Comparative Bioavailability of a Novel Fixed-dose Combination Etoricoxib and Tramadol.

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed-dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open-label, 3-way, crossover, single-dose, prospective, and longitudinal study with a 14-day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Forty-two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0-t), and (area under the plasma drug concentration-time curve from 0 up to infinity (AUC0-∞) data were within the range of 80%-125%. Non-serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed-dose combination are comparable to those of the reference products.

Etoricoxib Coated Tablets: Bioequivalence Assessment between Two Formulations Administered under Fasting Conditions.

Etoricoxib is a non-steroidal anti-inflammatory drug with high selectivity for cyclooxygenase 2 (COX-2), exerting a pronounced anti-inflammatory effect with fewer adverse events when compared to COX-1 inhibitors. The present study aimed to evaluate the bioequivalence between two etoricoxib-coated tablet formulations to meet regulatory requirements for a branded generic product registration in Brazil. A crossover study with an open-label, randomized design and a single-dose regimen with two treatments and two periods was conducted on healthy Brazilians of both genders. Subjects randomly received a single dose of a 90 mg etoricoxib coated tablet of test product Xumer® 90 mg (Adium S.A.) and the reference product Arcoxia® 90 mg (Merck Sharp & Dohme Farmacêutica Ltda.) under fasting conditions separated by a 14-day period. Blood samples were collected sequentially for up to 96 h following drug administration, and the concentrations of etoricoxib in plasma were determined using a validated UPLC-MS/MS method. Pharmacokinetic parameters were computed utilizing non-compartmental analysis methods. A total of 32 healthy subjects were enrolled, and 25 subjects completed the study. Geometric mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-inf were 103.98% (95.63-113.06), 96.82% (91.82-102.09), and 95.79% (90.70-101.16), respectively. In accordance with regulatory standards, the test formulation (Xumer® 90 mg) has been deemed bioequivalent to the reference product (Arcoxia® 90 mg). As a result, these formulations can be considered interchangeable in clinical practice, with both proving to be safe and well-tolerated. The need for in vivo testing for the Xumer® 60 mg strength was waived due to the proportional similarity of the formulations and the similar in vitro dissolution profiles observed across the various strengths.

[Selective cyclooxygenase-2 inhibitor hypersensitivity]. / Hipersensibilidad selectiva a inhibidores de la ciclooxigenasa-2.

BACKGROUND: The cyclooxygenase-2 inhibitors are usually recommended as a safe alternative in patients with multiple hypersensitivity to non-steroidal antiinflammatory drugs. Nevertheless, both immediate and delayed hypersensitivity reactions have been described, and the possibility of cross-reactivity with sulphonamides. CASE REPORT: A 66-year-old patient who, after taking a celecoxib tablet, presented with latency of several hours a skin reaction. Previously, he had presented a minor reaction during treatment with etoricoxib without establishing the correlation at that time. The patient underwent an allergological study by means of skin tests with negative results and an oral challenged test with etoricoxib with positive results. Tolerance to sulfonamides was proven. CONCLUSIONS: We present a singular case of a cross-reactivity skin reaction to etoricoxib and celecoxib, suggesting the need to perform challenge tests to confirm the tolerance or not of each drug before allowing their use. On the contrary, trimethropim/sulfamethoxazole could be safely used in our patients, if needed.

INTRODUCCIÓN: Los inhibidores de la ciclooxigenasa-2 suelen indicarse en pacientes con hipersensibilidad múltiple a los antiinflamatorios no esteroides. Sin embargo, se han descrito reacciones de hipersensibilidad inmediata y retardada, además de posible reactividad cruzada con sulfonamidas. REPORTE DE CASO: Paciente masculino de 66 años, que acudió al servicio de Alergia por una reacción cutánea, luego de haber consumido un comprimido de celecoxib. Previamente, durante el tratamiento con etoricoxib, tuvo una reacción menor, sin establecer la correlación farmacológica. Se realizaron pruebas cutáneas (intraepidérmicas y epicutáneas), con resultados negativos, y un examen de exposición oral controlada con etoricoxib, con resultado positivo. Se comprobó la tolerancia a las sulfamidas. CONCLUSIONES: El caso de reacción cutánea, mediante reactividad cruzada, entre etoricoxib y celecoxib expuesto en este artículo sugiere la necesidad de realizar pruebas de provocación para confirmar la tolerancia de cada fármaco antes de su prescripción. Por el contrario, trimetropim-sulfametoxazol pueden indicarse con seguridad, si fuese necesario.

Evaluating the efficacy of Etoricoxib in reducing post-operative pain associated with minor oral surgery. A randomized clinical trial / Avaliação da eficácia do Etoricoxibe na redução da dor pós-operatória associada à cirurgia oral menor: ensaio clínico randomizado

Etoricoxib, a new cyclooxygenase-2-selective inhibitor has demonstrated a rapid onset analgesic effect for relieving acute pain especially when prescribed as a pre-emptive medication. On these bases, this study may provide useful information and guidance for clinicians working in the field of oral surgery, as regards handling odontogenic pain and postoperative pain precisely with cyclooxygenase-2 inhibitors. Objective: the study aimed to measure the quantifiable efficacy of Etoricoxib in reducing post-extraction pain in subjects undergoing minor oral surgical intervention as compared to Naproxen (a traditional NSAID) which is commonly used to control postoperative pain. Material and Methods: a 120 mg film-coated tablet of Etoricoxib was given to each of the twenty patients representing the study group, and a 500 mg tablet of Naproxen was given to each of the other twenty subjects representing the positive control group. According to manufacturer instructions, the tablets were given to the subjects 30 minutes pre-operatively (before dental extraction). Post-operative pain was assessed for each subject using eleven points from zero to ten, visual analog scale. Results: showed no statistically significant difference between Etoricoxib and Naproxen in decreasing post-extraction odontogenic pain, suggesting that Etoricoxib is as efficient as Naproxen in the control of discomfort with dental origin taking into consideration the patient's status when prescribing the medication. Conclusion: this study suggests that Etoricoxib can be handled as a pre-emptive medication to reduce post-operative pain for subjects seeking traditional or surgical extraction of any of their teeth (AU)

O Etoricoxibe, um novo inibidor seletivo da ciclooxigenase-2, demonstrou um efeito analgésico de início rápido para aliviar a dor aguda, especialmente quando prescrito como medicação preventiva. Com base nesses fundamentos, este estudo pode fornecer informações úteis e orientação para clínicos que trabalham no campo da cirurgia oral, no que diz respeito ao manejo da dor odontogênica e da dor pós-operatória de forma precisa com inibidores da ciclooxigenase-2. Objetivo: o estudo teve como objetivo medir a eficácia quantificável do Etoricoxibe na redução da dor pós-extração em indivíduos submetidos a intervenção cirúrgica oral menor, comparado ao Naproxeno (AINE tradicional) que é comumente usado para controlar a dor pós-operatória. Material e Métodos: um comprimido revestido com um filme de 120 mg de Etoricoxibe foi administrado a cada um dos 20 pacientes representando o grupo de estudo, e um comprimido de 500 mg de Naproxeno foi administrado a cada um dos outros vinte sujeitos representando o grupo de controle positivo. De acordo com as instruções do fabricante, os comprimidos foram administrados aos indivíduos 30 minutos antes da cirurgia (antes da extração dentária). A dor pós-operatória foi avaliada para cada sujeito usando uma escala analógica visual de onze pontos, de zero a dez. Resultados: não mostraram diferença estatisticamente significativa entre o Etoricoxibe e o Naproxeno na diminuição da dor odontogênica pós-extração, sugerindo que o Etoricoxibe é tão eficiente quanto o Naproxeno no controle do desconforto de origem dentária, levando em consideração o estado do paciente ao prescrever a medicação. Conclusão: este estudo sugere que o Etoricoxibe pode ser administrado como medicação preventiva para reduzir a dor pós-operatória em indivíduos que buscam extração dentária tradicional ou cirúrgica de qualquer um de seus dentes. (AU)

Optimization and synthesis of etoricoxib-loaded low molecular weight chitosan nanoparticles / Otimização e síntese de nanopartículas de quitosana de baixo peso molecular carregadas com etoricoxib

This study reports the optimization of the preparation of etoricoxib (ETX)-loaded low molecular weight of chitosan (LMWC) nanoparticles (ETX-LMWC-NPs) by ionic gelation method with sodium tripolyphosphate (TPP) as cross-linking agent. The independent variables (LMWC/TPP mass ratio, LMWC, and poloxamer 188 concentration) were formulated and optimized using response surface methodology (RSM) Box-Behnken design (BBD) with three levels for each factor. Size of particles, polydispersity index (PDI), and encapsulation efficiency was investigated as the dependent variable. ETX-LMWC-NPs were characterized by particle size analyzer, scanning electron microscope, UV-Vis spectrophotometry, and Fourier transforms infrared spectroscopy. The ETX-LMWC-NPs have an average particle size of 259.91 nm, a PDI of 0.041, and encapsulation efficiency of 51.25%. ETX-LMWC-NPs are spherical and have a spectrum at wavenumber 1656 cm-1 and 718 cm-1, respectively, indicating the presence of C=N and C-Cl originating from the ETX compound. The ETX release profile at pH 1.2 and 6.8 mediums approach the Korsmeyer-Peppas model. ETX released pH 1.2 did not differ significantly from free ETX with a maximum 10-12% release. ETX release at pH 6.8 had a maximum release of 21% and showed a 19% increase in dissolution rate than free ETX. The ETX-LMWC-CSNPs prepared by optimum formula (2.65 % LMWC, 5.5 LMWC/TPP mass ratio, and 1 mg/mL) showed stable monodispersity nanoparticles and easily soluble in water.

Este experimento relata a otimização da preparação de nanopartículas de quitosana de baixo peso molecular (LMWC) (ETX-LMWC-NPs) carregadas com etoricoxibe (ETX) pelo método de gelificação iônica com tripolifosfato de sódio (TPP) como agente de reticulação. As variáveis ​​independentes (razão de massa LMWC / TPP, LMWC e concentração de poloxamer 188) foram formuladas e otimizadas usando metodologia de superfície de resposta (RSM) projeto Box-Behnken (BBD) com três níveis para cada fator. Tamanho das partículas, índice de polidispersidade (PDI) e eficiência de encapsulação foram investigados como a variável dependente. ETX-LMWC-NPs foram caracterizados por analisador de tamanho de partícula, microscópio eletrônico de varredura, espectrofotometria UV-Vis e espectroscopia de infravermelho com transformada de Fourier. Os ETX-LMWC-NPs têm um tamanho médio de partícula de 259,91 nm, um PDI de 0,041 e eficiência de encapsulação de 51,25%. ETX-LMWC-NPs são esféricos e apresentam um espectro no número de onda 1656 cm-1 e 718 cm-1, respectivamente, indicando a presença de C = N e C-Cl originários do composto ETX. O perfil de liberação de ETX em meios de pH 1,2 e 6,8 se aproxima do modelo Korsmeyer-Peppas. O ETX liberado em pH 1,2 não diferiu significativamente do ETX livre com uma liberação máxima de 10-12%. A liberação de ETX em pH 6,8 teve uma liberação máxima de 21% e mostrou um aumento de 19% na taxa de dissolução do que o ETX livre. Os ETX-LMWC-CSNPs preparados pela fórmula ótima (2,65% LMWC, 5,5 LMWC / razão de massa TPP e 1 mg / mL) mostraram nanopartículas de monodispersidade estáveis ​​e facilmente solúveis em água.

The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice.

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-1ß (IL-1ß), 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.

Analgesia na entorse de tornozelo: estudo com etoricoxibe / Analgesia in ankle sprain: study with etoricoxib

JUSTIFICATIVA E OBJETIVOS: A torção de tornozelo é uma das doenças mais frequentes nas emergências ortopédicas. Normalmente prescrevem-se analgésicos e anti-inflamatórios. O objetivo deste estudo foi avaliar se o etoricoxibe na dose diária de 60 mg é tão efetivo quanto à dose de 90 mg no tratamento da dor e inflamação em pacientes com torções de tornozelo graus I e II. MÉTODO: Estudo clínico aleatório, duplamente encoberto e controlado foram estudados 43 pacientes com diagnóstico de entorse de tornozelo graus I e II, com idade média de 32 anos. Os pacientes foram divididos em dois grupos aleatoriamente: grupo I, constituído por 23 pacientes tratados com 90 mg de etoricoxibe em dose única diária, e grupo I, constituído por 20 pacientes em uso de 60 mg em dose única diária. As avaliações pela escala analógica visual (EAV) e avaliação funcional foram feitas após 7 e 15 dias de tratamento. RESULTADOS: Observou-se diminuição significativa da dor entre as visitas pré e pós o uso do medicamento, com uma média de 4,1 pontos na EAV (p < 0,001), porém a diminuição da intensidade da dor não dependeu do esquema terapêutico utilizado. Um paciente teve a medicação suspensa, devido à tolerabilidade, que foi considerada boa em 90,7% dos pacientes. CONCLUSÃO: As doses de 60 e 960 mg de etoricoxibe foram efetivas e bem toleradas para o controle da dor aguda em pacientes com entorse do tornozelo.

BACKGROUND AND OBJECTIVES: Ankle sprain is one of the most frequent diseases in orthopedic emergencies. In general, analgesics and anti-inflammatory drugs are prescribed. This study aimed at evaluating whether 60 mg daily etoricoxib is as effective as 90 mg daily etoricoxib to treat pain and inflammation in patients with ankle sprain grades I and II. METHOD: This is a clinic, randomized, double-blind and controlled study which has evaluated 43 patients with ankle sprain grades I and II, with mean age of 32 years. Patients were randomly distributed in two groups: group I, made up of 23 patients treated with 90 mg daily bolus etoricoxib, and group II, made up of 20 patients under 60 mg daily bolus dose. Patients were evaluated by the visual analog scale (VAS) and by functional evaluation after 7 and 15 days of treatment. RESULTS: There has been significant pain improvement between visits before and after using the drug, with a mean of 4.1 VAS score (p < 0.001), however pain intensity improvement did not depend on therapeutic schedule. Drug was withdrawn from one patient due to tolerability, which was considered good for 90.7% of patients CONCLUSION: Both 60 mg and 90 mg etoricoxib doses were effective and well tolerated to control acute pain in ankle sprain patients.

Comparison of etoricoxib and indomethacin for the treatment of experimental periodontitis in rats

We investigated the effect of etoricoxib, a selective cyclooxygenase-2 inhibitor, and indomethacin, a non-selective cyclooxygenase inhibitor, on experimental periodontitis, and compared their gastrointestinal side effects. A ligature was placed around the second upper left molars of female Wistar rats (160 to 200 g). Animals (6 per group) were treated daily with oral doses of 3 or 9 mg/kg etoricoxib, 5 mg/kg indomethacin, or 0.2 mL saline, starting 5 days after the induction of periodontitis, when bone resorption was detected, until the sacrifice on the 11th day. The weight and survival rate were monitored. Alveolar bone loss (ABL) was measured as the sum of distances between the cusp tips and the alveolar bone. The gastric mucosa was examined macroscopically and the periodontium and gastric and intestinal mucosa were examined by histopathology. The ongoing ABL was significantly inhibited (P < 0.05) by 3 and 9 mg/kg etoricoxib and by indomethacin: control = 4.08 ± 0.47 mm; etoricoxib (3 mg/kg) = 1.89 ± 0.26 mm; etoricoxib (9 mg/kg) = 1.02 ± 0.14 mm; indomethacin = 0.64 ± 0.15 mm. Histopathology of periodontium showed that etoricoxib and indomethacin reduced inflammatory cell infiltration, ABL, and cementum and collagen fiber destruction. Macroscopic and histopathological analysis of gastric and intestinal mucosa demonstrated that etoricoxib induces less damage than indomethacin. Animals that received indomethacin presented weight loss starting on the 7th day, and higher mortality rate (58.3 percent) compared to etoricoxib (0 percent). Treatment with etoricoxib, even starting when ABL is detected, reduces inflammation and cementum and bone resorption, with fewer gastrointestinal side effects.