Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats

Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.

Adjunctive benefits of systemic etoricoxib in non-surgical treatment of aggressive periodontitis: Short-term evaluation

Background: This pilot study assessed the effect of short-duration treatment with etoricoxib as adjuvant therapy to scaling and root planing (SRP) on the clinical and radiographic parameters and prostaglandin E-2 (PGE(2)) levels in aggressive periodontitis. Methods: Subjects were randomly allocated to test or control treatment (n = 10 in each group) and submitted to SRP and treatment with etoricoxib, 120 mg/day, or placebo for 7 days. Probing depth, clinical attachment level (CAL), gingival recession, visible plaque index, bleeding on probing, linear distance (LD) from the cemento-enamel junction to the alveolar crest, and analysis of the gray levels were recorded before and 1 month after the therapies. The prostaglandin E-2 (PGE(2)) level in the gingival crevicular fluid (GCF) was measured by radioimmunoassay at the beginning of the study and 7 and 30 days after treatment. Results: No significant difference in the clinical parameters was observed between the groups at the end of the experimental period, although both groups presented significant improvement in all variables examined. There was a decrease in CAL from 5.54 +/- 0.47 mm to 3.59 +/- 0.53 mm in the test group and from 5.92 +/- 1.10 mmto 3.69 +/- 0.80 mm in the control group. A significant reduction in PGE(2) was found after 7 days of treatment. LD differed between the groups. Conclusion: Etoricoxib did not promote additional improvement in the clinical parameters; however, it produced an initial reduction in the PGE(2) levels in the GCF, which could be related to the discrete improvement in the bone condition.

Determination of etoricoxib in human plasma using automated on-line solid-phase extraction coupled with LC-APCI/MS/MS

A liquid chromatography-tandem mass spectrometry method with atmospheric pressure chemical ionization (LC-APCI/MS/MS) was validated for the determination of etoricoxib in human plasma using antipyrin as internal standard, followed by on-line solid-phase extraction. The method was performed on a Luna C18 column and the mobile phase consisted of acetonitrile:water (95:5, v/v)/ammonium acetate (pH 4.0; 10 mM), run at a flow rate of 0.6 mL/min. The method was linear in the range of 1-5000 ng/mL (r²>0.99). The lower limit of quantitation was 1 ng/mL. The recoveries were within 93.72-96.18%. Moreover, method validation demonstrated acceptable results for the precision, accuracy and stability studies.

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%) compared to etoricoxib (0%). Treatment with etoricoxib, even starting when ABL is detected, reduces inflammation and cementum and bone resorption, with fewer gastrointestinal side effects.

The Use of Etoricoxib and Celecoxib for Pain Prevention After Periodontal Surgery: A Double-Masked, Parallel-Group, Placebo-Controlled, Randomized Clinical Trial

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Preemptive dexamethasone and etoricoxib for pain and discomfort prevention after periodontal surgery: A double-masked, crossover, controlled clinical trial

Background: Several anti-inflammatory drugs have been used to reduce pain and discomfort after periodontal surgeries. This study evaluates the efficacy of using etoricoxib and dexamethasone for pain prevention after open-flap debridement surgery. Methods: For this prospective, double-masked, crossover, placebo-controlled, randomized clinical trial, open-flap debridement surgeries were performed on 15 patients (eight males and seven females, age range 20 to 56 years: mean age ± SD: 40 ± 9.7 years) who presented with chronic periodontitis after nonsurgical periodontal therapy at three quadrants. Each patient underwent three surgical procedures at intervals of 30 days and received one of the following premedication protocols 1-hour before surgery: group 1 = placebo, group 2 = 8 mg dexamethasone, and group 3 = 120 mg etoricoxib. Rescue medication (750 mg acetaminophen) was given to each patient who was instructed to take it when necessary. Pain intensity and discomfort were evaluated by a 101-point numeric rate scale and a four-point verbal rate scale, respectively, hourly for the first 8 hours after surgery and three times a day on the following 3 days. Results: The results demonstrate that groups 2 and 3 present reduced postoperative pain-intensity levels compared to group 1. There were statistically significant differences at the 4, 5, 6, 7, and 8 hour-periods after surgery (Friedman test; P<0.05). Furthermore, rescue-medication intake was significantly lower for groups 2 and 3 than for group 1 (analysis of variance; P<0.02). Conclusion: The adoption of a preemptive medication protocol using etoricoxib or dexamethasone may be considered effective for pain and discomfort prevention after open-flap debridement surgeries.

Estudo comparativo sobre a eficácia de duas drogas de ação anti-inflamatória (Etoricoxib e Diclofenaco) após exodontia de terceiros molares inferiores inclusos.

In this article the authors clinically compare the efficacy of two different anti-inflammatory drugs - Etoricoxib (Arcoxia®) and Diclofenac (Olfen®) – in the control of postoperative pain resulting from the surgical removal of impacted lower third molars. Fifteen patients requiring the extraction of bilaterally impacted lower third molars were selected at the Department of Oral and Maxillofacial Surgery at the Araraquara School of Dentistry – UNESP. The drugs were randomly administered during the first and second surgical procedures. Pain was evaluated by means of a visual analogic scale for 72 hours following the surgical procedure. After statistical analysis of the results, the authors concluded that there were no significant differences in terms of postopoerative pain control between the two drugs studied.

Effect of Isolated Fractions of Harpagophytum procumbens DC (Devil`s Claw) on COX-1, COX-2 Activity and Nitric Oxide Production on Whole-Blood Assay

The present study evaluates the effect of isolated fractions of Harpagophytum procumbens (devil`s claw) on cyclooxygenase (COX-1 and COX-2) activities and NO production using a whole blood assay. The activity of COX-1 was quantified as platelet thromboxane B(2) production in blood clotting and COX-2 as prostaglandin E(2) production in LPS-stimulated whole blood. Total NO(2)(-)/NO(3)(-) concentration was determined by Griess reaction in LPS stimulated blood. Assays were performed by incubation of isolated fractions obtained by flash chromatography monitored with HPLC, TLC and identified by (1)HNMR, containing different amounts of harpagoside with blood from healthy donors. Indomethacin and etoricoxib were the positive controls of COX-1 and COX-2 Inhibition. Data shows that fraction containing the highest concentration of harpagoside inhibited indistinctively COX-1 and COX-2 (37.2 and 29.5% respectively) activity and greatly inhibited NO production (66%). In contrast the fraction including iridoid pool increased COX-2 and did not alter NO and COX-1 activities. The fraction containing cinnamic acid was able to reduce only NO production (67%). Our results demonstrated that the harpagoside fraction is the main responsible for the effect of devils claw on these enzyme activities. However, other components from devil`s claw crude extract could antagonize or increase the synthesis of inflammatory mediators. Copyright (C) 2010 John Wiley & Sons, Ltd.

Effects of Cytochrome P450 Enzyme Inhibitors on the Pharmacokinetics of Nonsteroidal Anti-inflammatory Drugs and Venlafaxine

Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs. Inhibition of CYP enzymes usually increases the plasma concentrations of their substrate drugs and can thus alter the safety and efficacy of these drugs. The metabolism of many widely used nonsteroidal antiinflammatory drugs (NSAIDs) as well as the metabolism of the antidepressant venlafaxine is nown to be catalyzed by CYP enzymes. In the present studies, the effect of CYP inhibition on the armacokinetics and pharmacodynamics of NSAIDs and venlafaxine was studied in clinical trials with healthy volunteers and with a crossover design, by using different antifungal agents as CYP inhibitors. The results of these studies demonstrate that the inhibition of CYP enzymes leads to increased concentrations of NSAIDs. In most cases, the exposure to ibuprofen, diclofenac, etoricoxib, and meloxicam was increased 1.5to 2 fold when they were used concomitantly with antifungal agents. CYP2D6 inhibitor, terbinafine, substantially increased the concentration of parent venlafaxine, whereas the concentration of active moiety of venlafaxine (parent drug plus active metabolite) was only slightly increased. Voriconazole, an inhibitor of the minor metabolic pathway of venlafaxine, produced only minor changes in the pharmacokinetics of venlafaxine. These studies show that an evident increase in the concentrations of NSAIDs may be expected, if they are used concomitantly with CYP inhibitors. However, as NSAIDs are generally well tolerated, use of single doses of NSAIDs concomitantly with CYP inhibitors is not likely to adversely affect patient safety, whereas clinical relevance of longterm concomitant use of NSAIDs with CYP inhibitors needs further investigation. CYP2D6 inhibitors considerably affect the pharmacokinetics of venlafaxine, but the clinical significance of this interaction remains unclear.

Evaluación de intervención de alertas para riesgo cardiovascular por diclofenaco en afiliados al régimen contributivo 2014 -2015

El objetivo fue evaluar la intervención de las alertas en la prescripción de diclofenaco. Estudio observacional, comparativo, post intervención, de un antes después, en pacientes con prescripción de diclofenaco. Se evaluó la intervención de las alertas restrictivas antes y después de su implementación en los pacientes prescritos con diclofenaco y que tenían asociado un diagnóstico de riesgo cardiovascular según CIE 10 o eran mayores de 65 años. Un total de 315.135 transacciones con prescripción de diclofenaco, en 49.355 pacientes promedio mes. El 94,8% (298.674) de las transacciones fueron prescritas por médicos generales.

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Design Network meta-analysis. Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58 556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·46) and etoricoxib 60 mg/day (ES -0·58, -0·73 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0·030), diclofenac (p=0·031), and naproxen (p=0·026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Anti-inflamatórios não esteroides: automedicação versus regime de prescrição

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas Moniz