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PURPOSE: Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. METHODS: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. RESULTS: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. CONCLUSION: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052085).

AbstractThis study aims to develop and evaluate flurbiprofen-loaded polymeric nanoparticles to achieve sustained drug release, enhancing therapeutic efficacy and minimising dosing frequency for improved patient outcomes. Flurbiprofen-loaded polymeric nanoparticles were prepared using a tubular microreactor and spray drying, optimised via Box-Behnken Design. Characterisation included particle size, encapsulation efficiency, in vitro and in vivo drug release, and techniques like FTIR, DSC, XRD, and SEM. Statistical analysis ensured robust formulation optimisation and evaluation of performance. The optimised batch of flurbiprofen-loaded polymeric nanoparticles was characterised for mean diameter, PDI, zeta potential, drug release, and EE% were found to be 306.1 ± 6.00 nm, 0.184 ± 0.02 Mw, −23.6 ± 1.51 mV, 85.46 ± 0.53% and 92.31 ± 0.84 (% w/w) respectively. Pharmacokinetic analysis further confirmed the sustained release, extending up to 12 hours and enhancing permeation compared to the pure flurbiprofen. Sustained release of flurbiprofen-loaded polymeric nanoparticles significantly enhances therapeutic effectiveness for inflammatory conditions. [ABSTRACT FROM AUTHOR]

In this study, SeDeM–ODT parametric tests were performed to determine the use of ludipress as a directly compressible tableting excipient for the development of a flurbiprofen orally disintegrating tablet. The preformulation features of different formulations (F1 –F9) were analyzed by the SeDeM–ODT tool which showed that all the powder blends were appropriate for direct compression since all the blends had index of good compressibility and bucodispersibility (IGCB) values above 5, signifying direct compression is the most appropriate method. The powder blend of the optimized formulation was assessed by the DSC–TGA technique. The optimization of nine different formulations blends of orally disintegrating tablets (ODTs) was prepared in various ratios by the implementation of design of experiments (DoE), using the central composite design by selecting ludipress (X1) (49–55%) and croscarmellose sodium (X2) (1–5%) while hardness, friability, and disintegration tests were selected as responses. The optimized formulations were evaluated by various tests and the results indicated that all the formulations were found to be in adequate range. Formulations were subjected to stability studies at accelerated states following ICH guidelines. Shelf life was found to be 51.144–56.186 months. Results of multiple-point dissolution studies revealed that formulations followed the Higuchi kinetic model. This study revealed that the SeDeM—ODT tool has been successfully used to determine the compression behavior of active compounds and their powder blends for the direct compression (DC) method in formulating flurbiprofen–ODT tablets. [ABSTRACT FROM AUTHOR]

A metal-free strategy has been developed for the α-arylation of carboxylic acids, secondary amides, and esters employing arenes as key reagents. This process entails the Lewis-acid catalyzed reductive Friedel–Crafts alkylation of arenes utilizing α-ketoacids, facilitated by silane in HFIP solvent. The transformation exhibits exceptional functional group tolerance, enabling late-stage functionalization of natural products. This one-step protocol has been successfully used to synthesize commercially available drugs, such as adiphenine, piperidolate, derivatives of ketoprofen, ibuprofen, flurbiprofen, and the pesticide bromopropylate. [ABSTRACT FROM AUTHOR]

Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6–10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes. [ABSTRACT FROM AUTHOR]

Topic: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) for management of pain in patients after photorefractive keratectomy (PRK). Clinical Relevance: Pain after PRK is a major concern for both patients and surgeons. Although evidence supports the use of NSAIDs postoperatively, no consensus exists regarding the preferred regimen. The study aimed to compare the efficacy and safety of different topical NSAIDs. Methods: This study was prospectively registered with PROSPERO (ID: CRD42023417651). A systematic search of electronic databases was performed, for randomized controlled trials reporting topical NSAIDs' outcomes of corneal re-epithelization, rescue analgesics intake, and pain in days 0 to 3 after PRK (postoperative days [PODs] 0 to 3). Studies were graded for risk of bias. Data were extracted, and standardized mean differences (SMDs) were evaluated in a network meta-analysis in accordance with the Cochrane's guidelines, to which a frequentist approach model was fitted. Transitivity was assessed using the net split method. Treatment effectiveness was ranked using forest plots based on comparison with placebo. P-scores (P) and league tables were used to examine combined direct and indirect comparisons. Results: Of 1540 studies identified, 27 were included. These encompassed 2286 patients across 11 countries, evaluating 7 distinct topical NSAIDs. At POD0, ketorolac (P 0.764), flurbiprofen (P 0.763), and bromfenac (P 0.717) were the most efficient drugs overall and displayed significantly lower pain scores than placebo. Other than that, flurbiprofen held the highest rank for reported pain throughout, significantly outperforming placebo on POD1 (P 0.874, SMD -1.19, 95% CI -1.86 to -0.52), POD2 (P 0.882, SMD -1.05, 95% CI -1.82 to -0.27), and POD3 (P 0.939, SMD -1.14, 95% CI -2.1 to -0.18). Other NSAIDs were significantly better than placebo only on POD1 and POD0. Rescue analgesic intake analysis favored indomethacin (P 0.834, SMD-0.8, 95%CI-1.33 to-0.27), ketorolac, and diclofenac. Compared with placebo, re-epithelization was slowed to different significances with all NSAIDs but flurbiprofen (P 0.991, SMD -0.7, 95% CI -1.38 to -0.03). Conclusions: Flurbiprofen was favorable in pain scores on typically painful postoperative days and re-epithelization times. However, analgesics intake, a more objective outcome, suggested superiority of other NSAIDs. Inconsistencies may be explained by the small sample size. For clinical interpretation, NSAID effect sizes should be taken into consideration. [ABSTRACT FROM AUTHOR]

In order to effectively treat arthritis, this study formulated and evaluated a nanogel containing flurbiprofen and betamethasone. Using ionic gelation technology, nanogels were created by fine-tuning a number of process parameters, such as the concentration of the polymer and cross-linker, as well as the stirring speed, stirring duration, and sonication time. The results demonstrated that the particle size and drug loading efficiency were enhanced as the concentrations of the polymer and cross-linker were increased; the ideal concentrations were 0.4% w/v polymer and 0.4% w/v cross-linker. Particle size was also shown to be greatly affected by stirring duration and speed; particles were found to be smaller while stirring for longer periods of time and faster speeds. Particle size was further reduced to 174.16 nm by sonication for 5 minutes, and the drug loading efficiency was an acceptable 72.02%. The enhanced formulation had a PDI, zeta potential, and particle size distribution that were advantageous, which improved stability and medicine encapsulation. Because it ensures a controlled release of the drug and improves patient outcomes, this nanogel system offers potential as a novel approach to providing anti-inflammatory drugs for the treatment of arthritis. [ABSTRACT FROM AUTHOR]

The frequent use of anti‐inflammatory drugs and the side effects of existing drugs keep the need for new compounds constant. For this purpose, flurbiprofen and ibuprofen‐like compounds, which are frequently used anti‐inflammatory compounds in this study, were synthesized and their structures were elucidated. Like ibuprofen and flurbiprofen, the compounds contain a residue of phenylacetic acid. On the other hand, it contains a secondary amine residue. Thus, it is planned to reduce the acidity, which is the biggest side effect of NSAI drugs, even a little bit. The estimated ADME parameters of the compounds were evaluated. Apart from internal use, local use of anti‐inflammatory compounds is also very important. For this reason, the skin permeability values of the compounds were also calculated. And it has been found to be compatible with reference drugs. The COX enzyme inhibitory effects of the obtained compounds were tested by in vitro experiments. Compound 2a showed significant activity against COX‐1 enzyme with an IC50 = 0.123 + 0.005 μM. The interaction of the compound with the enzyme active site was clarified by molecular dynamics studies. [ABSTRACT FROM AUTHOR]

Abstract Background The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and postoperative acute kidney injury (AKI) remains controversial, with limited studies specifically examining flurbiprofen. Therefore, this research aimed to investigate the association between intraoperative flurbiprofen administration and postoperative AKI. Methods We retrospectively identified a cohort of patients at the Third Xiangya Hospital of Central South University. A total of 3882 adult patients undergoing spinal surgery between January 1, 2012, and July 31, 2018, were included and classified into two groups: those receiving flurbiprofen (50 or 100 mg once, 5 min after anesthesia start) and those not receiving flurbiprofen. The primary endpoint was the incidence of AKI. Result The flurbiprofen group (4.4%) had a lower incidence of AKI compared to the non-flurbiprofen group (6.5%, P

Background and Aims: This investigation aimed to enhance flurbiprofen’s (FB) pre-corneal residence period and ocular availability in the postoperative management of ocular inflammation. Methods: The microsphere (MS) material was poly (lactic-co-glycolic acid) PLGA, and FB-laden microspheres were prepared using a single emulsification/solvent evaporation process, loaded onto thermosensitive in situ gels, and then characterised. Results: The size of the microparticles was measured as 19.3±2.1 μm. Entrapment efficiency, zeta potential, and in vitro release; it was observed that the microspheres were released for six days. The optimum gelling capacity was obtained using 15% Poloxamer 407, 8% Poloxamer 188, and 1% HEC (viscosity 80-125 cp). Poloxamer 407 concentration was reduced, resulting in increased gelation temperature and duration. It was determined that the gelling temperature of the selected formulation was 35±0.1 °C, the pH was 6.9±0.02, and the viscosity at the gelling temperature was 11042±247 cP. The addition of hydroxyethyl cellulose increased the mucoadhesive strength. - in vitro release of FB from FB-PLGA MS followed the Korsmeyer-Peppas model, –, and the in situ gel preparation was found to be compatible with the Peppas-Sahlin model. In addition, MTT analysis of the ARPE-19 cell line revealed that the in situ gel formulation was biocompatible. Conclusion: Flurbiprofen release was sustained, ocular availability was improved, and residence time was increased when flurbiprofen-loaded microspheres were incorporated into in situ gel bases. [ABSTRACT FROM AUTHOR]

As a selective and potent inhibitor targeting the isocitrate dehydrogenase‐2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co‐administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0‐∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)‐fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)‐fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)‐fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)‐fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)‐fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib. [ABSTRACT FROM AUTHOR]

Launaea fragilis (Asso) Pau is a Cholistan desert medicinal plant. Launaea species are used as traditional remedies against various inflammatory conditions. The current research was designed to evaluate the anti-nociceptive, anti-inflammatory, and anti-arthritic potential of ethanolic extract of L. fragilis (Et-LF). The plant extract was prepared by triple maceration. GC–MS screening explored the presence of various bioactive phytoconstituents including n-tetracosanol-1, 1-heptacosanol, and n-hexadecanoic acid. DPPH assay demonstrated the antioxidant potential of Et-LF. Safety profile data indicated that Et-LF was safe up to the oral dose of 5000 mg/kg in female rats. Anti-nociceptive activity of Et-LF was assessed in hot plate method and acetic acid-induced writhing model and the results suggested that Et-LF had significant analgesic effects in both animal models. Carrageenan, histamine, and serotonin-induced edema models were used to estimate the anti-inflammatory effects of Et-LF and were found to prevent paw edema development dose dependently. The anti-arthritic effect of Et-LF was estimated in CFA-induced arthritic rat model. Treatment with Et-LF 125, 250, 500 and flurbiprofen (FP) 10 mg/kg/day significantly attenuated the paw edema, reversed the reduced body weight, and restored the altered hematological parameters in arthritic rats. Gene expression studies revealed the significant downregulation of IL-1β, TNF-α, IL-6, NF‑κB, and COX-2, and upregulation of IL-4 and IL-10 in arthritic rats treated with various doses of plant extract. Histological evaluation of ankle joints showed that Et-LF mitigated pannus formation, infiltration of inflammatory cells, and fibrous connective tissue formation in the diseased rats. Thereof, it may be concluded that the recent study demonstrated the anti-nociceptive, anti-inflammatory, and anti-arthritic effects ascribed to the signifying presence of phytoconstituents in L. fragilis. [ABSTRACT FROM AUTHOR]

Acute postoperative pain is commonly treated with flurbiprofen (FBP), but conventional delivery methods are suboptimal. This study prepared a new non-burst release microneedles (MNs) using genipin cross-linked gelatin (cGel). By adding varying amounts of genipin to modulate the crosslinking degree of cGel, the drug release behavior of the drug-loaded MNs in the skin can be altered. The crosslinking parameters that meet therapeutic requirements are selected, thus providing rapid and long-lasting analgesic effects. cGel solutions were successfully cross-linked, altering matrix material microstructure, confirmed by scanning electron microscope imaging and fourier transform infrared spectroscopy. MNs demonstrated increasing mechanical strength with higher crosslinking. Drug release rates were rapid initially, then slowed, exhibiting a characteristic of decreased release rates with increasing degrees of crosslinking. In vivo, FBP/cGel MNs significantly reduced allodynia and hyperalgesia post-surgery, with the greatest effect observed at 2–3 h post-surgery, and can maintain analgesia for up to 6 h. Biosafety tests confirmed good biocompatibility. FBP/cGel MNs effectively penetrate the stratum corneum, safely delivering drugs with significant analgesic effects, excellent mechanical properties, and good biocompatibility, representing a promising strategy for managing acute postoperative pain. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry faces a significant challenge from the low water solubility of nearly 90% of newly developed Active Pharmaceutical Ingredients (APIs). Despite extensive efforts to improve solubility, approximately 40% of these APIs encounter commercialization hurdles, impacting drug efficacy. In this context, a promising strategy will be introduced in which nanosuspensions, particularly polyvinyl alcohol (PVA) as a stabilizer, are applied to increase drug solubility. In this work using molecular dynamics simulations, the nanosuspension of four poorly water-soluble drugs (flurbiprofen, bezafibrate, miconazole, and phenytoin) stabilized with PVA is investigated. The simulation data showed van der Waals energies between polyvinyl alcohol with flurbiprofen and bezafibrate are − 101.12 and − 58.42 kJ/mol, respectively. The results indicate that PVA is an effective stabilizer for these drugs, and superior interactions are obtained with flurbiprofen and bezafibrate. The study also explores the impact of PVA on water molecule diffusion, providing insights into the stability of nanosuspensions. Obtained results also provide valuable insights into hydrogen bond formation, diffusion coefficients, and nanosuspension stability, contributing to the rational design and optimization of pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

Background: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and postoperative acute kidney injury (AKI) remains controversial, with limited studies specifically examining flurbiprofen. Therefore, this research aimed to investigate the association between intraoperative flurbiprofen administration and postoperative AKI. Methods: We retrospectively identified a cohort of patients at the Third Xiangya Hospital of Central South University. A total of 3882 adult patients undergoing spinal surgery between January 1, 2012, and July 31, 2018, were included and classified into two groups: those receiving flurbiprofen (50 or 100 mg once, 5 min after anesthesia start) and those not receiving flurbiprofen. The primary endpoint was the incidence of AKI. Result: The flurbiprofen group (4.4%) had a lower incidence of AKI compared to the non-flurbiprofen group (6.5%, P < 0.001). After adjusting for potential confounding variables, the multivariable regression analysis showed that the flurbiprofen group had a 49% reduced risk of postoperative AKI (OR 0.51; 95% CI 0.31 to 0.82) compared to the non-flurbiprofen group. Subgroup analysis indicated that flurbiprofen injection was associated with a reduced incidence of postoperative AKI in patients without diabetes (OR 0.61; 95% CI 0.19 to 0.74), surgical times of 2–5 h (OR 0.54; 95% CI 0.23 to 0.75), and preoperative anemia (OR 0.57; 95% CI 0.21 to 0.74). Conclusion: The study concluded that perioperative flurbiprofen treatment was associated with a lower risk of postoperative AKI in adult patients undergoing spinal surgery. [ABSTRACT FROM AUTHOR]

Flurbiprofen (FB), a nonsteroidal anti-inflammatory drug, is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects. However, the racemic nature of its commercially available formulation (Ocufen®) limits the full potential of its therapeutic activity, as the (S)-enantiomer is responsible for the desired antiinflammatory effects. Additionally, the limited corneal permeability of FB significantly restricts its bioavailability. In this study, we successfully separated the chiral isomers of FB to obtain the highly active (S)-FB. Subsequently, utilizing ion-pairing technology, we coupled (S)-FB with various counter-ions, such as sodium, diethylamine, trimethamine (TMA), and l-arginine, to enhance its ocular bioavailability. A comprehensive evaluation encompassed balanced solubility, octanol-water partition coefficient, corneal permeability, ocular pharmacokinetics, tissue distribution, and in vivo ocular anti-inflammatory activity of each chiral isomer salt. Among the various formulations, S-FBTMA exhibited superior water solubility (about 1-12 mg/ml), lipid solubility (1 < lg Pow < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher in vivo antiinflammatory activity and lower ocular irritability (such as conjunctival congestion and tingling). The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Herpes stromal keratitis (HSK) is an immune-mediated corneal inflammation that occurs after a herpes simplex virus infection. This paper aims to systematically identify and compare interventions for treating HSK and their patient outcomes. This systematic review followed the PRISMA methodology. Online databases were searched to obtain all relevant papers. Two independent reviewers screened through 168 records. Seven papers were included and used for data extraction. A qualitative analysis was conducted. HSK patients receiving prednisolone phosphate and acyclovir showed a higher treatment success rate and significantly longer time to failure compared to patients receiving only acyclovir (P <.001). No difference in resolution time was found between oral and topical acyclovir. Between groups receiving dexamethasone and flurbiprofen, resolution occurred in 93% and 67% of patients, and BCVA (LogMAR) improved from 1.0 to 0.30 and 0.48, respectively. BCVA improved in both cyclosporine-A (P <.001) and its control (prednisolone) groups (P =.002). A tacrolimus treatment group showed greater improvement in BCVA compared to its control (prednisolone) group (P <.001). Corticosteroids and antivirals managed HSK most effectively only when used concurrently. Oral acyclovir showed similar effectiveness to its ointment counterpart, a preferable alternative for easier administration. Corticosteroid use could induce greater therapeutic benefits when tapered in concentration and frequency and administrated for at least 10 weeks. Anti-inflammatory drugs including flurbiprofen, cyclosporine-A, and tacrolimus could be safe and effective for treating HSK. Future long-term follow-up and RCTs could provide insights on the therapeutic benefits of these potential alternatives. [ABSTRACT FROM AUTHOR]

Drugs that are poorly soluble in water are difficult to absorb orally, resulting in low bioavailability. Flurbiprofen (FLU) is an arylpropionic acid nonsteroidal anti‐inflammatory drug belonging to BCS class II, with low water solubility. In this study, a novel flurbiprofen‐ethylenediamine salt (FLU‐EDA) was successfully prepared via solvent crystallization. Its crystal structure was determined via single‐crystal X‐ray diffraction (SXRD). Further, the physicochemical properties of FLU‐EDA salt were characterized by powder X‐ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT‐IR). The solubility and intrinsic dissolution rate (IDR) of FLU‐EDA salt in water were investigated. The results showed that compared with FLU, the solubility and IDR of FLU‐EDA salt increased by 57‐fold and 32‐fold, respectively. This indicates that FLU‐EDA salt can significantly enhance the solubility and dissolution rate of flurbiprofen in water. This study provides basic data and theory for the development of new formulations of flurbiprofen. [ABSTRACT FROM AUTHOR]

This study presents the enantiomeric resolution of three profen drugs, viz., flurbiprofen (FLB), fenoprofen, and zaltoprofen by employing sitafloxacin (SIT) as a chiral selector within a direct thin-layer chromatography (TLC) method. Chromatographic resolution of three drugs was carried out using a mobile phase consisting of acetonitrile‒methanol‒trimethylamine (6:3:1, V/V, pH 8.5), with a stationary phase maintained at pH 5. Analytical validation of the FLB enantiomeric resolution exhibited consistent recovery rates, with coefficient of variation (%CV) values consistently below 2%. Furthermore, the method demonstrated sensitivity, with low limits of detection and quantification values of 0.058 and 0.172 µg per spot, respectively, for FLB enantiomers, indicating reliable detection at low concentrations. The analytical data validate the effectiveness and reliability of the developed TLC method for the enantiomeric resolution of profen drugs, offering significant implications for pharmaceutical research and development. [ABSTRACT FROM AUTHOR]

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin. [ABSTRACT FROM AUTHOR]

Abstract The aim of this randomized clinical study was to assess the comparative efficacy of flurbiprofen in tablet and spray formulations for postoperative pain management in oral soft tissue wounds undergoing primary closure while investigating the feasibility of achieving optimal analgesia with reduced dosage and risk. Forty patients who underwent epulis fissuratum and frenulum excision for pre-prosthetic surgery were randomly assigned to receive either tablet or spray forms of flurbiprofen. The lesion dimensions were measured preoperatively, followed by excision and primary closure. The tablet group received oral tablets containing 100 mg of flurbiprofen twice daily, whereas the spray group received an oral spray containing 0.25% flurbiprofen, administered as two sprays thrice daily. Postoperative pain was assessed using the Numerical Rating Scale (NRS) until the 7th day. Lesion size, drug consumption, and rescue analgesic use were compared between the groups. There were no statistically significant differences in the lesion size between the groups. However, the mean NRS score in the spray group was significantly lower in the spray group compared to than that in the tablet group at 6th hour postoperatively (p = 0.037). Significant differences favoring the tablet group were observed in the first three doses of the drug (p = 0.001). No patients required rescue analgesics. The spray formulation of flurbiprofen demonstrated effective and safe pain relief in oral soft tissue wounds undergoing primary closure, with no reported adverse effects.

This research is based on the synthesis, characterization and in vitro α‐glucosidase inhibitory activity of fourteen amides (2 a–2 n) of flurbiprofen drug. Seven compounds in the series displayed potent inhibitory activity having IC50 values (IC50=5.67±0.89 μM) to (IC50=17.87±2.39 μM) in comparison with acarbose standard (IC50=875.75±1.24 μM). The FMO of 2 a–2 n molecules was quantified by the DFT assay. The promising value for energygap explained the higher poteny agannist α‐glucosidase. MEP provides the insights into the distribution of electrostatic potential on the molecular surface of 2 a–2 n, showing that C=O group has the highest negative potential. The AIM investigation revealed minimal hydrogen bond energy and non‐covalent interactions. This suggests that these molecules may have limited hydrogen bonding and non‐covalent interactions, which could be relevant to their chemical behavior. Molecular docking and (MEP) showed the C=O group, with its high negative potential, is a key in recognizing the catalytic non‐polar regions of enzymes, such as TYR72, GLU277, and ARG442. Similarly, the hydrophobic regions of investigated compounds play a significant role in identifying essential amino acids like ASP352 and ARG442, which are vital for the ligand's proper orientation and subsequent biological activity. [ABSTRACT FROM AUTHOR]

Introduction: PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. Methods: The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. Results: A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. Conclusion: The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed. [ABSTRACT FROM AUTHOR]

In this study, we aimed to develop thermosensitive and bioadhesive in situ gelling systems containing solid dispersions of flurbiprofen (FB-SDs) using poloxamer 407 (P407) and 188 (P188) for ophthalmic delivery. FB-SDs were prepared with the melt method using P407, characterized by solubility, stability, SEM, DSC, TGA, and XRD analyses. Various formulations of poloxamer mixtures and FB-SDs were prepared using the cold method and P407/P188 (15/26.5%), which gels between 32 and 35 °C, was selected to develop an ophthalmic in situ gelling system. Bioadhesive polymers Carbopol 934P (CP) or carboxymethyl cellulose (CMC) were added in three concentrations (0.2, 0.4, and 0.6% (w/w)). Gelation temperature and time, mechanical properties, flow properties, and viscosity values were determined. The in vitro release rate, release kinetics, and the release mechanism of flurbiprofen (FB) from the ophthalmic formulations were analyzed. The results showed that FB-SDs' solubility in water increased 332-fold compared with FB. The oscillation study results indicated that increasing bioadhesive polymer concentrations decreased gelation temperature and time, and formulations containing CP gel at lower temperatures and in a shorter time. All formulations except F3 and F4 showed Newtonion flow under non-physiological conditions, while all formulations exhibited non-Newtonion pseudoplastic flow under physiological conditions. Viscosity values increased with an increase in bioadhesive polymer concertation at physiological conditions. Texture profile analysis (TPA) showed that CP-containing formulations had higher hardness, compressibility, and adhesiveness, and the gel structure of formulation F4, containing 0.6% CP, exhibited the greatest hardness, compressibility, and adhesiveness. In vitro drug release studies indicated that CP and CMC had no effect below 0.6% concentration. Kinetic evaluation favored first-order and Hixson–Crowell kinetic models. Release mechanism analysis showed that the n values of the formulations were greater than 1 except for formulation F5, suggesting that FB might be released from the ophthalmic formulations by super case II type diffusion. When all the results of this study are evaluated, the in situ gelling formulations prepared with FB-SDs that contained P407/P188 (15/26.5%) and 0.2% CP or 0.2% CMC or 0.4 CMC% (F2, F5, and F6, respectively) could be promising formulations to prolong precorneal residence time and improve ocular bioavailability of FB. [ABSTRACT FROM AUTHOR]

Background: Flurbiprofen 8.75 mg lozenges and oromucosal sprays are used for symptomatic relief of sore throat in patients aged 12 years and over. The documented adverse events of flurbiprofen use include those related to its pharmacological actions, namely, increased risk of haemorrhagic events, however other adverse events (such as nephrotoxicity and cardiac failure) have been known to occur. The likelihood of occurrence of adverse events increases when flurbiprofen is used concomitantly with some other medications. Therefore, the objective of this systematic review was to collate the current evidence on adverse events which occur with flurbiprofen 8.75 mg dose (any formulation), in particular as a result of interaction with other medicinal products, with a focus on non-haemorrhagic events. Methods: Systematic searches of the literature were conducted to identify literature on any formulation of flurbiprofen 8.75 mg up to the date of the electronic database search (data lock: 28 April 2020). Publications were screened to identify studies reporting non-haemorrhagic adverse events with flurbiprofen 8.75 mg and/or non-haemorrhagic adverse events in the comparator arm. Data extraction was performed for eligible studies according to pre-defined criteria and summarised in narratives, tables and figures. Risk of bias and certainty of evidence assessments were planned for each included study where results relating to the primary objective of the systematic review were available. Results: Of 1,528 publications identified by systematic literature searches, 26 met the inclusion criteria and were included in this review. None of these 26 studies contained information on non-haemorrhagic adverse events occurring as a result of a drug-drug interaction (interaction with concomitant medication used with flurbiprofen 8.75 mg), as per the primary objective and secondary objectives of the systematic review. Conclusion: Results from this systematic review on the risk of non-haemorrhagic events did not provide evidence for these events occurring as a result of interaction with other medicinal products. Additional appropriately designed studies would be required to confirm whether these findings suggest a true absence of risk or limitations in reporting. [ABSTRACT FROM AUTHOR]

Abstract Drugs that are poorly soluble in water are difficult to absorb orally, resulting in low bioavailability. Flurbiprofen (FLU) is an arylpropionic acid nonsteroidal anti‐inflammatory drug belonging to BCS class II, with low water solubility. In this study, a novel flurbiprofen‐ethylenediamine salt (FLU‐EDA) was successfully prepared via solvent crystallization. Its crystal structure was determined via single‐crystal X‐ray diffraction (SXRD). Further, the physicochemical properties of FLU‐EDA salt were characterized by powder X‐ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT‐IR). The solubility and intrinsic dissolution rate (IDR) of FLU‐EDA salt in water were investigated. The results showed that compared with FLU, the solubility and IDR of FLU‐EDA salt increased by 57‐fold and 32‐fold, respectively. This indicates that FLU‐EDA salt can significantly enhance the solubility and dissolution rate of flurbiprofen in water. This study provides basic data and theory for the development of new formulations of flurbiprofen.

Developed here is a robust electrochemical cross‐coupling reaction between aroyl hydrazine and NH‐sulfoximine via concomitant cleavage and formation of C(sp2)−N bonds with the evolution of H2 and N2 as innocuous by‐products. This sustainable protocol avoids the use of toxic reagents and occurs at room temperature. The reaction proceeds via the generation of an aroyl and a sulfoximidoyl radical via anodic oxidation under constant current electrolysis (CCE), affording N‐aroylated sulfoximine. The strategy is applied to late‐stage sulfoximidation of L‐menthol, (−)‐borneol, D‐glucose, vitamin‐E derivatives, and marketed drugs such as probenecid, ibuprofen, flurbiprofen, ciprofibrate, and sulindac. In addition, the present methodology is mild, high functional group tolerance with broad substrate scope and scalable. [ABSTRACT FROM AUTHOR]

Titanocene conjugates with four different non-steroidal anti-inflammatory drugs (flurbiprofen, naproxen, ibuprofen, and diclofenac; NSAIDs) were obtained for the first time. The spectra of the obtained compounds were recorded, and an unexpectedly strong effect of chiral ligands based on NSAIDs on the chemical shifts of protons of cyclopentadienyl rings of titanocene in 1H NMR spectra was discovered and explained. For all the obtained conjugates, the redox behavior in DMF solution was investigated; the reduction potentials of all titanocene–NSAID compounds were in the range of −0.80 to −0.98 V, which were suitable for their intracellular reduction. The stability of all the conjugates obtained in aqueous media turned out to be many times higher than the stability of titanocene dichloride (the half-life of titanocene–NSAID conjugates was 50–180 minutes, and for one of the conjugates it exceeded 400 minutes). The most cytotoxic of the obtained compounds, the titanocene conjugate with ibuprofen, showed IC50 against the A2780 cell line 35% lower than the original titanocene dichloride and SI = 1.54 in relation to non-tumor human fibroblast cells. [ABSTRACT FROM AUTHOR]

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect. [ABSTRACT FROM AUTHOR]

A rapid and sensitive ultra‐high performance liquid chromatography–tandem mass spectrometry method was developed to determine flurbiprofen in rat plasma. A triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) source was used in negative ion mode. Acetonitrile precipitation was selected to prepare samples. Flurbiprofen and internal standard flurbiprofen‐d5 were analyzed on an Acquity UPLC BEH C18 column with the mobile phase consisting of acetonitrile and water, and a gradient procedure was used for separation. The retention time of flurbiprofen was 0.67 min, and the whole running time was only 1.2 min. The detection was performed on a triple quadrupole tandem mass spectrometer using multiple reaction monitoring mode via an ESI source with optimized mass spectrometry parameters. The calibration curve was linear in the range of 25.0–1.00 × 104 ng/mL (r ≥ 0.99). The within‐run and between‐run relative standard deviations were not more than 13.9%. The within‐run and between‐run relative errors were from −9.0% to 3.4%. There was no significant matrix effect, and recovery was high. This method was fully validated, including whole blood stability in rat plasma, and successfully applied to the pharmacokinetic study in which 100% incurred sample reanalysis met the criteria. [ABSTRACT FROM AUTHOR]

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In this study, we present the synthesis of five novel compounds by combining flurbiprofen with various substituted 2-phenethylamines. The synthesized derivatives underwent comprehensive characterization using techniques such as 1H- and 13C-NMR spectroscopy, UV-Vis spectroscopy, and high-resolution mass spectrometry (HRMS). Detailed HRMS analysis was performed for each of these newly created molecules. The biological activities of these compounds were assessed through in vitro experiments to evaluate their potential as anti-inflammatory and antioxidant agents. Furthermore, the lipophilicity of these derivatives was determined, both theoretically using the cLogP method and experimentally through partition coefficient (RM) measurements. To gain insights into their binding affinity, we conducted an in silico analysis of the compounds' interactions with human serum albumin (HSA) using molecular docking studies. Our findings reveal that all of the newly synthesized compounds exhibit significant anti-inflammatory and antioxidant activities, with results statistically comparable to the reference compounds. Molecular docking studies further explain the observed in vitro results, shedding light on the molecular mechanisms behind their biological activities. Using in silico method, toxicity was calculated, resulting in LD50 values. Depending on the administration route, the novel flurbiprofen derivatives show lower toxicity compared to the standard flurbiprofen. [ABSTRACT FROM AUTHOR]

The current work comprises of development of a simple, rapid, and precise reverse phase‐high‐performance liquid chromatography method for simultaneous estimation of propyphenazone, flurbiprofen, and their mutual prodrug. Column C18 (Shimadzu Shim‐pack Gist, 250 × 4.6 mm, 5 μm) was employed as a stationary phase, and the ratio of acetonitrile:methanol:water (40:40:20 %v/v) was used as the mobile phase. The flow rate was held at 1 mL/min and detection was carried out at 245 nm using an ultraviolet detector. The retention time of propyphenazone, flurbiprofen, and their mutual prodrug was found to be 4.0, 2.5, and 10.0 min, respectively. The proposed method was validated according to the International Council on Harmonization Q2(R1) guideline in terms of accuracy, precision, linearity, limit of detection, limit of quantitation, and solution stability. Calibration plots were linear over the concentration ranges of 2–10 μg/mL (R2 = 0.9998, R2 = 0.9992 and R2 = 0.9994 for propyphenazone, flurbiprofen, and their mutual prodrug, respectively). Results of mean percentage recoveries were in the range of 99.6%–100.1% for flurbiprofen, 99.3%–100.2% for propyphenazone, and 99.9%–100.7% for prodrug, respectively. The developed method can be used for the assay of mutual prodrug and drug release study of the developed mutual prodrug also routine quality control evaluation of mutual prodrug in bulk form. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of anti-inflammatory drugs widely used for the treatment of musculoskeletal disorders, mild-to-moderate pain, and fever. This review aimed to explain the functional role and possible mechanisms of the antifungal effects of NSAIDs alone or in combination with antifungal drugs in vitro and in vivo. Several studies reported that NSAIDs such as aspirin, ibuprofen, diclofenac, indomethacin, ketorolac, celecoxib, flurbiprofen, and nimesulide had antifungal activities in vitro, either fungistatic or fungicidal, against different strains of Candida, Aspergillus, Cryptococcus, Microsporum, and Trichophyton species. These drugs inhibited biofilm adhesion and development, and yeast-to-hypha conversion which may be related to a prostaglandin E2 (PGE2)/PGEx-dependent mechanism. Modulating PGE2 levels by NSAIDs during fungal infection can be introduced as a possible mechanism to overcome. In addition, some important mechanisms of the antifungal activities of NSAIDs and their new derivatives on fungi and host immune responses are summarized. Overall, we believe that using NSAIDs along with classical antifungal drugs has the potential to be investigated as a novel therapeutic strategy in clinical studies. Furthermore, combination therapy can help manage resistant strains, increase the efficacy of antifungal drugs, and reduce toxicity. [ABSTRACT FROM AUTHOR]

Objectives: To determine the efficacy of flurbiprofen 8.75 mg lozenges for patients with laboratory-confirmed streptococcal pharyngitis both before and concomitant with antibiotics. Methods: This post hoc analysis comprised adult participants from 2 earlier randomized, double-blind, placebo-controlled studies evaluating the analgesic efficacy of flurbiprofen 8.75 mg lozenges in acute pharyngitis. Throat swabs were obtained to diagnose streptococcal infection. Prior to and 2 hours after each dose of study medication (flurbiprofen or placebo lozenges), patients rated 3 symptoms of acute pharyngitis (sore throat pain, difficulty swallowing, and swollen throat) using visual analogue scales. Appropriate antibiotic treatment was initiated when culture results were reported. Mean changes in each pharyngeal symptom were compared over the immediate 24 hours before and during the initial 24 hours of antibiotic treatment. Results: Twenty-four patients provided both preantibiotic and concomitant antibiotic efficacy outcomes. Relief of throat pain was 93% greater in the flurbiprofen group than in the placebo group before antibiotic coadministration and 84% greater than placebo during antibiotic administration (both P <.05). Relief of difficulty swallowing was 71% greater in the flurbiprofen group than in the placebo before antibiotic administration (P =.16) and 107% greater during concomitant antibiotic administration (P =.04). Relief of the sensation of throat swelling was 295% greater with flurbiprofen than placebo before antibiotic administration (P =.008) and 70% greater during concomitant antibiotic administration (P =.06). For placebo-treated patients, relief from throat pain and difficulty swallowing were similar before and during antibiotic treatment (P >.05), indicating no benefit with antibiotic administration for these symptoms. No treatment-related discontinuations or serious adverse events were reported. Conclusions: Irrespective of antibiotic use, flurbiprofen 8.75 mg lozenges provide well-tolerated, effective relief of pharyngeal symptoms in patients with streptococcal infection. In the 24 hours after administration, antibiotics provide no relief of throat pain or difficulty swallowing beyond the topical demulcent effects of placebo lozenges. [ABSTRACT FROM AUTHOR]

Spray-dried Flurbiprofen (FLB) loaded polymeric nanoformulation using Eudragit L 100 and Ethylcellulose. They were optimized and evaluated. This study determined drug release (%) and encapsulation efficiency (%) by developing a nanoparticulate system using the design of experiment (DoE) approach. FLB is slightly soluble in water; it dissolves slowly and has a low oral bioavailability. FLB-loaded polymeric nanoparticles were produced by solvent evaporation and Spray drying technology. In this research, nanoparticle formulation was prepared by screening and optimization by approaching two different statistical methods (Plackett-Burman and Central composite Designs). The polymeric nanoparticles were evaluated for various characteristics, including drug release, percentage of encapsulation efficiency, X-ray diffraction (X-RD), surface morphology, and Fourier transform infrared (FTIR) spectroscopy. Based on the X-RD analysis, it was found that the drug was successfully incorporated into the polymeric nanoparticles. As a result of nanoparticles containing FLB, % Drug release values were found to be nearly 85-90% increased while % EE was observed in the range of 79-89%. An excellent sustained release, i.e., 14 h, is possible by combining Ethylcellulose (EC) and Eudragit L 100 (ED-100) polymers. The results are beneficial in identifying the ideal formulation parameters for effective encapsulation. Abbreviations: FLB: Flurbiprofen; API: Active pharmaceutical ingredient; DR: Drug release; EE: Encapsulation efficiency; DoE: Design of experiment; X-RD: X-ray diffraction; FTIR: Fourier transform infrared spectroscopy.; PVA: Polyvinyl alcohol; EC: Ethylcellulose; EUGD: Eudragit L 100; NPs: Nanoparticles; PBD: Placket- Burman Design; CCD: Central Composite Design; CMV: Critical method variables; GIT: Gastrointestinal track; SLN: Solid lipid nanoparticles; NLC: Nanostructured lipid carriers; NSAID: Nonsteroidal anti-inflammatory drug; BCS: Biopharmaceutical classification system; PS: Particle size; PDI: Polydispersity Index; ZP: Zeta potential; FE-SEM: Field emission scanning electron microscopy; 2D: 2 Dimensional; 3D: 3 Dimensional [ABSTRACT FROM AUTHOR]