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1.
World J Gastroenterol ; 27(28): 4653-4666, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366627

RESUMO

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5' and 3' untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.


Assuntos
Neoplasias Gástricas , Anti-Inflamatórios não Esteroides , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2 , Variações do Número de Cópias de DNA , Humanos , Inflamação , Isoenzimas , Proteínas de Membrana , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral
2.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356673

RESUMO

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Assuntos
Antineoplásicos/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Celecoxib/efeitos adversos , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Pirazóis/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
J Enzyme Inhib Med Chem ; 36(1): 1810-1828, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338135

RESUMO

Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hidrazinas/química , Ibuprofeno/química , Indóis/química , Quinazolinonas/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Indóis/síntese química , Indóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodos
4.
Phytomedicine ; 90: 153638, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34275700

RESUMO

BACKGROUND: Cyclooxygenase-2 (COX-2) is an important enzyme with numerous biological functions. Overexpression of COX-2 has been associated with various inflammatory-related diseases and therefore, projected as an important pharmacological target. PURPOSE: We aimed to investigate the inhibitory potential of isolated bioactive compounds, 3-caffeoyl-4-dihydrocaffeoyl quinic acid (CDQ) and isorhamnetin 3-O-ß-d-glucopyranoside (IDG), from Salicornia herbacea against COX-2 using both computational and in vitro approaches. METHODS: Computational analysis, including molecular docking, molecular dynamics (MD) simulations, and post-simulations analysis, were employed to estimate the binding affinity and stability of CDQ and IDG in the catalytic pocket of COX-2 against Celecoxib as positive control. These predictions were further evaluated using in vitro enzyme inhibition as well as gene expression mediation in macrophages cells. RESULTS: Molecular docking analysis revealed substantial binding energy of CDQ (-6.1 kcal/mol) and IDG (-5.9 kcal/mol) with COX-2, which are lower than Celecoxib (-8.1 kcal/mol). MD simulations (100 ns) and post simulation analysis exhibited the substantial stability and binding affinity of docked CDQ and IDG compounds with COX-2. In vitro assays indicated significant COX-2 inhibition by CDQ (IC50 = 76.91 ± 2.33 µM) and IDG (IC50 = 126.06 ± 9.44 µM). This result supported the inhibitory potential of isolated bioactive compounds against COX-2. Also, a cellular level study revealed a downregulation of COX-2 expression in tumor necrosis factor-alpha stimulated RAW 264.7 macrophages treated with CDQ and IDG. CONCLUSION: Computational and experimental analysis of CDQ and IDG from S. herbacea established their potential in the inhibition and mediation of COX-2. Hence, CDQ and IDG can be considered for therapeutic development against COX-2 linked disorders, such as inflammation and cancer. Furthermore, CDQ and IDG structures can be served as a lead compound for the development of advanced novel anti-inflammatory drugs.


Assuntos
Chenopodiaceae , Inibidores de Ciclo-Oxigenase 2 , Quercetina/análogos & derivados , Ácido Quínico , Animais , Chenopodiaceae/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quercetina/farmacologia , Ácido Quínico/farmacologia , Células RAW 264.7 , Relação Estrutura-Atividade
5.
Fitoterapia ; 153: 105000, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303765

RESUMO

Six new polyketides, alternaritins A-D [(±)-1-4] and isoxanalteric acid I (8), and 25 known Alternaria toxins were isolated from the culture of an endophytic fungi Alternaria sp. MG1. 3 is a rare fungal metabolite. 6 is a new natural product, and 5, 7, and 9 are known previously but their absolute configurations have not been determined. Three enantiomers [(±)-1, (±)-7, and (±)-15] were separated via chiral HPLC resolution. The structures of those polyketides (1-9) were elucidated by spectrometric analysis using MS and NMR. The absolute configurations were established using X-ray diffraction analysis and statistical comparative analysis of the experimental ECD and OR data, in conjunction with quantum mechanical calculations. All of the compounds were evaluated for their bioactivities. Known compound 27 exerted the most potent cytotoxic activities against HT-1080 and NCI-H1299 cell lines. The new compounds, 2 and 3, showed moderate inhibition on COX-2, while a pair of isomers, 8 and 9, exhibited medium activity on COX-2 and uropathogenic Escherichia coli.


Assuntos
Alternaria/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Policetídeos/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Endófitos/química , Humanos , Estrutura Molecular , Policetídeos/isolamento & purificação , Estereoisomerismo , Escherichia coli Uropatogênica/efeitos dos fármacos , Vitis/microbiologia
6.
J Med Chem ; 64(15): 11570-11596, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34279934

RESUMO

Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.


Assuntos
Antineoplásicos/farmacologia , Celecoxib/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Etoricoxib/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Celecoxib/química , Celecoxib/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Etoricoxib/química , Etoricoxib/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade
7.
Front Cell Infect Microbiol ; 11: 669623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307194

RESUMO

Introduction: Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes. Methods: Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies. Results: Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls. Conclusion: COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Tuberculose , Eicosanoides , Humanos , Leucócitos Mononucleares , Lipoxigenase , Monócitos , Tuberculose/tratamento farmacológico
8.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200764

RESUMO

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a-e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, ß = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Indolizinas/química , Anti-Inflamatórios/química , Cristalografia por Raios X/métodos , Ciclo-Oxigenase 2/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indometacina/química , Relação Estrutura-Atividade
9.
Comput Math Methods Med ; 2021: 5576808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122616

RESUMO

Aim: To research the molecular mechanism of ghrelin in apoptosis, migratory, and invasion of gastric cancer (GC) cells. Methods: After GC AGS cells were handled with ghrelin (10-8 M), cyclooxygenase-2 inhibitor NS398 (100 µM), and Akt inhibitor perifosine (10uM), the rates of apoptosis were detected by TUNEL assay and flow cytometry assay. We assessed the expressions of PI3K, p-Akt, and COX-2 proteins by making use of Western blot analysis. The cell migratory and invasion were detected by using wound-healing and transwell analysis. Results: The migratory and invasion were increased in ghrelin-treated cells, while the rates of apoptosis were decreased. GC AGS cells treated with ghrelin showed an increase in protein expression of p-Akt, PI3K, and COX-2. After cells were treated with Akt inhibitor perifosine, the protein expression of p-Akt, PI3K, and COX-2 and the cell migratory, invasion, and apoptosis were partly recovered. After cells were treated with cyclooxygenase-2 inhibitor NS398, the protein expression of COX-2 and the cell migratory and invasion were decreased, while the rates of apoptosis were increased. Conclusion: Ghrelin regulates cell migration, invasion, and apoptosis in GC cells through targeting PI3K/Akt/COX-2. Ghrelin increases the expression of COX-2 in GC cells by targeting PI3K/Akt. Ghrelin is suggested to be one of the molecular targets in GC.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Grelina/metabolismo , Neoplasias Gástricas/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Biologia Computacional , Inibidores de Ciclo-Oxigenase 2/farmacologia , Progressão da Doença , Humanos , Invasividade Neoplásica , Nitrobenzenos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Sulfonamidas/farmacologia
10.
Cochrane Database Syst Rev ; 6: CD012978, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125958

RESUMO

BACKGROUND: Postoperative pain is a common consequence of surgery and can have many negative perioperative effects. It has been suggested that the administration of analgesia before a painful stimulus may improve pain control. We defined pre-emptive nonsteroidal anti-inflammatories (NSAIDs) as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. OBJECTIVES: To assess the efficacy of preventive and pre-emptive NSAIDs for reducing postoperative pain in adults undergoing all types of surgery. SEARCH METHODS: We searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED and CINAHL (up to June 2020). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication. SELECTION CRITERIA: We included parallel-group randomized controlled trials (RCTs) only. We included adult participants undergoing any type of surgery. We defined pre-emptive NSAIDs as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. We included studies that gave the medication by any route but not given on the skin. DATA COLLECTION AND ANALYSIS: We used the standard methods expected by Cochrane, as well as a novel publication bias test developed by our research group. We used GRADE to assess the certainty of the evidence for each outcome. Outcomes included acute postoperative pain (minimal clinically important difference (MCID): 1.5 on a 0-10 scale), adverse events of NSAIDs, nausea and vomiting, 24-hour morphine consumption (MCID: 10 mg reduction), time to analgesic request (MCID: one hour), pruritus, sedation, patient satisfaction, chronic pain and time to first bowel movement (MCID: 12 hours). MAIN RESULTS: We included 71 RCTs. Seven studies are awaiting classification. We included 45 studies that evaluated pre-emptive NSAIDs and 26 studies that evaluated preventive NSAIDs. We considered only four studies to be at low risk of bias for most domains. The operations and NSAIDs used varied, although most studies were conducted in abdominal, orthopaedic and dental surgery. Most studies were conducted in secondary care and in low-risk participants. Common exclusions were participants on analgesic medications prior to surgery and those with chronic pain. Pre-emptive NSAIDs compared to post-incision NSAIDs For pre-emptive NSAIDs, there is probably a decrease in early acute postoperative pain (MD -0.69, 95% CI -0.97 to -0.41; studies = 36; participants = 2032; I2 = 96%; moderate-certainty evidence). None of the included studies that reported on acute postoperative pain reported adverse events as an outcome. There may be little or no difference between the groups in short-term (RR 1.00, 95% CI 0.34 to 2.94; studies = 2; participants = 100; I2 = 0%; low-certainty evidence) or long-term nausea and vomiting (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 228; I2 = 29%; low-certainty evidence). There may be a reduction in late acute postoperative pain (MD -0.22, 95% CI -0.44 to 0.00; studies = 28; participants = 1645; I2 = 97%; low-certainty evidence). There may be a reduction in 24-hour morphine consumption with pre-emptive NSAIDs (MD -5.62 mg, 95% CI -9.00 mg to -2.24 mg; studies = 16; participants = 854; I2 = 99%; low-certainty evidence) and an increase in the time to analgesic request (MD 17.04 minutes, 95% CI 3.77 minutes to 30.31 minutes; studies = 18; participants = 975; I2 = 95%; low-certainty evidence). There may be little or no difference in opioid adverse events such as pruritus (RR 0.40, 95% CI 0.09 to 1.76; studies = 4; participants = 254; I2 = 0%; low-certainty evidence) or sedation (RR 0.51, 95% CI 0.16 to 1.68; studies = 4; participants = 281; I2 = 0%; low-certainty evidence), although the number of included studies for these outcomes was small. No study reported patient satisfaction, chronic pain or time to first bowel movement for pre-emptive NSAIDs. Preventive NSAIDs compared to post-incision NSAIDs For preventive NSAIDs, there may be little or no difference in early acute postoperative pain (MD -0.14, 95% CI -0.39 to 0.12; studies = 18; participants = 1140; I2 = 75%; low-certainty evidence). One study reported adverse events from NSAIDs (reoperation for bleeding) although the events were low which did not allow any meaningful conclusions to be drawn (RR 1.95; 95% CI 0.18 to 20.68). There may be little or no difference in rates of short-term (RR 1.26, 95% CI 0.49 to 3.30; studies = 1; participants = 76; low-certainty evidence) or long-term (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 456; I2 = 29%; low-certainty evidence) nausea and vomiting. There may be a reduction in late acute postoperative pain (MD -0.33, 95% CI -0.59 to -0.07; studies = 21; participants = 1441; I2 = 81%; low-certainty evidence). There is probably a reduction in 24-hour morphine consumption (MD -1.93 mg, 95% CI -3.55 mg to -0.32 mg; studies = 16; participants = 1323; I2 = 49%; moderate-certainty evidence). It is uncertain if there is any difference in time to analgesic request (MD 8.51 minutes, 95% CI -31.24 minutes to 48.27 minutes; studies = 8; participants = 410; I2 = 98%; very low-certainty evidence). As with pre-emptive NSAIDs, there may be little or no difference in other opioid adverse events such as pruritus (RR 0.56, 95% CI 0.09 to 3.35; studies = 3; participants = 211; I2 = 0%; low-certainty evidence) and sedation (RR 0.84, 95% CI 0.44 to 1.63; studies = 5; participants = 497; I2 = 0%; low-certainty evidence). There is probably little or no difference in patient satisfaction (MD -0.42; 95% CI -1.09 to 0.25; studies = 1; participants = 72; moderate-certainty evidence). No study reported on chronic pain. There is probably little or no difference in time to first bowel movement (MD 0.00; 95% CI -15.99 to 15.99; studies = 1; participants = 76; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There was some evidence that pre-emptive and preventive NSAIDs reduce both pain and morphine consumption, although this was not universal for all pain and morphine consumption outcomes. Any differences found were not clinically significant, although we cannot exclude this in more painful operations. Moreover, without any evidence of reductions in opioid adverse effects, the clinical significance of these results is questionable although few studies reported these outcomes. Only one study reported clinically significant adverse events from NSAIDs administered before surgery and, therefore, we have very few data to assess the safety of either pre-emptive or preventive NSAIDs. Therefore, future research should aim to adhere to the highest methodology and be adequately powered to assess serious adverse events of NSAIDs and reductions in opioid adverse events.


Assuntos
Dor Aguda/prevenção & controle , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Viés , Intervalos de Confiança , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Morfina/administração & dosagem , Morfina/efeitos adversos , Satisfação do Paciente/estatística & dados numéricos , Hemorragia Pós-Operatória/cirurgia , Náusea e Vômito Pós-Operatórios/epidemiologia , Prurido/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Reoperação
11.
BMC Vet Res ; 17(1): 205, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082759

RESUMO

BACKGROUND: Daxocox® [Ecuphar/Animalcare Group] contains the selective COX-2 inhibitor enflicoxib, approved in the EU for the treatment of pain and inflammation associated with osteoarthritis in dogs. The safety of Daxocox® was evaluated in a target animal safety study: Groups of 4 dogs per sex each were treated once weekly with placebo or Daxocox tablets at 1-, 3- and 5-times (1X, 3X and 5X) the maximum recommended therapeutic dose of enflicoxib (0, 4, 12 or 20 mg/kg, respectively). After an initial loading dose, dogs in the placebo control, 1X and 3X groups were administered for 32 weeks, and those in the 5X group were administered for 13 weeks. Dogs were subjected to daily food consumption measurements and clinical and dose observations. Body weight measurements, physical examinations, clinical pathology, urinalysis, faecal occult blood (FOB) and electrocardiographic (ECG) and blood pressure measurements, buccal mucosal bleeding time (BMBT), ophthalmology and gastroduodenal endoscopy examinations were conducted throughout the study. At study completion, all dogs were subjected to gross necropsy. Histopathology was performed on selected tissues from all animals in all groups. RESULTS: No clinical signs were noted, and no toxicologically relevant dose-associated effects were observed. CONCLUSIONS: Results show that Daxocox® is well-tolerated and has a broad safety margin when administered as directed in dogs.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Cães , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Masculino , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
12.
Front Immunol ; 12: 670088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122428

RESUMO

Chimeric antigen receptor T (CAR-T) cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include nonsteroidal anti-inflammatory drugs (NSAIDs) like cyclooxygenase (COX) inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10 red to JC-10 green CAR-T cells from 6.46 ± 7.03 (mean ± SD) to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10 red to JC-10 green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation of expression of CD27 on CD4+ and CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+ and CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.


Assuntos
Antígenos CD19/genética , Aspirina/farmacologia , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Imunoterapia Adotiva , Linfoma de Células B/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/efeitos dos fármacos , Antígenos CD19/imunologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Células K562 , Ativação Linfocitária/efeitos dos fármacos , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante
13.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071141

RESUMO

The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff's bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quinazolinonas/farmacologia , Quinoxalinas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
J Zoo Wildl Med ; 52(2): 529-537, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34130395

RESUMO

Postoperative antinociception control in fish is currently suboptimal, as commonly used antiinflammatory drugs last for only a few hours at tested temperatures. Therefore, long-acting anti-inflammatory drugs, such as robenacoxib, could improve the welfare of fish. The pharmacokinetics, duration of antinociceptive action, and potential adverse effects of robenacoxib were evaluated through two prospective randomized blinded trials in rainbow trout (Oncorhynchus mykiss). Six healthy rainbow trout received a single IM administration of robenacoxib (2 mg/kg), and two control fish received the same volume of saline IM. Blood samples were collected at predetermined time points for 5 d. Plasma robenacoxib concentrations were measured using high-performance liquid chromatography-high-resolution hybrid orbitrap mass spectrometry and noncompartmental pharmacokinetic analysis. Ten additional rainbow trout received an intralabial injection of 0.05 ml of 2% acetic acid following a previously validated nociceptive model. The treated group (n = 6) received 2 mg/kg of robenacoxib IM and the control group (n = 4) received an equivalent volume of saline IM. The behavior, appetite, and opercular rate of the fish were evaluated every hour for 5 h, then once daily for 3 d. All 12 treated trout and 6 controls underwent histopathologic evaluation. Average maximum plasma concentration (Cmax) was 329.9 ± 137.3 ng/ml observed at 2.1 ± 0.7 h (Tmax) and terminal half-life was 12.6 ± 2.27 h. Plasma concentrations described as antinociceptive in domestic carnivores were measured for 3-4 d. This dose was associated with a significant decrease in rocking behavior (P = 0.017). No adverse effects were detected clinically nor on histopathology. Robenacoxib administered IM at 2 mg/kg appears to be safe and may provide an antinociceptive effect in rainbow trout. This study presents a new therapeutic option to provide long-lasting antinociception in rainbow trout.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacocinética , Difenilamina/análogos & derivados , Oncorhynchus mykiss/sangue , Fenilacetatos/farmacocinética , Animais , Área Sob a Curva , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Difenilamina/efeitos adversos , Difenilamina/farmacocinética , Feminino , Meia-Vida , Masculino , Fenilacetatos/efeitos adversos
15.
Postgrad Med ; 133(7): 765-770, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34134576

RESUMO

A clinical vignette illustrates a typical presentation of a patient seeking help for acute angioedema. Despite the risks of SARS-CoV-2 (COVID-19) exposure, it is critical to evaluate patients with acute angioedema in person, because there is always the potential for angioedema to progress to the head, neck, or lungs, which can rapidly compromise the airways and require immediate intervention to avoid potential asphyxiation. There are three mediators of angioedema, histamine, leukotriene, or bradykinin, each requiring different management. This article provides clinicians essential information for differentiating between these types of angioedema, including an overview of the underlying pathogenies of angioedema, and the subjective and objective findings that are useful in differentiating between angioedema types. The article ends with the appropriate management for each type of acute angioedema, including the medications approved by the FDA for on-demand treatment of an HAE attack.


Assuntos
Angioedema/diagnóstico , COVID-19/epidemiologia , Doença Aguda , Angioedema/fisiopatologia , Angioedema/terapia , Antialérgicos/uso terapêutico , Bradicinina/biossíntese , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Diagnóstico Diferencial , Histamina/biossíntese , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Leucotrienos/biossíntese , Omalizumab/uso terapêutico , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Exame Físico , SARS-CoV-2
16.
J Med Chem ; 64(13): 9550-9566, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34137625

RESUMO

Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Inibidores de Lipoxigenase/farmacologia , Tartaratos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Humanos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Masculino , Camundongos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/química
17.
Eur J Med Chem ; 221: 113566, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34077833

RESUMO

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX enzymes and other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 µM) and breast (IC50: 11.35 µM) cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein BCL-2 and increased the expression of apoptogenic BAX. Besides, the BAX/BCL-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an anticancer agent.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
18.
Food Chem ; 359: 129889, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33934030

RESUMO

The objective was to analyze the phenolic composition, antioxidant capacity, and physical characteristics of 10 blackcurrant cultivars, their juices, and the enzymatic inhibition of dipeptidyl peptidase-IV, α-amylase, α-glucosidase, nitric oxide synthase, and cyclooxygenase-2. Fruit masses ranged from 0.47 to 1.22 g and diameters from 7.42 to 14.42 mm. For the juices, pH ranged from 2.80 to 2.96, soluble solids from 11.33% to 17.5%, total acidity from 3.17 to 4.26 g/100 mL, and viscosity from 1.28 to 273.83 mPa·s. Total anthocyanins (TA) ranged from 1.81 to 5.48 mg eq cyanidin 3-O-glucoside/100 g, total polyphenols (TP) from 7.67 to 39.70 mg eq gallic acid/100 g, total condensed tannins from 3.24 to 7.76 g eq catechin/100 g, and antioxidant capacity from 219.24 to 499.26 µmol eq Trolox/100 g. Juices of the cultivars Coronet and Consort contained the highest levels of TA, TP, and antioxidants. Whistler cultivar contained high concentrations of major anthocyanins. Juices from all cultivars favorably inhibited the activities of enzymes used as surrogate biochemical markers for T2 diabetes and inflammation.


Assuntos
Antocianinas/análise , Antioxidantes/análise , Extratos Vegetais/farmacologia , Polifenóis/análise , Proantocianidinas/análise , Ribes/química , Antocianinas/farmacologia , Inibidores de Ciclo-Oxigenase 2/análise , Inibidores da Dipeptidil Peptidase IV/análise , Frutas/química , Sucos de Frutas e Vegetais/análise , Inibidores de Glicosídeo Hidrolases/análise , Óxido Nítrico Sintase/antagonistas & inibidores , Fenóis/análise , Extratos Vegetais/química , Polifenóis/farmacologia , Proantocianidinas/farmacologia , alfa-Amilases/antagonistas & inibidores
20.
Int J Surg ; 90: 105962, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33932589

RESUMO

BACKGROUND: Parecoxib, a selective cyclooxygenase-2 inhibitor, is a potential alternative analgesic to reduce opioid consumption after Pancreaticoduodenectomy (PD). Further, the safety and efficacy of long-term use of parecoxib for patients after PD remain a major concern. MATERIALS AND METHODS: In this single-center, randomized clinical trial, 134 patients undergoing open PD were randomized into the parecoxib group (group P) and control group (group C) at a 1:1 ratio. Besides a routine patient-controlled epidural analgesia (PCEA) until 3 days postoperatively for both groups, patients in group P (n = 68) received parecoxib (40 mg, intravenously, Q 12 h) for the first 5 postoperative days and were encouraged to receive opioid analgesics to control severe pain as needed. Patients in group C (n = 66) received on-demand opioid analgesics (pethidine or morphine) postoperatively. The primary outcomes included the effectiveness of parecoxib in controlling pain (measured using the visual analog scale (VAS)) and reduction of opioid use (measured as accumulated doses). Secondary outcomes included the postoperative recovery process, rate of postoperative complications, and the anti-inflammatory effect of parecoxib. RESULTS: The VAS scores were not significantly different between the two groups. The number of doses of opioids for patients in group P (3.2 ± 0.3 doses) was significantly lower than in group C (8.5 ± 0.4 doses) (p = 0.0007). The incidence of opioid-related side effects was significantly lower in group P than in group C (p = 0.001). There were no significant differences in postoperative complications or readmission rates between the two groups. The postoperative time to first pass flatus, time to first mobilization out of bed, and time of removal of nasogastric tube in group P were significantly shorter than those in group C (P < 0.05). The postoperative serum IL-6 levels of patients in group P were significantly lower than those in group C at each time point (P < 0.05). CONCLUSIONS: Parecoxib effectively controls pain after PD. Prophylactic analgesia using parecoxib for up to 5 days after PD is safe, feasible, and can provide the same optimal pain control as opioids without adverse effects.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Isoxazóis/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Pancreaticoduodenectomia/efeitos adversos , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Dor Pós-Operatória/etiologia
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