The dose-response effects of flurbiprofen, indomethacin, ibuprofen, and naproxen on primary skeletal muscle cells.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, flurbiprofen, naproxen sodium, and indomethacin are commonly employed for their pain-relieving and inflammation-reducing qualities. NSAIDs work by blocking COX-1 and/or COX-2, enzymes which play roles in inflammation, fever, and pain. The main difference among NSAIDs lies in their affinity to these enzymes, which in turn, influences prostaglandin secretion, and skeletal muscle growth and regeneration. The current study investigated the effects of NSAIDs on human skeletal muscle cells, focusing on myoblast proliferation, differentiation, and muscle protein synthesis signaling. METHODS: Using human primary muscle cells, we examined the dose-response impact of flurbiprofen (25-200 µM), indomethacin (25-200 µM), ibuprofen (25-200 µM), and naproxen sodium (25-200 µM), on myoblast viability, myotube area, fusion, and prostaglandin production. RESULTS: We found that supraphysiological concentrations of indomethacin inhibited myoblast proliferation (-74 ± 2% with 200 µM; -53 ± 3% with 100 µM; both p < 0.05) compared to control cells and impaired protein synthesis signaling pathways in myotubes, but only attenuated myotube fusion at the highest concentrations (-18 ± 2% with 200 µM, p < 0.05) compared to control myotubes. On the other hand, ibuprofen had no such effects. Naproxen sodium only increased cell proliferation at low concentrations (+36 ± 2% with 25 µM, p < 0.05), and flurbiprofen exhibited divergent impacts depending on the concentration whereby low concentrations improved cell proliferation (+17 ± 1% with 25 µM, p < 0.05) but high concentrations inhibited cell proliferation (-32 ± 1% with 200 µM, p < 0.05). CONCLUSION: Our findings suggest that indomethacin, at high concentrations, may detrimentally affect myoblast proliferation and differentiation via an AKT-dependent mechanism, and thus provide new understanding of NSAIDs' effects on skeletal muscle cell development.

Novel Flurbiprofen Derivatives as Antioxidant and Anti-Inflammatory Agents: Synthesis, In Silico, and In Vitro Biological Evaluation.

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.

Determination of flurbiprofen in rat plasma using ultra-high performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.

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.

Ultrasound-guided pericapsular nerve group (PENG) block for early analgesia in elderly patients with hip fractures: a single-center prospective randomized controlled study.

BACKGROUND: The aim of this study was to compare the efficacy of ultrasound-guided PENG (pericapsular nerve group) block and drug therapy with intravenous flurbiprofen for early analgesia in elderly patients with hip fractures after hospitalization. METHODS: This is a single-center, observer-blinded, prospective, randomized, controlled trial. A total of 41 elderly patients (aged 60 or older) with hip fractures were enrolled in the current study. Patients were randomly assigned to two groups: Group P (ultrasound-guided PENG block, 20 mL of 0.375% ropivacaine) and Group F (intravenous flurbiprofen 50 mg). The primary outcome measure was the dynamic (passive straight leg raising 15°) NRS (numerical rating scale 0 to 10) pain scores at different time points. The secondary outcomes were the static NRS scores at different time points, the number of rescue analgesia sessions, patient satisfaction, and the incidence of complications. RESULTS: Patients in the two groups had comparable baseline characteristics. The group P had lower dynamic and static NRS scores at 15 min, 30 min, 6 h, and 12 h after intervention (P<0.05) than the group F. The highest NRS pain scores in the group P were still lower than the NRS scores in the group F at 30 min-12 h (Group F: 5.57±1.54 vs. Group P: 3.00±1.12, P<0.001), and there was no significant difference between the two groups at 12-24 h (Group F: 6.35±1.79 vs. Group P: 5.90±1.83, P>0.05). The group P had higher satisfaction scores (Group P: 9 (9,9) vs. Group F: 8 (7,8), P<0.001). There was no statistically significant difference in the number of rescue analgesics at 0-12 h or 12-24 h or the incidence of complications between the groups. CONCLUSIONS: Compared with intravenous flurbiprofen, ultrasound-guided PENG block provides better early analgesic effects in elderly patients with hip fractures, and a PENG block is safe for elderly patients with hip fractures after hospitalization. Trial registration This study was registered in the Chinese Clinical Trial Testing Center (ID: ChiCTR2200062400).

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 µM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation.

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.

Defining the Conformational Ensembles Associated with Ligand Binding to Cyclooxygenase-2.

Cyclooxygenases (COX) catalyze the committed step in the production of prostaglandins responsible for the maintenance of physiological homeostasis. While crystal structures of COX in complex with substrates and inhibitors have provided insight into the molecular interactions governing their binding, they have not uncovered specific details related to the protein conformational motions responsible for important aspects of the COX function. We created a cysteine-free COX-2 construct and introduced a free cysteine at position-122 to enable labeling with 3-bromo-1,1,1-trifluoroacetone (BTFA). Placement of the label adjacent to the cyclooxygenase channel entrance permitted the detection of alterations upon ligand binding. 19F-nuclear magnetic resonance spectroscopy (19F-NMR) was then used to probe the conformational ensembles arising from BTFA-labeled COX-2 constructs in the presence and absence of ligands known to allosterically activate or inhibit COX-2. 19F-NMR analyses performed in the presence of the time-dependent inhibitor flurbiprofen, as well as Arg-120, Tyr-355, and Glu-524 mutations, led to the classification of two ensembles as representing the relaxed and tightened states of the cyclooxygenase channel entrance. A third ensemble, generated in the presence of arachidonic acid and the Y355F mutant and modulated by the allosteric potentiators palmitic acid and oleic acid and the nonallosteric substrates 2-arachidonoyl glycerol ether and anandamide, was classified as being related to the allosteric regulation of COX activity. The ensemble-based insight into COX function demonstrated here complements the static information derived from crystal structure analyses, collectively providing a more detailed framework of the dynamics involved in the regulation of COX catalysis and inhibition.

Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies.

Totally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 µM against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the Ki value was calculated as 36.3 µM. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 µM) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 µM) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 µM strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.

Chiral resolution of (±)-flurbiprofen using molecularly imprinted hydrazidine-modified cellulose microparticles.

Flurbiprofen (FP) is one of the non-steroidal anti-inflammatory drugs (NSAIDs) commonly used to treat arthritic conditions. FP has two enantiomers: S-FP and R-FP. S-FP has potent anti-inflammatory effects, while R-FP has nearly no such effects. Herein, molecularly imprinted microparticles produced from hydrazidine-cellulose (CHD) biopolymer for the preferential uptake of S-FP and chiral resolution of (±)-FP were developed. First, cyanoethylcellulose (CECN) was synthesized, and the -CN units were transformed into hydrazidine groups. The developed CHD was subsequently shaped into microparticles and ionically interacted with the S-FP enantiomer. The particles were then imprinted after being cross-linked with glutaraldehyde, and then the S-FP was removed to provide the S-FP enantio-selective sorbent (S-FPCHD). After characterization, the optimal removal settings for the S- and R-FP enantiomers were determined. The results indicated a capacity of 125 mg/g under the optimum pH range of 5-7. Also, S-FPCHD displayed a noticeable affinity toward S-FP with a 12-fold increase compared to the R-FP enantiomer. The chiral resolution of the (±)-FP was successfully attempted using separation columns, and the outlet sample of the loading solution displayed an enantiomeric excess (ee) of 93 % related to the R-FP, while the eluent solution displayed an ee value of 95 % related to the S-FP.

Discovery of (S)-flurbiprofen-based novel azine derivatives as prostaglandin endoperoxide synthase-II inhibitors: Synthesis, in-vivo analgesic, anti-inflammatory activities, and their molecular docking.

The anti-inflammatory and analgesic drugs currently used are associated with several adverse effects and found to be highly unsafe for long-term use. Currently, nineteen novel bis-Schiff base derivatives (1-19) of flurbiprofen have been designed, prepared and assessed for in-vivo analgesic, anti-inflammatory and in vivo acute toxicity evaluation. The structures of the acquired compounds were deduced through modern spectroscopic techniques including HR-ESI-MS, 13C-, and 1H NMR. Amongst the series, compounds 7, 9, and 10 attributed potent activities with 93.89, 92.50, and 90.47% decreased edema, respectively compared to flurbiprofen (90.01%), however, compounds 11 and 15 exhibited significant activity of 90.00% decrease. Out of them, fourteen compounds (1-6, 8, 12-14, and 16-19) displayed good activity in the range of 68.96-86.95%. In case of an analgesic study, all the derivatives significantly (p 0.001) increased the pain threshold time particularly compound 7 had the best analgesic effect (24 ± 2.08 s) in comparison with flurbiprofen (21.66 ± 2.02 s) using hot plate test. Similarly, in the acetic acid-induced writhing test, compound 7 determined a potent inhibitory effect (60.47 %) close to flurbiprofen (59.28%). All the synthesized derivatives were found safe up to the dose of 30 mg/kg, in acute toxicity study. On a molecular scale, the synthesized compounds were modeled through a ligand-based pharmacophore study and molecular docking to have insight into the different possible interactions leading to high inhibition levels against the COX-2 enzyme.

Formulation and Development of Flurbiprofen Colon-Specific Eudragit Coated Matrix Tablets: Use of a Novel Crude Banana Peel Powder as a Time-Dependent Polymer.

The rationale for the current investigation is to study the crude banana peel (CBP) powder efficiency as a novel natural time-dependent polymer along with a pH-sensitive polymer to develop flurbiprofen colon-specific tablets. The direct compression method is utilized to prepare the flurbiprofen-CBP matrix tablets using 9 mm punches on the rotary tableting machine and subsequently coated with Eudragit® S 100 by a dip coating method. The tablets were evaluated for various tableting properties and in vitro drug release studies. From the results of dissolution studies, the F6 formulation showed negligible drug release (5.76% in 5 h) in the upper gastrointestinal tract and progressive release in the colon (99.08% in 24 h). Mean dissolution time, T10%, and T80% were found to be 13.33 h, 5.8 h, and 20.7 h, respectively, which explains the efficiency of the present combination of polymers for colon-specific drug release. From the dissolution studies results of stability studies, the similarity index was calculated and found to be 74.75. In conclusion, utilizing CBP as a natural, time-dependent polymer in conjunction with Eudragit® S 100 to develop the flurbiprofen tablets seems like a promising approach for delivering drugs specifically to the colon.

Retrospective evaluation of the incidence of gastrointestinal bleeding in dogs receiving ophthalmic nonsteroidal anti-inflammatory drugs.

OBJECTIVES: To report the incidence of gastrointestinal (GI) bleeding and associated risk factors in a population of dogs receiving ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs). ANIMAL STUDIED: Medical records of dogs prescribed ophthalmic NSAIDs (cases), dogs receiving systemic NSAIDs alone and dogs receiving systemic prednisone alone (controls). PROCEDURES: Data were collected retrospectively from the medical records of 204 dogs prescribed ophthalmic NSAIDs (diclofenac, ketorolac, or flurbiprofen), which were subdivided based on if they received any concurrent systemic NSAIDs or glucocorticoids, 136 dogs receiving a systemic NSAID (carprofen or meloxicam) alone, and 151 dogs receiving a systemic glucocorticoid (prednisone) alone at a referral hospital from 2015 to 2019. RESULTS: Gastrointestinal bleeds developed in 8/79 (10.1%) of topical NSAID-only cases, 10/136 (7.4%) of systemic NSAID controls, and 14/151 (9.3%) of systemic glucocorticoid controls, with no significant difference between the three groups (p = .6103). There were no significant differences in GI bleed rates between cases treated with ketorolac, diclofenac, or flurbiprofen (p = .160), although severe GI bleeding was only seen in ketorolac-treated dogs. Presence of a known concurrent risk factor for GI bleeding was significantly associated with the development of GI bleed in dogs on ophthalmic NSAIDs (p = .032). CONCLUSIONS: Dogs treated with ophthalmic NSAIDs developed GI bleeding at a frequency comparable to dogs receiving systemic NSAIDs or systemic glucocorticoids alone, suggesting that dogs receiving ophthalmic NSAIDs may be at increased risk of GI bleeding.

Contribution of prophylactic administration of flurbiprofen for mesenteric traction syndrome to postoperative leakage or bleeding in gastrointestinal surgery: a retrospective observational study.

PURPOSE: Mesenteric traction syndrome (MTS) sometimes occurs during abdominal surgery. Prophylactic administration of flurbiprofen, a non-steroidal anti-inflammatory drug, prevents the development of MTS. However, administration of non-steroidal anti-inflammatory drugs for postoperative pain increases the incidence of postoperative bleeding. Our aim was to examine the effect of prophylactic flurbiprofen administration on postoperative leakage or bleeding after gastrointestinal surgery. METHODS: A retrospective observational study on patients who underwent open or laparoscopic abdominal surgery was conducted. Perioperative, anesthesia and medical records were reviewed. Patients who did (Flurbio-Group) or did not receive (Control-Group) prophylactic flurbiprofen administration were compared. Then, the Flurbio-Group and Control-Group were each divided into two groups according to whether the patients did or did not develop MTS (Flurbio-MTS-Group and Flurbio-no-MTS-Group, respectively, Control-MTS-Group and Control-no-MTS-Group, respectively). RESULTS: This study included 188 patients (Flurbio-MTS-Group, 1 patient; Flurbio-no-MTS-Group, 31 patients; Control-MTS-Group, 59 patients; Control-no-MTS-Group, 97 patients). Seventeen patients developed postoperative leakage or bleeding. Eleven Flurbio-MTS-Group patients (18.6%), 4 Flurbio-no-MTS-Group patients (12.9%, 4/31), and only 2 Control-no-MTS-Group patients (2%, 2/97) developed postoperative leakage or bleeding. Multivariate logistic regression analysis demonstrated that there was a qualitative interaction effect between prophylactic administration of flurbiprofen and the development of MTS on postoperative leakage or bleeding. CONCLUSION: Prophylactic flurbiprofen administration increased the risk of postoperative leakage or bleeding among patients who did not develop MTS.

Efficacy of ultrasound guided superior laryngeal nerve block on sedation for delayed extubation in maxillofacial surgery with free flap reconstruction.

OBJECTIVE: Superior laryngeal nerve block (SLNB) is a regional anesthesia technique for addressing airway response. However, SLNB on the efficacy of sedation in patients with delayed extubation is unknown, particularly for maxillofacial surgery (MS). The aim of the study was to assess whether ultrasound guided (UG) SLNB reduces the incidence of moderate to severe cough for delayed extubation in MS with free flap reconstruction. METHODS: 60 patients were randomly assigned to the GEA group (control group) and the SLNB group (UG-SLNB postoperatively, study group). During the initial two postoperative hours, the incidence of moderate and severe cough, agitation, and the number of patients requiring rescue propofol and flurbiprofen were recorded. Additionally, the time spent under the target level of sedation, postoperative hemodynamics, and the total does of propofol during the postoperative 24 h were recorded. RESULTS: The data showed the SLNB group had a significantly lower incidence of moderate to severe cough and agitation (p < 0.05), and a longer sedation time (p < 0.05). The number of patients required rescue propofol and flurbiprofen, as well as the hemodynamic changes, were significantly different between the two groups (p < 0.05). CONCLUSION: The use of UG-SLNB is associated with reduced incidence of postoperative cough. Moreover, SLNB can enhance the efficacy of postoperative sedation with need of fewer agents postoperatively. CLINICAL TRIAL REGISTRATION: ChiCTR2000039982.

Efficacy and safety of flurbiprofen cataplasms versus loxoprofen sodium cataplasms in knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA. METHODS: This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1:1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0-10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events. RESULTS: Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147-0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00-22.50] vs . 16.00 [11.00-27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs . 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain. CONCLUSIONS: This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.

Effect of erector spinae plane block with different doses of dexmedetomidine as adjuvant for ropivacaine on the postoperative quality of recovery after video-assisted thoracoscopic lobectomy surgery: a randomized controlled trial.

BACKGROUND: Erector spinae plane block (ESPB) improves postoperative analgesia and significantly enhances the quality of recovery (QoR) after video-assisted thoracoscopic lobectomy surgery (VATLS). However, it is not known whether the use of dexmedetomidine (Dex) as an adjunct for ropivacaine to ESPB affects the QoR after VATLS. The purpose of this study was to explore the effects of different Dex dosages as an adjunct for ropivacaine in combination with ultrasound-guided ESPB on the quality of postoperative recovery in patients with VATLS. METHODS: In this single-center, double-blind, randomized study, 120 patients between the ages of 18 and 65 who were scheduled for VATLS from december 2021 and october 2022 in our hospital under general anesthesia were randomly divided into three groups: ultrasound-guided ESPB with 30 mL of 0.5% ropivacaine (Group R), ultrasound-guided ESPB 0.5% ropivacaine plus 0.5 µg/kg Dex (Group RD1), and ultrasound-guided ESPB 0.5% ropivacaine plus 1.0 µg/kg Dex (Group RD2), ultrasound-guided ESPB was administrated at the T5 vertebral level before surgery. The primary outcome was the QoR-15 score 24 h after the surgery. The secondary outcomes included the QoR-15 scores at 12 h, 48 h, and 72 h after the operation, visual analogue scale (VAS) scores at 8 h, 12 h, 24 h, and 48 h after surgery, cumulative flurbiprofen consumption, postoperative nausea and vomiting (PONV), postoperative bradycardia, and hypotension. RESULTS: The QoR-15 scores were higher in group RD2 than the R and RD1 groups on postoperative day 1 (P < 0.05), in addition, no significant difference was found in the QoR-15 scores between groups R and RD1 on postoperative day 1. The VAS scores were significantly lower in group RD2 than in groups RD1 and group R 12-24 h after surgery (P < 0.05). No significant differences were observed in the QoR-15 and VAS scores at 48 and 72 h after surgery between the three groups. The cumulative flurbiprofen consumption was markedly reduced during the 72 h after surgery in the RD2 group (P < 0.05). The incidence of postoperative nausea and vomiting was lower in the RD2 group (P < 0.05). CONCLUSIONS: The combination of 1 µg/kg dexmedetomidine as an adjunct with 0.5% ropivacaine 30 ml for erector spinae plane block significantly improved the postoperative quality of recovery and provided better postoperative analgesia on postoperative day 1 in patients undergoing Video-assisted thoracoscopic lobectomy surgery. However, dexmedetomidine (1 µg/kg) as an adjunct for ropivacaine combined with erector spinae plane block did not enhance the postoperative quality of recovery at 48 and 72 h postoperatively. TRIAL REGISTRY NUMBER: The number of this clinical trial registry is ChiCTR2100053230, date of registration: 16/11/ 2021).

Quality by design (QbD) approach to develop fast-dissolving tablets using melt-dispersion paired with surface-adsorption method: formulation and pharmacokinetics of flurbiprofen melt-dispersion granules.

Developing amorphous solid dispersions with good flow properties is always challenging for formulation scientists to convert into tablets. Hence, the present study investigates the impact of the combination of melt-dispersion and surface-adsorption methods to prepare melt-dispersion granules with enhanced dissolution rate and flow properties. This study covers the formulation and pharmacokinetic study of fast-dissolving flurbiprofen tablets using PEG 6000 (hydrophilic carrier) and lactose (adsorbent). Response surface methodology (RSM) using the central composite design (CCD) was used to optimize independent variables like carrier concentrations and adsorbent concentrations, and their interactions with the dependent variables (responses), including solubility, angle of repose, Carr's index, and cumulative % drug release, were investigated. The optimized formulation was selected based on the numerical optimization method and further investigated for FTIR spectroscopy, differential scanning calorimetry, and X-ray diffractometry. Then, the optimized formulation was compressed into tablets and evaluated for both in vitro dissolution and in vivo pharmacokinetics parameters. In vitro dissolution studies revealed that the prepared fast-dissolving tablets released the drug entirely within 15 min (Q15 of F4 tablets: 99.34 ± 1.24%), whereas conventional tablets took around 60 min for complete dissolution. Pharmacokinetic studies in rats revealed that fast-dissolving tablets showed 1.38-fold higher peak-plasma concentration (Cmax) and 1.39-fold higher bioavailability than conventional tablets. Overall, this study revealed the successful fabrication of fast-dissolving tablets via melt-dispersion paired with the surface-adsorption method to enhance the flow properties and the dissolution rate.

New Acetamide-Sulfonamide-Containing Scaffolds: Antiurease Activity Screening, Structure-Activity Relationship, Kinetics Mechanism, Molecular Docking, and MD Simulation Studies.

The development of novel scaffolds that can increase the effectiveness, safety, and convenience of medication therapy using drug conjugates is a promising strategy. As a result, drug conjugates are an active area of research and development in medicinal chemistry. This research demonstrates acetamide-sulfonamide scaffold preparation after conjugation of ibuprofen and flurbiprofen with sulfa drugs, and these scaffolds were then screened for urease inhibition. The newly designed conjugates were confirmed by spectroscopic techniques such as IR, 1HNMR, 13CNMR, and elemental analysis. Ibuprofen conjugated with sulfathiazole, flurbiprofen conjugated with sulfadiazine, and sulfamethoxazole were found to be potent and demonstrated a competitive mode of urease inhibition, with IC50 (µM) values of 9.95 ± 0.14, 16.74 ± 0.23, and 13.39 ± 0.11, respectively, and urease inhibition of 90.6, 84.1, and 86.1% respectively. Ibuprofen conjugated with sulfanilamide, sulfamerazine, and sulfacetamide, whereas flurbiprofen conjugated with sulfamerazine, and sulfacetamide exhibited a mixed mode of urease inhibition. Moreover, through molecular docking experiments, the urease receptor-binding mechanisms of competitive inhibitors were anticipated, and stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and that no conformational changes occurred during the simulation. The findings demonstrate that conjugates of approved therapeutic molecules may result in the development of novel classes of pharmacological agents for the treatment of various pathological conditions involving the urease enzyme.

Development of chitosan-graphene oxide blend nanoparticles for controlled flurbiprofen delivery.

The use of natural polymeric nanoparticles (Nps) as drug carriers is a highly promising area of research in the field of drug delivery systems because of their high efficiency. In this study, flurbiprofen (FB) loaded chitosan-graphene oxide (CS-GO) blend Nps were synthesized as a controlled delivery system using the emulsion method. The crystalline, molecular, and morphological structures of the prepared CS-GO Nps were characterized using a variety of analytical methods, including Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-Ray diffractometry (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM). It was found that the introduction of GO into the CS nanoparticle formulation increased its thermal stability. The range of the average particle size was between 362 ± 5.06 and 718 ± 2.21 nm, with negative zeta potential values between -7.67 ± 4.16 and - 27.93 ± 2.26 mV. The effects of the CS/GO ratio, the FB/polymer ratio, the amount of span 80, and the cross-linker concentration were assessed on FB release profiles. In vitro release studies displayed a two-stage release behaviour with a fast initial release of the FB, followed by sustained and extended release, and the incorporation of GO into the CS Nps made the FB release more sustained and controlled manner. Besides, the cytotoxicity test of the FB-loaded CS-GO Nps was studied through MTT assay, and it was found that they were biocompatible. Based on these findings, it can be inferred that the prepared CS-GO Nps might be a promising candidate drug carrier system for FB.

Topological effects in ultrafast photoinduced processes between flurbiprofen and tryptophan in linked dyads and within human serum albumin.

The interaction dynamics between flurbiprofen (FBP) and tryptophan (Trp) has been studied in covalently linked dyads and within human serum albumin (HSA) by means of fluorescence and ultrafast transient absorption spectroscopy. The dyads have proven to be excellent models to investigate photoinduced processes such as energy and/or electron transfer that may occur in proteins and other biological media. Since the relative spatial arrangement of the interacting units may affect the yield and kinetics of the photoinduced processes, two spacers consisting of amino and carboxylic groups separated by a cyclic or a long linear hydrocarbon chain (1 and 2, respectively) have been used to link the (S)- or (R)-FBP with the (S)-Trp moieties. The main feature observed in the dyads was a strong intramolecular quenching of the fluorescence, which was more important for the (S,S)- than for the (R,S)- diastereomer in dyads 1, whereas the reverse was true for dyads 2. This was consistent with the results obtained by simple molecular modelling (PM3). The observed stereodifferentiation in (S,S)-1 and (R,S)-1 arises from the deactivation of 1Trp*, while in (S,S)-2 and (R,S)-2 it is associated with 1FBP*. The mechanistic nature of 1FBP* quenching is ascribed to energy transfer, while for 1Trp* it is attributed to electron transfer and/or exciplex formation. These results are consistent with those obtained by ultrafast transient absorption spectroscopy, where 1FBP* was detected as a band with a maximum at ca. 425 nm and a shoulder at ∼375 nm, whereas Trp did not give rise to any noticeable transient. Interestingly, similar photoprocesses were observed in the dyads and in the supramolecular FBP@HSA complexes. Overall, these results may aid to gain a deeper understanding of the photoinduced processes occurring in protein-bound drugs, which may shed light on the mechanistic pathways involved in photobiological damage.