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1.
Rev. Pesqui. Fisioter ; 11(1): 11-31, Fev. 2021. ilus
Article in English, Portuguese | LILACS | ID: biblio-1252814

ABSTRACT

INTRODUÇÃO: Existem várias escalas para avaliar as percepções subjetivas e os componentes individuais em indivíduos com osteoartrite (OA) de joelho. Até o momento, não há escalas disponíveis conhecidas para medir o equilíbrio combinado entre mobilidade, AVD e QV em OA de joelho com base na Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF). OBJETIVO: Gerar itens e domínios relacionados aos problemas enfrentados pelos indivíduos com OA de joelhos e validar o conteúdo por especialistas. MÉTODOS: Os domínios e itens foram gerados através de pesquisa bibliográfica extensa (ELS) para extrair itens relacionados a equilíbrio, mobilidade, ADL e QV em indivíduos com OA em joelhos baseados na CIF e através de entrevista aprofundada direta (EAD) em 13 pessoas com OA de joelhos e três especialistas. A validação de conteúdo dos domínios e itens gerados foi validada por 10 especialistas por meio da pesquisa Delphi online. O índice mínimo de validação de conteúdo em nível de item (I-CVI) de 0,80 foi considerado para validar os itens identificados e o índice de validação de conteúdo em nível de escala geral (S-CVI) de 0,90 foi fixado para validar os itens gerados para uso no processo de desenvolvimento da escala. RESULTADOS: Os 117 itens gerados por EAD na ELS foram inicialmente agrupados em 18 domínios. A validação de conteúdo pelo método Delphi resultou em uma diminuição para 56 itens agrupados em 14 domínios com SCVI de 0, 93. CONCLUSÃO: O conjunto abrangente de itens de deficiência, limitação de atividade e restrição de participação para indivíduos com OA de joelhos nos domínios propostos foi desenvolvido e o conteúdo validado. Esses itens são recomendados para uso no desenvolvimento de uma nova escala abrangente de índice de osteoartrite do joelho (CKOAI).


INTRODUCTION: There are several scales to evaluate subjective perceptions and individual components in individuals with knee osteoarthritis (IKOA). Till date, no scale is available to measure the combined balance, mobility, ADL and QoL in IKOA based on the International Classification of Functioning, Disability and Health (ICF). OBJECTIVE: The purpose of the study was to generate items and domains related to problems faced by IKOA and to validate the content by experts. METHODS: The domains and items were generated through extensive literature search (ELS) to extract items related to symptoms, balance, mobility, ADL and QoL in IKOA based on the International Classification of Functioning, Disability and Health (ICF) and through in-depth direct interview (IDDI) from 13 IKOA and three experts. The content validation of domains and items generated were validated by 10 experts through online Delphi survey. Minimum itemlevel content validation index (I-CVI) of 0.80 was considered to validate the identified items and the overall scale-level content validation index (S-CVI) of 0.90 was fixed to validate the generated items to use in scale development process. RESULTS: 117 items generated by IDDI and ELS were grouped under 18 domains initially. Content validation by Delphi method resulted in reduction with 56 item pool being grouped under the 14 domains with SCVI is 0.93. CONCLUSION: The comprehensive impairment, activity limitation and participation restriction item pool for IKOA under the proposed domains, have been developed and content validated. These items are recommended for their use in development of new comprehensive knee osteoarthritis index scale (CKOAI).


Subject(s)
Osteoarthritis , Chemistry, Pharmaceutical , Knee
2.
Arch. endocrinol. metab. (Online) ; 63(6): 601-607, Nov.-Dec. 2019. tab
Article in English | LILACS | ID: biblio-1055017

ABSTRACT

ABSTRACT Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7


Subject(s)
Humans , Child , Adult , Human Growth Hormone/administration & dosage , Growth Disorders/drug therapy , Drug Administration Schedule , Drug Design , Chemistry, Pharmaceutical , Human Growth Hormone/pharmacokinetics , Human Growth Hormone/chemistry , Delayed-Action Preparations
3.
Article in Chinese | WPRIM | ID: wpr-773719

ABSTRACT

The contents of terrestroside B and terrestrosin K in Tribuli Fructus with different degree of stir-frying were determined by high performance liquid chromatography with evaporative light-scattering detector( HPLC-ELSD). The results showed that the contents of terrestroside B and terrestrosin K were increased at first and then decreased,and both of them had the highest content at the best time of heating. The results of simulated processing of Tribulus Terrestris saponins showed that when the processing time kept constant,the contents of terrestroside B and terrestrosin K were decreased gradually with the increase of processing temperature from 180 ℃ to240 ℃. At a certain temperature,the content of terrestrosin K was increased first and then decreased with the prolongation of processing time,and reached the highest level at 5 min. However,the content of terrestroside B was increased first and then decreased with the increase of processing time only at 180 ℃,and reached the highest level at 10 min. When the processing temperature was controlled at200,220 and 240 ℃ respectively,the content of terrestroside B was decreased gradually with the increase of processing time. The simulated processing products of tribuluside A,terrestroside B and terrestrosin K were qualitatively characterized by ultra-performance liquid chromatography-time of flight mass spectrometry( UPLC-TOF/MS). It was proved that tribuluside A and terrestrosin Ⅰ containing C-22-OH were dehydroxylated in the processing of Tribuli Fructus and transformed respectively into terrestroside B and terrestrosin K containing C-20-C-22 double bond. As a result,the contents of terrestroside B and terrestrosin K were increased. The sugar chains at C-3 and C-26 positions of terrestroside B and terrestrosin K could be deglycosylated and converted into monosaccharide chain saponins and short sugar chain saponins,so the contents of terrestroside B and terrestrosin K were reduced. The study provides reference for further revealing the processing principle of Tribuli Fructus.


Subject(s)
Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Fruit , Chemistry , Saponins , Tandem Mass Spectrometry , Tribulus , Chemistry
4.
Article in Chinese | WPRIM | ID: wpr-773718

ABSTRACT

To enhance in vitro dissolution of Cur by preparing Cur solid dispersions. The ability of HPMCAS-HF,HPMCAS-MF,HPMCAS-LF and PVPK30 to maintain supersaturated solution was investigated by supersaturation test. Amorphous solid dispersions were prepared by the solvent-evaporation method. The prepared samples were characterized using infrared spectroscopy( IR) and differential scanning calorimetry( DSC),and in vitro dissolution was investigated. DSC and IR results showed that in 1 ∶3 and 1 ∶9 solid dispersions,Cur was amorphously dispersed in the carrier,and the interaction existed between drug and carrier. The supersaturation test showed that the order of the ability of polymer to inhibit crystallization of Cur was MF>HF>LF>K30. The dissolution results showed that Cur-K30 amorphous solid dispersion had the highest drug release rate; Cur-K30 and Cur-LF amorphous solid dispersions had a quicker but not stable dissolution rate,and the drug concentration decrease after 4 h; Cur-MF and Cur-HF solid dispersions had a low dissolution,which however increased steadily,attributing to the strong ability of the polymers to inhibit the crystallization of Cur. HPMCAS could inhibit the degradation of Cur better than K30,especially MF and HF. The amorphous solid dispersions of cur significantly enhanced the dissolution of Cur and improved the chemical stability of Cur. This study can provide a basis for the rational selection of the polymer used for Cur solid dispersion.


Subject(s)
Chemistry, Pharmaceutical , Curcumin , Chemistry , Drug Stability , Methylcellulose , Chemistry , Polymers , Solubility
5.
HU rev ; 45(3): 254-260, 2019.
Article in Portuguese | LILACS | ID: biblio-1049302

ABSTRACT

Introdução: Dentre os corantes de fontes naturais disponíveis no mercado, os mais comuns são aquelas capazes de conferir as cores vermelha, roxa, laranja e amarela, sendo a coloração azul relativamente escassa. A espécie Ravenala madagascariensis, também conhecida como árvore dos viajantes, é uma planta oriunda da Ilha de Madagascar, África do Sul, característica por sementes recobertas por arilos fibrosos de coloração azul intensa. Objetivo: Descrever uma metodologia capaz de extrair e incorporar os corantes azuis presentes nos arilos em uma formulação dermocosmética estável. Metodologia: Foi realizado screening com distintos líquidos extratores para a obtenção do extrato dos arilos. O extrato em ciclometicone foi incorporado em preparações cosméticas empregando-se as bases Polawax® e Cold cream. Após a avaliação dos aspectos sensoriais, a formulação preparada com Polawax foi direcionada para avaliação de estabilidade acelerada (15 dias) de acordo com o protocolo definido pela ANVISA. Resultados: O melhor processo extrativo foi obtido pela utilização do ciclometicone, que é um excipiente compatível com o preparo de formulações cosméticas. O produto contendo 1% do extrato dos arilos em ciclometicone, incorporado à base Polawax, foi avaliado em relação às variáveis aspecto, cor (azul), odor, sensação ao tato e pH (5,5) e não apresentou alterações no ensaio de estabilidade acelerado. Conclusão: Com a metodologia apresentada, foi possível extrair e preparar uma formulação dermocosmética estável com nova proposta de corante azul, aplicável como excipiente para formulações.


Introduction: Among the dyes from natural sources available in the market, the most common are those capable of giving the colors red, purple, orange and yellow, being the blue coloration relatively scarce. The Ravenala madagascariensis species, also known as the traveler's tree, is a plant from Madagascar Island, South Africa, characterized by seeds covered by intense blue colored fibrous aryls. Objective: To describe a methodology capable of extracting and incorporating the blue dyes present in aryls in a stable dermocosmetic formulation. Methodology:Screening with different extracting liquids was performed to obtain the extract of the arils. The cyclomethicone extract was incorporated into cosmetic preparations using the Polawax® and Cold cream bases. After evaluation of sensory aspects, the formulation prepared with Polawax was directed to accelerated stability evaluation (15 days) according to the protocol defined by ANVISA. Results: The best extraction process was obtained by the use of cyclomethicone, which is an excipient compatible with the preparation of cosmetic formulations. The product containing 1% of the cyclomethicone aryl extract, incorporated into the Polawax base, was evaluated in relation to the variables appearance, color (blue), odor, touch sensation and pH (5.5) and showed no changes in the stability test accelerated. Conclusion:With the methodology presented, it was possible to extract and prepare a stable dermocosmetic formulation with new blue dye proposal, applicable as an excipient for formulations.


Subject(s)
Plants , Chemistry, Pharmaceutical , Color , Cosmetics , Protocols , Coloring Agents , Brazilian Health Surveillance Agency , Cosmetic Coloring Agents
6.
Article in Chinese | WPRIM | ID: wpr-773257

ABSTRACT

To establish and validate the design space of the Digeda-4 flavored decoction( DGD-4D) extraction process by using the quality by design( Qb D) concept. With DGD-4D decoction pieces as a model drug,with the transfer rate of aesculin,picroside I,picroside Ⅱ,geniposide and the yield of extract as critical quality attributes( CQAs),the single factor experiment design was used to determine the level of each factor; the Plackett-Burman experiment design was used to select the critical process parameters( CPPs);and the Box-Behnken experiment design was used to optimize the extraction process. The design space of the DGD-4D extraction process was established,and finally,four experimental points were selected to verify the established model. The single factor experiment determined the levels of each factor,including soaking time 60 min and 30 min,water adding volume 12 times and 8 times,extraction time 90 min and 30 min,number of extraction times 3 times and 1 time,as well as extraction temperature 100 ℃ and 90 ℃.By Plackett-Burman experimental design,the DGD-4D water addition,extraction time and number of extraction times were determined to be CPPs. The Box-Behnken experimental variance analysis showed that P of the regression model was less than 0. 01 and the misstated value was more than 0. 01,indicating that the model had good predictive ability,and the operation space of CPPs in the DGD-4D extraction process was determined as follows: the amount of water addition was 10-12 times; extraction time 50-80 min; and number of extraction times was 3 times. The design space of DGD-4D extraction process based on the concept of Qb D is conducive to improving the stability of product quality and laying a foundation for the future development of DGD-4D.


Subject(s)
Chemistry, Pharmaceutical , Methods , Drugs, Chinese Herbal , Chemistry , Research Design
7.
Article in Chinese | WPRIM | ID: wpr-771735

ABSTRACT

To compare the quality difference between Mahuang Xixin Fuzi decoction(MXF) prepared by traditional decocting method and that prepared by two commonly used decocting methods, and explore the scientific nature of the traditional decocting method. By taking effect-toxic components in MXF as the research object, this article investigated these three different decocting methods from the quantitative determination of effect-toxic components in MXF. By using multivariate statistical analysis methods, three characteristic constituents were identified as kakoul, mesaconitine (MA) and hypaconitine (HA) respectively. As compared with two commonly used decocting methods, MXF decoction prepared by traditional decocting method had the shortest boiling time, but with the lowest dissolution rates of MA and AC and the higher dissolution rates of mono-ester aconitum alkaloids. In addition, the traditional decocting method increased the dissolution of ephedra alkaloid and accelerated the hydrolysis of diester diterpenoid alkaloids. There were differences in the content of effect-toxic components in MXF decoctions prepared by three different decocting methods, which can provide a reference for use of the classical prescriptions.


Subject(s)
Alkaloids , Chemistry , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Chemistry , Reference Standards , Plant Extracts , Chemistry
8.
Article in Chinese | WPRIM | ID: wpr-771707

ABSTRACT

Ginger juice, a commonly used adjuvant for Chinese materia medica, is applied in processing of multiple Chinese herbal decoction pieces. Because of the raw materials and preparation process of ginger juice, it is difficult to be preserved for a long time, and the dosage of ginger juice in the processing can not be determined base on its content of main compositions. Ginger juice from different sources is hard to achieve consistent effect during the processing of traditional Chinese herbal decoction pieces. Based on the previous studies, the freeze drying of ginger juice under different shelf temperatures and vacuum degrees were studied, and the optimized freeze drying condition of ginger juice was determined. The content determination method for 6-gingerol, 8-gingerol, 10-gingerol and 6-shagaol in ginger juice and redissolved ginger juice was established. The content changes of 6-gingerol, 8-gingerol, 10-gingerol, 6-gingerol, 6-shagaol, volatile oil and total phenol were studied through the drying process and 30 days preservation period. The results showed that the freeze drying time of ginger juice was shortened after process optimization; the compositions basically remained unchanged after freeze drying, and there was no significant changes in the total phenol content and gingerol content, but the volatile oil content was significantly decreased(<0.05). Within 30 days, the contents of gingerol, total phenol, and volatile oil were on the decline as a whole. This study has preliminarily proved the feasibility of freeze-drying process of ginger juice as an adjuvant for Chinese medicine processing.


Subject(s)
Adjuvants, Pharmaceutic , Chemistry, Pharmaceutical , Methods , Drugs, Chinese Herbal , Reference Standards , Freeze Drying , Ginger , Chemistry , Materia Medica , Reference Standards
9.
Article in English | WPRIM | ID: wpr-773604

ABSTRACT

Analysis errors can occur in the desorbing process of ginkgo diterpene lactone meglumine injection (GDMI) by a conventional analysis method, due to several factors, such as easily crystallized samples, solvent volatility, time-consuming sample pre-processing, fixed method, and offline analysis. Based on risk management, near-infrared (NIR) and mid-infrared (MIR) spectroscopy techniques were introduced to solve the above problems with the advantage of timely analysis and non-destructive nature towards samples. The objective of the present study was to identify the feasibility of using NIR or MIR spectroscopy techniques to increase the analysis accuracy of samples from the desorbing process of GDMI. Quantitative models of NIR and MIR were established based on partial least square method and the performances were calculated. Compared to NIR model, MIR model showed greater accuracy and applicability for the analysis of the GDMI desorbing solutions. The relative errors of the concentrations of Ginkgolide A (GA) and Ginkgolide B (GB) were 2.40% and 2.89%, respectively, which were less than 5.00%. The research demonstrated the potential of the MIR spectroscopy technique for the rapid and non-destructive quantitative analysis of the concentrations of GA and GB.


Subject(s)
Chemistry, Pharmaceutical , Methods , Reference Standards , Drug Compounding , Reference Standards , Drugs, Chinese Herbal , Chemistry , Reference Standards , Ginkgolides , Chemistry , Reference Standards , Injections , Lactones , Least-Squares Analysis , Meglumine , Chemistry , Reference Standards , Reproducibility of Results , Risk Management , Spectrophotometry, Infrared , Reference Standards
10.
Article in English | WPRIM | ID: wpr-812393

ABSTRACT

Analysis errors can occur in the desorbing process of ginkgo diterpene lactone meglumine injection (GDMI) by a conventional analysis method, due to several factors, such as easily crystallized samples, solvent volatility, time-consuming sample pre-processing, fixed method, and offline analysis. Based on risk management, near-infrared (NIR) and mid-infrared (MIR) spectroscopy techniques were introduced to solve the above problems with the advantage of timely analysis and non-destructive nature towards samples. The objective of the present study was to identify the feasibility of using NIR or MIR spectroscopy techniques to increase the analysis accuracy of samples from the desorbing process of GDMI. Quantitative models of NIR and MIR were established based on partial least square method and the performances were calculated. Compared to NIR model, MIR model showed greater accuracy and applicability for the analysis of the GDMI desorbing solutions. The relative errors of the concentrations of Ginkgolide A (GA) and Ginkgolide B (GB) were 2.40% and 2.89%, respectively, which were less than 5.00%. The research demonstrated the potential of the MIR spectroscopy technique for the rapid and non-destructive quantitative analysis of the concentrations of GA and GB.


Subject(s)
Chemistry, Pharmaceutical , Methods , Reference Standards , Drug Compounding , Reference Standards , Drugs, Chinese Herbal , Chemistry , Reference Standards , Ginkgolides , Chemistry , Reference Standards , Injections , Lactones , Least-Squares Analysis , Meglumine , Chemistry , Reference Standards , Reproducibility of Results , Risk Management , Spectrophotometry, Infrared , Reference Standards
11.
São Paulo; s.n; s.n; 2018. 123 p. ilus, graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-998353

ABSTRACT

A tuberculose (TB) é considerada uma das principais doenças infecciosas e apresenta fatores críticos como a relação com o HIV/AIDS, tratamento longo e a resistência a múltiplos fármacos. A enzima di-hidrofolato redutase das micobactérias (mtDHFR) é um alvo pouco explorado e apresenta grande potencial para o desenvolvimento de novos fármacos contra TB. Estudos preliminares obtiveram fragmentos com baixa afinidade à mtDHFR, entretanto com potencial para otimização. Com isso, o fragmento foi usado como protótipo para a proposição de 22 análogos. Os compostos foram planejados utilizando informações sobre ligantes e a estrutura tridimensional de mtDHFR, além do biososterismo como estratégia norteadora. Os ensaios de docking molecular com a mtDHFR revelaram que os análogos propostos tiveram escores interessantes e, além disso, a inserção de substituintes demonstrou favorecer a ligação à enzima, o que corroborou o planejamento. Com isso, sintetizou-se 22 análogos planejados e o protótipo MB872, por meio de protocolos de alquilação, hidrólise e cicloadição 1,3 dipolar para os compostos com anéis triazol e tetrazol. Os compostos foram obtidos com rendimentos de bom a ótimo (60 ~ 90%) e suas estruturas foram elucidadas por RMN 1H e 13C. Os resultados do ensaio de inibição enzimática corroboraram com os dados de docking, uma vez que a presença do grupo carboxílico revelou ser importante para a atividade. Além disso, alguns dos compostos revelaram atividades interessantes, entre 8 a 40 µM, sendo que o mais ativo apresentou IC50 de 7 µM. Ensaios de cinética enzimática com o análogo mais ativo indicou uma inibição não competitiva com o substrato natural da enzima, uma vez que os valores de Km se mantiveram constantes, enquanto Vmax decaiu (0,22 µM e 0,43 - 0,34 ΔFU/min, respectivamente). Os análogos sintetizados foram mandados para ensaio in vitro para avaliar a atividade frente a micobactéria


Tuberculosis (TB) is an important infectious disease and presents critical factors such as the relationship with HIV / AIDS, long treatment and resistance to multiple drugs. The enzyme dihydrofolate reductase from mycobacteria (mtDHFR) is a poorly explored and presents great potential to be a target for new drugs against TB. Preliminary studies have obtained fragments with low affinity to mtDHFR, but with potential to become lead compounds. Therefore, the fragment was used as a prototype for 22 analogues proposed in this work. The compounds were designed using bioisosterism, information about ligands and the three-dimensional structure of mtDHFR. Molecular docking assays with mtDHFR revealed satisfactory scores for anlogues. Furthermore, the insertion of substituents seemed to increase the affinity with the enzyme. Thereby, twenty two analogues and prototype were synthesized using alkylation, hydrolysiss and 1,3-dipolar cycloaddition methods. The compounds were obtained in good yields (60 ~ 90%) and their structures were elucidated with 1H and 13C NMR spectroscopy. The enzymatic affinity assay corroborates docking results, because the presence of carboxyl group showed to be important for the activity. Furthermore, some of the compounds revealead interesting activities, ranging 8 to 40 µM. The most active showed IC50 of 7 µM and enzyme kinetics assays indicated noncompetitive inhibition with natural enzyme substrate. The synthesized analogs were sent for in vitro assay to assess mycobacteria activity


Subject(s)
Process Optimization , Molecular Docking Simulation/instrumentation , Mycobacterium/classification , Tetrahydrofolate Dehydrogenase/analysis , Tuberculosis/pathology , Chemistry, Pharmaceutical/methods
12.
São Paulo; s.n; s.n; 2018. 90 p. tab, graf, ilus.
Thesis in Portuguese | LILACS | ID: biblio-906084

ABSTRACT

A tuberculose (TB) é uma das maiores causas de morte por infecção no mundo, sendo que, em 2015, registraram-se 10,4 milhões de novos casos. O agente etiológico da doença, o Mycobacterium tuberculosis (Mtb), apresenta altos níveis de resistência frente aos quimioterápicos disponíveis para o tratamento da TB. Além disso, a terapia atual da doença explora poucos alvos essenciais ao Mtb. Neste sentido, explorar novos alvos, essenciais ao crescimento e sobrevivência da micobactéria é de grande interesse e poderia gerar fármacos mais efetivos, eficazes contra cepas resistentes e a forma latente da TB. Para este fim, o presente trabalho propôs o desenvolvimento de inibidores da enzima fosfopanteteína adenililtransferase (PPAT), a qual possui caráter regulatório na via de biossíntese da Coenzima A (CoA) da micobactéria. Inicialmente, propuseram-se 50 estruturas de potenciais inibidores da PPAT de M. tuberculosis (MtPPAT), baseando-se na estrutura de seu substrato, a fosfopanteteína, e na estrutura do sítio ativo da enzima. Em seguida, propuseram-se outros 28 ligantes. A fim de se prever as potenciais complementaridades entre os 78 inibidores propostos e o sítio ativo da MtPPAT, empregou-se a estratégia de docking. Posteriormente, realizaram-se cálculos semi-empíricos, com os complexos dos ligantes que se mostraram mais interessantes nas simulações de docking, a fim de se obter informações sobre a entalpia de interação dos ligantes com o sítio ativo da MtPPAT. A partir dos resultados obtidos nos estudos computacionais, selecionaram-se os inibidores que se mostraram mais promissores. A síntese destes ligantes e a de seus fragmentos foi realizada. Avaliaram-se a atividade microbiológica in vitro, bem como a citotoxicidade dos ligantes sintetizados. Alguns dos compostos sintetizados apresentaram atividade frente às cepas sensíveis e resistentes do Mtb na casa de micromolar. Todos os compostos ativos não foram considerados citotóxicos. A fim de validar o planejamento e o alvo dos possíveis inibidores, verificando a atividade inibitória desses frente à enzima MtPPAT, realizou-se a produção e purificação da enzima. Por fim, realizaram-se ensaios de inibição enzimática frente à MtPPAT, os quais permitiram a identificação dos primeiros inibidores da enzima já descritos, com atividade na casa de micromolar, validando-se o alvo em questão


Tuberculosis is one of the major causes of death by infection worldwide. In 2015, 10.4 thousand new cases of the disease were registered. The tuberculosis' causing agent Mycobacterium tuberculosis presents high levels of resistance for the available chemotherapy. Thereof, exploit new M. tuberculosis targets is of utmost importance to overcome drug resistant tuberculosis. In this sense, the enzyme phosphopantetheine adenylyltransferase (PPAT) generates scientific interest since it displays a regulatory role in the M. tuberculosis coenzyme A (CoA) biosynthesis. Therefore, the purpose of the present study was the development of M. tuberculosis PPAT (MtPPAT) inhibitors. Initially, 50 potentially MtPPAT inhibitors were designed based on MtPPAT's substrate and the enzyme's active site. After preliminary results, more 28 compounds were designed. Docking simulations were performed with the 78 compounds synthesized, leading to the prediction of the interaction between the proposed inhibitors and MtPPAT active site. Latelly, semi-empirical calculations were performed with the most promising compounds. These calculations were carried out to obtain information about the enthalpy interactions between compounds and MtPPAT active site. Computational studies led to the selection of the most promising inhibitors. Those compounds and some of their fragments were synthesized, purified, and characterized. The synthesized compounds had their in vitro microbiological activity and cytotoxicity evaluated. Some of the synthesized compounds showed activity against the Mtb sensitive and resistant strains in micromolar range. Besides that, the active compounds were not considered cytotoxic. To validate the potential inhibitors' design and evaluate their capacity to inhibit MtPPAT, the enzyme was produced and purified. MtPPAT inhibitory assays were performed, leading to the first inhibitors of the enzyme, with activity in micromolar range, validating the target


Subject(s)
Enzyme Inhibitors/analysis , Tuberculosis/prevention & control , Chemistry, Pharmaceutical/classification , Coenzyme A , Drug Compounding , Drug Discovery , Mycobacterium tuberculosis/metabolism
13.
An. acad. bras. ciênc ; 90(1,supl.1): 645-661, 2018. graf
Article in English | LILACS | ID: biblio-886933

ABSTRACT

ABSTRACT Scientific and technological breakthroughs have compelled the current players in drug discovery to increasingly incorporate knowledge-based approaches. This evolving paradigm, which has its roots attached to the recent advances in medicinal chemistry, molecular and structural biology, has unprecedentedly demanded the development of up-to-date computational approaches, such as bio- and chemo-informatics. These tools have been pivotal to catalyzing the ever-increasing amount of data generated by the molecular sciences, and to converting the data into insightful guidelines for use in the research pipeline. As a result, ligand- and structure-based drug design have emerged as key pathways to address the pharmaceutical industry's striking demands for innovation. These approaches depend on a keen integration of experimental and molecular modeling methods to surmount the main challenges faced by drug candidates - in vivo efficacy, pharmacodynamics, metabolism, pharmacokinetics and safety. To that end, the Laboratório de Química Medicinal e Computacional (LQMC) of the Universidade de São Paulo has developed forefront research on highly prevalent and life-threatening neglected tropical diseases and cancer. By taking part in global initiatives for pharmaceutical innovation, the laboratory has contributed to the advance of these critical therapeutic areas through the use of cutting-edge strategies in medicinal chemistry.


Subject(s)
Humans , Trypanocidal Agents/chemistry , Chemistry, Pharmaceutical , Drug Discovery/methods , Neglected Diseases/drug therapy , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Schistosomiasis/drug therapy , Tropical Medicine/trends , Chagas Disease/drug therapy
14.
Braz. J. Pharm. Sci. (Online) ; 54(4): e17361, 2018. tab, graf
Article in English | LILACS | ID: biblio-1001561

ABSTRACT

All-trans retinoic acid (ATRA) has been studied for the treatment of cancer, including leukemia and breast cancer. This work aims to develop nanoemulsions (NE) loaded with a hydrophobic ion pair (HIP) of all-trans retinoic acid (ATRA) and a lipophilic amine, stearylamine (SA), and coated with hyaluronic acid (HA) to enhance anticancer activity and reducing toxicity. Blank NE was prepared by spontaneous emulsification and optimized prior to HIP incorporation. NE-ATRA was electrostatically coated with different concentrations of HA. Incorporation of ATRA-SA led to monodisperse NE with small size (129 ± 2 nm; IP 0.18 ± 0.005) and positive zeta potential (35.7 ± 1.0 mV). After coating with 0.5 mg/mL HA solution, the mean diameter slightly increased to 158 ± 5 nm and zeta potential became negative (-19.7 ± 1.2 mV). As expected, high encapsulation efficiency (near 100%) was obtained, confirmed by polarized light microscopy and infrared analysis. Formulations remained stable over 60 days and release of ATRA from NE was delayed after the hydrophilic HA-coating. HA-coated NE-ATRA was more cytotoxic than free ATRA for MDA-MB-231 and MCF-7 breast cancer cell lines, especially in the CD44 overexpressing cells. Blank coated formulations showed no cytotoxicity. These findings suggest that this easily-made HA-coated NE-ATRA formulation is a promising alternative for parenteral administration, thus improving the breast cancer therapy with this drug.


Subject(s)
Tretinoin/analysis , Breast Neoplasms/drug therapy , Pharmaceutical Preparations/analysis , Chemistry, Pharmaceutical , Hyaluronic Acid
15.
São Paulo; s.n; s.n; 2018. 139 p. tab, graf, ilus.
Thesis in Portuguese | LILACS | ID: biblio-997679

ABSTRACT

As neoplasias malignas, doenças mundialmente conhecidas como câncer, possuem um dos tratamentos mais onerosos, tóxicos e de baixa seletividade na terapêutica atual. Adicionalmente, o contínuo crescimento da incidência da doença também representa em uma grande problemática. Os produtos de origem natural se apresentam como alternativas para o tratamento de diversas doenças, incluindo o câncer. A capsaicina, produto natural proveniente das pimentas do gênero Capsicum, apresenta propriedades antineoplásicas, portanto, pode ser utilizada como protótipo para obtenção de análogos. Quatro séries foram planejadas e sintetizadas, obtendo-se compostos ureídicos e tioureídicos. A estratégia sintética se baseou na reação da piperonilamina ou vanililamina com isocianatos ou isotiocianatos, ligados a substituintes aromáticos ou alquílicos. Vinte e sete análogos foram sintetizados com rendimentos variando entre 22 a 90 %. Todos os compostos apresentaram aspecto sólido variando a cor de branco a levemente amarelados. Para a caracterização das substâncias obtidas foram utilizados dados de RMN 1H e 13C, ponto de fusão e a determinação de pureza foi realizada mediante HPLC. Todos os compostos foram submetidos a ensaios de avaliação da atividade citotóxica por redução do MTT contra linhagens de células cancerígenas e células sadias. Os compostos RPF652, RPF 512 - 514) apresentaram atividade comparável ou superior ao protótipo com valores de IC50 na faixa de micromolar. Os resultados apontados pela modelagem molecular indicam que descritores eletrônicos como Ehomo e Elumo podem estar associados à atividade do composto, ClogP (3,92) pode favorecer melhor permeabilidade na membrana celular, e o maior número de sítios de acepção de ligação de hidrogênio podem corroborar com a citotoxidade em linhagem A2058. Particularmente, o análogo RPF652 apresentou atividade pronunciada com valores de IC50 de 55, 67, e 87 µM contra as células A2058, SK-MEL 25, e U87, respectivamente, o que representa atividade de superior à capsaicina. Como uma tendência o composto RPF652 causou parada no ciclo de linhagem B-RAF B16F10 não levando a célula à morte. Porém esta linhagem não apresenta mutação no códon V600E. Em contraponto, o análogo RPF652 apresentou maior potência contra linhagem V600EB-RAF A2058 mutada, indicando possível seletividade em linhagens que apresentam a mutação no códon V600E da proteína B-RAF. Ademais, novos esforços devem ser concentrados no análogo RPF652 para melhor elucidação mecanística de sua atividade


Malignant neoplasms have one of the most expensive, non-selective and toxic treatment of present times. This situation, combined with the rising incidence rate, represents a major problem for humanity. The use of natural products can be an alternative for treatment of several diseases, including cancer. Capsaicin is a natural product derived from Capsicum peppers, with reported anticancer activity and can be used as prototype for the design of new molecules with remarkable activity. Capsaicin analogues were designed and synthesized in four series of derivatives, replacing the prototype amide bond with urea and thiourea functions. The synthetic approach builds the urea/ thiourea scaffold using the reaction of piperonyl/ vanilyl amine with alkyl and aryl isocyanides/ isothiocyanides. Twenty-seven new compounds were obtained with yields from 22 to 90 %, and were fully characterized using 1H and 13C NMR, the purity was determined by melting point and HPLC. All of the obtained compounds were evaluated in MTT cytotoxic assays against different cancer cell-lines (B16F10, A2058, SK-MEL 25 and U-87), and compared with healthy human cells (T75). Additionally, the most active compound was submitted to a cell cycle arrest assay. The thiourea derivative RPF652 was the most active compound, and the urea derivatives RPF512, RPF513 and RPF514 showed good micromolar IC50 values. This results, when correlated with several in silico-calculated properties for the obtained molecules, suggests that ClogP, Ehomo, Elumo and the number of hydrogen-bond acception sites may be correlated to the anticancer activity reported. RPF652 especially, showed IC50 values with superior activity and better selectivity index when compared with capsaicin. The cell-cycle assay of RPF652 showed significant arrest in V600E-codon B-RAF non-mutated cell lines (B16F10) without killing it. V600E-codon B-RAF mutated cells A2058, were significantly more sensitive to the compound. These findings may suggest some insights about the mechanism of action and targets of this compounds


Subject(s)
Drug Screening Assays, Antitumor , Capsaicin/analysis , Antineoplastic Agents/classification , Capsicum/classification , Chemistry, Pharmaceutical/instrumentation , Genus Pimenta/adverse effects , Neoplasms/drug therapy
16.
Rev. cir. traumatol. buco-maxilo-fac ; 17(2): 6-11, abr.-jun. 2017. ilus
Article in Portuguese | LILACS, BBO | ID: biblio-1281196

ABSTRACT

Tumor Odontogênico Ceratocístico (TOC) é classificado como uma lesão intraóssea benigna, de origem odontogênica. Apresenta comportamento biológico agressivo e alta taxa de recidiva. Por sua heterogeneidade clínica e histológica, gera controvérsias em relação ao tipo de tratamento. Técnicas, como marsupialização, descompressão, enucleação, ou mesmo, ressecção cirúrgica, são algumas opções de tratamento, podendo associar com outras formas de terapias. O presente trabalho tem por objetivo relatar o caso de um paciente do gênero masculino que apresentava lesão osteolítica na região posterior direita da mandíbula, diagnosticada como tumor odontogênico ceratocístico. O tratamento proposto foi enucleação associada à aplicação de solução de Carnoy. Após 4 anos de pós-operatório, a técnica cirúrgica associada à terapia química mostrou-se eficaz, apresentando resultados satisfatórios. O paciente segue em acompanhamento, sem referir queixas álgicas e funcionais, além de não apresentar alterações estéticas... (AU)


Keratocystic odontogenic tumor is classified as a benign intraosseous and odontogenic lesion. It presents an aggressive biological behavior and great tendency to relapse. Also, it is a pathology that is noteworthy due to its clinical and histological heterogeneity. This diversity reflects on controversies in defining the adequate treatment for these lesions, opting for surgical techniques such as marsupialization, enucleation or resection, even associate with other conservative treatment. By upgrading the knowledge of cell biology, development of diagnostic tests and the improvement of surgical techniques, the treatment of oral diseases suffered major changes in recent decades, making it safer and leading to more predictable results. This study aims to report the case of a male patient, suffering from osteolytic lesion in the posterior mandible, diagnosed as keratocystic odontogenic tumor, which was treated by enucleation associated to application of Carnoy's solution, which is an alternative treatment already described. After 4 years follow-up, proposed treatment has been shown efficient presenting satisfactory results. Patient remains accompanied with no pain and functional complaints as well as no aesthetics alterations... (AU)


Subject(s)
Humans , Male , Adult , Odontogenic Cysts , Odontogenic Tumors , Chemistry, Pharmaceutical , Cell Biology , Neoplasms , Wounds and Injuries , Mandible
17.
Rev. colomb. enferm ; 14(1): 65-81, Abril de 2017.
Article in Spanish | LILACS, BDENF, COLNAL | ID: biblio-997712

ABSTRACT

La terapia anticoagulante tiene múltiples indicaciones en diversos contextos; va más allá de la prevención de la formación de \r\ntrombos o su propagación y tiene como objetivo final mejorar la calidad de vida de los pacientes. En efecto, la anticoagula\r\n-\r\nción se hace relevante en diversas situaciones clínicas que abarcan desde enfermedades crónicas hasta patologías quirúrgicas \r\ny situaciones especiales (obesidad, enfermedad renal crónica, trauma, cáncer) para evitar desenlaces adversos, tales como el \r\ntromboembolismo venoso, los estados hipercoagulables, el síndrome coronario agudo, la fibrilación y el aleteo (\r\nflutter\r\n) auricular, \r\nentre otros. En este sentido, la comprensión adecuada y la formulación de dosis óptimas de anticoagulantes recobran especial \r\nimportancia. El objetivo de este trabajo fue revisar la evidencia proveniente de estudios clínicos sobre el papel de los principales \r\nanticoagulantes orales y parenterales en el contexto de los pacientes con indicación de anticoagulación por antecedentes pato\r\n-\r\nlógicos, quirúrgicos y en situaciones especiales como las mencionadas. Existen diversos conceptos y recomendaciones sobre la profilaxis y el tratamiento anticoagulante en indicaciones habituales; sin embargo, se debe establecer un consenso de anticoagu\r\n-\r\nlación en situaciones especiales que se presentan en la práctica clínica diaria.


Anticoagulant therapy has multiple indications in diverse contexts; it \r\ngoes beyond preventing the formation and propagation of thrombi \r\nand has as its final objective improving the quality of life of patients. \r\nIn effect, anticoagulation becomes relevant in diverse clinical situ\r\n-\r\nations, ranging from chronic diseases to surgical pathologies and \r\nspecial situations (obesity, chronic kidney disease, trauma, cancer), \r\nin order to avoid adverse outcomes such as venous thromboem\r\n-\r\nbolism, hypercoagulable states, acute coronary syndrome, atrial \r\nflutter and fibrillation, among others. In this sense, adequate under\r\n-\r\nstanding and formulation of optimum doses of anticoagulants gain \r\nparticular importance.\r\nThe objective of this work was to review the evidence from \r\nclinical studies on the role of the main oral and parenteral \r\nanticoagulants in the context of patients with indication for \r\nanticoagulation for pathological, surgical and special situations \r\nlike the aforementioned. Although there are several concepts \r\nand recommendations in prophylaxis and anticoagulant \r\ntreatment in habitual indications, in special situations that are \r\npresented in daily clinical practice with patients, and for which \r\nthere is still no consensus about medications and dosages \r\noptimal, indications of anticoagulation should be established


A terapia anticoagulante tem múltiplas indicações em diversos \r\ncontextos. Além da prevenção da formação de trombos \r\nou sua propagação, ela tem como objetivo final melhorar a \r\nqualidade de vida dos pacientes. De fato, a anticoagulação é \r\nrelevante em diversas situações clínicas que abrangem desde \r\ndoenças crônicas até patologias cirúrgicas e situações especiais \r\n(obesidade, doença renal crônica, trauma, câncer) para evitar \r\nresultados adversos, tais como tromboembolismo venoso, \r\nestados hipercoaguláveis, síndrome coronária aguda, fibri\r\n-\r\nlação e flutter atrial, entre outros. Deste modo, a compreensão \r\nadequada e a formulação de doses ótimas de anticoagulantes \r\nsão particularmente importantes. O objetivo deste trabalho \r\nfoi revisar a evidência proveniente de estudos clínicos sobre \r\no papel dos principais anticoagulantes orais e parentais no \r\ncontexto dos pacientes com indicação de anticoagulação por \r\nantecedentes patológicos, cirúrgicos e em situações especiais, \r\ncomo as mencionadas. Existem diversos conceitos e reco\r\n-\r\nmendações sobre a profilaxia e o tratamento anticoagulante \r\nem indicações habituais. Entretanto, deve-se estabelecer um \r\nconsenso de anticoagulação em situações especiais que são \r\napresentadas na prática clínica diária


Subject(s)
Chemistry, Pharmaceutical , Anticoagulants
18.
Article in English | WPRIM | ID: wpr-812041

ABSTRACT

As the carrier of water-insoluble drugs, microspheres can play a role in increasing solubility and delaying releasing essence. The objective of this study was to improve the solubility and to delay the release of a newly discovered antitumor compound 3β-hydroxyolea-12-en-28-oic acid-3, 5, 6-trimethylpyrazin-2-methyl ester (T-OA). Early-stage preparation discovery concept (EPDC) was employed in the present study. The preparation, physicochemical characterization, and drug release properties of PLGA microspheres were evaluated. T-OA-loaded PLGA microspheres were prepared by an oil-in-water (O/W) emulsification solvent evaporation method. Characterization and release behaviors of the T-OA PLGA microspheres were evaluated by X-ray diffract (XRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and high performance liquid chromatography (HPLC). The results demonstrated that T-OA-loaded PLGA microspheres could be successfully obtained through solvent evaporation method with appropriate morphologic characteristics and high encapsulation efficiency. The XRD analysis showed that T-OA would be either molecularly dispersed in the polymer or distributed in an amorphous form. The DSC and FTIR analysis proved that there were interactions between T-OA and PLGA polymer. SEM observations displayed the morphology of the microspheres was homogeneous and the majority of the spheres ranged between 50 and 150 μm. The drug release behavior of the microspheres in the phosphate buffered saline medium exhibited a sustained release and the duration of the release lasted for more than 23 days, which was fit with zero-order release pattern with r = 0.9947. In conclusion, TOA-loaded PLGA microspheres might hold great promise for using as a drug-delivery system in biomedical applications.


Subject(s)
Antineoplastic Agents , Chemistry , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical , Delayed-Action Preparations , Chemistry , Drug Carriers , Chemistry , Lactic Acid , Chemistry , Microscopy, Electron, Scanning , Microspheres , Oleanolic Acid , Chemistry , Polyglycolic Acid , Chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Pyrazines , Chemistry , Solubility , Spectroscopy, Fourier Transform Infrared , X-Ray Diffraction
19.
Braz. j. pharm. sci ; 52(3): 509-516, July-Sept. 2016. tab, graf
Article in English | LILACS | ID: biblio-828274

ABSTRACT

ABSTRACT Abamectin is a drug with antiparasitic properties used in several pharmaceutical formulations. The objective of this research was to develop and validate a high performance liquid chromatographic (HPLC) method for quantification of the two abamectin homologs (H2B1a and H2B1b) in gel formulation. This HPLC method was validated using a LichroCart(r) 100 RP-18 (125 x 4 mm, 5 µm) column. The mobile phase contained of acetonitrile and water (95:5 v/v) with 1% acetic acid. The flow rate was 1.0 mL min-1 and UV detection was performed at 245 nm. Mobile phase solutions were prepared containing a nominal concentration 185.2 µg mL-1 H2B1a and 9.6 µg mL-1 H2B1b. The method displayed good linearity in the concentration range of 148.1 - 222.3 µg mL-1 and 7.7 - 11.5 µg mL-1, for H2B1a and H2B1b, respectively, with a correlation coefficient of (r)> 0.99 for both compounds, calculated by the least mean squares method. Detection limits (DLs) were 2.8 µg mL-1 and 1.2 µg mL-1 and quantitation limits (QLs) were 8.6 µg mL-1 and 3.8 µg mL-1, for H2B1a and H2B1b, respectively. The method is simple, economical and efficient for the quantitative determination of abamectin H2B1a and H2B1b homologs in pharmaceutical preparations.


Subject(s)
Antiparasitic Agents/analysis , Chemistry, Pharmaceutical , Chromatography, Liquid/classification , Chromatography, High Pressure Liquid/statistics & numerical data
20.
Braz. j. pharm. sci ; 52(3): 493-507, July-Sept. 2016. tab, graf
Article in English | LILACS | ID: biblio-828277

ABSTRACT

ABSTRACT The objective of the study is to formulate and evaluate a topical herbal gel containing Cardiospermum halicacabum and Vitex negundo leaf extracts for their anti-arthritic activity in rats. Twelve herbal gel formulations were prepared using 1.5% of gelling agents carbopol 934 (F1-F6) and carbopol 940 (F6-F12) and they were evaluated for physical appearance, net content, viscosity, extrudability, pH, spreadability, in vitro diffusion profile and primary skin irritation tests. The stability study for the topical herbal gel formulation was done as per ICH guidelines and anti-arthritic activity was evaluated by Freund's Complete Adjuvant (FCA) induced arthritis method. Assessment of body weight, paw volume, hematological and biochemical parameters, histopathological examination and In vitro determination of serum biomarkers were also carried out. Formulated gels were homogenous, stable and complied with the guidelines. Among the formulations, F4 showed better release (98.4 %) characteristics than other formulations. No erythema or edema was observed in the skin irritation test confirming the gel was non-toxic and safe. Topical application of the herbal gel F4 containing carbopol 934 displayed significant (p < 0.001) anti-arthritic activity compared to diseased rats. Reduction in paw volume, no agglutination in C - reactive protein and rheumatic factor, reduction in TNF level, regaining of normal hematological, and biochemical parameters, reduction in spleen and thymus weight and histopathological examination supported the anti-arthritic activity of the gel formulation.


Subject(s)
Rats , Arthritis/diagnosis , Chemistry, Pharmaceutical/methods , Evaluation Studies as Topic/methods , Plants, Medicinal/classification , Herbal , Sapindaceae/classification , Vitex/classification
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