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[PMID]:28935266
[Au] Autor:Mathew B; Hobrath JV; Connelly MC; Kiplin Guy R; Reynolds RC
[Ad] Endereço:Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
[Ti] Título:Diverse amide analogs of sulindac for cancer treatment and prevention.
[So] Source:Bioorg Med Chem Lett;27(20):4614-4621, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.
[Mh] Termos MeSH primário: Amidas/química
Antineoplásicos/química
Neoplasias/tratamento farmacológico
Sulindaco/análogos & derivados
[Mh] Termos MeSH secundário: Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Sobrevivência Celular/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Relação Estrutura-Atividade
Sulindaco/química
Sulindaco/farmacologia
Sulindaco/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Amides); 0 (Antineoplastic Agents); 0 (sulindac sulfide amide); 184SNS8VUH (Sulindac)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


  2 / 1301 MEDLINE  
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[PMID]:28737505
[Au] Autor:Pace S; Pergola C; Dehm F; Rossi A; Gerstmeier J; Troisi F; Pein H; Schaible AM; Weinigel C; Rummler S; Northoff H; Laufer S; Maier TJ; Rådmark O; Samuelsson B; Koeberle A; Sautebin L; Werz O
[Ad] Endereço:Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, University Hospital Jena, Jena, Germany.
[Ti] Título:Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.
[So] Source:J Clin Invest;127(8):3167-3176, 2017 Aug 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
[Mh] Termos MeSH primário: Androgênios/metabolismo
Leucotrienos/biossíntese
Fatores Sexuais
Testosterona/administração & dosagem
[Mh] Termos MeSH secundário: Proteínas Ativadoras de 5-Lipoxigenase/metabolismo
Animais
Araquidonato 5-Lipoxigenase/metabolismo
Di-Hidrotestosterona/metabolismo
Feminino
Seres Humanos
Hidroxiureia/análogos & derivados
Hidroxiureia/farmacologia
Leucócitos/metabolismo
Inibidores de Lipoxigenase/farmacologia
Masculino
Camundongos
Pirróis/administração & dosagem
Ratos
Ratos Wistar
Sulindaco/administração & dosagem
Sulindaco/análogos & derivados
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-Lipoxygenase-Activating Proteins); 0 (Androgens); 0 (Leukotrienes); 0 (Lipoxygenase Inhibitors); 0 (Pyrroles); 08J2K08A3Y (Dihydrotestosterone); 184SNS8VUH (Sulindac); 3XMK78S47O (Testosterone); 6UVA8S2DEY (sulindac sulfide); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); P5T6BYS22Y (licofelone); V1L22WVE2S (zileuton); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


  3 / 1301 MEDLINE  
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[PMID]:28717101
[Au] Autor:Kawamoto T; Ito Y; Morita O; Honda H
[Ad] Endereço:Safety Science Research, Kao Corporation.
[Ti] Título:Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.
[So] Source:J Toxicol Sci;42(4):427-436, 2017.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.
[Mh] Termos MeSH primário: Clorpromazina/administração & dosagem
Clorpromazina/toxicidade
Colestase/induzido quimicamente
Ciclosporina/administração & dosagem
Ciclosporina/toxicidade
Diclofenaco/administração & dosagem
Diclofenaco/toxicidade
Medição de Risco/métodos
Toxicogenética/métodos
[Mh] Termos MeSH secundário: Administração Oral
Animais
Colesterol/biossíntese
Relação Dose-Resposta a Droga
Flutamida/administração & dosagem
Flutamida/toxicidade
Expressão Gênica
Seres Humanos
Imipramina/administração & dosagem
Imipramina/toxicidade
Inflamação/genética
Cetoconazol/administração & dosagem
Cetoconazol/toxicidade
Fígado
Metiltestosterona/administração & dosagem
Metiltestosterona/toxicidade
Estresse Oxidativo/genética
Ratos
Sulindaco/administração & dosagem
Sulindaco/toxicidade
Tamoxifeno/administração & dosagem
Tamoxifeno/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
094ZI81Y45 (Tamoxifen); 144O8QL0L1 (Diclofenac); 184SNS8VUH (Sulindac); 76W6J0943E (Flutamide); 83HN0GTJ6D (Cyclosporine); 97C5T2UQ7J (Cholesterol); OGG85SX4E4 (Imipramine); R9400W927I (Ketoconazole); U42B7VYA4P (Chlorpromazine); V9EFU16ZIF (Methyltestosterone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.2131/jts.42.427


  4 / 1301 MEDLINE  
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[PMID]:28368394
[Au] Autor:Ko CJ; Lan SW; Lu YC; Cheng TS; Lai PF; Tsai CH; Hsu TW; Lin HY; Shyu HY; Wu SR; Lin HH; Hsiao PW; Chen CH; Huang HP; Lee MS
[Ad] Endereço:Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
[Ti] Título:Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis.
[So] Source:Oncogene;36(32):4597-4609, 2017 Aug 10.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1ß (IL-1ß) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E (PGE ) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.
[Mh] Termos MeSH primário: Inibidores de Ciclo-Oxigenase 2/uso terapêutico
Ciclo-Oxigenase 2/metabolismo
Proteínas de Membrana/biossíntese
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/patologia
Serina Endopeptidases/biossíntese
[Mh] Termos MeSH secundário: Animais
Celecoxib/farmacologia
Celecoxib/uso terapêutico
Movimento Celular/efeitos dos fármacos
Inibidores de Ciclo-Oxigenase 2/farmacologia
Dinoprostona/metabolismo
Células HEK293
Seres Humanos
Inflamação/enzimologia
Interleucina-2/metabolismo
Masculino
Camundongos
Camundongos SCID
Invasividade Neoplásica
Metástase Neoplásica
Neoplasias da Próstata/enzimologia
Sulindaco/análogos & derivados
Sulindaco/farmacologia
Sulindaco/uso terapêutico
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclooxygenase 2 Inhibitors); 0 (Interleukin-2); 0 (Membrane Proteins); 184SNS8VUH (Sulindac); 6UVA8S2DEY (sulindac sulfide); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS2 protein, human); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (matriptase 2); JCX84Q7J1L (Celecoxib); K619IIG2R9 (sulindac sulfone); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.82


  5 / 1301 MEDLINE  
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[PMID]:28331852
[Au] Autor:Tang YJ; Hu K; Huang WH; Wang CZ; Liu Z; Chen Y; Ouyang DS; Tan ZR; Zhou HH; Yuan CS
[Ad] Endereço:Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China; Department of Pediatrics, Xiangya Hospital, Central South Universit
[Ti] Título:Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.
[So] Source:Biomed Res Int;2017:4189678, 2017.
[Is] ISSN:2314-6141
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 ) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 ) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium ( ' = 0.977, = 0.944). The mean values of , AUC , and AUC of sulindac were significantly higher in FMO3 group than those of FMO3 group ( < 0.05), while the pharmacokinetic parameters except of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/administração & dosagem
Inflamação/tratamento farmacológico
Oxigenases/genética
Sulindaco/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Anti-Inflamatórios não Esteroides/farmacocinética
Frequência do Gene
Genótipo
Voluntários Saudáveis
Seres Humanos
Inflamação/genética
Desequilíbrio de Ligação
Masculino
Polimorfismo de Fragmento de Restrição
Sulindaco/análogos & derivados
Sulindaco/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 184SNS8VUH (Sulindac); 6UVA8S2DEY (sulindac sulfide); EC 1.13.- (Oxygenases); EC 1.14.13.8 (dimethylaniline monooxygenase (N-oxide forming)); K619IIG2R9 (sulindac sulfone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1155/2017/4189678


  6 / 1301 MEDLINE  
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[PMID]:28258069
[Au] Autor:Uehara S; Shimizu M; Uno Y; Inoue T; Sasaki E; Yamazaki H
[Ad] Endereço:Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Ce
[Ti] Título:Marmoset Flavin-Containing Monooxygenase 3 in the Liver Is a Major Benzydamine and Sulindac Sulfide Oxygenase.
[So] Source:Drug Metab Dispos;45(5):497-500, 2017 May.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Common marmosets ( ) are potentially primate models for preclinical drug metabolism studies because there are similarities in the molecular characteristics of cytochrome P450 enzymes between this species and humans. However, characterization of non-cytochrome P450 enzymes has not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenases FMO1-FMO5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93%-95%) and phylogenetic closeness with human homologous FMO forms. FMO1 and FMO3 mRNA were abundantly expressed in the liver and kidneys among five marmoset tissues examined, where FMO3 protein was detected by immunoblotting. FMO inhibition assays using preheated tissue microsomes indicated that benzydamine -oxygenation and sulindac sulfide -oxygenation in the marmoset liver was mainly catalyzed by FMO3, the major hepatic FMO. Marmoset FMO3 protein heterologously expressed in effectively catalyzed benzydamine -oxygenation and sulindac sulfide -oxygenation comparable to marmoset liver microsomes. These results indicate that the FMO3 enzyme expressed in marmoset livers mainly metabolizes benzydamine and sulindac sulfide (typical human FMO substrates), suggesting its importance for FMO-dependent drug metabolism in marmosets.
[Mh] Termos MeSH primário: Benzidamina/farmacocinética
Callithrix
Fígado/enzimologia
Oxigenases/metabolismo
Sulindaco/análogos & derivados
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Callithrix/genética
Callithrix/metabolismo
Avaliação Pré-Clínica de Medicamentos/métodos
Escherichia coli/genética
Feminino
Temperatura Alta
Seres Humanos
Masculino
Microssomos Hepáticos/enzimologia
Especificidade de Órgãos
Oxigenases/genética
Homologia de Sequência de Aminoácidos
Especificidade da Espécie
Sulindaco/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
184SNS8VUH (Sulindac); 4O21U048EF (Benzydamine); 6UVA8S2DEY (sulindac sulfide); EC 1.13.- (Oxygenases); EC 1.14.13.8 (dimethylaniline monooxygenase (N-oxide forming))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.117.075184


  7 / 1301 MEDLINE  
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[PMID]:28004480
[Au] Autor:Ni Y; Wong VH; Tai WC; Li J; Wong WY; Lee MM; Fong FL; El-Nezami H; Panagiotou G
[Ad] Endereço:Systems Biology and Bioinformatics Group, School of Biological Sciences, Faculty of Sciences, The University of Hong Kong, Hong Kong, China.
[Ti] Título:A metagenomic study of the preventive effect of Lactobacillus rhamnosus GG on intestinal polyp formation in Apc mice.
[So] Source:J Appl Microbiol;122(3):770-784, 2017 Mar.
[Is] ISSN:1365-2672
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIMS: To investigate the in vivo effects of Lactobacillus rhamnosus GG (LGG) on intestinal polyp development and the interaction between this single-organism probiotic and the gut microbiota therein. METHODS AND RESULTS: The Apc mouse model was used to study the potential preventive effect of LGG on intestinal polyposis, while shotgun metagenomic sequencing was employed to characterize both taxonomic and functional changes within the gut microbial community. We found that the progression of intestinal polyps in the control group altered the community functional profile remarkably despite small variation in the taxonomic diversity. In comparison, the consumption of LGG helped maintain the overall functional potential and taxonomic profile in the resident microbes, thereby leading to a 25% decrease of total polyp counts. Furthermore, we found that LGG enriched those microbes or microbial activities related to short-chain fatty acid production (e.g. Roseburia and Coprococcus), as well as suppressed the ones that can lead to inflammation (e.g. Bilophila wadsworthia). CONCLUSIONS: Our study using shotgun metagenomics highlights how single probiotic LGG may exert its beneficial effects and decrease polyp formation in mice by maintaining gut microbial functionality. SIGNIFICANCE AND IMPACT OF THE STUDY: This probiotic intervention targeting microbiota may be used in conjugation with other dietary supplements or drugs as part of prevention strategies for early-stage colon cancer, after further clinical validations in human.
[Mh] Termos MeSH primário: Pólipos Intestinais/prevenção & controle
Lactobacillus rhamnosus/crescimento & desenvolvimento
Microbiota/efeitos dos fármacos
Probióticos/uso terapêutico
Sulindaco/uso terapêutico
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Animais
Seres Humanos
Metagenômica/métodos
Camundongos
Filogenia
Probióticos/farmacologia
Organismos Livres de Patógenos Específicos
Sulindaco/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (adenomatous polyposis coli protein, mouse); 184SNS8VUH (Sulindac)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1111/jam.13386


  8 / 1301 MEDLINE  
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[PMID]:27840824
[Au] Autor:Shazly GA
[Ad] Endereço:Department of Pharmaceutics, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
[Ti] Título:Effect of Sulindac Binary System on In Vitro and In Vivo Release Profiles: An Assessment of Polymer Type and Its Ratio.
[So] Source:Biomed Res Int;2016:3182358, 2016.
[Is] ISSN:2314-6141
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The bioavailability of sulindac (SDC), a nonsteroidal anti-inflammatory drug, is low due to poor aqueous solubility and poor dissolution rate. For this reason it is necessary to enhance the solubility and enhance dissolution of the drug by dispersing SDC in polyethylene glycols 6000 (PEG 6000) and polyvinyl pyrrolidone 40000 (PVP 40000) matrices using the coevaporation technique. Studying the influence of SDC to polymer ratio on drug content, percent yield, particle size, and in vitro release was performed. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize any change in crystal habit of SDC in the prepared formulae. The anti-inflammatory effect of SDC was studied using the hind paw edema model. It was found that incorporation of SDC in PEG 6000 and PVP 40000 matrices resulted in improving the dissolution rate, which was found to depend on the polymer and its weight ratio of the drug. It is clearly obvious that the dissolution rate was remarkably improved in drug PVP 40000 molecular dispersions when compared to drug PEG 6000 systems. Solid dispersion of SDC in PEG and PVP improved the anti-inflammatory effect of SDC and it was found that formula SDV5 exhibited a more pronounced inhibition of swelling than other formulae.
[Mh] Termos MeSH primário: Portadores de Fármacos/química
Inflamação/tratamento farmacológico
Povidona/química
Sulindaco/administração & dosagem
Sulindaco/química
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios não Esteroides/administração & dosagem
Anti-Inflamatórios não Esteroides/química
Difusão
Composição de Medicamentos/métodos
Avaliação Pré-Clínica de Medicamentos/métodos
Inflamação/diagnóstico
Inflamação/imunologia
Masculino
Polietilenoglicóis/química
Ratos
Ratos Wistar
Solubilidade
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Drug Carriers); 184SNS8VUH (Sulindac); 30IQX730WE (Polyethylene Glycol 6000); 30IQX730WE (Polyethylene Glycols); FZ989GH94E (Povidone)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161115
[St] Status:MEDLINE


  9 / 1301 MEDLINE  
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[PMID]:27768711
[Au] Autor:Mathew B; Hobrath JV; Ross L; Connelly MC; Lofton H; Rajagopalan M; Guy RK; Reynolds RC
[Ad] Endereço:Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205, United States of America.
[Ti] Título:Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis.
[So] Source:PLoS One;11(10):e0164100, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics.
[Mh] Termos MeSH primário: Proteínas de Bactérias/antagonistas & inibidores
Proteínas do Citoesqueleto/antagonistas & inibidores
Mycobacterium tuberculosis/metabolismo
[Mh] Termos MeSH secundário: Animais
Antituberculosos/farmacologia
Linhagem Celular
Camundongos
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/efeitos dos fármacos
Sulindaco/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Bacterial Proteins); 0 (Cytoskeletal Proteins); 0 (FtsZ protein, Bacteria); 184SNS8VUH (Sulindac)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161022
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0164100


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[PMID]:27480131
[Au] Autor:Burke CA; Dekker E; Samadder NJ; Stoffel E; Cohen A
[Ad] Endereço:Department Gastroenterology & Hepatology, Cleveland Clinic, Mail Code A30, 9500 Euclid Ave, Cleveland, OH, 44195, USA. burkec1@ccf.org.
[Ti] Título:Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial.
[So] Source:BMC Gastroenterol;16(1):87, 2016 Aug 02.
[Is] ISSN:1471-230X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. METHODS: Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. DISCUSSION: The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).
[Mh] Termos MeSH primário: Polipose Adenomatosa do Colo/tratamento farmacológico
Antineoplásicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Eflornitina/uso terapêutico
Sulindaco/uso terapêutico
[Mh] Termos MeSH secundário: Polipose Adenomatosa do Colo/metabolismo
Adulto
Antineoplásicos/efeitos adversos
Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/metabolismo
Progressão da Doença
Método Duplo-Cego
Neoplasias Duodenais/tratamento farmacológico
Neoplasias Duodenais/metabolismo
Eflornitina/efeitos adversos
Feminino
Seres Humanos
Mucosa Intestinal/metabolismo
Masculino
Poliaminas/antagonistas & inibidores
Poliaminas/metabolismo
Sulindaco/efeitos adversos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Polyamines); 184SNS8VUH (Sulindac); ZQN1G5V6SR (Eflornithine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160803
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1186/s12876-016-0494-4



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