First electrochemical investigation and determination of non-steroidal anti-inflammatory drug etofenamate using disposable pencil graphite electrode with voltammetric techniques.

In this study, the electrochemical properties of etofenamate, an active ingredient belonging to the non-steroidal anti-inflammatory drug group, were investigated using cyclic voltammetry (CV) and square wave voltammetry (SW) techniques on a disposable pencil graphite electrode (PGE). With the CV technique, reversible voltammetric waves of around +0.470 V and irreversible voltammetric waves of around +1.02 V were produced on the PGE. An environmentally friendly, selective and highly sensitive SW voltammetric method was developed using disposable PGE. This voltammetric method gave very good analytical working range on PGE in PBS (pH = 3.0) medium at concentrations ranging from 0.017 µM to 0.306 µM. The LOD value of this analytical method in PBS (pH = 3.0) medium was calculated as 0.0011 µM (0.406 µg L-1). The developed voltammetric method was successfully applied to urine and drug samples. The results of the voltammetric method were compared with the results of the spectrophotometric method. The results were found to be compatible with each other.

The evaluation of the efficacy of etofenamate spray in postoperative cesarean pain: Randomized, double-blind, placebo-controlled trial.

OBJECTIVE: It was aimed to investigate the effect of etofenamate spray to be applied around the postoperative incision on pain control in cesarean section in this trial. MATERIAL AND METHODS: This was a prospective, randomized, double-blind, and placebo-controlled trial. 187 patients (93 cases and 94 controls) were recruited for the study. In the trial group, we applied the etofenamate spray (Doline® 50 ml) after closing the cesarean skin incision and go on four times a day on the skin incision for 24 h. In the control group, we applied a placebo. All patients received paracetamol IV (Paracerol®) as standard analgesic doses. If analgesia was insufficient, tramadol (Contramal®) 50 mg IV doses were added and recorded. A visually analog pain scale (VAS) was performed on both groups at 6-12-18-24th hours. Independent t-tests were performed for data showing normal distributions. RESULTS: There were no significant differences in the mean of differences VAS scores between the two groups at 6-12, and 6-18 h. However, a significant difference was obtained in the mean of differences VAS score at the 6-24th hour (p < 0.05). When the groups were compared in terms of additional paracetamol need, a significant difference was found again (p < 0.05). There was no significant difference between the groups in terms of tramadol need. CONCLUSION: Postoperative administration of etofenamate spray provided an analgesic effect at 24 h and additional analgesic usage decreased. Postoperative analgesia can also be used by administering NSAIDs around the cesarean section incision. In this way, the side effects of other systemic analgesics are avoided. CLINICAL TRIAL ID: PACTR201811864509898. CLINICAL TRIAL WEB LINK: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=5745.

Cocktail drug usage and etofenamate detection in post-race equine urine sample: A case report.

A recent trend in the use of high-resolution accurate mass screening (HRAMS) for doping control testing in both human and animal sports has emerged owing to significant improvement in high-resolution mass spectrometry in terms of sensitivity, mass accuracy, mass resolution and mass stability. Several HRAMS methods have been reported for the detection of multidrug residues in human or equine urine. These improved analytical technologies have led to changes in the use of prohibited substances, and the administration of more than one substance at low concentrations as a "cocktail" has become one of the methods used to alter performance in racehorses. In one of horse urine samples transferred to the analytical laboratory in Turkey for analysis, 5-hydroxymethyl meloxicam (2.96 ng/ml), etofenamate (2.15 ng/ml), flufenamic acid (108.92 ng/ml) and cobalt (200 ng/ml) were detected. These findings reveal that more than one prohibited substance was used together as a cocktail to alter the racing performance at low doses. In this case report, flufenamic acid was detected as a metabolite of etofenamate along with the parent drug. This case study also supports the advantages of metabolite analysis for anti-doping laboratories.

New topical microemulsions of etofenamate as sufficient management of osteoarthritis

Abstract In this study, microemulsions containing etofenamate were prepared and evaluated as dermal delivery carriers. The developed microemulsions consist of oleic acid, Span 80, Tween 20, Cremophor EL, Transcutol and ethanol. The percentage of etofenamate loading in the microemulsions was 5% (w/w). The characterization of formulations included droplet size, zeta potential, pH, conductivity, PDI, refractive index and viscosity. Moreover, ex vivo penetration study was carried out using mice abdominal skin. The developed formulations were analyzed for their cytotoxicity via MTT assay and tested for their anti-inflammatory properties opposed to LPS-stimulated nitrite prοduction in RAW 264.7 cells. As ideal formulation, M2ETF, was chosen due to its greater permeation, lower penetration as well as higher anti-inflammatory

Optimization and Evaluation of the In Vitro Permeation Parameters of Topical Products with Non-Steroidal Anti-Inflammatory Drugs through Strat-M® Membrane.

Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study in vitro drug diffusion and permeation, however, it suffers from many limitations. Therefore, to perform in vitro permeation test (IVPT), we used a Strat-M® membrane with diffusion characteristics well-correlated to human skin. This study's objective was to optimize the IVPT conditions using Plackett-Burman experimental design for bio-predictive evaluation of the in vitro permeation rates of five non-steroidal anti-inflammatory drugs (diclofenac, etofenamate, ibuprofen, ketoprofen, naproxen) across Strat-M® membrane from commercial topical formulations. The Plackett-Burman factorial design was used to screen the effect of seven factors in eight runs with one additional center point. This tool allowed us to set the sensitive and discriminative IVPT final conditions that can appropriately characterize the NSAIDs formulations. The permeation rate of etofenamate (ETF) across the Strat-M® membrane was 1.7-14.8 times faster than other NSAIDs from selected semisolids but 1.6 times slower than the ETF spray formulation.

Efficacy and Safety of an Etofenamate Medicated Plaster for Acute Ankle Sprain: A Randomized Controlled Trial.

BACKGROUND: The favorable benefit-risk profile of topical nonsteroidal anti-inflammatory drugs (NSAIDs) makes them a preferred treatment for pain relief in soft tissue injuries. PURPOSE: To assess the efficacy and safety of a novel etofenamate 70-mg medicated plaster in patients with acute uncomplicated ankle sprain. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with grade 1 or 2 ankle sprain of recent onset were randomized to etofenamate or placebo plasters (1:1) applied twice daily for 7 days. Clinical assessments, including ankle pain on movement (POM) in mm on a 100-mm visual analog scale (VAS), were made at predefined intervals during the treatment period. RESULTS: In total, 156 male or female adult patients (mean age, 35.3 ± 11.8 years) were enrolled. The fall in VAS values for POM from baseline to 72 hours was markedly in favor of the etofenamate plaster, with respective reductions of 52.7% and 24.0% for active and placebo plasters (least squares mean treatment difference, 22.1 mm; P value for analysis of covariance < .0001). Similar clinically relevant differences between etofenamate and placebo were seen for POM at the 48-, 96-, and 168-hour visits (P < .0001). These differences between etofenamate and placebo plasters were reflected in area under the curve for POM, pain at rest, and ankle swelling measured at various time points during the 7 days. Time taken to achieve a meaningful (30%) and optimal (50%) reduction of POM was significantly shorter in the etofenamate group. The responder rate (proportion of patients with at least 50% pain reduction at 72 hours) was 52.5% for the etofenamate plaster and 7.7% for the placebo. A significantly greater proportion of patients randomized to etofenamate rated their progress and/or the treatment as "good" or "very good." The medicated plasters adhered well over the 12-hour dosing period and were very well-tolerated. CONCLUSION: With respect to the investigated indication, uncomplicated ankle sprain, the etofenamate plaster has therapeutic efficacy that is similar to that for the best available topical NSAID formulations. REGISTRATION: 2016-000252-99 (EudraCT number).

Increased Therapeutic Efficacy of SLN Containing Etofenamate and Ibuprofen in Topical Treatment of Inflammation.

Innovative formulations, including solid lipid nanoparticles (SLNs), have been sought to improve skin permeation of non-steroidal anti-inflammatory drugs (NSAIDs). The present study explores the use of SLNs, prepared using a fusion-emulsification method, to increase skin permeation and in vivo activity of two relevant NSAIDs: A liquid molecule (etofenamate) and a solid one (ibuprofen), formulated in a 2% hydroxypropyl methylcellulose gel through the gelation of SLN suspensions. Compritol® 888 ATO and Tween® 80 were used as a solid lipid and a surfactant, respectively. All production steps were up scalable, resulting in SLNs with high encapsulation efficiency (>90%), a mean particle size of <250 nm, a polydispersity index <0.2, and that were stable for 12 months. In vitro permeation, using human skin in Franz diffusion cells, showed increased permeation and similar cell viability in Df and HaCaT cell lines for SLN formulations when compared to commercial formulations of etofenamate (Reumon® Gel 5%) and ibuprofen (Ozonol® 5%). In vivo activity in the rat paw edema inflammation model showed that SLN hydrogels containing lower doses of etofenamate (8.3 times lower) and ibuprofen (16.6 times lower) produced similar effects compared to the commercial formulations, while decreasing edema and inflammatory cell infiltration, and causing no histological changes in the epidermis. These studies demonstrate that encapsulation in SLNs associated to a suitable hydrogel is a promising technological approach to NSAIDs dermal application.

Clinical Efficacy and Safety Profile of Topical Etofenamate in the Treatment of Patients with Musculoskeletal Disorders: A Systematic Review.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are, in general, the cornerstone of musculoskeletal pain management; however, systemic adverse events with oral formulations of NSAIDs are common. To address this problem and limit systemic exposure, topical formulations of some NSAIDs have been developed. The aim of this systematic review was to assess the available evidence on the efficacy and safety of the topical formulations of the NSAID etofenamate in patients with musculoskeletal disorders. METHODS: A systematic search of PubMed and Web of Science was conducted using the key words "topical etofenamate efficacy" OR "topical etofenamate safety" OR "topical etofenamate effectiveness" to identify studies of etofenamate published from inception to November 2018. Some published manuscripts of interest known by the authors but not identified in the PubMed search were also included to ensure the review article was as comprehensive as possible. RESULTS: Overall, 12 studies were identified. These studies demonstrate that topical etofenamate [administered either in gel (5 or 10%), cream (10%) or lotion (10%) formulations)] can improve pain and reduce inflammation in patients with musculoskeletal disorders, including blunt injuries and rheumatic diseases. Etofenamate was shown to have an overall efficacy that was superior to other topical NSAIDs, such as 1% indomethacin and 1% diclofenac, and to be as effective as topical formulations of 2.5% ketoprofen gel and 2% ketorolac gel (although ketorolac showed better elimination of pain at some time points). Also, clinical evidence indicates that etofenamate is generally well tolerated in these indications. CONCLUSIONS: The clinical evidence currently available suggests that etofenamate is an effective therapeutic option for the management of musculoskeletal disorders, such as blunt traumas, lumbago or osteoarthrosis. However, larger and well-controlled clinical trials comparing the efficacy and safety of etofenamate with other newer topical NSAIDs are warranted.

Case Report: Nicolau syndrome due to etofenamate injection.

Nicolau syndrome, also known as embolia cutis medicomentosa, is a rare complication characterized by tissue necrosis that occurs after injection of drugs. The exact pathogenesis is uncertain, but there are several hypotheses, including direct damage to the end artery and cytotoxic effects of the drug. Severe pain in the immediate postinjection period and purplish discoloration of the skin with reticulate pigmentary pattern is characteristic of this syndrome. Diagnosis is mainly clinical and there is no standard treatment for the disease. Etofenamate is a non-steroidal anti-inflammatory drug and a non-selective cyclooxygenase inhibitor. Cutaneous adverse findings caused by etofenamate are uncommon. Herein, we present a case with diagnosis of Nicolau syndrome due to etofenamate injection, which is a rare occurrence.

Novel Drug Delivery System for Dermal Uptake of Etofenamate: Semisolid SLN Dispersion.

BACKGROUND: Semisolid SLNs are novel strategy for dermal drug administration instead of incorporating the SLN dispersions into conventional semisolids. Etofenamate loaded semisolid SLNs were successfully prepared and in vitro characterization of formulations were performed in our previous study. The present study is an attempt to evaluate the dermal behavior of the semisolid SLNs selected on the basis of previous research and investigate the properties in terms of the convenience for topical applications. OBJECTIVE: The objective of this study is to evaluate the skin penetration characteristics of semisolid SLN formulations. The occlusive and mechanical properties of semisolid SLNs were also evaluated because of their impression on the dermal behavior of the formulations. METHOD: The occlusive properties were investigated by in vitro occlusion test. Texture analysis was performed to define the hardness, compressibility, adhesiveness, cohesiveness and elasticity of the formulations. Rat skin was chosen to evaluate the ex vivo penetration of etofenamate loaded semisolid SLNs and commercial gel product. Coumarin-6 was used to visualize the dermal distribution of the semisolid SLN formulations. For monitorizing the penetration of coumarin-6 into the skin samples Confocal Laser Scanning Microscopy was employed. RESULTS: The occlusive and mechanical properties of C1 coded semisolid SLN formulation were found more favorable in comparison with P1. The cumulative etofenamate amount in skin samples was found to be 39.88 ± 1.50 µg/cm2 for C1 and 30.56 ± 2.10 µg/cm2 for P1 coded formulations. According to CLSM images, greater fluorescence intensities and deeper skin penetrations were obtained with both of the semisolid SLNs in comparison to plain Carbopol gel. CONCLUSION: It can be concluded that the semisolid SLNs are promising alternative dermal drug delivery systems to the conventional dosage forms.

Phonophoresis of Etofenamate Gel for Postoperative Analgesia after Total Knee Arthroplasty / 中国医科大学学报

Objective To evaluate the efficacy of phonophoresis of etofenamate gel for postoperative analgesia after total knee arthroplasty (TKA).Methods A total of 80 adult patients were randomly divided into experimental and control groups (n =40 in each group).The same basic analgesia protocol was performed in both groups,while phonophoresis of etofenamate gel was performed only in the experimental group (twice per day,from day 1 to day 7,postoperatively).Data recorded during an 8-week follow-up included Visual Analogue Scale (VAS) scores at rest and during continuous passive motion before surgery and 1 d,3 d,5 d,and 7 d after surgery,range of motion before surgery and 3 d,5 d,7 d,and 8 weeks after surgery,and Hospital for Special Surgery (HSS) scores before surgery and 8 weeks after surgery.SPSS 18.0 was used for statistical analysis.Results The VAS scores at rest and during continuous passive motion 3 d,5 d,and 7 d after surgery were lower in the experimental group than in the control group (P ＜ 0.05).The range of motion 3 d,5 d,7 d,and 8 weeks after surgery was better in the experimental group than in the control group (P ＜ 0.05).The HSS scores 8 weeks after surgery were better in the experimental group than in the control group (P ＜ 0.05).Conclusion Phonophoresis of etofenamate gel provides effective pain control after TKA and is helpful for early functional recovery.

Effectiveness of etofenamate for treatment of knee osteoarthritis: a randomized controlled trial.

The intramuscular application of etofenamate in the treatment of knee osteoarthritis was not observed in the existing English language literature. The objectives of this study were to compare the efficacy of etofenamate versus hyaluronic acid (HA) in reducing joint pain and functional improvement for mild to moderate knee osteoarthritis. The patients were randomly divided into etofenamate (n=29) and HA (n=30) groups. Intramuscular etofenamate injection was administered as a series of seven intramuscular injections at intervals of 1 day. Intra-articular HA injection was administered as a series of three intra-articular injections at intervals of 1 week. Clinical evaluation was made before the first injection and again both 6 and 12 months after the last injection. The evaluation consisted of patient-assessed pain on a visual analog scale (VAS) and on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Statistical significance was found for the etofenamate group when comparing preinjection with 12 months postinjection VAS scores (P<0.05). Statistical significance was also found for the HA group when comparing preinjection with 12 months postinjection VAS and WOMAC scores (P<0.05). However, there was no significant difference between the etofenamate and HA groups in terms of VAS or WOMAC scores measured at 12 months after injection (P>0.05). Results from this study indicated that, etofenamate treatment was not significantly more effective than HA treatment. However, both methods were effective and successful in treating knee osteoarthritis.

Analytical Quality by Design Approach in RP-HPLC Method Development for the Assay of Etofenamate in Dosage Forms.

By considering the current regulatory requirement for an analytical method development, a reversed phase high performance liquid chromatographic method for routine analysis of etofenamate in dosage form has been optimized using analytical quality by design approach. Unlike routine approach, the present study was initiated with understanding of quality target product profile, analytical target profile and risk assessment for method variables that affect the method response. A liquid chromatography system equipped with a C18 column (250×4.6 mm, 5 µ), a binary pump and photodiode array detector were used in this work. The experiments were conducted based on plan by central composite design, which could save time, reagents and other resources. Sigma Tech software was used to plan and analyses the experimental observations and obtain quadratic process model. The process model was used for predictive solution for retention time. The predicted data from contour diagram for retention time were verified actually and it satisfied with actual experimental data. The optimized method was achieved at 1.2 ml/min flow rate of using mobile phase composition of methanol and 0.2% triethylamine in water at 85:15, % v/v, pH adjusted to 6.5. The method was validated and verified for targeted method performances, robustness and system suitability during method transfer.

Topical gels of etofenamate: in vitro and in vivo evaluation.

Non-steroid anti-inflammatory drugs (NSAIDs), such as etofenamate, are among the most prescribed drugs used for their analgesic, anti-rheumatic, antipyretic and anti-inflammatory properties. Topical formulations have the main advantage of targeted delivery. However, drugs must overcome the skin due to its role as a physical and chemical barrier against the penetration of chemicals and microorganisms. This barrier must be altered to allow the permeation of drugs at a suitable rate to the desired site of activity. Permeation modulators can intercalate the skin outer layers causing structure disruption, opening an energetically favourable route for the drug to diffuse through. The aim of this work was the development of hydroalcoholic gels containing 5.0% (w/w) of etofenamate for topical administration with anti-inflammatory activity and enhanced drug delivery. The physical and chemical characterization, in vitro release and permeation studies and in vivo anti-inflammatory activity were assessed. The gel with 30% ethanol showed in vivo anti-inflammatory activity with suitable physical chemical and microbiologic characteristics. In vitro release and permeation studies revealed that the different amounts of ethanol used influenced the release profiles of etofenamate. Moreover, it was demonstrated that this formulation is an adequate vehicle for the etofenamate skin permeation.

Development and Validation of a Stability-Indicating Assay of Etofenamate by RP-HPLC and Characterization of Degradation Products.

A validated stability-indicating RP-HPLC method for etofenamate (ETF) was developed by separating its degradation products on a C18 (250 mm × 4.6 mm 5 µm) Qualisil BDS column using a phosphate buffer (pH-adjusted to 6.0 with orthophosphoric acid) and methanol in the ratio of 20:80 % v/v as the mobile phase at a flow rate of 1.0 mL/min. The column effluents were monitored by a photodiode array detector set at 286 nm. The method was validated in terms of specificity, linearity, accuracy, precision, detection limit, quantification limit, and robustness. Forced degradation of etofenamate was carried out under acidic, basic, thermal, photo, and peroxide conditions and the major degradation products of acidic and basic degradation were isolated and characterized by (1)H-NMR, (13)C-NMR, and mass spectral studies. The mass balance of the method varied between 92-99%.

Adverse reaction of topical etofenamate: petechial eruption / Reacción adversa del etofenamato tópico: erupción petequial

Etofenamate is a non-steroidal anti-inflammatory drug (NSAID). Clinical findings caused by etofenamate are uncommon. Allergic contact dermatitis is the most common cutaneous reaction reported. But petechial eruption due to etofenamate had not been reported yet. This report concerns an 11-year old male with petechial eruption after application of topical etofenamate. Physicians need to be aware that patients can develop an asymptomatic purpuric eruption when etofenamate is ordered.

El etofenamato es un antiinflamatorio no esteroideo (AINE). Los hallazgos clínicos sobre los efectos del etofenamato son poco comunes. La dermatitis alérgica por contacto es la reacción cutánea más comúnmente reportada. En cambio, la erupción petequial a causa del etofenamato no se había reportado hasta ahora. Este reporte trata de un varón de 11 años de edad con erupción petequial tras la aplicación del etofenamato tópico. Es necesario que los médicos tomen conciencia de que los pacientes pueden desarrollar una erupción púrpura asintomática, a la hora de prescribir el etofenamato.