COX-2 inhibitor delivery system aiming intestinal inflammatory disorders.

Selective COX-2 inhibitors such as etoricoxib (ETX) are potentially indicated for the treatment of intestinal inflammatory disorders. However, their systemic administration provokes some off-site secondary effects, decreasing the desirable local effectiveness. To circumvent such limitations, herein an ETX delivery system based on electrospun fibrous meshes (eFMs) was proposed. ETX at different concentrations (1, 2, and 3 mg mL-1) was loaded into eFMs, which not affect the morphology and the mechanical properties of this drug delivery system (DDS). The ETX showed a burst release within the first 12 h, followed by a faster release until 36 h, gradually decreasing over time. Importantly, the ETX studied concentrations were not toxic to human colonic cells (i.e. epithelial and fibroblast). Moreover, the DDS loading the highest concentration of ETX, when tested with stimulated human macrophages, promoted a reduction of PGE2, IL-8 and TNF-α secretion. Therefore, the proposed DDS may constitute a safe and efficient treatment of colorectal diseases promoted by inflammatory disorders associated with COX-2.

Heterotopic ossification after total hip arthroplasty: When is development completed?

BACKGROUND: Heterotopic ossifications (HO) are a common complication after total hip arthroplasty (THA). Nonsteroidal anti-inflammatory drugs have proven to reduce the occurrence of HO. It is still unclear when the formation of HO is finished. Aim of our study was to answer this question. METHODS: In a prospective study, the occurrence of periarticular HO was checked during the follow-up (FU) examinations. In total, 75 consecutive patients who underwent THA were included. To ensure a high follow-up rate, only patients with a life expectancy of at least 10 years were included. A medical ossification prophylaxis with mostly etoricoxib (90 mg once daily) was administered. Follow-up examinations were performed at 3 months, 1 year, 3, 5, and 10 years postoperatively. Each time, a clinical and radiological examination was carried out. The HO was graded according to Brooker's method. RESULTS: Low-grade HO classified by Brooker grade I and II occurred significantly more frequent than HO grade III. In patients with present HO, a possible increase in Brooker stage could further be observed within 3 years postoperatively. After 3 years, the formation of HO was completed in all patients. CONCLUSION: Three years after THA, the formation of HO is complete. After more than 3 years postoperatively, if HO occurs or increases, other triggering causes such as new trauma, periarticular infection, or implant loosening should be considered.

Preemptive Oral Etoricoxib on Health-Related Quality of Life after Mandibular Third Molar Surgery: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

This study was aimed at evaluating the use of oral etoricoxib for preemptive analgesia on the health-related quality of life (QoL) outcome after the extraction of mandibular third molar. The study population consisted of 60 participants that required extraction of a single partial bony impacted mandibular third molar under local anesthesia and met the inclusion criteria. The participants were randomized into two groups. The etoricoxib group orally received 60 mg etoricoxib 30 min before surgery, whereas the control group was given a placebo. The patients were assessed postoperatively after 1, 2, 3, 4, 5, 6, and 7 days using the United Kingdom oral health-related QoL questionnaire and visual analog scale for maximum postoperative pain. The total dose of ibuprofen rescue intake and total number of days the drug was taken were recorded. Surgical removal of impacted teeth had a negative influence on the patient's QoL across various physical, social, and psychological aspects. The scores for postoperative pain in the etoricoxib group were significantly lower than those in the control group on each postoperative observation day. The number of patients without analgesic rescue medication, the average amount, and total number of days emergency analgesics were taken were significantly lower in the etoricoxib group than in the control group. The etoricoxib group showed better QoL score than the control group. Preemptive oral etoricoxib is an effective therapeutic strategy for improving the QoL after surgical removal of the impacted lower third molar.

Meloxicam and/or Etoricoxib Could Be Administered Safely in Two Equal Doses during an Open Oral Challenge in Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity.

BACKGROUND: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. OBJECTIVE: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. METHODS: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. RESULTS: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. CONCLUSIONS: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice.

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.

Repairing effects of glucosamine sulfate in combination with etoricoxib on articular cartilages of patients with knee osteoarthritis.

PURPOSE: To evaluate the repairing effects of glucosamine sulfate combined with etoricoxib on articular cartilages of patients with knee osteoarthritis (KOA). METHODS: A total of 106 KOA patients were randomly divided into control (n = 40) and experimental groups (n = 66) and treated with etoricoxib alone and glucosamine sulfate plus etoricoxib, respectively. Changes in WOMAC score and clinical efficacy were observed. The synovial fluid was extracted. Bone metabolism indices, growth factors, inflammatory factors, matrix metalloproteinases (MMPs), and NO-induced apoptosis-related factors were measured by ELISA. JNK and Wnt5a mRNA levels were determined using RT-PCR. RESULTS: After treatment, the total WOMAC scores of both groups significantly declined (P < 0.05), being lower in experimental group. The total effective rate of experimental group was higher (P < 0.05). BGP and OPG levels rose, especially in experimental group (P < 0.05). CTX-II, COMP, and RANKL levels decreased, particularly in experimental group (P < 0.05). TGF-ß, IGF-1, and FGF-2 levels increased, especially in experimental group (P < 0.05). Both groups, particularly experimental group, had decreased levels of IL-1ß, IL-17, IL-18, TNF-α, MMP-3, MMP-9, and MMP-13 (P < 0.05). JNK and Wnt5a mRNA levels of both groups dropped, which were lower in experimental group (P < 0.05). NO and LPO levels reduced, being lower in experimental group. SOD level rose, especially in experimental group (P < 0.05). CONCLUSION: Glucosamine sulfate plus etoricoxib can repair the articular cartilages of KOA patients. Probably, JNK and Wnt5a are downregulated to inhibit the secretion of MMPs through lowering the levels of inflammatory factors, thereby delaying cartilage matrix degradation. NO-induced chondrocyte apoptosis may be suppressed via the SOD pathway.

Etoricoxib-loaded bio-adhesive hybridized polylactic acid-based nanoparticles as an intra-articular injection for the treatment of osteoarthritis.

Osteoarthritis is a major problem in elder people. Etoricoxib-loaded bio-adhesive hybridized nanoparticles were prepared using polylactic acid (PLA) and chitosan hydrochloride (CS-HCl) in presence of Captex®200 as a liquid oil, polyvinyl alcohol (PVA) and Tween®80 as surfactants. The study aimed to present a new intra-articular treatment of osteoarthritis with anti-inflammatory as well as bone rebuilding effects. Hybridized nanoparticles were fabricated applying the emulsion solvent evaporation technique then assessed for particle size, zeta potential, entrapment efficiency and in-vitro drug release. Furthermore, FT-IR and DSC in addition to morphological examination were done. Results revealed that the formulation composed of PLA:Captex®200 in ratio 1:2 (w/w), 1%w/v Tween®80, 0.3% w/v CS-HCl and 3%w/v PVA possessed the smallest particle size and the most sustained drug release, thus was sorted for further analyses. The selected formulation ability to interact with the negatively charged sodium fluroscein was evaluated to predict its binding with the naturally occurring hyaluronic acid in the knee joint where promising results were obtained. Results showed the cytocompatibility of the formulation when tested using MC3T3-E1 normal bone cell line, enhanced ALP activity and increased calcium ion deposition and binding. Results suggested that the presented formulation can be considered as an innovative approach for osteoarthritis.

Design and optimization of film-forming gel of etoricoxib using research surface methodology.

The present investigation is focused on the development of transdermal film-forming gel (FFG) loaded with etoricoxib employing research surface methodology (RSM). Box-Behnken surface design method was used to develop experimental run using different concentrations of etoricoxib, hydroxypropyl methylcellulose (HPMC K100M), and eudragit RL100 as independent variables, and Derringer's optimization tool was employed to optimize best possible formulation. The dependent variables considered in this study were viscosity and drug permeation at 24 h (Q24, µg/cm2). Anti-inflammatory study was performed on Wistar albino rats for 8 h. Skin irritation studies and accelerated stability studies were performed for validated FFG formulations. Quadratic model was found to be best fit model (p < 0.0001) for both the responses. The influence of HPMC concentration on the viscosity was found to be highest whereas concentration of etoricoxib was maximum for Q24. The optimum composition of the FFG was observed to be 4% of etoricoxib, 1.1246% of HPMC, and 0.4% of eudragit. Above composition resulted in viscosity of 1549.5 mPa.s and maximum Q24 of 4639.11 µg/cm2 with desirability 0.918. The in vivo anti-inflammatory study demonstrated better sustained release effect (for 8 h) of optimized FFG compared to orally administered drug suspension. An average irritation score of 0.555 was observed on Draize scoring system. The validated FFG formulation was found to be stable for the 3 months in accelerated conditions. It can be concluded from the above investigations that the validated FFG formulation of etoricoxib is well tolerated and could provide sustained drug release for 8 h. Graphical abstract.

Facile synthesis of mesoporous alumina using hexadecyltrimethylammonium bromide (HTAB) as template: simplified sol-gel approach.

Herein the authors present the synthesis of surface functionalised mesoporous alumina (MeAl) for textural characterisation by a simplified sol-gel method obtained by using hexadecyltrimethylammonium bromide as a template. Etoricoxib (ETOX) was used as a model drug for the study. Alumina supported mesoporous material containing drug was characterised using instrumental technique namely Brunauer-Emmett-Teller surface area, Fourier transform-infrared, differential scanning calorimetry, transmission electron microscopy, X-ray diffraction, and field emission scanning electron microscopy. Diffusion study using a dialysis bag method used to check the release pattern of ETOX-loaded-MeAl. Results of characterisation study revealed the successful surface functionalisation of the drug on nanocomposite. The IC50 value obtained from cell viability study demonstrated the non-toxic behaviour of synthesised drug-loaded mesoporous alumina up to the tested concentration range. The present work has demonstrated that synthesised MeAl showed excellent stability with an expanded surface area suitable for carrier material for drug delivery system.

Exantema fijo medicamentoso por etoricoxib / Fixed drug eruption induced by etoricoxib

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Pain on the first postoperative day after tonsillectomy in adults: A comparison of metamizole versus etoricoxib as baseline analgesic.

OBJECTIVE: To compare the effect of metamizole versus etoricoxib as baseline analgesic for treating postoperative pain after tonsillectomy. DESIGN: Single centre prospective cohort study. SETTING: Two consecutive cohorts of tonsillectomy patients. PARTICIPANTS: 124 patients (n = 55 treated with etoricoxib, n = 69 with metamizole); median age 30.5 years; 50% women. MAIN OUTCOME MEASURES: Patients rated their pain on first postoperative day using the questionnaires of the German-wide project Quality Improvement in Postoperative Pain Treatment (QUIPS) including numeric rating scales (NRS, 0-10) for pain determination. The influence of preoperative and postoperative parameters on patients' pain was estimated by univariate and multivariate statistical analysis. RESULTS: The demographic parameters showed no differences between the patients in the metamizole group and the etoricoxib group (all p>0.05) with one exception: Patients in the metamizole group had significantly more preoperative pain than patients in the etoricoxib group (p = 0.001). The metamizole group had a mean postoperative pain in activity of 4.4 ± 2.1 and the etoricoxib group of 4.5 ± 2.2. Maximal pain for the metamizole group and the etoricoxib group were 5.6 ± 2.2 and 6.1 ± 1.9, respectively. Pain in activity, maximal pain and minimal pain were not different between both groups (p = 0.652, p = 0.113, p = 0.276, respectively). Patients of the etoricoxib group received more frequently piritramide in recovery room as demand medication (p = 0.046). In the whole cohort, patients with peritonsillar abscess had more preoperative pain in comparison to chronic tonsillitis (p<0.001). Patients under 30.5 years reported higher maximal pain than older patients (p = 0.049). On the other hand, a significant influence of patients' age on the pain in activity and minimal pain could not be demonstrated (p = 0.368, p = 0.508, respectively). Men reported lower minimal pain than women (p = 0.041). Also, patients with ASA status I had lower minimal pain than patients with higher ASA status (p = 0.019). The multivariate analysis did not show an association between postoperative pain in activity and preoperative counseling on postoperative pain management (p = 0.588, p = 0.174, respectively). Special preoperative counseling on postoperative pain management resulted in lower levels of maximal pain (p = 0.024). Linear regression demonstrated an independent association of higher pain in activity with higher mobility impairment (p = 0.034) and respiratory impairment (p = 0.002). The linear regression of minimal pain identified female gender (p = 0.005) as an independent influencing factor with higher pain levels. In terms of satisfaction, no preoperative pain therapy (p = 0.016) could be found as an independently significant influencing factor with higher satisfaction. CONCLUSION: Etoricoxib does not have an advantage as baseline analgesic for post tonsillectomy pain in comparison to metamizole.

Bilateral subcostal transversus abdominis plane block does not improve the postoperative analgesia provided by multimodal analgesia after laparoscopic cholecystectomy: A randomised placebo-controlled trial.

BACKGROUND: Laparoscopic cholecystectomy might be considered minor surgery, but it may result in severe postoperative pain. Subcostal transversus abdominis plane (TAP) block, which produces long-lasting supra-umbilical parietal analgesia, might improve analgesia after laparoscopic cholecystectomy. OBJECTIVE: We investigated whether subcostal TAP block would reduce opioid consumption and pain after laparoscopic cholecystectomy in patients provided with multimodal analgesia. DESIGN: A randomised, placebo-controlled, double-blind study. SETTING: The study was conducted at a university teaching hospital from December 2017 to June 2018. PATIENTS: Sixty patients scheduled for laparoscopic cholecystectomy were included. Anaesthesia and postoperative analgesia (etoricoxib, paracetamol, ketamine and dexamethasone) were standardised. INTERVENTION: After induction of anaesthesia, patients were allocated into two groups: ultrasound-guided bilateral subcostal TAP block with 20 ml of levobupivacaine 0.375% and epinephrine 5 µg ml or 0.9% saline with epinephrine 5 µg ml. MAIN OUTCOME MEASURES: Opioid consumption in the recovery room and during the first 24 h after surgery were recorded. Postoperative somatic and visceral pain scores, fatigue and nausea were measured. Intra-operative end-tidal concentrations of sevoflurane (FETSEVO) were also recorded. RESULTS: Twenty-four hour postoperative opioid consumption were similar in both groups: 21.2 mg (95% CI 15.3 to 27.1) vs. 25.2 (95% CI 15.1 to 35.5) oral morphine equivalent in the levobupivacaine and 0.9% saline groups, respectively; P = 0.48. No significant between-group differences were observed with regards to parietal (P = 0.56) and visceral (P = 0.50) pain scores, fatigue and nausea. FETSEVO was slightly lower in the levobupivacaine group (P < 0.01). CONCLUSION: Subcostal TAP block does not improve the analgesia provided by multimodal analgesia after laparoscopic cholecystectomy. It allows for a small reduction in intra-operative sevoflurane requirements. TRIAL REGISTRATION: NCT0339153.

PEG-PLGA- hybrid nanoparticles loaded with etoricoxib - phospholipid complex for effective treatment of inflammation in rat model.

The aim of the present study was to increase the bioavailability of the etoricoxib by making PEG-PLGA-Hybrid nanoparticles using emulsion solvent evaporation method. Then the prepared nanoparticles were further characterised using TEM, particle size, PDI, zeta potential, encapsulation efficiency and drug release study. Lipid (Phospholipon 90-G) and drug thermal behaviour were studied using DSC, TGA. The results of optimised formulation of Particle size, PDI and zeta potential was found 216.6 ± 4.0 nm, 0.24 ± 0.19 and +36.3 ± 1.9 mV. Encapsulation efficiency was found in the range of 77.15% w/v to 93.88% w/v. In-vivo study shows that the optimised formulation at a particular dose decreases the swelling index and number of writhes. Stability study indicated that the nanoparticles can be stored at a temperature of 4 ± 2 °C/60 ± 5% RH in well-closed container, away from heat and damp places. The prepared formulation has significantly increased the bioavailability of etoricoxib via oral administration.

Noninvasive Interactive Neurostimulation Therapy for the Treatment of Low-Grade Lateral Ankle Sprain in the Professional Contact Sport Athlete Improves the Short-Term Recovery and Return to Sport: A Randomized Controlled Trial.

Ankle injuries are very common between professional athletes and recreational sports. Lateral stable ligaments injury can be treated conservatively. Noninvasive interactive neurostimulation (NIN) is a form of electric therapy that works by locating areas of lower skin impedance. The objective of this prospective, double-blinded, randomized controlled trial was to compare the results in terms of improvement of a foot functional score, lower level of reported pain, and return to sports in 2 groups of contact sport athlete affected by a grade I or II lateral ankle sprain. Patients were randomized using random blocks to the NIN program (group I) or a sham device (group II). The outcome measurements were the use of a self-reported Inability Walking Scale, patient-reported subjective assessment of the level of pain using a standard visual analogue scale, and daily intake of nonsteroidal antiinflammatory drugs (etoricoxib 60 mg). Patients were also reached by telephone at 2 and 4 months of follow-up to register their return to sport activity. Beyond baseline evaluation, follow-ups were done after 5 (1 week) and 10 sessions (2 weeks) of treatment, and then at 30 days after the end of therapy. Of the 70 athletes admitted to the study, 61 eligible patients were randomized using random blocks to group I (n = 32) and group II (n = 29). Group I patients showed better improvement in terms of functional impairment (Inability Walking Scale), reported pain (visual analogue scale), and daily intake of etoricoxib 60 mg. Athletes of group I registered a faster resuming of sport activities. This prospective, randomized trial showed NIN can improve short-term outcomes in athletes with acute grade I or II ankle sprain and that it can hasten resuming of sport activities.

The lymphocyte transformation test is useful in the diagnosis of fixed drug eruption induced by etoricoxib

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Comparing the effectiveness profile of pharmacological interventions used for orthodontic pain relief: an arm-based multilevel network meta-analysis of longitudinal data.

BACKGROUND AND OBJECTIVES: We compare the effectiveness profile of various analgesics used for orthodontic pain relief over a 1-week time period by conducting a longitudinal network meta-analysis (NMA). SEARCH METHODS: The MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases were searched till 31st December 2015 to identify the relevant studies. Additional studies were identified by hand searching journals and reference lists. Unpublished literature was also searched. SELECTION CRITERIA: Eligible studies were randomized-controlled trials (RCTs) evaluating the effectiveness of pharmacological interventions for pain relief after placement of separator or initial aligning arch wire. DATA COLLECTION AND ANALYSIS: Pain intensity data at 2, 6, 12, 24, 36, 48, 72, 96, and 168 hours was collected. In addition, data were also extracted for potential covariates (age, sex, and procedure). A covariate-adjusted arm-based multilevel random coefficient model was used for evidence synthesis. RESULTS: Fifteen RCTs (1341 participants; male/females 595, 44.6%/746 55.4%; mean age 17.3 years, SD 4.1) were included. A total of 11 nodes (Acetaminophen, Aspirin, Etoricoxib, Flurbiprofen, Ibuprofen, Lumiracoxib, Meloxicam, Naproxen, Piroxicam, Placebo, and Control) were identified out of which five nodes (Placebo, Ibuprofen, Naproxen, Acetaminophen, and Aspirin) had subnodes (based on timing of administration). Compared to Control, Placebo, Flurbiprofen, Lumiracoxib, and Meloxicam were not significantly effective. Etoricoxib (most effective) and Piroxicam (second most effective) were effective over a long period which lasted up to 96 and 72 hours, respectively. Ibuprofen, Acetaminophen, Naproxen, and Aspirin were effective at 6, 12, and 24 hours. The effectiveness of these analgesics was significantly influenced by the timing of administration. Assessment of heterogeneity, transitivity, inconsistency, and publication bias revealed no major threat to the NMA derived estimates. CONCLUSION: Compared to the Control, Placebo was least effective whereas Etoricoxib was the most effective analgesic in reducing orthodontic pain. Administration timing has significant influence on the effectiveness profile of analgesics routinely used for managing orthodontic pain.