pancreas and intestines. The aqueous extract of cock-spur in their three doses (70, 200 and 600 mg/kg) did not submit multiple dose diuretic activity and only because it has not increased the excretion of water, electrolytes and metabolites of neither. The extract was framed in the class 5 (substance with Ld50 more than 2000 mg/kg and less than 5000 mg/kg), being considered of low toxicity, but histopathological findings cardiotoxicity and nephrotoxicity suggested does not extract any acute oral toxicity test (2000mg/kg), with an increase of absolut weight from the kidney and heart of male rats and mices treated with the extract and microscopic examination of kidney of male rats showing marked presence of cylinder hialinos no glomerulus.Item Desenvolvimento e validação de metodologia analítica aplicável ao desenvolvimento farmacotécnico de comprimidos de olanzapina(Universidade Federal de Goiás, 2009-12-14) MOURA, Julliana Rodrigues; LIMA, Eliana Martins; http://lattes.cnpq.br/7248774319455970Olanzapine is an antipsychotic active ingredient and its marketing in Brazil, in the form of terminated product, is protected by patent up to 2011. As it is recent in the pharmaceutical market and there is not a methodology described in officials forms that is capable of assuring the quality of new formulations, the objective of this paper was to characterize Olanzapine physical-chemical parameters, to develop and validate, in accordance with RE N°899, from May 29 th 2003, the analytical methodology for assay and dissolution and to apply the developed and validated methodologies in the pharmacotechnical development of tablets. It was characterized some physicalchemical parameters of solubility and of light absorption (from 200 to 400nm) in several solvents and it was developed and validated assay and dissolution methodologies by spectrophotometry with ultraviolet detection (UV) and the assay by high efficiency liquid chromatography with ultraviolet detection (HPLC-UV) for the quantification of olanzapine present in film coated tablets of 2.5, 5.0 and 10.0mg. The active ingredient presented a low solubility in water and the wave lengths of maximum light absorption were within the range of 254 and 273nm. For the dissolution methodology by UV spectrophotometry, the parameters were chloride acid 0.1 mol/L as the dissolution media, volume of 1,000mL (5 and 10mg of Olanzapine) and 500mL (2.5mg of Olanzapine), apparatus II (paddles) and a rotation of 50 rpm. The spectrophotometric parameters were chloride acid 0.1 mol/L as blank and 259nm of wave length. For the assay methodology by UV spectrophotometry, it was used as a solvent and as a blank solution chloride acid 0.1 mol/L and a wave length of 259nm. It was used a ProStar 210 UV/VIS VARIAN high efficient liquid chromatographer, a C18 (150x4,6)mm 5μm column in room temperature (25ºC), a flux of 0,8mL/min, a wave length of 254nm and a mobile phase constituted of a mixture of monobasic potassium phosphate buffer 0,01 mol/L pH 2,5 and acetonitrile (70:30) for the assay methodology by HPLC-UV. The results found from the parameters of specificity, linearity, accuracy, precision, quantification and detection limits and stability in the methodologies validations confirm that they were adequate for the purpose proposed. The methodologies developed and validated were applied in Olanzapine determination in several formulation propositions which have been developed and they assisted the pharmacotechnical development team in the definition of the best olanzapine formulation in the 2.5mg strength.Item Estudo Farmacognóstico, Investigação das Atividades Antimicrobiana, Leishmanicida e Toxicidade Aguda de Rhamnidium elaeocarpum Reissek RHAMNACEAE (Cafezinho)(Universidade Federal de Goiás, 2009-08-27) OLIVEIRA, Tiago Branquinho; PAULA, José Realino de; http://lattes.cnpq.br/3191837532986128In the last years the treatment with medicines made from medicinal plants has increased. A concern about the useful of these natural products is the quality control pharmacobotanical, phytochemical and purity tests, which make up the technical specifications of a particular plant species. Moreover, pharmacological and toxicological studies must be conducted in order to effectiveness and safety. This study aimed to carry out the assessment pharmacognostic, acute toxicity and evaluation of antimicrobial and leishmanicidal of the ethanol extract of the leaves, fruit, stem bark and root bark of R. elaeocarpum Reissek. Samples of R. elaeocarpum were collected in the municipality of Campestre-GO, a description of the macroscopic aspects of the leaves, stem bark and root bark was carried to the naked eye by observing the macroscopic general of vegetal drugs; the microscopical analysis was performed by observing the histological stained. The qualitative analysis of the major classes of secondary metabolites present in the sprayed sample. The tests for water content, total ashes and acid insoluble ashes had been carried through according to the brazilian pharmacopoeia IV. The rude ethanol extract was obtained by maceration and the fractions were obtained by partition, liquid-liquid, successive with hexane, dichloromethane and ethyl acetate. Minimum inhibitory concentration (MIC) was determined by agar dilution. The procedure was performed according to NCCLS standards 2004 (M7-A7). The evaluation of acute toxicity of ethanol extracts had reference to the Guidelines of 423 Organization for Economic Co-Operation and Development (OECD). The leishmanicidal activity was tested for the promastigotes forms of Leishmania (L) chagasi. Most of the morphological and anatomical characteristics observed are consistent with the typical family. In phytochemical screening of leaf, root bark, stem bark and fruit of R. elaeocarpum verified the presence of flavonoids and alkaloids. It was also the presence of heterosides saponins and tannins in leaf, root bark, stem bark and is absent in the fruit. The extracts and fractions that had obtained the lowest value of minimum inhibitory concentration (0,390 mg.mL-1) against microorganisms tested showed moderate inhibitory activity. None of the extracts and fractions showed good inhibitory activity. As is said about the toxicological research, throughout the period of observation of animals during the evaluation of acute toxicity was not death. Through behavioral observations made through the hippocratic screening is assigned a zero score for all evaluated items. The necropsy of the animals did not evidence any macroscopic alterations to justify the histopathology of the organs (kidney, spleen and liver) selected for analysis. This study demonstrated that the use of rude extract and fractions of leaves of R. elaeocarpum induced death of promastigotes forms of L. (L) chagasi in vitro. The presented results open perspectives for the future isolation, purification and identification of bioactive substances of R. elaeocarpum