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Rev Rene (Online) ; 22: e59963, 2021. graf
Article in Portuguese | LILACS, BDENF | ID: biblio-1149524


RESUMO Objetivo identificar as atividades farmacológicas da manteiga de bacuri (Platonia insignis Mart.). Métodos revisão integrativa, realizada nas bases de dados Literatura Latino-americana e do Caribe em Ciências da Saúde, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library e SCOPUS, sem delimitação temporal e de idioma. A seleção se constituiu de 13 ensaios pré-clínicos. A avaliação das informações ocorreu de forma descritiva, confrontando com os achados pertinentes. Resultados observou-se que 50,0% das publicações foram indexadas na MEDLINE/PubMed, maioria das publicações ocorreram na Inglaterra (61,5%), seguidas do Brasil e dos Estados Unidos, ambos com 13,3%. Destaca-se que 100,0% dos artigos foram ensaios pré-clínicos; atividades farmacológicas para antioxidante (38,4%) e antileishmanicidas (30,7%). Registrou-se que 38,4% dos ensaios apresentaram testes de toxicidade. Conclusão a manteiga de bacuri (Platonia insignis Mart.) apresentou atividades farmacológicas em ensaios pré-clínicos, como antioxidantes, antileshimaniose, anticonvulsivante e cicatrização de feridas.

ABSTRACT Objective to identify the pharmacological activities of bacuri butter (Platonia insignis Mart.). Methods an integrative review, carried out in the databases of Latin American and Caribbean Literature in Health Sciences, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library and SCOPUS, without the time and language restriction. The selection consisted of 13 pre-clinical trials. The information assessment descriptively took place, comparing with the pertinent findings. Results it was observed that 50.0% of the publications were indexed in MEDLINE/PubMed, most publications were from England (61.5%), followed by Brazil and the United States, both with 13.3%. It is noteworthy that 100.0% of the articles were pre-clinical trials; pharmacological activities for antioxidants (38.4%) and antileishmanicides (30.7%). It was found that 38.4% of the trials presented toxicity tests. Conclusion bacuri butter (Platonia insignis Mart.) Showed pharmacological activities in pre-clinical trials, such as antioxidants, antileshimaniasis, anticonvulsant and wound healing.

Benzophenones , Clusiaceae , Drug Compounding , Drug Synergism , Drug Therapy
Säo Paulo med. j ; 138(1): 40-46, Jan.-Feb. 2020. tab, graf
Article in English | LILACS | ID: biblio-1099387


BACKGROUND: Statins are used as cholesterol-lowering drugs and may also have direct antimicrobial effects. OBJECTIVE: To evaluate synergic interactions between simvastatin and both amphotericin B and fluconazole, against environmental strains of Cryptococcus neoformans isolated from captive birds' droppings. DESIGNAND SETTING: Experimental study conducted at Federal University of Piauí, Parnaíba, in collaboration with Federal University of Triângulo Mineiro, Uberaba, Brazil. METHODS: Statin susceptibility tests of Cryptococcus neoformans samples were performed as prescribed in standards. Interactions of simvastatin with amphotericin and fluconazole were evaluated using the checkerboard microdilution method. Presence of these interactions was quantitatively detected through determining the fractional inhibitory concentration index (FICI). RESULTS: Isolates of Cryptococcus neoformans were obtained from 30 of the 206 samples of dry bird excreta (14.5%) that were collected from pet shops and houses. Ten isolates were selected for susceptibility tests. All of them were susceptible to amphotericin and fluconazole. All presented minimum inhibitory concentration (MIC) > 128 µg/ml and, thus, were resistant in vitro to simvastatin. An in vitro synergic effect was shown through combined testing of amphotericin B and simvastatin, such that six isolates (60%) presented FICI < 0.500. Two isolates showed considerable reductions in MIC, from 1 µg/ml to 0.250 µg/ml. No synergic effect was observed through combining fluconazole and simvastatin. CONCLUSION: These results demonstrate that simvastatin should be considered to be a therapeutic alternative, capable of potentiating the action of amphotericin B. However, further studies are necessary to clarify the real effect of simvastatin as an antifungal agent.

Humans , Amphotericin B/pharmacology , Simvastatin/pharmacology , Cryptococcus neoformans , Brazil , Microbial Sensitivity Tests , Fluconazole , Prospective Studies , Drug Synergism , Antifungal Agents/pharmacology
Article in Chinese | WPRIM | ID: wpr-828059


In this study, we explored the antibacterial effect and mechanism of dihydroartemisinin(DHA) combined with cefuroxime(CFX) or ampicillin against Escherichia coli. The minimum inhibitory concentration(MIC) of DHA, cefuroxime, and ampicillin against E. coli was 300,25,25 μmol·L~(-1), respectively, determined by broth microdilution method and 2,3,5-triphenyltetrazolium chloride(TTC) method. The minimum bactericidal concentration(MBC) was 25 μmol·L~(-1) for cefuroxime, above 600 μmol·L~(-1) for DHA. The fractional inhibitory concentration index(FICI) of DHA combined with cefuroxime or ampicillin was 0.375 and 0.75, respectively, determined by checkerboard microdilution assay, suggesting the synergistic effect or additive effect of the drug combination. Moreover, the time-effect curve showed that the antibacterial activity of DHA and CFX combination was much stronger than that of either of the drugs, suggesting that combination with DHA can decrease the CFX dosage. Then we studied the synergistic mechanism of DHA combined with cefuroxime and found that the combination of the two drugs had a significant inhibitory effect on the total protein bands, as shown by the results of polypropylene gel electrophoresis. The results of conductivity method and alkaline phosphatase test respectively showed that its conductivity value and alkaline phosphatase(AKP) leak were significantly higher than either of the drugs, suggesting that the integrity of bacteria may be damaged. The scanning electron microscope(SEM) results showed that the morphology of E. coli was destroyed most in the combination group. The quantitative fluorescence PCR technology showed that the combination of two drugs can inhibit the expression of superoxide stress gene soxS. In summary, the combination of dihydroartemisinin and cefuroxime has a synergistic antibacterial effect on E. coli.

Anti-Bacterial Agents , Artemisinins , Cefuroxime , Drug Synergism , Escherichia coli , Microbial Sensitivity Tests
Braz. arch. biol. technol ; 63: e20190640, 2020. tab, graf
Article in English | LILACS | ID: biblio-1132235


Abstract Nitrogen (N) and potassium (K) in potato crop planting synergistically increase tuber yield, but there are no studies on this interaction in sidedressing. In two experiments with 'Atlantic' potato combinations of four N rates (0, 50, 100, and 150 kg ha-1) with four K2O rates (0, 100, 200, and 300 kg ha-1) were applied in sidedressing in a 4×4 factorial scheme with three replications in a completely randomized design. Adjacent commercial fields were sampled to economic comparisons with experimental results. Significant interaction between N and K sidedressing rates with tuber yields increase also was confirmed and classified as Liebig-synergism. Compared to the isolated N and K applications in sidedressing, joint N and K fertilizations, respectively, increases by 11% and 48% marketable tuber yields in the summer-fall experiment, and 12% and 7% in the spring experiment. Joint N and K applications as sidedressing was more profitable than planting fertilization, mainly at higher N and K rates. The response of specific gravity of 'Atlantic' potato tubers to the N and K sidedressing rates was mediated by interactions between edaphoclimatic conditions and inputs of N and K. The combined application of N and K sidedressing rates increased specific gravity in the summer-fall experiment, but had a negative effect in the spring experiment. Therefore, our results provide strong evidence that the fertilization management for potato crop in Brazil can be modified by applying higher amounts of N and K in sidedressing to match nutritional needs of the crop.

Humans , Potassium/administration & dosage , Solanum tuberosum/growth & development , Solanum tuberosum/economics , Agriculture/economics , Fertility Agents/administration & dosage , Nitrogen/administration & dosage , Drug Synergism , Fertility Agents/economics
Dement. neuropsychol ; 13(4): 422-426, Oct.-Dec. 2019.
Article in English | LILACS | ID: biblio-1056009


ABSTRACT Despite recent advances in cognitive rehabilitation of patients with cognitive disorders, there are many major obstacles to the optimized global use of this therapeutic resource. Objective: The authors outline the concept of 'therapeutic synergism', i.e. the concurrent use of pharmacological and cognitive rehabilitation therapies to maximize functional benefits, addressing the optimization of therapeutic approaches for cognitive disorders. Methods: Three psychopharmacological and rehabilitation interrelationship paradigms are presented in three different clinical settings. Results: Paradigm 1: Behavioral and cognitive symptoms that hinder a cognitive rehabilitation program, but can be improved with psychopharmacology. Paradigm 2: Cognitive symptoms that hinder cognitive rehabilitation, but can be improved with anticholinesterases. Paradigm 3: Behavioral symptoms that hamper the use of cognitive rehabilitation, but can be improved by psychotropic drugs. Conclusion: Judicious use of psychotropic drugs in cognitive disorders can benefit, directly or indirectly, cognitive functions, thereby favoring other treatment modalities for cognitive impairment, such as neuropsychological rehabilitation.

RESUMO Apesar dos recentes avanços na reabilitação cognitiva de pacientes com distúrbios cognitivos, existem muitos e graves obstáculos ao uso otimizado globalmente desse recurso terapêutico. Objetivo: Os autores destacam o conceito de 'sinergismo terapêutico', ou seja, o uso simultâneo de terapias de reabilitação farmacológica e cognitiva, maximizando os benefícios funcionais, a fim de abordar a otimização da abordagem terapêutica dos distúrbios cognitivos. Métodos: Três paradigmas de inter-relacionamento psicofarmacológico e de reabilitação são apresentados em três contextos clínicos diferentes. Resultados: Paradigma 1: sintomas comportamentais e cognitivos que dificultam um programa de reabilitação cognitiva, mas podem ser melhorados com a psicofarmacologia. Paradigma 2: sintomas cognitivos que dificultam a reabilitação cognitiva, mas podem ser melhorados com anticolinesterásicos. Paradigma 3: sintomas comportamentais que dificultam o uso da reabilitação cognitiva melhorada por drogas psicotrópicas. Conclusão: O uso criterioso das drogas psicotrópicas nos distúrbios cognitivos pode beneficiar, direta ou indiretamente, as funções cognitivas, favorecendo, portanto, outras modalidades de tratamento para o comprometimento cognitivo, como a reabilitação neuropsicológica.

Humans , Psychopharmacology , Therapeutics , Drug Synergism , Neurological Rehabilitation
Rev. chil. infectol ; 36(5): 556-564, oct. 2019. tab
Article in Spanish | LILACS | ID: biblio-1058081


Resumen Durante las últimas décadas, especies del género Enterococcus han emergido como importantes agentes etiológicos de bacteriemia, osteomielitis, endocarditis e infecciones de tejidos blandos. La combinación de antibacterianos ha sido la estrategia terapéutica más utilizada para dichas infecciones, buscando un potencial efecto sinérgico bactericida. Sin embargo, aparte de los modelos in vitro e in vivo, la utilidad clínica del tratamiento combinado genera controversia, especialmente en infecciones sistémicas no endocárdicas. Aunque las combinaciones entre β-lactámicos y aminoglucósidos o el tratamiento dual con β-lactámicos, han mejorado las tasas de curación de la endocarditis, aún no se ha esclarecido cuál es su tratamiento óptimo o si estas combinaciones también son útiles en otro tipo de infecciones graves sistémicas. El propósito de esta revisión es analizar y resumir los resultados obtenidos de diferentes modelos experimentales de combinaciones anti-enterocócicas y de los estudios clínicos disponibles en PubMed/Medline, a fin de evaluar mejor la evidencia que soporta la utilización de estas combinaciones. En conclusión, la información disponible es escasa, e indica la necesidad de mejores modelos in vivo y estudios clínicos que permitan comprobar la potencial actividad sinérgica de las combinaciones anti-enterocóciccas.

During the last decades, enterococci have emerged as important etiological agents in bacteremia, osteomyelitis, endocarditis and soft tissue infections. Antimicrobial combinations have been the most used therapeutic strategies for these infections, aiming for a bactericidal synergistic effect. However, besides in vitro and in vivo models, the clinical usefulness of such combinations is controversial, especially in non-endocardic systemic infections. For example, although beta-lactam and aminoglycoside combinations or double beta-lactam treatment have achieved high cure rates in endocarditis, the optimal treatment has not yet been clarified or if these combinations are useful in other infections. The aim of this review was to analyze and summarize the results from several experimental models of antienterococcal combined therapy and from clinical trials available in PubMed/Medline, to better assess the evidence that supports the use of these combinations. In conclusion, the available information is scarce, and more and better in vivo models and clinical studies are required to confirm the potential synergistic activity of antienterococcal combinations.

Humans , Gram-Positive Bacterial Infections/drug therapy , Enterococcus/drug effects , Anti-Bacterial Agents/pharmacology , Reproducibility of Results , Clinical Trials as Topic , Treatment Outcome , Drug Synergism , Drug Therapy, Combination , Endocarditis/chemically induced
Odovtos (En línea) ; 21(2): 73-81, May.-Aug. 2019. tab, graf
Article in Spanish | LILACS, BBO | ID: biblio-1091483


RESUMEN Los materiales a base de silicato de calcio han demostrado ser bioactivos debido a su capacidad para producir apatita carbonatada biológicamente compatible. El objetivo de este estudio fue analizar la bioactividad de Biodentine™ y MTA Repair HP® en contacto con discos de dentina humana, que se obturaron y dividieron aleatoriamente para formar cuatro grupos: grupo 1 Biodentine™, grupo 2 MTA Repair HP®, grupo control positivo MTA Angelus® y grupo control negativo IRM®, los cuales se incubaron en solución PBS durante 10 días, para posterior análisis por medio de MEB-EDS y Espectroscopía Raman. Los tres materiales a base de silicato de calcio analizados en este estudio demostraron ser bioactivos pues al entrar en contacto con una solución a base de fosfato desencadenaron la precipitación inicial de fosfato de calcio amorfo, que actúa como precursor durante la formación de apatita carbonatada.

ABSTRACT Calcium silicate-based materials have been shown to be bioactive due to their ability to produce biologically compatible carbonated apatite. The objective of this study was to analyze the bioactivity of Biodentine ™ and MTA Repair HP® in contact with human dentine discs, which were sealed and divided randomly to form four groups: group 1 Biodentine™, group 2 MTA Repair HP®, positive control group MTA Angelus® and negative control group IRM®, which were incubated in PBS solution for 10 days, for a subsequent analysis by means of MEB-EDS and Raman spectroscopy. The three calcium-based materials analyzed in this study proved to be bioactive because upon contact with a phosphate-based solution they were triggered at the onset of amorphous calcium phosphate, as the precursor during the formation of carbonated apatite.

Apatites/analysis , Spectrum Analysis, Raman , Calcarea Silicata/analysis , Dental Materials/analysis , Drug Synergism
Mem. Inst. Invest. Cienc. Salud (Impr.) ; 17(1): 47-53, abr. 2019. ilus, tab
Article in Spanish | LILACS, BDNPAR | ID: biblio-1007944


Se evaluó la actividad sinérgica de los alcaloides crotsparina y esparsiflorina, aislados de Croton bomplandianum Baill. con los antibacterianos gentamicina y ciprofloxacina frente a Pseudomonas aeruginosa, microorganismo frecuentemente responsable de infecciones intrahospitalarias. Se empleó el método del "tablero de damas". Se encontraron combinaciones que presentaban efecto sinérgico, logrando la reducción de 87,5% de la CMI de gentamicina, mientras que para ciprofloxacina se logró una reducción del 25,0%. Esto abre interesantes perspectivas sobre el uso combinado de productos naturales puros y fármacos en uso clínico para el tratamiento de infecciones producidas por este microrganismo(AU)

Pseudomonas aeruginosa/drug effects , Gentamicins/pharmacology , Ciprofloxacin/pharmacology , Croton , Alkaloids/pharmacology , Anti-Bacterial Agents/pharmacology , Gentamicins/isolation & purification , Drug Synergism , Alkaloids/chemistry
Odovtos (En línea) ; 21(1): 10-14, Jan.-Apr. 2019. graf
Article in English | LILACS, BBO | ID: biblio-1091466


Abstract Dental pain is usually managed by clinical interventions and pharmacological coadjuvants such as NSAIDs. However, its perception and modulation is mediated by different nociceptive mechanisms and these strategies can be insufficient. The multimodal analgesia refers to the use of 2 or more analgesic drugs that attenuate or blockade different mechanisms of pain, obtaining a greater clinical effect. Within this concept, pharmacological synergism plays a leading role, combining different molecules in lower doses to diminish also side effects. Since there are no standard prescriptions to be use in all the patients, multimodal approaches allow the clinician to make responsible effective combinations, individualizing analgesia as the pathway to success.

Resumen El dolor dental generalmente se trata con intervenciones clínicas y coadyuvantes farmacológicos como los AINEs. Sin embargo, su percepción y modulación está mediada por diferentes mecanismos nociceptivos y estas estrategias pueden ser insuficientes. La analgesia multimodal se refiere al uso de 2 o más fármacos analgésicos que atenúan o bloquean diferentes mecanismos de dolor, obteniendo un mayor efecto clínico. Dentro de este concepto, el sinergismo farmacológico juega un papel importante, combinando diferentes moléculas en dosis más bajas para disminuir también los efectos secundarios. Dado que no hay prescripciones estándar para ser usadas en todos los pacientes, los enfoques multimodales permiten al clínico realizar combinaciones responsables y eficaces, individualizando la analgesia como el camino hacia el éxito.

Toothache/drug therapy , Combined Modality Therapy , Drug Synergism , Analgesia/methods , Anesthesia, Dental/methods
Rev. bras. anestesiol ; 69(2): 144-151, Mar.-Apr. 2019. tab, graf
Article in English | LILACS | ID: biblio-1003406


Abstract Background and objective: Thoracic paravertebral blockade is an alternative regional technique for comforting post-thoracotomy pain, thereby decreasing opioid consumption, postoperative nausea and vomiting, dizziness, respiratory depression and health care costs. The objective of this study was to investigate the effects of bupivacaine and bupivacaine plus dexmedetomidine on postoperative pain score and analgesic consumption in thoracotomy patients who had undergone ultrasonography-guided paravertebral blockade. Material and method: 93 ASA I-II patients aged 18-65 years were included in the study and scheduled for thoracic surgery. Prior to anesthesia induction, the paravertebral blockade procedure was performed by an anesthetist with ultrasonography. Cases were randomly stratified into three groups. The paravertebral blockade procedure was performed with 20 mL 0.5% bupivacaine injection in Group B (n = 31) and 20 mL 0.5% bupivacaine + 1 mL dexmedetomidine (100 µg) injection in Group BD. Group C received postoperative i.v. morphine via patient-controlled analgesia without paravertebral blockade. Post-operative pain scores were recorded in the recovery room and post-operatively using a VAS. Hemodynamic parameters, adverse effects and morphine consumption were also recorded. Results: No significant difference was determined between Group B and Group C regarding intra-operative adverse effects such as bradicardia and hypotension, while these adverse effects were significantly higher in Group BD (p = 0.04). VAS scores with rest and upon movement were significantly lower in Group BD compared to Group C (p < 0.001). Total morphine consumption was significantly lower in both Group B and Group BD in comparison with Group C (p < 0.001). In Group BD, HR and MAP were lower, but this was not clinically significant (p < 0.05). Conclusion: The addition of dexmedetomidine to bupivacaine lowers postoperative pain scores and morphine consumption in thoracotomy patients who receive ultrasonography guided paravertebral blockade.

Resumo Justificativa e objetivo: O bloqueio paravertebral torácico é uma técnica regional opcional para o alívio da dor pós-toracotomia, deste modo diminui o consumo de opioides, náuseas e vômitos no pós-operatório, tontura, depressão respiratória e custos com saúde. O objetivo deste estudo foi investigar os efeitos de bupivacaína isolada e bupivacaína + dexmedetomidina no escore de dor pós-operatória e no consumo de analgésicos em pacientes submetidos à toracotomia sob bloqueio paravertebral guiado por ultrassom. Material e método: Noventa e três pacientes, ASA I-II, com idades entre 18 e 65 anos, foram incluídos no estudo e programados para cirurgia torácica. Antes da indução anestésica, o procedimento de bloqueio paravertebral foi realizado por um anestesista com o uso de ultrassom. Os casos foram estratificados aleatoriamente em três grupos. O procedimento de bloqueio paravertebral foi realizado com injeção de 20 mL de bupivacaína a 0,5% no Grupo B (n = 31) e de 20 mL de bupivacaína a 0,5% + 1 mL de dexmedetomidina (100 µg) no Grupo BD. O Grupo C recebeu morfina intravenosa via analgesia controlada pelo paciente sem bloqueio paravertebral. Os escores de dor pós-operatória foram registrados na sala de recuperação e no pós-operatório usando a escala VAS. Parâmetros hemodinâmicos, efeitos adversos e consumo de morfina também foram registrados. Resultados: Não houve diferença significativa entre os grupos B e C em relação a efeitos adversos intraoperatórios, como bradicardia e hipotensão, enquanto esses efeitos adversos foram significativamente maiores no Grupo BD (p = 0,04). Os escores VAS em repouso e movimento foram significativamente menores no Grupo BD em relação ao Grupo C (p < 0,001). O consumo total de morfina foi significativamente menor nos grupos B e BD em comparação com o Grupo C (p < 0,001). No Grupo BD, a frequência cardíaca e a pressão arterial média foram menores, mas esse resultado não foi clinicamente significativo (p < 0,05). Conclusão: A adição de dexmedetomidina à bupivacaína reduz os escores de dor pós-operatória e o consumo de morfina em pacientes submetidos à toracotomia sob bloqueio paravertebral guiado por ultrassom.

Humans , Male , Female , Adolescent , Adult , Aged , Young Adult , Pain, Postoperative/prevention & control , Bupivacaine/administration & dosage , Dexmedetomidine/administration & dosage , Nerve Block/methods , Thoracotomy/methods , Double-Blind Method , Prospective Studies , Analgesia, Patient-Controlled/methods , Ultrasonography, Interventional/methods , Analgesics, Non-Narcotic/administration & dosage , Drug Synergism , Drug Therapy, Combination , Analgesics, Opioid/administration & dosage , Anesthetics, Local/administration & dosage , Middle Aged , Morphine/administration & dosage
Article in Chinese | WPRIM | ID: wpr-772087


OBJECTIVE@#To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.@*METHODS@#MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo.@*RESULTS@#Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation.@*CONCLUSIONS@#Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.

Antineoplastic Agents , Apoptosis , Bortezomib , Cell Line, Tumor , Drug Synergism , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Proteolysis , Proto-Oncogene Proteins c-bcl-2 , Pyrroles
Chinese Journal of Lung Cancer ; (12): 255-263, 2019.
Article in Chinese | WPRIM | ID: wpr-775634


BACKGROUND@#Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells.@*METHODS@#PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression.@*RESULTS@#In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins.@*CONCLUSIONS@#The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.

Antineoplastic Agents , Pharmacology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cell Survival , Drug Resistance, Neoplasm , Drug Synergism , Enhancer of Zeste Homolog 2 Protein , ErbB Receptors , Gefitinib , Pharmacology , Humans , Lung Neoplasms , Pathology , Protein Kinase Inhibitors , Pharmacology
Braz. arch. biol. technol ; 62: e19180345, 2019. tab, graf
Article in English | LILACS | ID: biblio-1019548


Abstract The aim of this study was to investigate in vitro antioxidant properties and in vivo protective effects of the methanol extract of the Hypericum triquetrifolium Turra (HT) seed against acute hepatotoxicity, myelotoxicity and hematotoxicity in rats induced by cyclophosphamide (CP). In order to investigate in vivo protective effects of the HT extract on rat tissues, the rats were divided into nine groups. The toxic effects of CP and the protective effects of HT extract on nucleated cells that are produced by bone marrow, serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and oxidative stress index (OSI) levels were investigated biochemically. Additionally, liver tissue samples were examined for histopathological changes and apoptosis by Bcl-2, Bax and caspase-3 immunohistochemistry. The results of this study show that HT seed methanol extract has high total phenolic content (179.52 μg GAE/mg) and antioxidant activity (87.48% in 500 μg/mL concentration). CP administration caused hepatotoxicity, myelotoxicity and hematotoxicity in the rats. Whereas, the groups of rats that were injected with different concentrations of HT (25, 50 and 100 mg/kg) and CP (150 mg/kg) showed significant protective effects on bone marrow nucleated cells and important decreases on serum ALT, ALP, LDH and OSI levels were observed when compared with the CP injected group.

Hypericum/chemistry , Cyclophosphamide/toxicity , Drug Synergism , Hepatoprotector Drugs , Antioxidants
Braz. dent. j ; 29(4): 359-367, July-Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-974167


Abstract The aim of this study was to evaluate the antifungal activity of Terpinen-4-ol associated with nystatin, on single and mixed species biofilms formed by Candida albicans and Candida tropicalis, as well as the effect of terpinen-4-ol on adhesion in oral cells and the enzymatic activity. The minimum inhibitory concentrations and minimum fungicide concentrations of terpinen-4-ol and nystatin on Candida albicans and Candida tropicalis were determined using the microdilution broth method, along with their synergistic activity ("checkerboard" method). Single and mixed species biofilms were prepared using the static microtiter plate model and quantified by colony forming units (CFU/mL). The effect of Terpinen-4-ol in adhesion of Candida albicans and Candida tropicalis in coculture with oral keratinocytes (NOK Si) was evaluated, as well as the enzymatic activity by measuring the size of the precipitation zone, after the growth agar to phospholipase, protease and hemolysin. Terpinen-4-ol (4.53 mg mL-1) and nystatin (0.008 mg mL-1) were able to inhibit biofilms growth, and a synergistic antifungal effect was showed with the drug association, reducing the inhibitory concentration of nystatin up to 8 times in single biofilm of Candida albicans, and 2 times in mixed species biofilm. A small decrease in the adhesion of Candida tropicalis in NOK Si cells was showed after treatment with terpinen-4-ol, and nystatin had a greater effect for both species. For enzymatic activity, the drugs showed no action. The effect potentiated by the combination of terpinen-4-ol and nystatin and the reduction of adhesion provide evidence of its potential as an anti-fungal agent.

Resumo O objetivo desse estudo foi avaliar a atividade antifúngica do Terpinen4-ol associado à nistatina em biofilmes simples e misto, formados por Candida albicans e Candida tropicalis, bem como o efeito do terpinen-4-ol na adesão em células orais e atividade enzimática. As concentrações inibitórias mínimas e as concentrações fungicidas mínimas do terpinen-4-ol e da nistatina em Candida albicans e Candida tropicalis foram determinadas pelo método de microdiluição em caldo, juntamente com a atividade sinérgica (método do tabuleiro de "xadrez"). Biofilmes simples e misto foram preparados usando o modelo de placa de microtitulação estática e quantificados por unidades formadoras de colônias (CFU/mL). O efeito do Terpinen-4-ol na adesão de Candida albicans e Candida tropicalis em co-cultura com queratinócitos orais (NOK Si) foi avaliado, bem como a atividade enzimática, medindo o tamanho da zona de precipitação, após o crescimento em ágar fosfolipase, protease e hemolisina. O terpinen-4-ol (4.53 mg mL-1) e a nistatina (0,008 mg mL-1) conseguiram inibir o crescimento de biofilmes e um efeito antifúngico sinérgico foi demonstrado com a associação de fármaco, reduzindo a concentração inibidora de nistatina até 8 vezes em biofilme simpes de Candida albicans e 2 vezes em biofilme misto. Uma pequena diminuição na adesão de Candida tropicalis em células NOK Si foi mostrada após o tratamento com terpinen-4-ol e a nistatina teve um efeito maior para ambas as espécies. Para a atividade enzimática, as drogas não apresentaram ação. O efeito potencializado pela combinação de terpinen-4-ol e nistatina e a redução de adesão evidenciam seu potencial como agente anti-fúngico.

Terpenes/pharmacology , Candida albicans/drug effects , Nystatin/pharmacology , Biofilms/drug effects , Candida tropicalis/drug effects , Antifungal Agents/pharmacology , Cell Line, Transformed , Microbial Sensitivity Tests , Drug Synergism
Braz. j. microbiol ; 49(2): 407-413, Apr.-June 2018. tab, graf
Article in English | LILACS | ID: biblio-889247


Abstract Fungal infections have become a concern for health professionals, and the emergence of resistant strains has been reported for all known classes of antifungal drugs. Among the fungi causing disease, we highlight those that belong to the genus Aspergillus. For these reasons, the search for new antifungals is important. This study examines the effects of a coumarin derivative, 4-acetatecoumarin (Cou-UMB16) both alone and together with antifungal drugs, and its mode of action against Aspergillus spp. Cou-UMB16 was tested to evaluate its effects on mycelia growth, and germination of Aspergillus spp. fungal conidia. We investigated its possible action on cell walls, on the cell membrane, and also the capacity of this coumarin derivative to enhance the activity of antifungal drugs. Our results suggest that Cou-UMB16 inhibits Aspergillus spp. virulence factors (mycelia growth and germination of conidia) and affects the structure of the fungal cell wall. When applying Cou-UMB16 in combination with azoles, both synergistic and additive effects were observed. This study concludes that Cou-UMB16 inhibits mycelial growth and spore germination, and that the activity is due to its action on the fungal cell wall, and that Cou-UMB16 could act as an antifungal modifier.

Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Aspergillus/drug effects , Coumarins/isolation & purification , Coumarins/pharmacology , Drug Synergism , Aspergillus/growth & development , Azoles/pharmacology , Cell Membrane/drug effects , Cell Wall/drug effects , Hyphae/drug effects , Hyphae/growth & development , Spores, Fungal/drug effects , Spores, Fungal/growth & development
Acta cir. bras ; 33(6): 518-523, June 2018. graf
Article in English | LILACS | ID: biblio-949357


Abstract Purpose: To investigate the therapeutic potential of honey, Nigella sativa (N. sativa) and their combination in rat model of excisional wound healing. Methods: A circular excision wound was established in the back region of 50 Wistar rats. Subsequently, they were divided into 5 groups and daily topical administration of lanolin in the control group, honey in the honey group, cold-pressed N. sativa seed oil in the N. sativa groups, mix of 1:1 ratio of honey and N. sativa seed oil in the mix group, and phenytoin cream in the phenytoin group were used. Then, wound surface areas were evaluated using digital camera immediately after the injury and at post excision days 5, 10, 15 and 20. Results: Significant reduction in wound surface area was observed within and between the groups (P < 0.001). In the post excision days 5, 10, 15 and 20 the wound surface areas in the mix group were significantly lower than the other groups followed by the phenytoin, honey, N. sativa, and control groups. Conclusion: The wound healing may be improved and accelerated by using topical solutions of honey, N. sativa seed oil and especially their mixture.

Animals , Male , Wound Healing/drug effects , Plant Oils/pharmacology , Nigella sativa/chemistry , Honey , Phenytoin/pharmacology , Time Factors , Administration, Cutaneous , Random Allocation , Reproducibility of Results , Treatment Outcome , Rats, Wistar , Drug Combinations , Drug Synergism , Lanolin/pharmacology
Mem. Inst. Oswaldo Cruz ; 113(3): 153-160, Mar. 2018. graf
Article in English | LILACS | ID: biblio-894905


BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.

Triose-Phosphate Isomerase/chemistry , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/immunology , Nitroimidazoles/pharmacology , Antibodies, Protozoan , Drug Synergism , Drug Therapy, Combination
Article in English | WPRIM | ID: wpr-773598


Cardiovascular disease (CVD) is the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). New therapeutic strategies which have the potential for slowing down the evolution of NAFLD and reducing CVD-related mortality are urgently needed. Statins are well recognized in the treatment of dyslipidemia, but their use in the treatment of NAFLD is limited due to the safety concerns. Ilexgenin A (IA) is one of the main bioactive compounds in 'Shan-lv-cha', an herbal tea commonly used in China. In the present study, we investigated the possible synergistic therapeutic effects of IA and simvastatin (SV) on NAFLD. IA or SV showed beneficial effects on the rats with NAFLD by lowering the liver weight, liver index and plasma levels of alanine aminotransferase and aspartate aminotransferase, regulating abnormal metabolism of lipids and ameliorating steatosis in liver. IA significantly enhanced the hypolipidemic and anti-inflammation effects of SV. Furthermore, a sensitive, accurate, convenient and reproducible LC-MS method was developed to investigate the effects of IA on the pharmacokinetics of SV. No significant changes were observed in pharmacokinetic parameters of SV and simvastatin hydroxy acid in the IA plus SV co-treated group in comparison with those in the group treated with SV alone. The mRNA levels and activity of CYP3A1 were not altered by IA. In conclusion, the results obtained from the present study should be helpful for further clinical application of SV and IA alone or in combination.

Alanine Transaminase , Metabolism , Animals , Aspartate Aminotransferases , Metabolism , Cytochrome P-450 CYP3A , Genetics , Metabolism , Diet, High-Fat , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Lipids , Blood , Liver , Metabolism , Pathology , Male , Molecular Structure , Non-alcoholic Fatty Liver Disease , Blood , Drug Therapy , Rats , Rats, Sprague-Dawley , Simvastatin , Pharmacokinetics , Therapeutic Uses , Transcription, Genetic , Triterpenes , Chemistry , Therapeutic Uses
Article in English | WPRIM | ID: wpr-773571


Multi-components in herbal formulae exert holistic effects in synergistic or additive manners. However, appropriate strategies and supportive evidences are still lacking to uncover the synergistic or additive combinations. The present investigation aimed at seeking a screening strategy to identify the targeted combinations in GuGe FengTong Tablet (GGFTT), an herbal formula. Two compounds, belonging to different chemical classes, were combined with different concentration ratios and their anti-inflammation effects were investigated. The most significant anti-inflammatory combinations were evaluated by combination index (CI) method (additive effect, CI = 1; synergism, CI 1). The modulating effects of candidate combinations on pro-inflammatory cytokines and MAPKs signaling pathway were also detected. Two combinations, "biochanin A + 6-gingerol" (Bio-6G) and "genistein + 6-gingerol" (Gen-6G), showed synergistic effects (CI < 1), and Bio-6G was selected for further study. Compared with single compound, Bio-6G could synergistically inhibit the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and the activation of MAPKs signaling pathway in LPS-stimulated RAW264.7 cells. The combined results showed that Bio-6G was a synergistic anti-inflammatory combination in GGFTT. Our results could provide a useful strategy to screen the synergistic combinations in herbal formulae.

Animals , Anti-Inflammatory Agents , Chemistry , Pharmacology , Drug Compounding , Drug Synergism , Drugs, Chinese Herbal , Chemistry , Pharmacology , Interleukin-1beta , Allergy and Immunology , Macrophages , Allergy and Immunology , Mice , NF-kappa B , Allergy and Immunology , Tablets , Chemistry , Pharmacology , Tumor Necrosis Factor-alpha , Allergy and Immunology
Neuroscience Bulletin ; (6): 303-311, 2018.
Article in English | WPRIM | ID: wpr-777061


Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.

Animals , Antidepressive Agents , Pharmacology , Behavior, Animal , Brain-Derived Neurotrophic Factor , Metabolism , Depression , Drug Synergism , Drug Therapy, Combination , Fluoxetine , Pharmacology , Hippocampus , Metabolism , Male , Melatonin , Pharmacology , Membrane Glycoproteins , Metabolism , Mice, Inbred C57BL , Protein-Tyrosine Kinases , Metabolism , Restraint, Physical , Signal Transduction