RESUMO
Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.
Assuntos
Ansiedade , Comportamento Animal , Celecoxib , Inibidores de Ciclo-Oxigenase 2 , Depressão , Lipopolissacarídeos , Estresse Oxidativo , Animais , Masculino , Camundongos , Lipopolissacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Ansiedade/tratamento farmacológico , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Celecoxib/farmacologia , Celecoxib/administração & dosagem , Etoricoxib/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismoRESUMO
PURPOSE: The primary objective of this study was to conduct a comparative analysis of the anti-inflammatory activity between Etoricoxib (ETO) and Matcha green tea (MG) in the context of acute kidney injury (AKI) induced by ionizing gamma radiation (IR) in female rats. Furthermore, the potential impact of whole body IR exposure on the intestinal system and serum estradiol levels was investigated. Additionally, it was acknowledged that the ETO and MG treatments might have exerted favorable effects on the intestinal and hormonal responses. MATERIALS AND METHODS: Six groups of rats were assigned to different treatments: control, ETO, MG, irradiation (IRR), ETO + IRR, and MG + IRR. The evaluation included measuring the total phenolic and flavonoid contents of ETO and MG, as well as assessing their antioxidant activity, radical scavenging capacity, reducing power, and total antioxidant capacity. Kidney function was assessed through serum creatinine and urea levels. Oxidative stress markers, including superoxide dismutase, glutathione, malondialdehyde, and catalase, were measured to evaluate the antioxidant effects of ETO and MG. The anti-inflammatory potential of the treatments was evaluated by measuring STAT-3 and interleukins (IL-6, IL-23, and IL-17) using an ELISA assay. Prostaglandin E2 receptor (PGE-2) mRNA expression, histopathological examination, and immunohistochemistry for NF-κB inhibitors were performed to investigate the underlying mechanisms in kidney tissue homogenates. Histopathological changes and DNA fragmentation in the intestinal tissues were determined, and the characterization of Matcha green tea was performed using liquid chromatography-mass spectrometry (LC-MS). This allowed for the identification and quantification of various compounds present in Matcha green tea. Furthermore, the study assessed the effect of IR and treatments on estrogen levels in female rats. RESULTS: Data showed that both ETO and MG had the potential to mitigate the adverse effects of AKI induced by IR. Notably, MG exhibited greater efficacy in attenuating oxidative stress and inflammation associated with renal injury. These findings revealed and compared the effects of ETO and MG in alleviating AKI caused by IR. MG demonstrated greater anti-inflammatory and antioxidant properties, highlighting its potential as a natural therapeutic agent. CONCLUSIONS: These results contribute to the growing evidence supporting the use of MG in managing IR-induced renal complications. Future studies should focus on elucidating the molecular mechanisms and optimizing the application of MG in clinical settings.
This study is of significant importance as it compares the therapeutic potential of ETO and MG in mitigating AKI and intestinal damage induced by IR. The findings reveal that MG exhibits greater anti-inflammatory and antioxidant properties compared to ETO. These results provide valuable insights into the potential use of MG as a natural therapeutic agent for managing IR-induced renal and intestinal complications. As radiation therapy is commonly used in cancer treatment, identifying effective agents to protect the kidneys from radiation damage is crucial. The study contributes to the growing evidence supporting the application of MG in clinical settings, offering a promising alternative approach with potential benefits in terms of reduced side effects and improved patient outcomes.
Assuntos
Injúria Renal Aguda , Anti-Inflamatórios , Etoricoxib , Raios gama , Chá , Animais , Ratos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Feminino , Raios gama/efeitos adversos , Etoricoxib/farmacologia , Anti-Inflamatórios/farmacologia , Chá/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Ratos Wistar , Piridinas/farmacologia , Sulfonas/farmacologiaRESUMO
BACKGROUND: Current tuberculosis treatment regimens could be improved by adjunct host-directed therapies (HDT) targeting host responses. We investigated the antimycobacterial capacity of macrophages from patients with tuberculosis in a phase 1/2 randomized clinical trial (TBCOX2) of the cyclooxygenase-2 inhibitor etoricoxib. METHODS: Peripheral blood mononuclear cells from 15 patients with tuberculosis treated with adjunctive COX-2i and 18 controls (standard therapy) were collected on day 56 after treatment initiation. The ex vivo capacity of macrophages to control mycobacterial infection was assessed by challenge with Mycobacterium avium, using an in vitro culture model. Macrophage inflammatory responses were analyzed by gene expression signatures, and concentrations of cytokines were analyzed in supernatants by multiplex. RESULTS: Macrophages from patients receiving adjunctive COX-2i treatment had higher M. avium loads than controls after 6 days, suggesting an impaired capacity to control mycobacterial infection compared to macrophages from the control group. Macrophages from the COX-2i group had lower gene expression of TNF, IL-1B, CCL4, CXCL9, and CXCL10 and lowered production of cytokines IFN-ß and S100A8/A9 than controls. CONCLUSIONS: Our data suggest potential unfavorable effects with impaired macrophage capacity to control mycobacterial growth in patients with tuberculosis receiving COX-2i treatment. Larger clinical trials are required to analyze the safety of COX-2i as HDT in patients with tuberculosis. CLINICAL TRIALS REGISTRATION: NCT02503839.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Citocinas , Etoricoxib/farmacologia , Leucócitos Mononucleares , Macrófagos/microbiologia , Tuberculose/microbiologiaRESUMO
Selective COX-2 inhibitors such as etoricoxib (ETX) are potentially indicated for the treatment of intestinal inflammatory disorders. However, their systemic administration provokes some off-site secondary effects, decreasing the desirable local effectiveness. To circumvent such limitations, herein an ETX delivery system based on electrospun fibrous meshes (eFMs) was proposed. ETX at different concentrations (1, 2, and 3 mg mL-1) was loaded into eFMs, which not affect the morphology and the mechanical properties of this drug delivery system (DDS). The ETX showed a burst release within the first 12 h, followed by a faster release until 36 h, gradually decreasing over time. Importantly, the ETX studied concentrations were not toxic to human colonic cells (i.e. epithelial and fibroblast). Moreover, the DDS loading the highest concentration of ETX, when tested with stimulated human macrophages, promoted a reduction of PGE2, IL-8 and TNF-α secretion. Therefore, the proposed DDS may constitute a safe and efficient treatment of colorectal diseases promoted by inflammatory disorders associated with COX-2.
Assuntos
Inibidores de Ciclo-Oxigenase 2 , Sistemas de Liberação de Medicamentos , Doenças Inflamatórias Intestinais , Humanos , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona , Etoricoxib/administração & dosagem , Etoricoxib/farmacologia , Fator de Necrose Tumoral alfa , Doenças Inflamatórias Intestinais/tratamento farmacológicoRESUMO
Etoricoxib is a nonsteroidal anti-inflammatory drug (NSAID) that possesses properties that include reducing inflammation and relieving pain and fever. Etoricoxib is an oral medication that selectively inhibits cyclooxygenase-2 with high efficacy. Controversies about its cardiovascular side effects have long existed. The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor that plays a key role in the metabolism of xenobiotics and many physiological functions. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a tryptophan metabolite and endogenous AhR agonist. Activation of AhR by its ligand induces upregulation of AhR-targeted cytochrome P450 (CYP) 1A1 expression. We found that etoricoxib (10-60 µM) induced CYP1A1 mRNA and protein expressions and the transcriptional activity of AhR mediated by the aryl hydrocarbon response element (AHRE) in both mouse Hepa-1c1c7 and human HepG2 cells. Its induction did not appear in AhR signaling-deficient cells, and was inhibited by the AhR antagonist, CH-223191. Etoricoxib was able to induced the translocalization of AhR from cytosol into nucleus. Etoricoxib also worked synergistically with ITE to further increase the expression of CYP1A1 mRNA and protein in human cells. The synergistic effect was higher in cells with than cells without overexpression of AhR. In summary, etoricoxib is an agonist of AhR in both mouse and human cells. Etoricoxib has a synergistic effect on ITE-induced CYP1A1 expression in human cells. The effect of etoricoxib on AhR and ITE on endothelial cells and cardiomyocytes should be further elucidated to in hope to clarify the mechanism of increased cardiovascular events in COX-2 inhibitors and etoricoxib.
Assuntos
Citocromo P-450 CYP1A1 , Receptores de Hidrocarboneto Arílico , Camundongos , Animais , Humanos , Citocromo P-450 CYP1A1/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Etoricoxib/farmacologia , Células Endoteliais , RNA Mensageiro/genéticaRESUMO
The current investigation aimed to explore the potential of etoricoxib nanostructured lipid carriers (ET-NLCs) as an anti-inflammatory drug in radiation-exposed rats, with a focus on assessing its efficacy in reducing inflammation while minimizing cardiac toxicity compared to conventional etoricoxib (ET) treatment. The ET-NLCs were prepared by the low-temperature melt emulsification solidification technique. Various techniques were employed to characterize the NLCs. Rats were exposed to gamma-irradiation (6 Gy) to induce cardiac inflammation and injury, followed by oral administration of ET or ET-NLCs (10 mg/kg b.w.) for 14 consecutive days. Results demonstrated a significant increase in the levels of malondialdehyde (MDA), cyclooxygenase-2 (COX-2), nuclear factor kappa-B p65 (NF-κB-p65), and poly ADP-ribose polymerase (PARP-1) in the heart tissues of gamma-irradiated rats compared to the control group. This increase was accompanied by a reduction in the activity of antioxidant enzymes. However, treatment with ET and ET-NLCs exhibited a positive impact on these levels. Interestingly, the efficacy of ET-NLCs in mitigating radiation-induced inflammation in heart tissue was found to be superior to that of ET. In conclusion, the study suggests that the utilization of NLCs as a drug delivery system for ET may not only enhance its therapeutic efficacy but also help reduce the cardiovascular risks associated with ET, specifically focused on individuals who had been exposed to gamma radiation. These findings open new avenues for further research in the development of effective and safer therapeutic strategies for managing inflammatory diseases and their impact on cardiovascular health.
Assuntos
Cardiotoxicidade , NF-kappa B , Humanos , Animais , Ratos , Ciclo-Oxigenase 2 , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Etoricoxib/farmacologia , Inflamação/tratamento farmacológico , LipídeosRESUMO
Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Cobre/química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Etoricoxib/síntese química , Etoricoxib/farmacologia , Nanopartículas Metálicas , Quinolinas/síntese química , Quinolinas/farmacologia , Sulfetos/síntese química , Sulfetos/farmacologia , Acetatos/química , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Técnicas de Química Sintética , Ciclopropanos/química , Composição de Medicamentos , Etoricoxib/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Quinolinas/química , Análise Espectral , Relação Estrutura-Atividade , Sulfetos/químicaRESUMO
SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications-including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)-have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.
Assuntos
Enzima de Conversão de Angiotensina 2 , Anti-Inflamatórios não Esteroides/farmacologia , COVID-19/genética , Acetaminofen/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/patologia , Células CACO-2 , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Etoricoxib/farmacologia , Flurbiprofeno/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Ibuprofeno/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacosRESUMO
In the present work, novel modality for lung cancer intervention has been explored. Primary literature has established the potential role of cyclooxygenase-2 (COX-2) inhibitor in regression of multiple forms of carcinomas. To overcome its poor water solubility and boost anticancer activity, etoricoxib (ETO) was chosen as a therapeutic candidate for repurposing and formulated into a nanoemulsion (NE). The prepared ETO loaded NE was characterized for the surface charge, droplet size, surface morphology, and in vitro release. The optimized ETO loaded NE was then investigated for its anticancer potential employing A549 lung cancer cell line via cytotoxicity, apoptotic activity, mitochondrial membrane potential activity, cell migration assay, cell cycle analysis, Caspase-3, 9, and p53 activity by ELISA and molecular biomarker analysis through RT-PCR test. The developed ETO-NE formulation showed adequate homogeneity in the droplet size distribution with polydispersity index (PDI) of (0.2 ± 0.03) and had the lowest possible droplet size (124 ± 2.91 nm) and optimal negative surface charge (-8.19 ± 1.51 mV) indicative of colloidal stability. The MTT assay results demonstrated that ETO-NE exhibited substantial anticancer activity compared to the free drug. The ETO-NE showed a substantially potent cytotoxic effect against lung cancer cells, as was evident from the commencement of apoptosis/necrotic cell death and S-phase cell cycle arrests in A549 cells. The study on these molecules through RT-PCR confirmed that ETO-NE is significantly efficacious in mitigating the abundance of IL-B, IL-6, TNF, COX-2, and NF-kB as compared to the free ETO and control group. The current study demonstrates that ETO-NE represents a feasible approach that could provide clinical benefits for lung cancer patients in the future.
Assuntos
Apoptose , Emulsões/química , Etoricoxib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Células A549 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Movimento Celular , Proliferação de Células , Etoricoxib/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/fisiopatologia , Potencial da Membrana MitocondrialRESUMO
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-AtividadeRESUMO
Long residence time enzyme inhibitors with a two-step binding mechanism are characterized by a high internal energy barrier for target association. This raises the question of whether optimizing residence time via further increasing this internal energy barrier would inevitably lead to insufficient target occupancy in vivo due to slow, time-dependent binding. We attempted to address this question during optimization of cyclooxygenase-2 (COX-2) inhibitors. Defining long residence time drugs with acceptable association and dissociation rate constants required for sufficient target occupancy and sustained efficacy, which we termed "balanced internal energetics", provides an important criterion for successful progression during lead optimization. Despite the advancement of several COX-2 inhibitors to marketed drugs, their detailed inhibition kinetics have been surprisingly limiting especially during the structure-activity relationship process mainly due to the lack of robust kinetic assays. Herein, we describe a reoptimized COX enzymatic assay and a novel MS-based assay enabling detailed mechanistic studies for identifying long residence time COX-2 inhibitors with balanced internal energetics. These efforts led to the discovery of promising leads possessing dissociation half-lives of ≤40 h, much greater than the values of 6 and 0.71 h for two marketed drugs, etoricoxib and celecoxib, respectively. Importantly, the inhibition rate constants remain comparable to those of the marketed drugs and above the lower limits set by the criteria of balanced internal energetics, predicting sufficient target occupancy required for efficacy. Taken together, this study demonstrates the feasibility of increasing the internal energy barrier as a viable approach for lead optimization toward discovering long residence time drug candidates.
Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Descoberta de Drogas/métodos , Ensaios Enzimáticos/métodos , Furanos/química , Espectrometria de Massas/métodos , Piridinas/química , Celecoxib/química , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Etoricoxib/química , Etoricoxib/farmacologia , Fluorescência , Furanos/farmacologia , Humanos , Hidrogênio/química , Cinética , Modelos Teóricos , Oxigênio/química , Pirazóis/química , Pirazóis/farmacologia , Piridinas/farmacologia , Termodinâmica , Fatores de TempoRESUMO
BACKGROUND: Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/ß-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/ß-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. METHODS: Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of ß-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. RESULTS: Wnt/ß-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. CONCLUSIONS: Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.
Assuntos
Neoplasias Encefálicas/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Glioblastoma/metabolismo , Proteínas de Neoplasias/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Idoso , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Metilases de Modificação do DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Etoricoxib/farmacologia , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Isoxazóis/farmacologia , Lactonas/farmacologia , Masculino , Metilação , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Receptores de Prostaglandina E Subtipo EP4/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Sulfonas/farmacologia , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , beta Catenina/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.
Assuntos
Neoplasias da Mama/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinoprostona/biossíntese , Açúcares/efeitos adversos , Regulação para Cima , 9,10-Dimetil-1,2-benzantraceno/efeitos adversos , Animais , Aromatase/metabolismo , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Etoricoxib/administração & dosagem , Etoricoxib/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Células MCF-7 , Acetato de Medroxiprogesterona/efeitos adversos , CamundongosRESUMO
The main focus of this study was to determine the role of etoricoxib in counterbalancing the oxidative stress, metabolic disturbances, and inflammation in high-fat (HF) diet-induced obese rats. To conduct this study, 28 male Wistar rats (weighing 190-210 g) were distributed randomly into four groups: control, control + etoricoxib, HF, and HF + etoricoxib. After 8 weeks of treatment with etoricoxib (200 mg/kg), all the animals were sacrificed followed by the collection of blood and tissue samples in order to perform biochemical tests along with histological staining on hepatic tissues. According to this study, etoricoxib treatment prevented the body weight gain in HF diet-fed rats. Furthermore, rats of HF + etoricoxib group exhibited better blood glucose tolerance than the rats of HF diet-fed group. In addition, etoricoxib also markedly normalized HF diet-mediated rise of hepatic enzyme activity. Etoricoxib treatment lowered the level of oxidative stress indicators significantly with a parallel augmentation of antioxidant enzyme activities. Furthermore, etoricoxib administration helped in preventing inflammatory cell invasion, collagen accumulation, and fibrotic catastrophe in HF diet-fed rats. The findings of the present work are suggestive of the helpful role of etoricoxib in deterring the metabolic syndrome as well as other deleterious pathological changes afflicting the HF diet-fed rats.
Assuntos
Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Etoricoxib/farmacologia , Fígado/efeitos dos fármacos , Animais , Catalase/metabolismo , Dieta Hiperlipídica , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Síndrome Metabólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVES: The non-steroidal anti-inflammatory drug etoricoxib is the most highly selective inhibitor of cyclooxygenase-2 available (344:1) and has been approved for postoperative pain therapy following dental interventions in Europe. At clinically relevant doses it has been reported to only have marginal effects on the velocity of orthodontic tooth movement (OTM). Its effects on associated dental root resorptions, osteoclastogenesis, trabecular number in the alveolar bone and periodontal bone loss during OTM, however, have not yet been investigated. MATERIAL AND METHODS: 40 male Fischer344 rats were divided into four groups: 1.5ml tap water/day p.o. (control, 1), additional 7.8mg/kg/day etoricoxib (normal dose) for three (2) or seven (3) days/week and 13.1mg/kg/day (high dose) for seven days/week, respectively (4). After a week of premedication, OTM in anterior direction of the first left upper molar was performed for 28 days by means of a nickel-titanium coil spring (0.25N). We quantified OTM-associated dental root resorptions, osteoclastogenesis, trabecular number and periodontal bone loss by histomorphometrical, histochemical and µCT analyses of the disected tooth-bearing upper jaw sections. RESULTS: After 28 days of OTM, associated reduction of trabecular number seemed to be slightly alleviated by high doses of etoricoxib, whereas no significant other etoricoxib effects in the doses administered could be detected regarding OTM-induced or -associated dental root resorptions, osteoclastogenesis or periodontal bone loss. CONCLUSIONS: Dental root resorptions, osteoclastogenesis and periodontal bone loss during OTM in rats were not significantly affected by etoricoxib in the clinically relevant dosages investigated with only a slight inhibitory effect on bone remodelling to be expected at high dosages. Etoricoxib is therefore not suitable for the prevention of these detrimental effects, but could be a suitable analgesic during OTM, as it has been reported not to affect tooth movement.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Etoricoxib/farmacologia , Técnicas de Movimentação Dentária/efeitos adversos , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Etoricoxib/uso terapêutico , Masculino , Modelos Animais , Osteogênese/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/etiologia , Ratos Endogâmicos F344 , Coloração e Rotulagem , Fosfatase Ácida Resistente a Tartarato , Reabsorção de Dente/tratamento farmacológico , Reabsorção de Dente/prevenção & controleRESUMO
AIM: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. MATERIALS AND METHODS: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. RESULTS: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). CONCLUSION: E-M14C is a potential system for possible colon targeting of etoricoxib.
Assuntos
Colo/efeitos dos fármacos , Etoricoxib/farmacologia , Etoricoxib/farmacocinética , Voluntários Saudáveis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Administração Oral , Adulto , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Colo/metabolismo , Liberação Controlada de Fármacos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Adulto JovemRESUMO
Background and objectives: The main objective of this study is to highlight the efficiency of different therapeutic means in patients with ankylosing spondylitis, resulting in the improvement of their quality of life. Materials and Methods: We conducted a randomized, longitudinal, controlled trial on 92 patients with ankylosing spondylitis over a period of 6 years. Disease activity was assessed using the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) score. The assessment of functional disabilities was performed using BASFI (Bath Ankylosing Spondylitis Functional Index). We assessed the quality of life using the HAQ questionnaire (Health Assessment Questionnaire). Based on the HAQ, we calculated the minimum number of patients to be treated for 52 weeks to prevent a decrease in the quality of life for at least one of them (the number needed to treat (NNT)). Results: For the combination therapy group, the result we obtained was 2, lower than the other therapies compared (the medication group and the group with physical exercise). We point out a correlation between the improvement of the functional status (BASFI) and the increase of the quality of life (HAQ), estimated as moderately high (0.8). The superiority of the effects of the combined treatment, in which we combined a nonsteroidal anti-inflammatory drug (etoricoxib) to the exercise program, is reflected by the model of the significant improvements (p < 0.05) obtained for the functional status and quality of life scores (BASFI and HAQ). Conclusions: The nonsteroidal anti-inflammatory drugs, in our case, etoricoxib, facilitate the application of individualized exercise programs in patients with ankylosing spondylitis.
Assuntos
Etoricoxib/farmacologia , Terapia por Exercício/métodos , Amplitude de Movimento Articular/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Adulto , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Sedimentação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , Etoricoxib/uso terapêutico , Terapia por Exercício/instrumentação , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Romênia , Índice de Gravidade de Doença , Espondilite Anquilosante/complicações , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Although cisplatin (CIS) acts as potent chemotherapy, nephrotoxicity still its major life-threatening side effect. The purpose of this study was to discuss and compare the renoprotective effects of curcumin (CUR) and etoricoxib (ETB) against CIS-induced nephrotoxicity. MATERIALS & METHODS: Thirty six adult female rats were divided equally into 6 groups: Group I (control), Group II (CIS) received cisplatin (7.5 mg/kg i.p), Group III (CUR) and group IV (ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) respectively via gavage for seven continuous days. Group V (CIS + CUR) and Group VI (CIS + ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) via gavage for seven continuous days. On the 4th day, the rats received cisplatin (7.5 mg/kg i.p) as a single injection 1 h after last curcumin or etoricoxib administration. At the assigned time, blood and tissue samples were collected for biochemical, histochemical, histopathological, immunohistochemical, and RT-PCR gene expression studies. RESULTS: Curcumin administration significantly decreased CIS-induced elevation of serum creatinine and blood urea nitrogen (BUN), and reversed oxidative stress markers; glutathione (GSH) and malondialdehyde (MDA) to control level. Suppression of inflammatory and apoptotic responses by CUR co-treatment was evidenced by decreased iNOS and BAX immunohistochemical reactions, and TNF-α and Caspase3 gene expressions which were detected by RT-PCR in kidney tissues. To our knowledge, this is the first time to discuss the effect of ETB on CIS induced nephrotoxicity. Although ETB reduced the previously mentioned inflammatory and apoptotic markers, its effect was less than that of CUR. Administration of ETB couldn't modify the disturbed levels of creatinine, BUN, GSH, and MDA. CONCLUSION: In conclusion, CUR provided a promising renoprotective effect against CIS induced nephrotoxicity. Further studies are recommended to approve or disapprove the protective role of ETB in CIS induced nephrotoxicity.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Curcumina/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Etoricoxib/farmacologia , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RatosRESUMO
Human periodontal ligament (hPDL) fibroblasts play a major role during periodontitis and orthodontic tooth movement, mediating periodontal inflammation, osteoclastogenesis, and collagen synthesis. The highly COX-2-selective NSAID etoricoxib has a favorable systemic side effect profile and high analgesic efficacy, particularly for orthodontic pain. In this in vitro study, we investigated possible side effects of two clinically relevant etoricoxib concentrations on the expression pattern of mechanically strained hPDL fibroblasts and associated osteoclastogenesis in a model of simulated orthodontic compressive strain occurring during orthodontic tooth movement. hPDL fibroblasts were incubated for 72 h under physiological conditions with etoricoxib at 0 µM, 3.29 µM, and 5.49 µM, corresponding to clinically normal and subtoxic dosages, with and without mechanical strain by compression (2 g/cm2) for the final 48 h, simulating conditions during orthodontic tooth movement in compressive areas of the periodontal ligament. We then determined gene and/or protein expression of COX-2, IL-6, PG-E2, RANK-L, OPG, ALPL, VEGF-A, P4HA1, COL1A2, and FN1 via RT-qPCR, ELISA, and Western blot analyses as well as apoptosis, necrosis, cell viability, and cytotoxicity via FACS, MTT, and LDH assays. In addition, hPDL fibroblast-mediated osteoclastogenesis was assessed by TRAP staining in coculture with RAW267.4 cells for another 72 h. Gene and protein expression of all evaluated factors was significantly induced by the mechanical compressive strain applied. Etoricoxib at 3.29 µM and 5.49 µM significantly inhibited PG-E2 synthesis, but not COX-2 and IL-6 gene expression nor RANK-L-/OPG-mediated osteoclastogenesis or angiogenesis (VEGF-A). Extracellular matrix remodeling (COL1A2, FN1) and bone anabolism (ALPL), by contrast, were significantly stimulated particularly at 5.49 µM. In general, no adverse etoricoxib effects on hPDL fibroblasts regarding apoptosis, necrosis, cell viability, or cytotoxicity were detected. Clinically dosed etoricoxib, that is, a highly selective COX-2 inhibition, did not have substantial effects on hPDL fibroblast-mediated periodontal inflammation, extracellular matrix remodeling, RANK-L/OPG expression, and osteoclastogenesis during simulated orthodontic compressive strain.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Etoricoxib/farmacologia , Fibroblastos/efeitos dos fármacos , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Adolescente , Adulto , Apoptose/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Masculino , Ligante RANK/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Mecânico , Técnicas de Movimentação Dentária , Adulto JovemRESUMO
BACKGROUND: NSAID analgesics have found widespread use in the treatment of pain, inflammation and fever. The highly COX-2-selective NSAID etoricoxib has shown a favorable side effect profile and excellent analgesic efficacy, particularly for dental and orthodontic pain, surpassing the current standard analgesic in orthodontics, acetaminophen. However, potential side effects on the rate of orthodontic tooth movement (OTM) and cranial growth, relevant for clinical usability during orthodontic treatment, have not yet been investigated. MATERIAL AND METHODS: 40 male Fischer344 rats were randomly assigned to 4 groups (n=10) - controls receiving only 1.5ml tap water per day by oral gavage for a total of 5 weeks (1) as well as rats receiving an additional daily normal etoricoxib dosage of 7.8mg/kg for 3d (2) and 7d/week (3) and a high dosage of 13.1mg/kg for 7d/week (4) with serum bioavailability assessed by liquid chromatography-mass spectrometry. After one week of premedication, the first upper left molars (M1) were moved orthodontically in anterior direction for 4 weeks using a closed NiTi coil spring (0.25N) and OTM as well as sagittal cranial growth were quantified cephalometrically by CBCT imaging at the start and end of OTM. RESULTS: OTM, quantified as anterior metric tipping of M1, was significantly inhibited by about 33% only in rats receiving high-dose etoricoxib 7d/week (p=0.046) with a respective, but insignificant tendency also detectable for the normal dosages, whereas sagittal cranial growth was by tendency slightly increased with rising etoricoxib dosages, reflected by corresponding steady-state serum concentrations, confirming etoricoxib bioavailability. CONCLUSIONS: An etoricoxib-induced clinically relevant deceleration of OTM is not to be expected at dosage regimens used in clinical practice to treat dental or orthodontic pain in contrast to a continuously administered high dosage. Due to its favorable side effect profile and higher analgesic efficiency regarding dental and orthodontic pain, etoricoxib should be a clinically valid alternative to the current standard orthodontic analgesic acetaminophen with its associated higher risk profile.