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1.
Cardiovasc Revasc Med ; 52: 67-74, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36870799

RESUMO

As medical device development becomes increasingly global, the opportunities and potential advantages offered by international clinical trial and regulatory approval strategies are also growing. In particular, medical device clinical trials involving sites in both the United States and Japan and intended to support marketing in both countries may warrant particular consideration, given the similarities in their regulatory systems, patients and clinical practice patterns, and market sizes. Since 2003, the US-Japan Harmonization By Doing (HBD) initiative has been focused on identifying and addressing clinical and regulatory barriers to medical devices access in both countries via collaboration between governmental, academic, and industry stakeholders. Through the efforts of HBD participants, US-Japanese clinical trials have been conducted and the resulting data have supported regulatory approval for marketing in both countries. Based on these experiences, this paper outlines some of the key factors to consider when developing a global clinical trial involving US and Japanese participation. These considerations include the mechanisms for consultation with regulatory authorities on clinical trial strategies, the regulatory framework for clinical trial notification and approval, recruitment and conduct of clinical sites, and lessons learned from specific US-Japanese clinical trial experiences. The goal of this paper is to promote global access to promising medical technologies by assisting potential clinical trial sponsors in understanding when an international strategy may be appropriate and successful.


Assuntos
Aprovação de Equipamentos , Humanos , Estados Unidos , Japão
2.
Environ Sci Technol ; 54(3): 1522-1532, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31906621

RESUMO

The objective of this study was to advance analytical methods for detecting oil sands process-affected water (OSPW) seepage from mining containments and discriminating any such seepage from the natural bitumen background in groundwaters influenced by the Alberta McMurray formation. Improved sampling methods and quantitative analyses of two groups of monoaromatic acids were employed to analyze OSPW and bitumen-affected natural background groundwaters for source discrimination. Both groups of monoaromatic acids showed significant enrichment in OSPW, while ratios of O2/O4 containing heteroatomic ion classes of acid extractable organics (AEOs) did not exhibit diagnostic differences. Evaluating the monoaromatic acids to track a known plume of OSPW-affected groundwater confirmed their diagnostic abilities. A secondary objective was to assess anthropogenically derived artificial sweeteners and per- and polyfluoroalkyl substances (PFAS) as potential tracers for OSPW. Despite the discovery of acesulfame and PFAS in most OSPW samples, trace levels in groundwaters influenced by general anthropogenic activities preclude them as individual robust tracers. However, their inclusion with the other metrics employed in this study served to augment the tiered, weight of evidence methodology developed. This methodology was then used to confirm earlier findings of OSPW migrations into groundwater reaching the Athabasca River system adjacent to the reclaimed pond at Tar Island Dyke.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Alberta , Ácidos Carboxílicos , Hidrocarbonetos , Campos de Petróleo e Gás , Areia
3.
Environ Sci Technol ; 52(24): 14480-14486, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30457844

RESUMO

Previous studies of uptake and effects of nanoplastics by marine organisms have been conducted at what may be unrealistically high concentrations. This is a consequence of the analytical challenges in tracking plastic particles in organisms at environmentally relevant concentrations and highlights the need for new approaches. Here, we present pulse exposures of 14C-radiolabeled nanopolystyrene to a commercially important mollusk, Pecten maximus, at what have been predicted to be environmentally relevant concentrations (<15 µg L-1). Uptake was rapid and was greater for 24 nm than for 250 nm particles. After 6 h, autoradiography showed accumulation of 250 nm nanoplastics in the intestine, while 24 nm particles were dispersed throughout the whole-body, possibly indicating some translocation across epithelial membranes. However, depuration was also relatively rapid for both sizes; 24 nm particles were no longer detectable after 14 days, although some 250 nm particles were still detectable after 48 days. Particle size thus apparently influenced the biokinetics and suggests a need for chronic exposure studies. Modeling extrapolations indicated that it could take 300 days of continued environmental exposure for uptake to reach equilibrium in scallop body tissues although the concentrations would still below 2.7 mg g-1. Comparison with previous work in which scallops were exposed to nonplastic (silver) nanomaterials of similar size (20 nm), suggests that nanoparticle composition may also influence the uptake tissue distributions somewhat.


Assuntos
Pecten , Pectinidae , Animais , Moluscos , Tamanho da Partícula , Prata
4.
Chemosphere ; 160: 303-13, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27391053

RESUMO

The acid-extractable organic compounds (AEOs), including naphthenic acids (NAs), present within oil sands process-affected water (OSPW) receive great attention due to their known toxicity. While recent progress in advanced separation and analytical methodologies for AEOs has improved our understanding of the composition of these mixtures, little is known regarding any variability (i.e., spatial, temporal) inherent within, or between, tailings ponds. In this study, 5 samples were collected from the same location of one tailings pond over a 2-week period. In addition, 5 samples were collected simultaneously from different locations within a tailings pond from a different mine site, as well as its associated recycling pond. In both cases, the AEOs were analyzed using SFS, ESI-MS, HRMS, GC×GC-ToF/MS, and GC- & LC-QToF/MS (GC analyses following conversion to methyl esters). Principal component analysis of HRMS data was able to distinguish the ponds from each other, while data from GC×GC-ToF/MS, and LC- and GC-QToF/MS were used to differentiate samples from within the temporal and spatial sample sets, with the greater variability associated with the latter. Spatial differences could be attributed to pond dynamics, including differences in inputs of tailings and surface run-off. Application of novel chemometric data analyses of unknown compounds detected by LC- and GC-QToF/MS allowed further differentiation of samples both within and between data sets, providing an innovative approach for future fingerprinting studies.


Assuntos
Ácidos Carboxílicos/análise , Campos de Petróleo e Gás , Compostos Orgânicos/análise , Lagoas/química , Poluentes Químicos da Água/análise , Canadá , Cromatografia Gasosa-Espectrometria de Massas , Lagoas/análise , Espectrometria de Fluorescência
6.
Environ Sci Technol ; 48(5): 2660-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24446583

RESUMO

The objective of this study was to identify chemical components that could distinguish chemical mixtures in oil sands process-affected water (OSPW) that had potentially migrated to groundwater in the oil sands development area of northern Alberta, Canada. In the first part of the study, OSPW samples from two different tailings ponds and a broad range of natural groundwater samples were assessed with historically employed techniques as Level-1 analyses, including geochemistry, total concentrations of naphthenic acids (NAs) and synchronous fluorescence spectroscopy (SFS). While these analyses did not allow for reliable source differentiation, they did identify samples containing significant concentrations of oil sands acid-extractable organics (AEOs). In applying Level-2 profiling analyses using electrospray ionization high resolution mass spectrometry (ESI-HRMS) and comprehensive multidimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOF/MS) to samples containing appreciable AEO concentrations, differentiation of natural from OSPW sources was apparent through measurements of O2:O4 ion class ratios (ESI-HRMS) and diagnostic ions for two families of suspected monoaromatic acids (GC × GC-TOF/MS). The resemblance between the AEO profiles from OSPW and from 6 groundwater samples adjacent to two tailings ponds implies a common source, supporting the use of these complimentary analyses for source identification. These samples included two of upward flowing groundwater collected <1 m beneath the Athabasca River, suggesting OSPW-affected groundwater is reaching the river system.


Assuntos
Monitoramento Ambiental , Água Subterrânea/análise , Resíduos Industriais/análise , Campos de Petróleo e Gás/química , Poluição por Petróleo/análise , Poluentes Químicos da Água/análise , Alberta , Cromatografia Gasosa-Espectrometria de Massas , Dióxido de Silício/análise , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por Electrospray
7.
Curr Biol ; 23(23): 2388-92, 2013 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-24309271

RESUMO

Inadequate products, waste management, and policy are struggling to prevent plastic waste from infiltrating ecosystems [1, 2]. Disintegration into smaller pieces means that the abundance of micrometer-sized plastic (microplastic) in habitats has increased [3] and outnumbers larger debris [2, 4]. When ingested by animals, plastic provides a feasible pathway to transfer attached pollutants and additive chemicals into their tissues [5-15]. Despite positive correlations between concentrations of ingested plastic and pollutants in tissues of animals, few, if any, controlled experiments have examined whether ingested plastic transfers pollutants and additives to animals. We exposed lugworms (Arenicola marina) to sand with 5% microplastic that was presorbed with pollutants (nonylphenol and phenanthrene) and additive chemicals (Triclosan and PBDE-47). Microplastic transferred pollutants and additive chemicals into gut tissues of lugworms, causing some biological effects, although clean sand transferred larger concentrations of pollutants into their tissues. Uptake of nonylphenol from PVC or sand reduced the ability of coelomocytes to remove pathogenic bacteria by >60%. Uptake of Triclosan from PVC diminished the ability of worms to engineer sediments and caused mortality, each by >55%, while PVC alone made worms >30% more susceptible to oxidative stress. As global microplastic contamination accelerates, our findings indicate that large concentrations of microplastic and additives can harm ecophysiological functions performed by organisms.


Assuntos
Absorção Intestinal/fisiologia , Plásticos/farmacologia , Poliquetos/efeitos dos fármacos , Cloreto de Polivinila/farmacologia , Poluentes da Água/farmacologia , Animais , Biodiversidade , Ingestão de Alimentos , Monitoramento Ambiental , Trato Gastrointestinal/fisiologia , Sedimentos Geológicos , Éteres Difenil Halogenados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenantrenos/farmacologia , Fenóis/farmacologia , Poliquetos/imunologia , Eliminação de Resíduos , Dióxido de Silício , Distribuição Tecidual , Triclosan/farmacologia
8.
Eur Heart J ; 33(1): 120-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21733913

RESUMO

AIMS: The Genous™ Bio-engineered R™ stent (GS) aims to promote vascular healing by capture of circulatory endothelial progenitor cells (EPCs) to the surface of the stent struts, resulting in accelerated re-endothelialization. Here, we assessed the function of the GS in comparison to bare-metal stent (BMS), when exposed to the human and animal circulation. METHODS AND RESULTS: First, 15 patients undergoing coronary angiography received an extracorporeal femoral arteriovenous (AV) shunt containing BMS and GS. Macroscopical mural thrombi were observed in BMS, whereas GS remained visibly clean. Confocal and scanning electron microscopic (SEM) analysis of GS showed an increase in strut coverage. Quantitative polymerase chain reaction (qPCR) analysis of captured cells on the GS demonstrated increased expression of endothelial markers KDR/VEGFR2 and E-selectin, and a decrease in pro-thrombogenic markers tissue factor pathway inhibitor and plasminogen activator inhibitor-1 compared with BMS. Secondly, a similar primate AV shunt model was used to validate these findings and occlusion of BMS was observed, while GS remained patent, as demonstrated by live imaging of indium-labelled platelets. Thirdly, in an in vitro cell-capture assay, GS struts showed increased coverage by EPCs, whereas monocyte coverage remained similar to BMS. Finally, the assessment of re-endothelialization was studied in a rabbit denudation model. Twenty animals received BMS and GS in the aorta and iliac arteries for 7 days. Scanning electron microscopic analysis showed a trend towards increased strut coverage, confirmed by qPCR analysis revealing increased levels of endothelial markers (Tie2, CD34, PCD31, and P-selectin) in GS. CONCLUSION: In this proof-of-concept study, we have demonstrated that the bio-engineered EPC-capture stent, Genous™ R™ stent, is effective in EPC capture, resulting in accelerated re-endothelialization and reduced thrombogenicity.


Assuntos
Derivação Arteriovenosa Cirúrgica/métodos , Bioengenharia , Doença da Artéria Coronariana/terapia , Células Endoteliais/fisiologia , Células-Tronco/fisiologia , Stents , Idoso , Angioplastia Coronária com Balão/métodos , Animais , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Cateterismo Cardíaco/métodos , Reestenose Coronária/prevenção & controle , Citocinas/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/citologia , Feminino , Oclusão de Enxerto Vascular/prevenção & controle , Humanos , Leucócitos Mononucleares/fisiologia , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Papio , Adesividade Plaquetária/fisiologia , Coelhos
9.
Bioorg Med Chem Lett ; 21(3): 1041-6, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21215624

RESUMO

Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.


Assuntos
Amidas/química , Indóis/química , Naftalenos/química , Quinolinas/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinética
10.
Bioorg Med Chem Lett ; 21(1): 484-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21126875

RESUMO

A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.


Assuntos
Indóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Ratos , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade
12.
Circ Cardiovasc Interv ; 3(3): 257-66, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20442358

RESUMO

BACKGROUND: We aimed to demonstrate that, by separating endothelial progenitor cell capture from sirolimus delivery through the application of drug to the abluminal surface of the stent, the degree of endothelialization can be enhanced. METHODS AND RESULTS: Stainless steel R Stents, with biodegradable SynBiosys polymer coating with sirolimus abluminally applied and surface modified with anti-CD34 antibody were prepared at 2 dosages (low-dose sirolimus [LD-Combo, 2.5 microg sirolimus/mm] and full-dose sirolimus [Combo, 5 microg sirolimus/mm). These Combo stents and the Cypher stent (10 microg sirolimus/mm) were deployed in 98 normal porcine arteries and harvested for pharmacokinetic analysis at 0.25, 1, 3, 7, 14, 28, and 35 days. The LD-Combo stents showed faster early release (50%total dose in 72 hours) than the Combo and Cypher. At 30 days, drug release was near complete with both Combo stents, whereas 20% of drug remained on the Cypher stents. To assess efficacy, a total of 50 stents (Xience V=8, Cypher=8, Genous bioengineered R stent=6, LD-Combo=14, and Combo=14) were implanted in 18 pigs for 14 and 28 days. Optical coherence tomography was performed, and stents were harvested for histology. At 28 days, there was less neointimal thickness with Combo (0.173+/-0.088 mm) compared with Cypher (0.358+/-0.225 mm), LD-Combo (0.316+/-0.228 mm), and Xience V (0.305+/-0.252 mm; P<0.00001). Immunohistochemical analysis of endothelialization showed that Genous bioengineered R stent had the highest degree of platelet endothelial cell adhesion molecule expression (87%) followed by the Combo (75%), LD-Combo (65%), and Cypher (58%). CONCLUSIONS: Both optical coherence tomography and histology demonstrate that anti-CD34 sirolimus-eluting stents promote endothelialization while reducing neointimal formation and inflammation.


Assuntos
Albuminas/administração & dosagem , Artérias/efeitos dos fármacos , Células Endoteliais/metabolismo , Implantação de Prótese , Sirolimo/administração & dosagem , Implantes Absorvíveis , Albuminas/efeitos adversos , Albuminas/química , Angiografia , Animais , Anticorpos Monoclonais , Antígenos CD34/química , Antígenos CD34/imunologia , Antígenos CD34/metabolismo , Artérias/metabolismo , Artérias/patologia , Artérias/cirurgia , Stents Farmacológicos , Células Endoteliais/patologia , Imuno-Histoquímica , Inflamação/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Polímeros/química , Implantação de Prótese/instrumentação , Sirolimo/efeitos adversos , Sirolimo/química , Sirolimo/farmacocinética , Suínos
13.
J Med Chem ; 53(5): 2227-38, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20163116

RESUMO

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.


Assuntos
Analgésicos/síntese química , Benzoatos/síntese química , Ciclopropanos/síntese química , Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Dor/tratamento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinética
14.
Anal Biochem ; 388(1): 134-9, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19258005

RESUMO

Plasma renin activity (PRA) is a well-established biomarker for assessing the efficacy of various antihypertensive agents such as direct renin inhibitors, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors (ACEIs). PRA measurements are obtained through the detection and quantification of angiotensin I (Ang I) produced by the action of renin on its natural substrate angiotensinogen. The most accepted and reproducible method for PRA measurement uses an antibody capture Ang I methodology that employs specific antibodies that recognize and protect Ang I against angiotensinase activities contained in plasma. The amount of Ang I is then quantified by either radioimmunoassay (RIA) or enzyme immunoassay (EIA). In the current report, we describe the optimization of a novel homogeneous immunoassay based on the AlphaScreen technology for the detection and quantification of antibody-captured Ang I using AlphaLISA acceptor beads in buffer and in the plasma of various species (human, rat, and mouse). Ex vivo measurements of renin activity were performed using 10 microl or less of a reaction mixture, and concentrations as low as 1 nM Ang I were quantified. Titration curves obtained for the quantification of Ang I in buffer and plasma gave similar EC(50) values of 5.6 and 14.4 nM, respectively. Both matrices generated an equivalent dynamic range that varies from approximately 1 to 50 nM. Renin inhibitors have been successfully titrated and IC(50) values obtained correlated well with those obtained using EIA methodology (r(2)=0.80). This assay is sensitive, robust, fast, and less tedious than measurements performed using nonhomogeneous EIA. The AlphaLISA methodology is homogeneous, does not require wash steps prior to the addition of reagents, and does not generate radioactive waste.


Assuntos
Angiotensina I/sangue , Imunoensaio/métodos , Angiotensina I/imunologia , Animais , Anticorpos/imunologia , Humanos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Renina/metabolismo
15.
Bioorg Med Chem Lett ; 18(6): 2048-54, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291643

RESUMO

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.


Assuntos
Artrite Experimental/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Cães , Cobaias , Humanos , Macaca mulatta , Estrutura Molecular , Quinolinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
16.
J Pharmacol Exp Ther ; 319(3): 1043-50, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16973887

RESUMO

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE(2) and PGI(2) act as mediators of pain and inflammation. Most of the data indicating a role for PGI(2) in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI(2) in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI(2) receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI(2) is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI(2) synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE(2), contributes to their efficacy in treating the signs of arthritis.


Assuntos
Artrite Experimental/complicações , Artrite Experimental/tratamento farmacológico , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Dor/tratamento farmacológico , Dor/etiologia , Prostaglandinas I/antagonistas & inibidores , Animais , Carragenina , Cromatografia Líquida de Alta Pressão , Doença Crônica , Colágeno/imunologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Edema/induzido quimicamente , Edema/patologia , Epoprostenol/análogos & derivados , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Temperatura Alta , Iodoacetatos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Ovalbumina , Ratos , Ratos Sprague-Dawley , Receptores de Epoprostenol/genética
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