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Introduction: Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. Methods: We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90 mg/tramadol 50 mg (one packet of granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. Results: One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% − 0.648 (− 0.010 to 1.306)] and 5 days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061–0.421)]. An improvement in LBP's disability to perform activities of daily routine (Oswestry and Roland–Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). Conclusions: The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. Trial registration: ClinicalTrials.gov identifier, NCT04968158. [ABSTRACT FROM AUTHOR]

Abstract Introduction Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. Methods We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90 mg/tramadol 50 mg (one packet of granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. Results One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% − 0.648 (− 0.010 to 1.306)] and 5 days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061–0.421)]. An improvement in LBP’s disability to perform activities of daily routine (Oswestry and Roland–Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). Conclusions The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. Trial registration ClinicalTrials.gov identifier, NCT04968158.

BackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models.MethodsAA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent.ResultsIn HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E2 generation with an IC50 of 0.10 (95% CI: 0.05–0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells.ConclusionWe have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in treating pain, fever, and inflammation by inhibiting prostaglandin synthesis. However, these agents have a substantial burden of side effects. As a result of the search for a better aspirin, cyclooxygenase-2 (COX-2) was discovered and specific COX-2 antagonists or coxibs were synthesized. Anti-inflammatory benefits were maintained, gastric ulcers occurred, and decreased vascular prostacyclin production (antithrombotic) without a change in thromboxane levels (prothrombotic) caused hypertension and thrombosis and withdrawal of some coxibs. [ABSTRACT FROM AUTHOR]

Determining the influence of environmental factors on the stability of drugs is very helpful when choosing excipients, storage conditions or packaging materials. In addition, information about possible toxic degradation products enables detecting and avoiding the harmful side effects of the drug. We used the thin-layer chromatographic-densitometric procedure for the assay of five coxibs, conducted degradation studies in various environments and at different temperatures along with the determination of pharmacokinetic parameters. The results were subjected to chemometric analysis, to investigate and visualize the similarities and differences of the studied coxibs. Samples of the tested drug were also analyzed by UPLC-MS/MS in order to identify degradation products, and determine possible drug degradation pathways. Using the human liver cancer HepG2 cell line, the hepatotoxic effect of the degradation products was also determined. It was observed that all substances were relatively stable under the analyzed conditions and degraded more in acidic than alkaline environments. Robenacoxib is the drug that decomposes the fastest, and cimicoxib turned out to be the most stable. Robenacoxib also showed significant hepatotoxicity at the highest tested concentration, which correlates with the high degree of its degradation, and the probable formation of a more hepatoxic product. The obtained mass spectra of compounds formed as a result of hydrolysis of the protonated drug leading to the formation of several product ions, which enabled us to propose probable degradation pathways. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the pharmacokinetics of robenacoxib (RX), a COX‐2 selective non‐steroidal anti‐inflammatory drug, in goats after single intravenous (IV), subcutaneous (SC) and oral (PO) administrations. 5‐month‐old healthy female goats (n = 8) were used. The animals were subjected to a three‐phase, two‐dose (2 mg/kg IV, 4 mg/kg SC, PO) unblinded, parallel study design, with a four‐month washout period between the IV and SC treatment, and a one‐week period between the SC and PO treatment. Blood was drawn from the jugular vein in heparinized vacutainer tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10 and 24 h. Plasma RX concentrations were measured using HPLC coupled to a UV multiple wavelength detector, and the data were pharmacokinetically analysed using ThothPro™ 4.3 software in a non‐compartmental approach. Following IV administration, terminal elimination half‐life, volume of distribution and total clearance were 0.32 h, 0.24 L/kg and 0.52 L/h/kg, respectively. For SC and PO, the mean peak plasma concentrations were 2.34 and 3.34 μg/mL at 1.50 and 0.50 h, respectively. The t1/2λz was significantly different between the IV and the extravascular (EV) administrations (0.32 h IV vs 1.37 h SC and 1.63 h PO), suggesting the occurrence of a flip‐flop phenomenon. The significant difference in Vd values between IV (0.24 L/kg) and EV (0.95 L/kg SC and 1.71 L/kg; corrected for F %) routes might have also triggered the t1/2λz difference. The absolute average SC and PO bioavailability were high (98% and 91%, respectively). In conclusion, the IV administration of RX might not be suitable for goats, due to its short t1/2λz. The EV routes, however, appear to be convenient for the drug's occasional use. [ABSTRACT FROM AUTHOR]

Drug repositioning, also known as drug repurposing, reprofiling, or rediscovery, is considered to be one of the most promising strategies to accelerate the development of new original drug products. Multiple examples of successful rediscovery or therapeutic switching of old molecules that did not show clinical benefits or safety in initial trials encourage the following of the discovery of new therapeutic pathways for them. This review summarizes the efforts that have been made, mostly over the last decade, to identify new therapeutic targets for celecoxib. To achieve this goal, records gathered in MEDLINE PubMed and Scopus databases along with the registry of clinical trials by the US National Library of Medicine at the U.S. National Institutes of Health were explored. Since celecoxib is a non-steroidal anti-inflammatory drug that represents the class of selective COX-2 inhibitors (coxibs), its clinical potential in metronomic cancer therapy, the treatment of mental disorders, or infectious diseases has been discussed. In the end, the perspective of a formulator, facing various challenges related to unfavorable physicochemical properties of celecoxib upon the development of new oral dosage forms, long-acting injectables, and topical formulations, including the latest trends in the pharmaceutical technology, such as the application of mesoporous carriers, biodegradable microparticles, lipid-based nanosystems, or spanlastics, was presented. [ABSTRACT FROM AUTHOR]

Coxibs are a group of non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase 2 inhibitors, characterized by a much lower gastrotoxicity compared to classic NSAIDs. They are often used in conjunction with other drugs, which greatly increases the likelihood of adverse drug interactions. The presented study analyzed the degradation rate of celecoxib and cimicoxib in solutions under the influence of other medicinal substances at different temperatures. For this purpose, triple-drug mixtures were prepared, consisting of coxib and eleven different commonly used drugs (paracetamol, ketoprofen, diclofenac, acetylsalicylic acid, ibuprofen, meloxicam, tramadol, doxycycline, bisoprolol, and caffeine). Then, the mixtures were incubated at two temperatures. Within the time specified by the research plan, further aliquots of the mixtures were subjected to a chromatographic analysis. Separation was conducted on HPTLC F254 silica gel chromatographic plates as a stationary phase, using chloroform: acetone: toluene as a mobile phase, and was detected densitometrically at wavelengths of 254 nm. The percentage changes in the tested coxibs content, depending on the time and conditions of incubation, were presented. Based on the obtained data, the basic kinetic parameters of the degradation processes were determined. The celecoxib and cimicoxib showed a relatively high durability in changing environmental conditions. It was observed that the rate of decomposition of cimicoxib and celecoxib in the tested mixtures was different and depended on the temperature and presence of other components, with cimicoxib turning out to be a more stable compound. [ABSTRACT FROM AUTHOR]

Determining the influence of environmental factors on the stability of drugs is very helpful when choosing excipients, storage conditions or packaging materials. In addition, information about possible toxic degradation products enables detecting and avoiding the harmful side effects of the drug. We used the thin-layer chromatographic-densitometric procedure for the assay of five coxibs, conducted degradation studies in various environments and at different temperatures along with the determination of pharmacokinetic parameters. The results were subjected to chemometric analysis, to investigate and visualize the similarities and differences of the studied coxibs. Samples of the tested drug were also analyzed by UPLC-MS/MS in order to identify degradation products, and determine possible drug degradation pathways. Using the human liver cancer HepG2 cell line, the hepatotoxic effect of the degradation products was also determined. It was observed that all substances were relatively stable under the analyzed conditions and degraded more in acidic than alkaline environments. Robenacoxib is the drug that decomposes the fastest, and cimicoxib turned out to be the most stable. Robenacoxib also showed significant hepatotoxicity at the highest tested concentration, which correlates with the high degree of its degradation, and the probable formation of a more hepatoxic product. The obtained mass spectra of compounds formed as a result of hydrolysis of the protonated drug leading to the formation of several product ions, which enabled us to propose probable degradation pathways.

Introduction: Cyclooxygenase-2 (COX-2) inhibitors (COXIBS) are considered a suitable option for the treatment of hemophilic arthropathy., Areas Covered: The role of traditional non-steroidal anti-inflammatory drugs; (NSAIDS) and COXIBS in people with hemophilia (PWH) and in the non-hemophiliac population has been reviewed in order to know which of them is more advisable in PWH and whether they should be used as the first or second therapeutic step for the treatment of musculoskeletal pain (since there is a discrepancy between what is advised by the WFH and the WHO)., Expert Opinion: For the treatment of chronic musculoskeletal pain related to hemophilic arthropathy, it is reasonable to use as a first step a combination of oral paracetamol (650 mg per every 6 h) or metamizole (575 mg per every 6 h), one of the COXIBS (e.g. celecoxib 200 mg per once a day) and a proton pump inhibitor (e.g. omeprazole 20 mg per once a day). The possible side effects of COXIBS should never be forgotten. For the treatment of hemophilic arthropathy pain, the risk/benefit ratio of COXIBS should be carefully assessed on an individual basis, although they are more advisable than traditional NSAIDS.

Background: PPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models., Methods: AA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent., Results: In HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E 2 generation with an IC 50 of 0.10 (95% CI: 0.05-0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE 2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells., Conclusion: We have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ammazzalorso, Tacconelli, Contursi, Hofling, Cerchia, Di Berardino, De Michele, Amoroso, Lavecchia and Patrignani.)

L'efficacité des AINS n'est plus à prouver dans bon nombre d'indications rhumatologiques, à visée antalgique et anti-inflammatoire. Mais leurs prescriptions peuvent être contrariées du fait de comorbidités qui peuvent être aggravées par ces médicaments, comme une coronaropathie, une insuffisance rénale ou un antécédent d'ulcère gastrique hémorragique. Cet article fait le point sur les mesures préventives à adopter pour éviter ces complications. The efficacy of NSAIDs in many rheumatological indications, for analgesic and anti-inflammatory purposes, is no longer in question. However, their prescription may be hindered by co-morbidities that could be aggravated by these drugs, such as coronary artery disease, chronic renal failure or a history of bleeding gastric ulcers. This article provides an update on preventive measures to avoid these complications. [ABSTRACT FROM AUTHOR]

The introduction of selective COX-2 inhibitors (so-called 'coxibs') has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs 'controversial me-too' saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer's disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed. [ABSTRACT FROM AUTHOR]

Abstract Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.

Abstract 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/β-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/β-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 β-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/β-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.

Gopa Mahesh, Kotha Anil Kumar, Pallu Reddanna Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, IndiaCorrespondence: Pallu Reddanna Tel +91-40-23134542Email preddanna@gmail.comAbstract: Inflammation is a protective response that develops against tissue injury and infection. Chronic inflammation, on the other hand, is the key player in the pathogenesis of many inflammatory disorders including cancer. The cytokine storm, an inflammatory response flaring out of control, is mostly responsible for the mortality in COVID-19 patients. Anti-inflammatory drugs inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastric and renal side-effects, as they inhibit both the constitutive COX-1 and the inducible COX-2. The majority of selective COX-2 inhibitors (COXIBs) are without gastric side-effects but are associated with cardiac side-effects on long-term use. The search for anti-inflammatory drugs without side-effects, therefore, has become a dream and ongoing effort of the Pharma companies. As PGE2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE2 alone without affecting other metabolites may form a better choice for the development of next generation anti-inflammatory drugs. In this direction the options being explored are on synthesis of PGE2-mPGES-1; PGE2 degradation through a specific PG dehydrogenase, 15-PGDH, and by blocking its activity mediated through a specific PGE receptor, EP4. As leukotrienes formed via the 5-lipoxygenase (5-LOX) pathway also play an important role in the mediation of inflammation, efforts are also being made to target both COX and LOX pathways. This review focuses on addressing the following three points: 1) How NSAIDs and COXIBs are associated with gastric, renal and cardiac side-effects; 2) Should the focus be on the targets upstream or downstream of PGE2; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects.Keywords: inflammation, cyclooxygenase, COX, NSAIDs, COXIBs, microsomal PGE synthase-1, mPGES-1, 15-hydroxy prostaglandin dehydrogenase, 15-PGDH, 5-lipoxygenase, 5-LOX

Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2. [ABSTRACT FROM AUTHOR]

The introduction of selective COX-2 inhibitors (so-called ‘coxibs’) has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs ‘controversial me-too’ saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer’s disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed.

In this article, we review controversies in assessing the risk of serious adverse effects caused by administration of nonsteroidal anti-inflammatory drugs (NSAIDs). Our focus is upon NSAIDs used in short courses for the management of acute postoperative pain. In our review of the literature, we found that the risks of short-term NSAID use may be overemphasized. Specifically, that the likelihood of renal dysfunction, bleeding, nonunion of bone, gastric complications, and finally, cardiac dysfunction do not appear to be significantly increased when NSAIDs are used appropriately after surgery. The importance of this finding is that in light of the opioid epidemic, it is crucial to be aware of alternative analgesic options that are safe for postoperative pain control. [ABSTRACT FROM AUTHOR]

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/β-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/β-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 β-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/β-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. [ABSTRACT FROM AUTHOR]

Inflammation is a protective response that develops against tissue injury and infection. Chronic inflammation, on the other hand, is the key player in the pathogenesis of many inflammatory disorders including cancer. The cytokine storm, an inflammatory response flaring out of control, is mostly responsible for the mortality in COVID-19 patients. Anti-inflammatory drugs inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastric and renal side-effects, as they inhibit both the constitutive COX-1 and the inducible COX-2. The majority of selective COX-2 inhibitors (COXIBs) are without gastric side-effects but are associated with cardiac side-effects on long-term use. The search for anti-inflammatory drugs without side-effects, therefore, has become a dream and ongoing effort of the Pharma companies. As PGE2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE2 alone without affecting other metabolites may form a better choice for the development of next generation anti-inflammatory drugs. In this direction the options being explored are on synthesis of PGE2-mPGES-1; PGE2 degradation through a specific PG dehydrogenase, 15-PGDH, and by blocking its activity mediated through a specific PGE receptor, EP4. As leukotrienes formed via the 5-lipoxygenase (5-LOX) pathway also play an important role in the mediation of inflammation, efforts are also being made to target both COX and LOX pathways. This review focuses on addressing the following three points: 1) How NSAIDs and COXIBs are associated with gastric, renal and cardiac side-effects; 2) Should the focus be on the targets upstream or downstream of PGE2; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects. [ABSTRACT FROM AUTHOR]

Development of highly selective COX-2 inhibitors – coxibs has proved a decreased risk of gastrointestinal toxicity, which was typical for non-selective NSAIDS, according to the evidence-based medicine. But such situation caused an imbalance in the impact on the synthesis of arachidonic acid metabolites: inhibition of COX-2 vasodilatatory prostacyclins and activation of thromboxane synthesis by platelets, which is accompanied by the increase in the frequency of thrombotic complications – myocardial infarctions and strokes. Some meta-analyses have proved this association: the higher is COX-2 inhibitors selectivity – the higher are CV-risks and cardiovascular toxicity of coxibs. Discontinuation or limitation of indications of coxibs, assessment of risk / benefit ratio is recommended in the conditions of comorbidity of CVS pathology, pain syndromes in rheumatology. Drugs of choice are moderately selective COX-2 inhibitors = meloxicam and nimesulide.

Background: Persisting inflammatory stimuli cause chronic inflammation recognized as the major factor contributing to the development of a number of diseases. One group of drugs used in the treatment of chronic inflammation is the group of non-steroidal anti-inflammatory drugs and, more specifically, the selective COX-2 inhibitors (coxibs). However, most of the coxibs were withdrawn from the market in view of their safety profile. In the present study, 2-[3-Acetyl-5-(4-chlorophenyl)- 2-methyl-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (compound 3e), an Npyrrolylcarboxylic acid derivative structurally related to celecoxib, is evaluated for anti-inflammatory activity after single and multiple (14 days) administration using an animal inflammation model.

Introduction: Drug utilization of analgesics in a private healthcare setting is useful to examine their prescribing patterns, especially the newer injectable cyclooxygenase (COX)-2 inhibitors (coxibs). Objectives: To evaluate the utilization of coxibs and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) indicated for postoperative orthopaedic pain control using defined daily dose (DDD) and ratio of use density to use rate (UD/UR). Method: A retrospective drug utilization review (DUR) of nonsteroidal anti-inflammatory drugs (NSAIDs) at an inpatient department of a private teaching hospital in Seremban, Malaysia was conducted. Patients’ demographic characteristics, medications prescribed, clinical lab results, visual analogue scale (VAS) pain scores and length of hospital stay were documented. Orthopaedic surgeries, namely arthroscopy, reconstructive, and fracture fixation, were included. Stratified random sampling was used to select patients. Data were collected through patients’ medical records. The DDD per 100 admissions and the indicator UD/UR were calculated with the World Health Organization’s DDD as a benchmark. The inclusion criteria were patients undergoing orthopaedic surgery prescribed with coxibs (celecoxib capsules, etoricoxib tablets, parecoxib injections) and tNSAIDs (dexketoprofen injections, diclofenac sodium tablets). Data were analysed descriptively. This research was approved by the academic institution and the hospital research ethics committee. Result: A total of 195 records of patients who received NSAIDs were randomly selected among 1169 cases. In term of the types of orthopaedic surgery, the ratio of included records for arthroscopy: fracture fixation: reconstructive surgery was 55.4:35.9:8.7. Most of the inpatients had low rates of common comorbidities such as cardiovascular disease as supported by their baseline parameters. The majority were not prescribed with other concomitant prescriptions that could cause drug interaction (74.9%), or gastroprotective agents (77.4%). Overall, DDDs per 100 admissions for all NSAIDs were less than 100, except for parecoxib injections (389.23). The UD/UR for all NSAIDs were less than 100, except for etoricoxib tablets (105.75) and parecoxib injections (108.00). Discussion: As per guidelines, the majority (96.9%) received other analgesics to ensure a multimodal approach was carried out to control pain. From the UD/UR results, the arthroscopy surgery was probably the most appropriate in terms of NSAID utilization. Conclusion: The prescribing pattern of NSAIDs except parecoxib was appropriate based on adverse effect and concurrent medication profile. The findings of this DUR provide insight for a low-risk patient population at a private specialized teaching hospital on the recommended use of NSAIDs for postoperative orthopaedic pain control. [ABSTRACT FROM AUTHOR]

Abstract Background Mycobacterium tuberculosis (TB) is one of the world’s most devastating public health threats. Our goal is to evaluate whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) affect the risk of new incident active TB disease. Methods We conducted a nested case-control analysis by using a 1 million longitudinally followed cohort, from Taiwan’s national health insurance research database. Effects of NSAIDs on active TB were estimated by conditional logistic regression and adjusted using a TB-specific disease risk score (DRS). NSAIDs exposures were defined as having a prescription record of NSAIDs ≧ 7 days that ended between 31 and 90 days prior to the index date. Results A total of 123,419 users of traditional NSAIDs, 16,392 users of cyclooxygenase-2 selective inhibitor (Coxibs), and 4706 incident cases of active TB were identified. Compared with nonusers, use of traditional NSAIDs was associated with an increased risk of TB in the unadjusted analysis ([RR], 1.39; 95% [CI], 1.24 – 1.57 and DRS adjusted analysis ([ARR], 1.30; 95% [CI], 1.15– 1.47). However, use of Coxibs was not associated with a significant increase in the risk of TB after DRS adjustment ([ARR], 1.23; 95% [CI], 0.89 – 1.70). Conclusions In this large population-based study, we found that subjects using traditional NSAIDs were associated with increased risk for active TB. We did not find evidence for a causative mechanism between traditional NSAIDs and TB, and more research is required to verify whether the association between traditional NSAIDs and TB is causal, or simply reflects an increased use of anti-inflammatory drugs in the early phases of TB onset.

Are high cyclooxygenase-2 (COX-2) selectivity and the absence of its impact on COX-1 the most important benefit of coxibs? Based on the classical concepts that nonsteroidal anti-inflammatory drugs (NSAIDs) are implicated in the pathogenesis of the most well-known complication – NSAID gastropathy, this must be so. Indeed, the development of gastrointestinal tract (GIT) diseases associated with NSAID use is mainly related to the blockade of COX-1 and to the decreased synthesis of cytoprotective prostaglandins. However, the clinical experience with etoricoxib, one of the most selective coxibs, casts doubt on this fact. There are well-known data of the MEDAL study, which show the equal rate of gastrointestinal bleeding in patients receiving etoricoxib and diclofenac. At the same time, moderately selective NSAIDs that include very popular meloxicam demonstrate a good tolerability and a low risk for GIT complications. A network meta-analysis of 36 studies covering a total of 112,351 patients indicates that there are no significant differences in the incidence of complicated and uncomplicated ulcers in patients receiving coxibs (a group analysis) and moderately selective NSAIDs (meloxicam, nabumetone, and etodolac). It is important that meloxicam demonstrates not only the low total frequency of GIT complications, but a quite moderate (as compared with diclofenac and etoricoxib) risk for cardiovascular and renal complications, which determines its benefit when used in real clinical practice.

The purpose of this study was to determine the pharmacokinetics and dose‐scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC‐MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a Tmax of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MATfed). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg−1 hr−1) was 95.22 ± 23.53 ml kg−1 hr−1. Plasma concentrations scaled linearly with dose, with Cmax (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study. [ABSTRACT FROM AUTHOR]

The instigation of chronic inflammation begins with the release of arachidonic acid (AA) from the membranous phospholipids through a biochemical reaction catalyzed by cytosolic phospholipase A2, which selectively hydrolyzes the arachidonyl phospholipid at the sn-2 position, thereby releasing a lysophospholipid and AA into the cytosol. This intracellular event swiftly progresses to the production of pro-inflammatory leukotrienes and prostaglandins by the catalytic action of the enzymes lipoxygenases and cyclooxygenases (COXs) on AA, respectively, whose anomalous production may manifest into chronic inflammation and related disorders. Despite several developments from aspirin to non-steroidal anti-inflammatory drugs and COX-2 inhibitors, the anti-inflammatory therapy, due to its associated side effects even in the advanced formulations, has suffered frequent setbacks and commercial withdrawals. The contemporary research therefore aims at designing novel candidate molecules with superior viability and an enhanced acceptability towards biological systems with a minimum conceivable side effect. [ABSTRACT FROM AUTHOR]

Chronic pain syndromes as a cause of suffering, short-term or persistent disability, and social losses greatly worsen quality of life. The mechanisms leading to the occurrence and maintenance of chronic pain are traditionally of interest for in-depth study since each of them is potentially a target for pharmacotherapy. Peripheral and central sensitizations, as well as disinhibition make different contributions to the development of chronic pain. The fact that cyclooxygenase-2 (COX-2) inhibitors may affect at both the peripheral and central, spinal levels, by modulating such a phenomenon as central sensitization, has been recently discussed. There are theoretical prerequisites for a discussion of this action of COX-2 inhibitors; however, clinical findings supporting this hypothesis have been scarce so far. In this connection, of interest is the clinical trial published in 2016, which may suggest to a high degree of accuracy that some analgesic effect of the selective COX-2 inhibitor etoricoxib is realized through the central mechanisms of pain modulation.

Introduction: Drug utilization of analgesics in a private healthcare setting is useful to examine their prescribing patterns, especially the newer injectable cyclooxygenase (COX)-2 inhibitors (coxibs). Objectives: To evaluate the utilization of coxibs and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) indicated for postoperative orthopaedic pain control using defined daily dose (DDD) and ratio of use density to use rate (UD/UR). Method: A retrospective drug utilization review (DUR) of nonsteroidal anti-inflammatory drugs (NSAIDs) at an inpatient department of a private teaching hospital in Seremban, Malaysia was conducted. Patients’ demographic characteristics, medications prescribed, clinical lab results, visual analogue scale (VAS) pain scores and length of hospital stay were documented. Orthopaedic surgeries, namely arthroscopy, reconstructive, and fracture fixation, were included. Stratified random sampling was used to select patients. Data were collected through patients’ medical records. The DDD per 100 admissions and the indicator UD/UR were calculated with the World Health Organization’s DDD as a benchmark. The inclusion criteria were patients undergoing orthopaedic surgery prescribed with coxibs (celecoxib capsules, etoricoxib tablets, parecoxib injections) and tNSAIDs (dexketoprofen injections, diclofenac sodium tablets). Data were analysed descriptively. This research was approved by the academic institution and the hospital research ethics committee. Result: A total of 195 records of patients who received NSAIDs were randomly selected among 1169 cases. In term of the types of orthopaedic surgery, the ratio of included records for arthroscopy:fracture fixation:reconstructive surgery was 55.4:35.9:8.7. Most of the inpatients had low rates of common comorbidities such as cardiovascular disease as supported by their baseline parameters. The majority were not prescribed with other concomitant prescriptions that could cause drug interaction (74.9%), or gastroprotective agents (77.4%). Overall, DDDs per 100 admissions for all NSAIDs were less than 100, except for parecoxib injections (389.23). The UD/UR for all NSAIDs were less than 100, except for etoricoxib tablets (105.75) and parecoxib injections (108.00). Discussion: As per guidelines, the majority (96.9%) received other analgesics to ensure a multimodal approach was carried out to control pain. From the UD/UR results, the arthroscopy surgery was probably the most appropriate in terms of NSAID utilization. Conclusion: The prescribing pattern of NSAIDs except parecoxib was appropriate based on adverse effect and concurrent medication profile. The findings of this DUR provide insight for a low-risk patient population at a private specialized teaching hospital on the recommended use of NSAIDs for postoperative orthopaedic pain control.

Les anti-inflammatoires non stéroïdiens (AINS) sont des médicaments très largement prescrits en ville depuis de nombreuses années. Pour autant, ils ne sont pas toujours évidents à manier et peuvent être à l'origine d'effets indésirables graves. Si la plupart des molécules de cette classe pharmacologique sont maintenant assez anciennes, les connaissances sur leur mécanisme d'action et leur tolérance continuent d'évoluer. Les événements cardiovasculaires autrefois très largement attribués aux inhibiteurs sélectifs de Cox-2 ne leur sont plus réservés. Il est établi que des AINS non sélectifs tels que l'ibuprofène et le naproxène prescrits à des doses élevées et sur des durées prolongées doivent inciter à la prudence. Les risques cardiovasculaire, gastro-intestinal et rénal sont autant d'éléments clés à évaluer avant d'envisager la prescription d'un AINS et d'arrêter son choix sur une molécule. [ABSTRACT FROM AUTHOR]

Vitacoxib, a selective COX-2 inhibitor, is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. In the current study, a chronic toxicity research was performed to evaluate the safety of vitacoxib in male and female rats for long-term. Vitacoxib was dosed orally to groups of rats for 180 days at 1.2, 6, 30 mg/kg bw/day by gavage. The chronic study oral administration of vitacoxib did not show observational or toxicological effects on the body or organ weights, food consumption, hematology and biochemistry at dose 6 mg/kg bw. However, vitacoxib (30 mg/kg) showed minor alterations to histopathology of liver, kidney and stomach related to treatment. These results provide further indication that vitacoxib is safe and well-tolerated in rats after 180 days of daily oral administration at 6 mg/kg bw and the NOAEL for both sexes was 6 mg/kg bw for 180 consecutive days. [ABSTRACT FROM AUTHOR]

Objectives: To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential.Methods: Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed.Results: Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription.Conclusions: NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted. [ABSTRACT FROM AUTHOR]

Over-the-counter analgesics are used globally for the relief of acute pain. Although effective, these agents can be associated with adverse effects that may limit their use in some people. In the early 2000s, observations from clinical trials of prescription-strength and supratherapeutic doses of nonselective and cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) raised safety concerns regarding the risk of cardiovascular adverse effects with the use of these medications. Subsequently, the US Food and Drug Administration mandated additional study of the cardiovascular safety of NSAIDs for a more comprehensive understanding of their risk. As these data were being collected, and based on a comprehensive review of prescription data and the recommendations of the US Food and Drug Administration Advisory Committee, the warning labels of over-the-counter NSAIDs were updated to emphasize the potential cardiovascular risks of these agents. The recently reported "Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen" (PRECISION) trial, in which participants with osteoarthritis or rheumatoid arthritis and underlying cardiovascular risk factors were treated with prescription-strength celecoxib, ibuprofen, or naproxen, revealed similar rates of cardiovascular events (death from cardiovascular causes including hemorrhagic death, nonfatal myocardial infarction, or nonfatal stroke) among the 3 treatment groups. Although informative, the cardiovascular safety findings derived from PRECISION cannot be extrapolated to the safety of the over-the-counter pain relievers ibuprofen and naproxen, given that the doses used were higher (mean [standard deviation]: ibuprofen, 2045 [246] mg; naproxen, 852 [103] mg) and the durations of use longer (∼20 months) than recommended with over-the-counter use of NSAIDs, which for ibuprofen is up to 10 days. This review discusses the cardiorenal safety of the most commonly used over-the-counter analgesics, ibuprofen, naproxen, and acetaminophen. Available data suggest that there is little cardiovascular risk when over-the-counter formulations of these agents are used as directed in their labels. [ABSTRACT FROM AUTHOR]

El objetivo del presente estudio fue determinar los efectos de diclofenaco, etoricoxib, ibuprofeno y paracetamol sobre la magnitud del movimiento dentario ortodóntico. Participaron 50 ratas Holtzman distribuidas en 5 grupos de 10 ratas cada uno. Al inicio del trabajo, en cada uno de los animales, se midió la distancia entre los ángulos incisodistales de los incisivos maxilares empleando un calibrador, e inmediatamente se adhirió un dispositivo ortodóntico con una fuerza de acción recíproca de 35 g en dichos incisivos. Cada grupo recibió tratamientos diferentes por vía intraperitoneal (A: NaCl, grupo control, B: diclofenaco, C: etoricoxib, D: ibuprofeno, E: paracetamol) durante 5 días. En todos los controles hechos al 1er, 3er, 5to y 7mo día, la distancia interincisiva fue significativamente menor en los grupos ibuprofeno y diclofenaco, y sin diferencia significativa en los grupos etoricoxib y paracetamol; comparados todos con el grupo control. Se demostró que la administración de ibuprofeno y diclofenaco disminuyen significativamente la magnitud del movimiento dentario ortodóntico en ratas. Se demostró que la administración de paracetamol y etoricoxib no disminuyen significativamente la magnitud del movimiento dentario ortodóntico en ratas.

Pain is one of the most disabling symptoms of rheumatoid diseases. Patients with pain secondary to osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or gout require effective analgesic treatment, and the physician's task is to select a drug that is best suited for an individual patient. The choice of pharmacotherapy should be based both on drug potency and clinical efficacy, and its safety profile, particularly in the elderly population, as the number of comorbidities (and hence the risk of treatment complications and drug interactions) rises with age. In cases involving a high risk of gastrointestinal complications or concerns about hepatotoxicity, with a low cardiovascular risk, the first-line nonsteroidal anti-inflammatory drugs to consider should be coxibs including etoricoxib. [ABSTRACT FROM AUTHOR]

Vitacoxib, is a newly developed coxibs NSAID (selective inhibitors of cyclooxygenase-2). To date, no experimental data have been published concerning its safety for use as an additive in the human diet. In the present study, we assessed the acute and sub-chronic toxicity of vitacoxib administered by gavage. The acute toxicity tests in Sprague Dawley (SD) rats and ICR mice demonstrated that vitacoxib at a dose of 5000 mg/kg BW failed to alter any of the parameters studied. In the 90-day sub-chronic toxicity test, vitacoxib was administered to SD rats at the doses of 0 (control), 5, 10, 20, 30, and 60 mg/kg BW. The results demonstrated that there were no significant differences for most indexes of sub-chronic toxicity throughout the experiment at the dose of 5–20 mg/kg BW, indicating no apparent dose-dependent. However, there were significant histopathology changes in the liver and kidney, and alterations in some biochemical parameters in the 60 mg/kg BW group. Based on these findings, the gavage LD 50 was determined to be > 5000 mg/kg in SD rats and ICR mice, and the 90-day gavage no-observed-adverse-effect level (NOAEL) of vitacoxib was considered to be 20 mg/kg BW under the present study conditions. [ABSTRACT FROM AUTHOR]