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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 PGE 2 , 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: COX-2 inhibition in pro-tumoral M2 polarization of Tumor-Associated Macrophages (TAMs) underscore the improved prognosis and response to cancer therapy. Thus, etoricoxib, a COX-2 inhibiting NSAID drug is highly effective against tumorigenesis, but its compromised solubility and associated hepatotoxicity, and cardiotoxicity limit its clinical translation., Objective: In view of the consequences, the proposed study entails the development of a liposomal formulation for etoricoxib and evaluates its anticancer potential., Methods and Result: Etoricoxib loaded liposome was prepared by thin layer hydration method and characterized as a nearly monodisperse system with particle size (91.64 nm), zeta potential (-44.5 mV), drug loading (17.22%), and entrapment efficiency (94.76%). The developed formulation was administered subcutaneously into the orthotopic 4T1/Balb/c mice model. Its treatment significantly reduced tumor size and skewed M2 polarization of TAMs to a greater extent against free etoricoxib. Furthermore, Tumor tissues analyzed through immunoblotting study confirmed the reduction in Akt phosphorylation at Thr308 residue and pro-tumoral VEGF, MMP-9, and MMP-2 proteins; Moreover, histology studies and microCT analysis of bones revealed the enhanced anti-metastatic potential of etoricoxib delivered through developed formulation against free etoricoxib., Conclusion: As an epilogue, the developed formulation efficiently delivers poorly soluble etoricoxib, enhances its therapeutic potential as an anti-tumor and anti-metastatic agent, and directs explorative research for clinical translation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX), which forms prostaglandins involved in pain and inflammation. COX inhibitors have analgesic and anti-inflammatory effects, but also increase risks for gastrointestinal ulcers, bleeding, and renal and cardiovascular adverse events. Identification of two isoforms of COX, COX-1 and COX-2, led to the development of selective COX-2 inhibitors, which were launched as having fewer gastrointestinal side effects since gastroprotective prostaglandins produced via COX-1 are spared. The balance between COX-1 mediated prothrombotic thromboxane and COX-2 mediated antithrombotic prostacyclin is important for thrombotic risk. An increased risk of suffering myocardial infarction and death with COX-2 inhibitor treatment is well established from clinical trials and observational research. Rofecoxib (Vioxx) was withdrawn from the market for this reason, but the equally COX-2 selective etoricoxib has replaced it in Europe but not in the United States. The "traditional" NSAID diclofenac is as COX-2 selective as celecoxib and increases cardiovascular risk dose dependently. COX inhibitor dosages should be lower in osteoarthritis than in rheumatoid arthritis. Randomized trials comparing COX-2 inhibitors with NSAIDs have exaggerated their gastrointestinal benefits by using maximal NSAID doses regardless of indication, and/or hidden the cardiovascular risk by comparing with COX-2 selective diclofenac instead of low-dose ibuprofen or naproxen. Observational studies show increased cardiovascular risks within weeks of treatment with COX-2 inhibitors and high doses of NSAIDs other than naproxen, which is the safest alternative. COX inhibitors are symptomatic drugs that should be used intermittently at the lowest effective dosage, especially among individuals with an increased cardiovascular risk., (© 2022 The Association for the Publication of the Journal of Internal Medicine.)

A narrative review of papers published from January 2011 to December 2021, after a literature search in selected databases using the terms "pharmacokinetics", "ibuprofen", "diclofenac", "acemetacin", "naproxen", "etodolac" and "etoricoxib" was performed. From 828 articles identified, only eight met the inclusion criteria. Selective COX-2 inhibitors are associated with higher cardiovascular risk, while non-selective COX inhibitors are associated with higher gastrointestinal risk. NSAIDs with lower renal excretion with phase 2 metabolism are less likely to induce adverse effects and drug-drug interactions. Patients with frequent NSAID use needs, such as elderly patients and patients with cardiovascular disease or impaired renal function, will benefit from lower renal excretion (e.g. acemethacin, diclofenac, and etodolac) (level of evidence 3). Polymedicated patients, elderly patients, and patients with chronic alcohol abuse will be at a lower risk for adverse effects with NSAIDs that undergo phase 2 liver biotransformation, namely, acemethacin and diclofenac (level of evidence 3). Young patients, patients dealing with acute pain, or with active and/or chronic symptomatic gastritis, selective COX-2 inhibitors (celecoxib or etoricoxib) may be a better option (level of evidence 2). Knowing the individual characteristics of the patients, combined with knowledge on basic pharmacology, offers greater safety and better adherence to therapy. PERSPECTIVE: Although there are several NSAIDs options to treat pain, physicians usually take special care to its prescription regarding cardiovascular and gastrointestinal side effects, despite the age of the patient. In this paper, based on the best evidence, the authors present a review of the safest NSAIDs to use in the elderly., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors., (© 2021. The Author(s).)

Background: Heterotopic ossifications are a common complication after total hip arthroplasty. Low-dose radiation therapy and non-steroidal anti-inflammatory drugs have proven to effectively reduce the rate of heterotopic ossification after total hip arthroplasty. However, a low number of studies describe an equal efficiency of etoricoxib. This work shows first results on the examination of a larger group with 194 subjects to analyze efficiency and rate of side effects under treatment with etoricoxib., Methods: Clinical examinations were performed the day before surgery and after at least 12 months. The survey of clinical and functional outcome was done with Harris Hip Score (HHS). Conventional antero-posterior radiographs and second plane in frog leg position were assessed., Results: In total, 14 undesirable side effects (7.4%) and only four early terminations of therapy (2.1%) were documented. A complete 1-year follow-up examination including radiographs could be done in 143 subjects (79.4%). Only 28 subjects (19.6%) developed heterotopic ossifications from which 92.9% were classified in type 1 and 7.1% in type 2 using the method described by Brooker. The results do not show correlations with body mass index, extended treatment (more than ten days), or clinical and functional outcome (measured by "Harris Hip Score"). However, male subjects show a significantly higher rate of heterotopic ossifications., Conclusions: The investigations presented in this study confirm a good efficiency of etoricoxib for the prevention of heterotopic ossifications in comparison with classical methods such as radiation or drug therapy and show a low rate of undesirable side effects.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Etoricoxib, a selective inhibitor of cyclooxygenase-2, is used in the treatment of many inflammatory diseases and dental pain in humans. The aim of this study was to determine the pharmacokinetics and metabolism of etoricoxib in horses. Six horses weighing an average of 475 ± 25 kg were administered a single oral dose of etoricoxib at 1 mg/kg body weight. The results show that the drug reached a maximum concentration of 505.2 ± 67.8 ng/mL in 48 minutes after administration. The elimination half-life was calculated to be 10.20 ± 1.30 hours. Mass spectrometric analysis confirmed that etoricoxib is metabolized in horses via the oxidation of its 6'-methyl group to form a hydroxyl methyl etoricoxib which can further be oxidized to form either an acid or be glucuronidated. In addition, the 1'-N terminal of 6'-hydroxymethyl metabolite is oxidized to form the corresponding 1'-N oxide metabolite. The present results have clearly demonstrated that etoricoxib is mainly excreted in urine as metabolites. From these data, it is also possible to postulate a detection time for the metabolites which in turn can assist in the control of illegal use of the drug in horse racing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe a case of likely etoricoxib-induced severe thrombocytopenia., Clinical Presentation and Intervention: A 32-year-old woman was referred to our hospital for disseminated petechial rash after 7 days of therapy with etoricoxib. At admission, the patient's platelet count was 3,000/mm3. At Naranjo's scale correlation between thrombocytopenia and drug was considered as "probable." With the diagnostic tests performed we did not find other causes of thrombocytopenia. Etoricoxib was discontinued. The patient was treated with intravenous immunoglobulin and corticosteroids with a complete resolution of the thrombocytopenia in a few days., Conclusion: The prevalence of thrombocytopenia induced by etoricoxib should be studied as it may not be very rare., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

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., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Cyclooxygenase inhibitors were developed in the quest of enhanced analgesic efficacy devoid of gastric side effects. High usage of etoricoxib by prescription as well as self-administered routes has led to increasing reports of side effects and adverse reactions including dermatologic reactions in 0.1%-0.3% of cases. The present report enumerates a case of toxic epidermal necrolysis induced by etoricoxib., Competing Interests: There are no conflicts of interest.

Etoricoxib is a selective cyclooxygenase-2 inhibitor, with a lower risk of gastrointestinal toxicity compared to traditional nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the effectiveness and tolerability of etoricoxib in extremely elderly patients with chronic pain due to osteoarthritis (OA). A prospective, single-center, single-arm study was conducted, enrolling 19 extremely elderly men with OA (mean age 85.9, range 79-96 years), who responded inadequately to NSAIDs or other analgesics. Patients were switched to etoricoxib, 60 mg once daily for 4 weeks, without prior medication washout. Data were recorded before and after etoricoxib treatment. The primary endpoint was improvement in pain, assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) after the 4-week treatment. Other endpoints included the Brief Pain Inventory Short Form (BPI-SF), Treatment Satisfaction Questionnaire for Medication (TSQM), Short Form 36 (SF36), and European Quality of Life-5 Dimensions (EQ-5D). Safety and tolerability were assessed by collecting adverse events data. Pain and disability scores measured by WOMAC index were lower after treatment (pain, p ≤ 0.001; disability, p = 0.020). BPI-SF showed a significant improvement in joint function when walking and performing normal work (walking, p = 0.021; normal work, p = 0.030). SF36 scores improved for 7 out of 11 items after etoricoxib treatment (#1, p = 0.032; #4, p = 0.026; #5, p = 0.017; #6, p = 0.008; #7, p = 0.009; #8, p = 0.013; and #10, p = 0.038). EQ-5D showed a significant improvement in visual analogue scale scores (p = 0.036). TSQM results demonstrated a higher patient perception of overall satisfaction. No adverse events were reported. Pain relief, joint function, quality of life, and treatment satisfaction improved significantly in elderly patients with OA after etoricoxib administration.

Objective: To ascertain if etoricoxib increases the risk of gastrointestinal adverse events (GAEs) compared with placebo, diclofenac, and naproxen in the treatment of patients with osteoarthritis (OA) or rheumatoid arthritis (RA)., Methods: Studies were searched in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials from inception to August 2017. Randomized Clinical Trials (RCTs) that compared etoricoxib with placebo and other active drug for patients with OA or RA and reported data on gastrointestinal safety (which is of interest to patients and clinicians) were included. The follow-up time window for GAEs was defined as within 28 days subsequent to the last dose of study medication. A meta-analysis was conducted using a fixed-effect model. Risk ratios (RRs) and 95% confidence intervals (CIs) were measured., Results: We found nine randomized clinical trials (RCTs) that included information on gastrointestinal safety during follow-up time. Among them, five RCTs compared etoricoxib with placebo, four RCTs compared etoricoxib with diclofenac, and three RCTs compared etoricoxib with naproxen. Etoricoxib did not increase the risk of GAEs compared with placebo. Compared with diclofenac and naproxen, etoricoxib reduced the GAE risk (RR, 0.67; 95% CI, 0.59-0.76; p < 0.00001; 0.59; 0.48-0.72; < 0.00001) during follow-up time., Conclusions: In patients with OA or RA, etoricoxib did not increase the GAE risk compared with placebo, but reduced the GAE risk effectively compared with diclofenac and naproxen during follow-up time.

This study aimed to evaluate whether pre-emptive analgesia modifies the tissue expression of tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), and whether there is an association with postoperative surgical outcomes. A triple-blind, randomized, placebo-controlled study of patients undergoing mandibular third molar removal was performed. Volunteers were allocated randomly to receive etoricoxib 120 mg, ibuprofen 400 mg, or placebo 1h before surgery. Twenty-four surgical sites per group were required (95% confidence level and 80% statistical power). Pain scores differed significantly between groups (P<0.001). Etoricoxib and ibuprofen reduced pain scores compared to placebo (P<0.05). Pain scores peaked at 4h postoperative in the experimental groups, but at 2h postoperative in the placebo group (P<0.05). A significant reduction in TNF-α concentration from time 0' to time 30' was seen for ibuprofen (P=0.001) and etoricoxib (P=0.016). The ibuprofen group showed a significant reduction in IL-1β levels from time 0' to time 30' (P=0.038). In conclusion, TNF-α and IL-1β levels and the inflammatory events in third molar surgery were inversely associated with the degree of cyclooxygenase 2 selectivity of the non-steroidal anti-inflammatory drugs used pre-emptively. Patients given pre-emptive analgesia showed significant reductions in the clinical parameters pain, trismus, and oedema when compared to the placebo group., (Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Rationale: Pachydermoperiostosis (PDP) is a rare hereditary disorder that affects the skin and bones. PDP is characterized by periostosis, digital clubbing, and pachydermia. Previous studies demonstrated that increased prostaglandin E2 (PGE2) levels resulting from defective protein degradation pathways play a crucial role in PDP pathogenesis, and males were more commonly and severely affected than females. Moreover, nearly all PDP patients suffer from refractory arthralgia. Although several different treatment modalities are used for PDP, therapy for this disease remains challenging., Patients Concerns: Two cases of PDP showing symptoms consistent with polyarthritis and arthralgia that mainly affected the knees and ankles., Diagnoses: The diagnostic criteria for PDP include digital clubbing, periostosis, and pachydermia. The 2 patients were diagnosed as PDP based on the finger clubbing, facial cutis furrowing, knee and ankle arthritis, and radiographic evidence of periosteal proliferation., Interventions: Patient 1 had massive joint effusion that was treated by oral administration of etoricoxib and aescin combined with arthroscopic synovectomy, whereas Patient 2 had mild joint swelling and accepted only oral medication., Outcomes: Clinical symptoms of the 2 patients greatly improved after the treatment. During the 1-year follow-up, the patient experienced no adverse effects or recurrence., Lessons: The therapeutic results showed that oral etoricoxib could reduce inflammation and retard progression of pachydermia, or even relieve facial skin furrowing, but had limited efficacy for arthralgia. However, oral aescin had satisfactory efficacy for arthralgia. Thus, etoricoxib combined with aescin is a safe and effective treatment for PDP. Meanwhile, arthroscopic synovectomy can be used to treat joint effusion, but had no therapeutic effect on arthralgia. Therefore, postoperative oral medications would be needed as subsequent therapy for joint problems. In conclusion, this study proposes an effective and safe treatment plan to address symptoms experienced by PDP patients., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Mounting evidence points to the heterogeneity of osteoarthritis (OA) pain, increasing the need for more comprehensive assessment of the efficacy of standard interventions. This study investigated whether 14 days of the selective Cox-2 inhibitor etoricoxib (60 mg/day) would modify self-report of pain intensity and quality, and physical measures of hyperalgesia and function in individuals with knee OA., Design: This double-blind placebo-controlled trial included 80 community-recruited volunteers with painful knee OA (≥3/10 VAS), randomly allocated to Active or Placebo groups. Self-report measures of pain, stiffness, function Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and pain quality (PainDETECT, Pain Quality Assessment Scale [PQAS]) and physical measures of locomotion and local (knee) and widespread (elbow) hyperalgesia were assessed at Days 0, 4 and 14. Repeated Measures ANOVA analysed group differences., Results: Significant group × time interaction effects were found for all measures of pain (all p < 0.001), with WOMAC pain sub-score improving by 30.7% by Day 14 and index knee mechanical hyperalgesia improving by 32.6%, whilst Placebo group values worsened. Both self-report and physical tests of function improved (p < 0.001-p = 0.006): WOMAC-function by 28.4%, sit-to-stand and walk time by 13%, pain during locomotion tasks by 12.4-32.6%. Pain quality also significantly improved for the Active and declined for the Placebo group (p < 0.001): PainDETECT score reduced by 23.6% and PQAS paroxsysmal and surface sub-scores by 36.9% and 29.4%. There were also significant improvements in local cold hyperalgesia and widespread mechanical hyperalgesia (10-13.8%)., Conclusion: Just 14 days of etoricoxib significantly improves pain intensity and quality, function and local and widespread hyperalgesia, measured by both self-report and physical tests., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Seizures increase prostaglandin and cytokine levels in the brain. However, it remains to be determined whether cyclooxygenase-2 (COX-2) derived metabolites play a role in seizure-induced cytokine increase in the brain and whether anticonvulsant activity is shared by all COX-2 inhibitors. In this study we investigated whether three different COX-2 inhibitors alter pentylenetetrazol (PTZ)-induced seizures and increase of interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex of mice. Adult male albino Swiss mice received nimesulide, celecoxib or etoricoxib (0.2, 2 or 20mg/kg in 0.1% carboxymethylcellulose (CMC) in 5% Tween 80, p.o.). Sixty minutes thereafter the animals were injected with PTZ (50mg/kg, i.p.) and the latency to myoclonic jerks and to generalized tonic-clonic seizures were recorded. Twenty minutes after PTZ injection animals were killed and cytokine levels were measured. PTZ increased cytokine levels in the cerebral cortex and hippocampus. While celecoxib and nimesulide attenuated PTZ -induced increase of proinflammatory cytokines in the cerebral cortex, etoricoxib did not. Nimesulide was the only COX-2 inhibitors that attenuated PTZ-induced seizures. This effect coincided with an increase of IL-10 levels in the cerebral cortex and hippocampus, constituting circumstantial evidence that IL-10 increase may be involved in the anticonvulsant effect of nimesulide., (Copyright © 2017. Published by Elsevier B.V.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents because of their ability in blocking cellular proliferation, and thereby tumor development, and also by promoting apoptosis. GSK-3β, a serine threonine kinase and a negative regulator of the oncogenic Wnt/β-catenin signaling pathway, plays a critical role in the regulation of oncogenesis. Celecoxib and etoricoxib, the two cyclooxygenase-2 (COX-2) selective NSAIDs, and Diclofenac, a preferential COX-2 inhibitory NSAID, had shown uniformly the chemopreventive and anti-neoplastic effects in the early stage of colon cancer by promoting apoptosis as well as an over-expression of GSK-3β while down-regulating the PI3-K/Akt oncogenic pathway.

What Is Known and Objective: Previous studies indicate that the implementation of a prior authorization requirement for coxibs was followed by a sharp decline in their use. There are no studies showing what happens if coxib prior authorization is removed. The objective of this study is to assess the trend in the use of coxibs marketed in Spain, following removal of their respective prior authorization requirements in November 2006 for celecoxib and February 2007 for etoricoxib., Methods: We calculated the monthly number of defined daily doses per thousand inhabitants per day (DDD/TID) of coxibs dispensed in a health area of Spain from mid-2005 to December 2007. Data were analysed both graphically and by means of a segmented regression model., Results and Discussion: At the start of the study period, use of coxibs showed no growth. At the date when prior authorization of celecoxib was removed (November 2006), however, DDD/TID of the coxib whose prior authorization had not been removed - namely etoricoxib - remained unchanged, whereas consumption of celecoxib increased significantly (by the end of the study period, celecoxib use displayed a relative increase of 615% in terms of the DDD/TID prescribed before the removal of its prior authorization requirement). Similarly, etoricoxib use remained unchanged until its prior authorization was removed (February 2007), from which time DDD/TID of etoricoxib also underwent a considerable increase (by the end of the study period, etoricoxib use displayed a relative increase of 793% in terms of the DDD/TID prescribed before the removal of its prior authorization). Segmented regression analysis showed a sharp, statistically significant rise and change in slope in both celecoxib and etoricoxib use immediately after removal of their respective prior authorizations., What Is New and Conclusion: Use of celecoxib and etoricoxib rose sharply after removal of their respective prior authorizations., (© 2016 John Wiley & Sons Ltd.)

Two new series of 4,6-diaryl-3-cyanopyridine 4a-r and 1,3,5-triaryl-2-pyrazolines 6a-f and were prepared. The new compounds were evaluated for their in vitro COX-2 selectivity and in vivo anti-inflammatory activity. Compounds 4o,r and 6d,f had moderate to high selectivity index (S.I.) compared to celecoxib (selectivity indexes of 4.5, 3.14, 4.79 and 3.21, respectively) and also, showed in vivo anti-inflammatory activity approximately equal to or higher than celecoxib (edema inhibition %=60.5, 64.5, 59.3 and 59.3, after 3h, respectively) and the effective anti-inflammatory doses were (ED 50 =10.1, 7.8, 8.46 and 10.7mg/kg respectively, celecoxib ED 50 =10.8mg/kg) and ulcerogenic liability were determined for these compounds which showed promising activity by being more potent than celecoxib with nearly negligible ulcerogenic liability compared to celecoxib (reduction in ulcerogenic liability versus celecoxib=85, 82, 74 and 67%, respectively)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Several literatures reported that highly selective cycloxygenase-2 inhibitors (COX-2 inhibitors) had no effect on platelet function. However, some experts suggested stopping all non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors at least five elimination half-lives prior to surgery. We, therefore, systematically summarized the risk of clinical bleeding or platelet dysfunction in healthy or surgical subjects who received COX-2 inhibitors., Methods: Two electronic databases, MEDLINE and EMBASE, were searched for randomized, controlled studies published during 1980-December 2015. Additionally, manual search was performed to identify potential eligible studies. Intervention was perioperative use of any available COX-2 inhibitors in current practice (celecoxib, parecoxib, or etoricoxib), compared to non-selective NSAIDs, analgesics, or placebo. Two independent reviewers selected eligible studies, extracted the data, and assessed the quality of the included studies. The primary outcome was postoperative bleeding. All analyses were performed using RevMan-5.3., Results: Of 3900 abstracts reviewed, 35 studies met the inclusion criteria. The data from 16 out of 35 studies were used in this meta-analysis, and outcomes of other 19 remaining studies were descriptively summarized. COX-2 inhibitors did not significantly increase the risk of postoperative bleeding events (relative risk or RR = 0.92; 95% confidence interval or CI: 0.63-1.33; p = 0.65), intraoperative blood loss (mL) (weighted mean difference or WMD = -4.38; 95% CI: -14.69 to 5.92; p = 0.4), postoperative blood loss (mL) (WMD = -13.89; 95% CI: -30.24 to 2.47; p = 0.10), and 24-h postoperative hemoglobin loss (g/dL) (WMD = 0.47; 95% CI: -0.14 to 1.09; p = 0.13). Platelet function analyzer closure time (second) significantly decreased with the use of COX-2 inhibitors (WMD = -22.22; 95% CI: -44.03 to -0.41; p < 0.00001). In the 19 remaining studies, COX-2 inhibitors did not significantly increase risk of bleeding in both clinical and laboratory outcomes., Conclusion: Highly selective COX-2 inhibitors did not significantly increase the risk of intraoperative, postoperative bleeding, or blood loss. They also had no significant effect on platelet function. Therefore, perioperative, single dose, or short course of COX-2 inhibitors can be safely used in individuals who are undergoing surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.

Background and Objectives: Postoperative pain is one of the significant problems in laparoscopic surgery, especially during the first 6-12 h. This randomized controlled trial aimed to investigate the effect of combined preemptive etoricoxib 120 mg and low-pressure pneumoperitoneum for the management of pain after laparoscopic cholecystectomy (LC)., Patients and Methods: One hundred and twenty patients aged 18-75 with American Society of Anesthesiologists class I-II who were candidates for elective LC were recruited into the study. The patients were randomly divided into two groups, by 'block of four' randomization. The treatment group received preemptive etoricoxib 120 mg and intraabdominal pressure of 7 mmHg, and the control group received placebo and intraabdominal pressure of 14 mmHg. The postoperative pain score at rest was recorded utilizing a numeric rating scale at 1, 2, 6, 10, 14, 18, 22, and 24 h. Pain on movement/ambulation (cough) was also recorded at 6, 10, 14, 18, 22, and 24 h., Results: There were no significant differences in the baseline characteristics of the two groups. The pain scores of the treatment versus control group of abdominal pain and incisional pain were significant on movement. Abdominal pain scores of the treatment group were decreased 0.98 when compared with the control group (p = 0.017), and incisional pain scores were also decreased 0.99 (p = 0.001). The incidences of postoperative shoulder/back pain were statistically significant: 41.8 % vs. 66.7 % in the treatment and control group, respectively (p = 0.009). The postoperative hospital stay in the treatment group and control group was: 1 day = 96.4 and 75.0 %, >1 day = 3.6 and 25.0 %, respectively (p = 0.001)., Conclusions: A combination of preemptive etoricoxib and low-pressure pneumoperitoneum had significant effects in decreasing overall pain and the incidence of shoulder/back pain after LC and also shortened the hospital stay., Clinical Trials Registration Number: TCTR20140213001.

Background: Optimal postoperative analgesia is a challenge for the anaesthesiologist, with the ideal combination of methods, drugs, doses and timing of administration still the subject of research. The COX-2 inhibitors are a class of NSAIDs that may provide useful perioperative analgesia but the optimal timing of administration has not been elucidated., Objective: We hypothesised that etoricoxib given 1 h before total knee arthroplasty under spinal anaesthesia will decrease the cumulative dose of intravenous and subcutaneous morphine required to maintain pain intensity of 3 or less on a 10-point numerical rating scale (NRS) during the first postoperative 48 h compared with the same dose of etoricoxib given after surgery., Design: Randomised, double-blind, placebo-controlled trial., Setting: University hospital, between January and September, 2014., Patients: Overall, 165 patients scheduled for total knee arthroplasty under spinal anaesthesia., Interventions: The patients were randomised into one of three groups: the ETORICOX-PREOP group received etoricoxib 120 mg orally 1 h before surgery, one placebo pill at the end of surgery and a further 120 mg etoricoxib after 24 h; the ETORICOX-POSTOP group received one placebo pill 1 h before surgery and etoricoxib 120 mg at the end of surgery and after 24 h. The PLACEBO group received one placebo pill 1 h before surgery, one at end of surgery and a third after 24 h., Main Outcome Measures: The primary outcome measure was the cumulative dose of intravenous and subcutaneous morphine required during the first postoperative 48 h to maintain a 10-point numerical pain rating scale value of 3 or less. Secondary outcomes measures were duration of analgesia from initiation of spinal anaesthesia until the first analgesic requirement and the side-effects of the treatment., Results: The quantity of morphine over the first postoperative 48 h required by the ETORICOX-PREOP group (44 ± 16 mg) and the ETORICOX-POSTOP group (52 ± 23 mg) were both significantly less than the PLACEBO group (71 ± 20 mg) (P = 0.001), demonstrating a morphine-sparing effect of etoricoxib of the order of 30%; the difference between the PRE vs. POST groups was statistically significant (P = 0.02), favouring a preemptive analgesic effect. Also, there was evidence of a longer time to first analgesia compared with PLACEBO in the PREOP group (P = 0.02) but no significant difference between PREOP and POSTOP groups (P = 0.30). There was no difference in side-effects among the three study groups and there were no serious adverse effects of etoricoxib., Conclusion: Preemptive administration of etoricoxib 120 mg orally in patients undergoing total knee arthroplasty under spinal anaesthesia is superior to postoperative administration of the same dose in terms of its morphine-sparing effect during the first postoperative 48 h, but not in prolonging the time to first analgesia, and is associated with a similar incidence of side-effects., Trial Registration: Clinicaltrials.gov identifier: NCT 02534610.

Background: This study evaluated two doses of etoricoxib (60 and 90 mg) vs. naproxen 1000 mg in subjects with ankylosing spondylitis (AS)., Methods: This was a 2-part, double-blind, active comparator-controlled non-inferiority study in subjects ≥18 years of age with AS. In Part I, subjects were randomized to naproxen 1000 mg; etoricoxib 60 mg, and 90 mg. In Part II, naproxen and etoricoxib 90 mg subjects continued on the same treatment; subjects on etoricoxib 60 mg either continued on 60 mg or escalated to 90 mg. Part I (6 weeks) assessed the efficacy of A) etoricoxib 60 mg vs. naproxen and B) 90 mg vs. naproxen according to the time-weighted average change from baseline in Spinal Pain Intensity (SPI; 0-100 mm VAS) (primary endpoint). The non-inferiority margin was set at 8 mm for SPI. In Part II (20 weeks) we evaluated the potential benefit of increasing from 60 to 90 mg (predefined minimum clinically important difference = 6 mm in SPI) for inadequate responders (<50 % improvement from baseline in SPI) on etoricoxib 60 mg in Part I., Results: In total, 1015 subjects were randomized to receive etoricoxib 60 mg (N = 702), etoricoxib 90 mg (N = 156), and naproxen 1000 mg (N = 157); 70.9 % were male and the mean age was 45.2 years. There were 919 subjects who completed Part I and all continued to Part II. In Part I, SPI change was non-inferior for both etoricoxib doses vs. naproxen. In both Part I and II, the incidence of adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) were similar between the 3 treatment groups., Conclusion: Both doses of etoricoxib were non-inferior to naproxen. All treatments were well tolerated. Etoricoxib 60 and 90 mg effectively control pain in patients with AS, with 60 mg once daily as the lowest effective dose for most patients., Trial Registration: Clinical Trials Registry # NCT01208207 . Registered on 22 September 2010.

Background: Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease., Methods: This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0-100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study., Results: In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p = 0.004 for 60 mg and p = 0.034 for 90 mg for DAS28-CRP; p < 0.001 for both doses for PGAP) in Part I. Further in Part I, etoricoxib 90 mg was not significantly different from 60 mg for DAS28-CRP, but did demonstrate a small, but statistically significant decrease in baseline PGAP score vs. 60 mg (p = 0.019). In Part II, there was no significant decrease in PGAP score after increasing to 90 mg in subjects with inadequate pain relief on 60 mg as compared to subjects who stayed on 60 mg. The incidence of AEs and SAEs were similar between etoricoxib 60 mg and 90 mg in both Part I and II., Conclusion: Both etoricoxib 90 mg and 60 mg are superior to placebo in relieving the symptoms of RA. Etoricoxib 90 mg vs 60 mg resulted in a statistically significant, though small, improvement in PGAP score, but not DAS28-CRP. Dose escalation from 60 mg to 90 mg in pain inadequate responders did not significantly improve efficacy. These results confirm the efficacy and tolerability of etoricoxib 90mg in patients with RA. In addition, this study demonstrated that etoricoxib 60 mg is also efficacious and well-tolerated in RA., Clinical Trial Registration: NCT01208181 (registered September 22, 2010).

The COX-2 inhibitor etoricoxib modulates the peripheral and central nociceptive mechanisms in animals. This interaction has not been studied in patients with pain. This randomized, double-blind, placebo-controlled, 2-way crossover, 4-week treatment study investigated the pain mechanisms modulated by etoricoxib in patients with painful knee osteoarthritis. Patients were randomized to group A (60 mg/d etoricoxib followed by placebo) or B (placebo followed by 60 mg/d etoricoxib). The quantitative, mechanistic pain biomarkers were pressure pain thresholds, temporal summation (TS), and conditioning pain modulation. Clinical readouts were Brief Pain Inventory, WOMAC, painDETECT questionnaire (PD-Q), and time and pain intensity during walking and stair climbing. Etoricoxib as compared with placebo significantly modulated the pressure pain thresholds (P = 0.012, localized sensitization) at the knee and leg (control site) (P = 0.025, spreading sensitization) and TS assessed from the knee (P = 0.038) and leg (P = 0.045). Conditioning pain modulation was not modulated. The Brief Pain Inventory (pain scores), PD-Q, WOMAC, and walking and stair climbing tests were all significantly improved by etoricoxib. Based on a minimum of 30% or 50% pain alleviation (day 0-day 28), responders and nonresponders were defined. The nonresponders showed a significant association between increased facilitation of TS and increased pain alleviation. None of the other parameters predicted the degree of pain alleviation. Generally, a responder to etoricoxib has the most facilitated TS. In conclusion, etoricoxib (1) modulated central pain modulatory mechanisms and (2) improved pain and function in painful osteoarthritis. Stronger facilitation of TS may indicate a better response to etoricoxib, supporting the central mode-of-action of the drug.

Purpose: This study investigated whether etoricoxib (COX-II blocker) has a superior efficacy of preventing heterotopic ossification (HO) after total hip arthroplasty (THA) compared to diclofenac (non-selective NSAID)., Methods: One hundred patients were included (50 in each group) in this single centre, prospective, double-blinded, randomized, controlled trial. Etoricoxib (90 mg) was administered once and diclofenac (75 mg) twice per day for a perioperative period of nine days. The incidence of HO was evaluated on radiographs of the pelvis six months after surgery., Results: Eighty nine of 100 (89 %) patients could be analysed. The overall HO incidence was 37.8 %. There was no significant difference between both study groups. Twelve patients (27.3 %) of the DIC group and 13 patients (28.9 %) of the ETO group showed Brooker grade I ossifications. Five patients (11.4 %) of the DIC and four patients of the ETO (8.9 %) group showed grade II HO formations. No class III or IV HO formations occured in both groups. Ad hoc analysis detected a negative correlation between HO incidence and limited abduction and internal rotation of the hip., Conclusions: Etoricoxib and diclofenac are equally effective for oral HO prophylaxis after primary cementless THA when given for nine peri-operative days to ensure a full recovery and high patient satisfaction.

Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ± 2.74 μM)>celecoxib (IC50: 14.92 ± 6.40 μM)>valdecoxib (IC50: 161.4 ± 28.6 μM)>rofecoxib (IC50: 238.4 ± 79.2 μM)>etoricoxib (IC50: 405.1 ± 116.3 μM). Mechanism based inhibition of ATP synthesis (Kinact 0.078 min(-1) and KI 21.46 μM and Kinact/KI ratio 0.0036 min(-1)μM(-1)) was shown by lumiracoxib and data suggest that the opening of the MPT pore may not be the mechanism of toxicity. A positive correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs and these metabolites did not alter the inhibition profile of ATP synthesis of the parent compound. The results suggest that coxibs themselves could be involved in the hepatotoxic action through inhibition of ATP synthesis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design., Methods: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection., Results: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups., Conclusions: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery., (© 2015 European Pain Federation - EFIC®)

Objectives: Current therapeutic approaches to fibromyalgia syndrome (FMS) do not provide satisfactory pain control to a high percentage of patients. This unmet need constantly fuels the pursuit for new modalities for pain relief. This randomised, double-blind, controlled study assessed the efficacy and safety of adding etoricoxib vs. placebo to the current therapeutic regimen of female patients with FMS., Methods: In this double-blind, placebo-controlled study, female patients were randomised to receive either 90 mg etoricoxib once daily or placebo for 6 weeks. Several physical and mental parameters were assessed throughout the study. The primary end-point was the response to treatment, defined as ≥ 30% reduction in the average Brief Pain Inventory score. Secondary outcomes were changes in the Fibromyalgia Impact Questionnaire, SF-36 Quality of Life assessment questionnaire and Hamilton rating scales for anxiety and depression., Results: Overall, 73 patients were recruited. Although many outcome measures improved throughout the study, no difference was recorded between the etoricoxib- and placebo-treated groups. The Brief Pain Inventory, Fibromyalgia Impact Questionnaire, The Hamilton Anxiety and Depression scores did not differ between the two groups., Conclusions: This is the first randomised, double-blind study assessing the effect of adding etoricoxib to pre-existing medications for female patients with FMS. Although being mildly underpowered this study clearly has shown that etoricoxib did not improve pain scores and did not lead to any beneficial mental or physical effects., (© 2016 John Wiley & Sons Ltd.)

The aim is to study the efficacy and safety of etoricoxib in the treatment of acute gout, as compared with non-steroidal anti-inflammatory drugs (NSAIDs). We conducted a computerized search of electronic databases: PubMed, EMBASE, Web of Science, China Biology Medicine disc, and Cochrane Library. The search terms were as follows: gout arthritis, tophus, etoricoxib, indometacin naproxen, diclofenac, and NSAIDs. Articles were searched from 1983 until August 2014. A manual search of peer-reviewed English documents was performed by cross-checking the bibliographies of selected studies. These trials reported pain relief as the primary outcome. Tenderness, swelling, patients' global assessments of response to treatment, and investigators' global assessments of response to treatment were reported as the secondary outcomes. All adverse events were recorded for safety assessment. Six trials including 851 patients were identified. Both etoricoxib and NSAIDs had an effect on inflammation and analgesia. Compared with indometacin and diclofenac, etoricoxib had a lower incidence of adverse events. Etoricoxib 120 mg administered orally once daily has the same efficacy on acute gout as indometacin and diclofenac. Etoricoxib is tolerated better by patients than NSAIDs such as indometacin and diclofenac.

Objectives: To evaluate the efficacy of etoricoxib in patients with axial ankylosing spondyloarthritis (AS) refractory to traditional NSAIDs., Methods: This was an open label, multicentric, randomised, prospective (4 weeks with and open extension to 6 months), non-controlled study. Consecutive patients with axial AS refractory to traditional NSAID eligible for anti-TNF-α therapy were selected. The primary outcomes were the rate of patients with good clinical response (not eligible for anti-TNF-α therapy after etoricoxib) and the Assessment of Spondyloarthritis International Society response criteria for biologic therapies (ASASBIO) response at 4 weeks. Secondary outcomes included: ASAS20 and 40 responses, ASDAS-CRP response, BASDAI, BASFI, back and night back pain, global patient and physician assessment of the disease, and biologic parameters like C-reactive protein (CRP) at 2, 4 weeks and 6 months., Results: A total of 57 axial AS patients were recruited, 46 men, with mean age of 43 years. After 4 weeks of treatment, 26 patients (46%) achieved a good clinical response and 11 (20%) an ASASBIO response. These results at 24 weeks were 19 (33%) and 13 (23%) respectively. All individual clinical variables improved significantly after 4 weeks of treatment. CRP serum levels decreased after 4 weeks but reached no statistical significance, although 30% of patients showed a normalisation of CRP., Conclusions: Etoricoxib provided a clear clinical improvement in around a third of patients with axial AS refractory to traditional NSAIDs. Special care should be required when deciding to start anti-TNF-α therapy; it seems reasonable to keep in mind these results of etoricoxib treatment.

Cancer cells require nourishment for the growth of the primary tumor mass and spread of the metastatic colony. These needs are fulfilled by tumor-associated neovasculature known as angiogenesis, which also favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore, targeting angiogenesis is profitable as a mechanism to inhibit tumor growth. Furthermore, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in the neoplastic and proinflammatory milieu. We studied the role of two important chemokines (monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1β [MIP-1β]) along with VEGF and MMPs in nonsteroidal anti-inflammatory drug (NSAID)-induced chemopreventive effects in experimental colon cancer in rats. 1,2-Dimethylhydrazine dihydrochloride (DMH) was used as cancer-inducing agent and three NSAIDs (celecoxib, etoricoxib, and diclofenac) were given orally as chemopreventive agents. Analysis by immunofluorescence and western blotting shows that the expression of VEGF, MMP-2, and MMP-9 was found to be significantly elevated in the DMH- treated group and notably lowered by NSAID coadministration. The expression of MCP-1 was found to be markedly decreased, whereas that of MIP-1β increased after NSAID coadministration. NSAID coadministration was also able to induce apoptosis, confirmed using studies by Hoechst/propidium iodide (PI) costaining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results from the present study indicate the potential role of these chemokines along with VEGF and MMPs against angiogenesis in DMH-induced cancer. The inhibition of angiogenesis and induction of apoptosis by NSAIDs were found to be possible mechanisms in the chemoprevention of colon cancer.

Pain after third molar extraction has been considered the most suitable pharmaceutical model to evaluate acute pain. This study aimed to evaluate the pre-emptive analgesic/anti-inflammatory efficacy of etoricoxib 120 mg following mandibular third molar surgery. A split-mouth, randomized, triple-blind, placebo-controlled study was conducted with patients undergoing the surgical removal of mandibular third molars. All volunteers were allocated randomly to receive either etoricoxib 120 mg or placebo 1h preoperatively, and inflammatory events were evaluated. An estimated sample of 18 surgical units per group was required based on a pilot study (95% confidence level and 80% statistical power). Rescue medication was analyzed by Kaplan-Meier method through log-rank Mantel-Cox test and Pearson linear correlation (P<0.05). Pre-emptive etoricoxib reduced postoperative pain scores significantly in comparison to placebo (P<0.001), with a pain score peak at 6h after surgery (P<0.001). The mean rescue medication consumption was lower in the etoricoxib group compared to the placebo group over the study period (P<0.05). There was no statistically significant difference between groups related to swelling and trismus. The pre-emptive administration of etoricoxib 120 mg significantly reduced the postoperative pain intensity and the need for rescue medication, but did not reduce swelling or trismus., (Copyright © 2015 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, or nonselective NSAIDs or totally unexposed to NSAIDs., Methods: We performed a national register-based cohort study on patients with AS or SpA (n = 21,872) identified in the Swedish national patient register from 1987-2009. Treatment exposure was assessed time dependently based on the prescription drug register from 2006-2009, adjusting for sociodemographics and comorbidities derived from national population-based registers., Results: Exposure to etoricoxib, celecoxib, and nonselective NSAIDs was 7.6%, 3.9%, and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal, or renal adverse events were seen among the 3 exposure groups. Patients unexposed to NSAIDs had more baseline comorbidities and an increased relative risk for congestive heart failure events during the study period (2.0, 95% confidence interval [95% CI] 1.3-3.2). The relative risk for atherosclerotic events was nonsignificant when compared to the nonselective NSAID group (1.0, 95% CI 0.7-1.5), while the relative risk for gastrointestinal events was lower for unexposed patients (0.5, 95% CI 0.4-0.7)., Conclusion: Overall, serious adverse events related to nonselective NSAIDs, etoricoxib, and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerably more baseline comorbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAIDs in clinical practice., (© 2015, American College of Rheumatology.)

The origin of Debye-like relaxation in some hydrogen-bonded liquids is a matter of hot debate over the past decade. While a relatively clear picture of the issue has been established for monohydroxy alcohols, the Debye-type dynamics in other glass-forming systems still remains a not fully understood phenomenon. In this paper we present the results of dielectric measurements performed in the frequency interval 10(-1) to 10(9)Hz, both in the supercooled and normal liquid state of etoricoxib anti-inflammatory agent. Our investigations reveal the presence of slow Debye-like relaxation with features similar to that found for another active pharmaceutical ingredient, ibuprofen. Our results provide a fresh insight into the molecular nature of Debye-type relaxation in H-bonded pharmaceutically relevant materials and thus may stimulate the academic community for further discussion concerning the molecular dynamics of hydrogen-bonded fluids in general.

Different data suggest the involvement of specific inflammatory pathways in the pathogenesis of epilepsy. Cyclooxygenase (COX), which catalyses the production of pro-inflammatory prostaglandins, may play a significant role in seizure-induced neuroinflammation and neuronal hyperexcitability. COX-2 is constitutively expressed in the brain and also increased during/after seizures. COX-2 inhibitors may thus attenuate inflammation associated with brain disorders. We studied whether early long-term treatment (17 consecutive weeks starting from 45 days postnatal age) with the non-steroidal anti-inflammatory drug etoricoxib (10 mg/kg/day per os), a selective COX-2 inhibitor, was able to prevent/reduce the development of absence seizures in WAG/Rij rats, a recognized animal model of absence epilepsy and epileptogenesis. Drug effects on the incidence, duration and properties of absence seizure spike-wave discharges (SWDs) were measured both 1 and 5 months after treatment withdrawal; furthermore, the acute effects of etoricoxib on SWDs in 6-month-old WAG/Rij rats were measured. Early long-term treatment (ELTT) with etoricoxib led to an ∼40% long-lasting (5 months) reduction in the development of spontaneous absence seizures in adult WAG/Rij rats thus exhibiting antiepileptogenic effects. Acutely administered etoricoxib (10 and 20mg/kg i.p.) also had anti-absence properties, significantly reducing the number and duration of SWDs by ∼50%. These results confirm the antiepileptogenic effects of COX-2 inhibitors and suggest the possible role of COX-2, prostaglandin synthesis and consequent neuroinflammation in the epileptogenic process underlying the development of absence seizures in WAG/Rij rats., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Various selective and nonselective cyclooxygenase (COX) inhibitors are known to have effects on development and progression of seizures. In the present study, the effect of the selective COX-2 inhibitor etoricoxib on seizures, oxidative stress, and learning and memory was studied., Method: Male Wistar rats were kindled using subconvulsant dose of pentylenetetrazole (PTZ) (30mg/kg, i.p.), on alternating days until animals were fully kindled. After a one-week PTZ-free period, kindled rats were challenged with PTZ 30mg/kg, and the latency, duration, and severity of seizures were recorded. Etoricoxib was then administered intraperitoneally at 1mg/kg and 10mg/kg in kindled rats for nine days (days 6-14). On the ninth day of etoricoxib treatment, PTZ challenge (30mg/kg) was given, and seizure parameters were noted. On day 15, behavioral assessment was carried out. The Morris water maze (MWM) apparatus and the passive avoidance (PA) apparatus were used for studying cognitive impairment. The rats were then sacrificed, and malondialdehyde (MDA) and glutathione (GSH), markers of oxidative stress, were estimated in the brain samples., Results: Etoricoxib at lower dose (1mg/kg) had an anticonvulsant effect which was reduced or reversed at higher dose (10mg/kg). Etoricoxib also impaired the learning and memory in rats as tested by passive avoidance and Morris water maze tests., Conclusion: The results of the present study suggest that use of etoricoxib, especially at low dose, in patients with epilepsy may not be detrimental with regard to seizure control. However, attention should be paid to cognitive parameters., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesics for treatment of variety of pain and inflammatory conditions. Their effects on the gastrointestinal tract are well described, but their possible propensity to cause clinical relapse in patients with inflammatory bowel disease (IBD) remains somewhat unclear., Aim: We reviewed case reports, case-control and cohort studies, as well as clinical trials of NSAIDs in patients with quiescent IBD in order to better assess the magnitude and type of effect., Results: The published literature on this subject is of mixed quality and many of the studies are open to criticism. The majority of patients with IBD tolerate these medications, while in the sole clinical trial of NSAIDs 20% experienced a clinical and laboratory documented relapse of disease, within 7-10 days of NSAID ingestion. The data on cyclooxygenase (COX)-2-selective anti-inflammatory analgesic are somewhat unclear, but nimesulide, celecoxib and etoricoxib do not appear to be associated with relapse of disease., Conclusion: Conventional NSAIDs may cause clinical relapse in about 20% of patients with quiescent IBD, which may be due to dual inhibition of the COX enzymes. Certain COX-2-selective NSAIDs appear to be safe.

Etoricoxib is a selective cyclo-oxygenase 2 (COX-2) enzyme inhibitor and is exploited for its analgesic activity in various disease conditions like osteoarthritis, gouty arthritis, acute pain including postoperative dental pain and primary dysmenorrhea, etc. Although highly efficacious in pain management the safety profile of this COX-2 inhibitor is yet to be established in a broader sense. Short-term clinical trials and postmarketing surveillance have shown a very rare incidence of very serious skin reactions like Steven Johnson syndrome or toxic epidermal necrolysis (TEN). In this case report, we summarize regarding a patient who developed TEN after treatment with etoricoxib for osteoarthritis that later resolved in 15 days after withdrawal and symptomatic treatment.

Background: Our objective was to evaluate the effect of background biological disease-modifying anti-rheumatic drugs (bDMARDs) and/or corticosteroids (CS) on response to nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients., Methods: The following efficacy endpoints were evaluated using time-weighted change from baseline in a 12-week, randomized controlled clinical trial with etoricoxib: Patient Global Assessment of Pain, Swollen Joint Count, Tender Joint Count, Health Assessment Questionnaire. The following three treatment groups were evaluated: placebo, pooled etoricoxib 10/30/60 mg, and etoricoxib 90 mg. Screening values, values post flare, as well as changes after treatment were analyzed., Results: Of the 1014 patients screened, 761 were randomized; 50% were on no background bDMARDs and/or CS therapy, 23% used bDMARDs, 34% used CS, and 8% used both bDMARDs and CS. It was demonstrated that RA patients on bDMARDs or CS had similar pain levels at screening as patients without this co-medication. They experienced flare upon NSAID withdrawal and demonstrated dose-dependent pain improvement with etoricoxib., Conclusion: These results support that RA patients receiving bDMARDs or CS may still require the use of concomitant analgesics to treat pain. Clinicians should continue to monitor and treat pain even after initiating a bDMARD and/or CS., Trial Registration: [clinicaltrials.gov; NCT00264147].

Aim: To evaluate the safety of etoricoxib in patients with acute nonspecific back pain associated with the high risk of cardiovascular events (CVE) in clinical practice., Subjects and Methods: The open prospective follow-up by a simple randomization method included 80 patients, including 49 women and 31 men (mean 60.8±4.7 years). The patients were randomized into 4 groups of 20 persons each: 1) etoricoxib 90 mg/day; 2) nimesulide 100 mg/day; 3) diclofenac 100 mg/day; 4) meloxicam 15 mg/day. The investigation lasted 90±4.5 days. The interim evaluation criteria (study points) were pain changes using a visual analog scale (VAS); blood pressure (BP) changes; diurnal BP rhythm; and changes in coagulation hemostatic parameters and blood biochemical markers. The primary evaluation criteria (study endpoints) were the incidence of CVE in the use of nonsteroidal anti-inflammatory drugs (NSAIDs)., Results: The patients with acute back pain were shown to have a high incidence of comorbidities during outpatient care. The administration of NSAIDs resulted in a significant reduction in the magnitude and intensity of pain syndrome according to VAS in all the groups just on day 3 of therapy with a more marked analgesia in patients receiving etoricoxib and diclofenac. All the groups exhibited an increase in average daily systolic and diastolic BP with the most favorable profile in Group 1 patients. The intake of etoricoxib and other NSAIDs provided no evidence for changes in hemostatic parameters and biochemical markers during 10 weeks. The safety of etoricoxib was comparable with that of NSAIDs in its effect on the plasma hemostatic system., Conclusion: Unlike nimesulide, diclofenac, and meloxicam, etoricoxib was characterized by a rapid steady-state analgesic effect with a less pronounced action on diurnal BP rhythm. Within 3 months after treatment, no acute CVE was recorded in the patients taking etoricoxib.

Aim: To study the clinical and laboratory efficiency and safety of different etoricoxib (ET) regimens in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis., Subjects and Methods: Forty patients with high axSpA activity (Bath Ankylosing Disease Activity Index (BASDAI 4) were examined and randomized to 2 groups: 1) 30 patients who received ET 90 mg continuously every day; 2) 10 patients who took the drug in the same dose intermittently 1-3 times weekly. The activity of axSpA (BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), erythrocyte sedimentation rate (ESR), and high-sensitivity C-reactive protein (hs-CRP)) was evaluated at baseline, 2 and 12 weeks; adverse events were recorded at baseline, 2, 6, and 12 weeks. The number of patients who had achieved an ASAS40 response at 2 and 12 weeks were taken into consideration. RESULTS At 12 weeks, the continuous administration group displayed decreases in BASDAI from 8 to 4, in ASDAS from 3.8 to 2.6, and in hs-CRP levels from 9.5 to 3.9 mg/l; the intermittent administration group exhibited decreases in BASDAI from 7.6 to 6.0, in ASDAS from 3.5 to 3.1, and hs-CRP from 8.8 to 4.5 mg/l (p<0.05). At this time, an AS40 response was achieved by 22 (73.3%) and 2 (20%) patients in Groups 1 and 2, respectively (p<0.05 for all). No serious adverse events were recorded., Conclusion: The efficacy of ET given in a daily dose of 90 mg was much higher than that of the drug used thrice or less weekly in the patients with axSpA.