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The therapeutic effect of 5-amino salicylic acid (5-ASA), a first-line therapeutic agent for the treatment of ulcerative colitis (UC), is limited by the modest bioavailability afforded by its oral administration. In this study, a 5-ASA oral delivery system was developed using Eudragit S100-coated iron oxide-chitosan nanocomposites (ES-IOCS/5-ASA) to address this issue. According to drug release studies in vitro, ES-IOCS/5-ASA only released a small amount of drug in simulated gastric fluid with a pH of 1.2. However, in a medium with a pH of 7.5, a relatively rapid and complete release was noted. 5-ASA-loaded iron oxide-chitosan nanocomposites (IOCS/5-ASA) could be effectively taken up by NCM460 cells and performed better anti-inflammatory effects than free 5-ASA. At the same time, IOCS/5-ASA improved barrier damage in DSS-induced NCM460 cells. In vivo models of dextran sulphate sodium (DSS)-induced colitis were used to assess the therapeutic efficacy of oral administration of ES-IOCS/5-ASA. ES-IOCS/5-ASA significantly relieved DSS-induced colitis and enhanced the integrity of the intestinal epithelial barrier. ES-IOCS/5-ASA also reduced the expression of NLRP3, ASC and IL-1β. Additionally, iron oxide nanoparticles used as nanozymes could alleviate inflammation. In summary, this study indicates that ES-IOCS/5-ASA exert anti-inflammatory effects on DSS-induced colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome expression, presenting a viable therapeutic choice for the treatment of UC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Establishing a physical barrier between the peritoneum and the cecum is an effective method to reduce the risk of postoperative abdominal adhesions. Meloxicam (MX), a nonsteroidal anti-inflammatory drug has also been applied to prevent postoperative adhesions. However, its poor water solubility has led to low bioavailability. Herein, we developed an injectable hydrogel as a barrier and drug carrier for simultaneous postoperative adhesion prevention and treatment. A third-generation polyamide-amine dendrimer (G3) was exploited to dynamically combine with MX to increase the solubility and the bioavailability. The formed G3@MX was further used to crosslink with poly-γ-glutamic acid (γ-PGA) to prepare a hydrogel (GP@MX hydrogel) through the amide bonding. In vitro and in vivo experiments evidenced that the hydrogel had good biosafety and biodegradability. More importantly, the prepared hydrogel could control the release of MX, and the released MX is able to inhibit inflammatory responses and balance the fibrinolytic system in the injury tissues in vivo. The tunable rheological and mechanical properties (compressive moduli: from ∼ 57.31 kPa to ∼ 98.68 kPa;) and high anti-oxidant capacity (total free radical scavenging rate of ∼ 94.56 %), in conjunction with their syringeability and biocompatibility, indicate possible opportunities for the development of advanced hydrogels for postoperative tissue adhesions management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment., Methods: Participants (≥ 65 years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89 mL/min for mild and 30-59 mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25 mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75 mg/h continuous intravenous (IV) infusion over 24 h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15 mg every 6 h. There were four treatment periods of 24 h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored., Results: Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred., Conclusions: NTM-001 was considered safe and well tolerated in this population of participants ≥ 65 years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects., (© 2024. The Author(s).)

Background: Parenteral ketorolac and intravenous (IV) acetaminophen have been used for prehospital analgesia, yet limited data exist on their comparative effectiveness., Study Objectives: To evaluate the comparative effectiveness of IV acetaminophen and parenteral ketorolac for analgesia in the prehospital setting., Methods: We conducted a retrospective cross-sectional evaluation of patients receiving IV acetaminophen or parenteral ketorolac for pain management in a large suburban EMS system between 1/1/2019 and 11/30/2021. The primary outcome was change in first to last pain score. Subgroup analysis was performed on patients with traumatic pain. We used inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) to estimate the treatment effect of acetaminophen versus ketorolac among all patients and the subgroup of those with traumatic pain., Results: Of 2178 patients included, 856 (39.3%) received IV acetaminophen and 1322 (60.7%) received parenteral ketorolac. The unadjusted mean change in pain score was -1.9 (SD 2.4) for acetaminophen group and -2.4 (SD 2.4) for ketorolac. In the propensity score analyses, there was no statistically significant difference in pain score change for the acetaminophen group versus ketorolac among all patients (mean difference, IPTW: 0.11, 95% confidence interval [CI] -0.16, 0.37; PSM: 0.15, 95% CI -0.13, 0.43) and among those with traumatic pain (unadjusted: 0.18, 95% CI -0.35, 0.72; IPTW: 0.23, 95% CI -0.25, 0.71; PSM: -0.03, 95% CI -0.61, 0.54)., Conclusions: We found no statistically significant difference in mean pain reduction of IV acetaminophen and parenteral ketorolac for management of acute pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aimed to develop a thermosensitive in situ gel formulation for rectal delivery of Ibuprofen as an efficient alternative dosage form. Utilizing poloxamer 188, poloxamer 407, and HPMC via cold technique method, a thermosensitive in situ gel was successfully prepared. The concentration of Ibuprofen in the formulations was 1.2 % (w/w). The prepared gels underwent assessment for clarity, gelation temperature, gelation time, gel strength, spread ability, syringe-ability, pH, viscosity, FTIR, and drug content. The selected formulations exhibited a gelation temperature within the range of 30 °C to 36 °C, with consistent amount of drug soluble in the formulations (93 % - 110 %). Mucoadhesive studies, in vitro release tests, ex vivo modeling of drug release, kinetic studies modeling, and histopathology testing were also conducted. The formulation comprising 18 % poloxamer 407, 12 % poloxamer 188, and 1 % sodium chloride (FS15) demonstrated suitable gelation temperature and desirable drug release rate. In vitro drug release tests indicated completion within one hour for both FS10 (20 % P407 & 10 % P188) and FS15 (18 % P407 & 12 % P188), with consistent and predictable release patterns observed through kinetic modeling analysis. Microscopic histopathology examination confirmed the safety of the selected formula, exhibiting no irritation in the mucosal membrane of the sheep. In conclusion, Ibuprofen thermosensitive in situ gel presents a promising and convenient strategy as a rectal carrier and an alternative dosage form to solid suppositories., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Aceclofenac (ACE) is a drug that was precisely devised to circumvent the shortcomings associated with diclofenac. However, ACE too corresponds to nonsteroidal anti-inflammatory drug (NSAID)-related adverse effects, but with a lower amplitude. The present investigation seeks to develop liposomes loaded with ACE adopting a central composite design (CCD) and formulate a chitosan-based hydrogel for synergistic anti-inflammatory efficacy and improved ACE dermal administration. On the basis of preliminary vesicle size, Poly Dispersity Index (PDI), and drug entrapment, the composition of lipid, cholesterol, and vitamin E TPGS were chosen as independent variables. The formulation composition met the specifications for an optimum liposomal formulation, with total lipid concentration (13.5% w/w), cholesterol concentration (10% w/w), and surfactant concentration (2% w/w). With particle size and PDI of 174.22 ± 5.46 nm and 0.285 ± 0.01 respectively, the optimised formulation achieved an entrapment effectiveness of 92.08 ± 3.56%. Based on the CCD design, the optimised formulation Acec-Lipo opt was chosen and was subsequently transformed to a chitosan-based gel formulation for in vitro drug release, penetration through the skin, in vivo analgesic therapeutic activity, and skin irritation testing. % age oedema inhibition was found to be greatest with the Acec-Lipo opt gel formulation, followed by Acec gel. These results reinforce the notion that the inclusion of chitosan resulted in a synergistic effect despite the same strength of the drug. The findings suggested that Acec-Lipo incorporated in chitosan gel for skin targeting might be an effective formulation for topical ACE administration in clinical subjects., (© 2024. Controlled Release Society.)

Medical therapy is the cornerstone of ulcerative colitis (UC) management and aims to induce and maintain remission. In case of mild-to-moderate UC, mesalamine (5-ASA) is the first-line option. 5-ASA requires local release at the level of the inflamed mucosa to exert its therapeutic action. While rectal preparations are useful in distal colitis, in cases of UC of at least rectosigmoid extent, guidelines suggest the association of oral and rectal 5-ASA. Mesalamine with Multi Matrix System® technology (MMX mesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-ASA, designed to provide delayed and prolonged release throughout the entire colon. Clinical trials demonstrated a strong efficacy in inducing and maintaining clinical and endoscopic remission in active mild-to-moderate UC. The efficacy is related to specific colonic drug-delivery, to its high-dosage and once-daily administration, thus improving patients' adherence and outcomes. The specific colonic-delivery is also associated with very low rates of systemic absorption and adverse events (AEs). With this comprehensive review we aimed to summarize current knowledge on MMX mesalamine in mild-to-moderate UC, in terms of clinical pharmacology, efficacy and safety, also compared to other 5-ASA products. In addition we provided an expert opinion on the topic, examining the implications on clinical practice., Competing Interests: Conflict of interest F D'Amico has served as a speaker for Sandoz, Janssen, Galapagos, and Omega Pharma; he has also served as advisory board member for Abbvie, Ferring, Galapagos, and Nestlè. L Peyrin-Biroulet has served as a speaker, consultant and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance. S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferrin.g, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, NikkisoEurope GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. The other authors declare no conflicts of interest., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Drug repurposing is a potential strategy to overcome the huge economic expenses of wound healing products. This work aims to develop a topical gel of piroxicam encapsulated into a nanospanlastics vesicular system as an effective, dermal wound dressing. Firstly, piroxicam was entrapped into nanospanlastics formulations and optimized utilizing 2 3 full factorial experimental designs. The scrutinized factors were Span 60: Edge activator ratio, edge activator type, and permeation enhancer type. The measured responses were vesicle size (VS), polydispersity index (PDI), and% entrapment efficiency (EE). The optimized formula was further adopted into an alginate-pectin gel matrix to maximize adherence to the skin. The rheology and in-vitro release were studied for the developed nanospanlastics gel. Cytotoxicity and wound healing potential using scratch assay were assessed on human adult dermal fibroblast cells. The optimal piroxicam nanospanlastics formula demonstrated a VS of 124.1 ± 1.3 nm, PDI of 0.21 ± 0.01, and EE% of 97.27±0.21%. About 70.0 ± 0.9% and 57.4 ± 0.1% of piroxicam were released from nanospanlastics dispersion and gel within 24 h, respectively. Nanospanlastics gel of piroxicam flowed in a non-Newtonian pseudoplastic shear thinning pattern. It was also biocompatible with the human dermal fibroblast cells and significantly promoted their migration rate which suggests an auspicious cutaneous wound healing aptitude., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

This study aimed to evaluate the association between low-dose aspirin use and the risk of GC and gastric adenoma according to a family history of GC. We conducted a population-based study of 7,596,003 participants screened for GC between 2013 and 2014. Aspirin users and non-users were matched in a 1:1 ratio through propensity score matching (PSM). After PSM, 51,818 participants with a family history of GC and 359,840 without a family history of GC were analyzed (mean follow-up periods: 4.9 ± 0.8 and 4.8 ± 0.8 years, respectively). In patients with a family history of GC, aspirin use was significantly associated with a reduced risk of GC (adjusted hazard ratio [aHR]=0.80; 95 % confidence interval [CI]=0.65-0.995) and gastric adenoma (aHR=0.81; 95% CI=0.69-0.94). In those without a family history of GC, aspirin use was associated with a reduced risk of gastric adenoma (aHR = 0.92; 95 % CI = 0.86-0.98), but not with that of GC (aHR = 0.99; 95 % CI = 0.90-1.08). Low-dose aspirin use was associated with a reduced risk of gastric adenoma, regardless of a family history of GC, and may play a role in the early stages of gastric carcinogenesis. However, the association between aspirin and GC was only observed in those with a family history of GC., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: .In this study, we investigated the potential of meloxicam (MLX) developed as transferosomal gel as a novel lipidic drug delivery system to address osteoarthritis (OTA), a degenerative joint disease that causes pain and stiffness. By incorporating meloxicam into a transferosomal gel, our aim was to provide a targeted and efficient delivery system capable of alleviating symptoms and slowing down the progression of OTA., Material and Methods: Classical lipid film hydration technique was utilized to formulate different transferosomal formulations. Different transferosomal formulations were prepared by varying the molar ratio of phospholipon-90H (phosphodylcholine) to DSPE (50:50, 60:40, 70:30, 80:20, and 90:10) and per batch, 80mg of total lipid was used. The quality control parameters such as entrapment efficiency, particle size and morphology, polydispersity and surface electric charge, in vitro drug release, ex vivo permeation and stability were measured., Results: The optimized transferosomal formulations revealed a small vesicle size (121±12nm) and greater MLX entrapment (68.98±2.3%). Transferosomes mediated gel formulation MLX34 displayed pH (6.3±0.2), viscosity (6236±12.3 cps), spreadability (13.77±1.77 gm.cm/sec) and also displayed sustained release pattern of drug release (81.76±7.87% MLX released from Carbopol-934 gel matrix in 24h). MLX34 revealed close to substantial anti-inflammatory response, with ∼81% inhibition of TNF-α in 48h. Physical stability analysis concluded that refrigerator temperature was the preferred temperature to store transferosomal gel., Conclusion: MLX loaded transferosomes containing gel improved the skin penetration and therefore resulted into increased inhibition of TNF-α level., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Diclofenac sodium (DS) and celecoxib (CEL) are primary anti-inflammatory agents used in the treatment of osteoarthritis (OA). Formulating these drugs into extended-release versions can effectively address the issue of multiple daily doses. In this study, we designed and synthesized a novel poly(lactic-co-glycolic acid) (PLGA) nanoliposome as a dual-drug delivery sustained-release formulation (PPLs-DS-CEL) to achieve long-lasting synergistic treatment of OA with both DS and CEL., Methods: PPLs-DS-CEL was synthesized by the reverse evaporation method and evaluated for its physicochemical properties, encapsulation efficiency, drug release kinetics and biological properties. A rat OA model was established to assess the therapeutic efficacy and biosafety of PPLs-DS-CEL., Results: The particle size of PPLs-DS-CEL was 218.36 ± 6.27 nm, with a potential of 32.56 ± 3.28 mv, indicating a homogeneous vesicle size. The encapsulation of DS and CEL by PPLs-DS-CEL was 95.18 ± 4.43% and 93.63 ± 5.11%, with drug loading of 9.56 ± 0.32% and 9.68 ± 0.34%, respectively. PPLs-DS-CEL exhibited low cytotoxicity and hemolysis, and was able to achieve long-lasting synergistic analgesic and anti-inflammatory therapeutic effects in OA through slow release of DS and CEL, demonstrating good biosafety properties., Conclusion: This study developed a novel sustained-release nanoliposomes formulation capable of co-loading two drugs for the long-acting synergistic treatment of OA. It offers a new and effective therapeutic strategy for OA treatment in the clinic settings and presents a promising approach for drug delivery systems., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Ibuprofen is one of the most commonly used analgesic and antipyretic drugs in children. However, its potential causal role in childhood asthma pathogenesis remains uncertain. In this systematic review, we assessed the association between ibuprofen administration in children and the risk of developing or exacerbating asthma., Methods: We searched MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, and Scopus from inception to May 2022, with no language limits; searched relevant reviews; and performed citation searching. We included studies of any design that were primary empirical peer-reviewed publications, where ibuprofen use in children 0-18 years was reported. Screening was performed in duplicate by blinded review. In total, 24 studies met our criteria. Data were extracted according to PRISMA guidelines, and the risk of bias was assessed using RoB2 and NOS tools. Quantitative data were pooled using fixed effect models, and qualitative data were pooled using narrative synthesis. Primary outcomes were asthma or asthma-like symptoms. The results were grouped according to population (general, asthmatic, and ibuprofen-hypersensitive), comparator type (active and non-active) and follow-up duration (short- and long-term)., Results: Comparing ibuprofen with active comparators, there was no evidence of a higher risk associated with ibuprofen over both the short and long term in either the general or asthmatic population. Comparing ibuprofen use with no active alternative over a short-term follow-up, ibuprofen may provide protection against asthma-like symptoms in the general population when used to ease symptoms of fever or bronchiolitis. In contrast, it may cause asthma exacerbation for those with pre-existing asthma. However, in both populations, there were no clear long-term follow-up effects., Conclusions: Ibuprofen use in children had no elevated risk relative to active comparators. However, use in children with asthma may lead to asthma exacerbation. The results are driven by a very small number of influential studies, and research in several key clinical contexts is limited to single studies. Both clinical trials and observational studies are needed to understand the potential role of ibuprofen in childhood asthma pathogenesis., (© 2024. The Author(s).)

Background: Topical non-steroidal anti-inflammatory drugs have the potential to reduce treatment burden and improve outcomes of anti-VEGF therapy for a number of retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. In this review, we focused on the advantages of topical bromfenac as an adjunct to intravitreal anti-VEGF therapy in VEGF-driven maculopathies., Methods: Cochrane Library, PubMed, and EMBASE were systematically reviewed to identify the relevant studies of neovascular age-related macular degeneration, diabetic macular edema, macular edema associated with retinal vein occlusion, myopic choroidal neovascularization, and radiation maculopathy which reported changes in central retinal thickness, visual acuity, and the number of anti-VEGF injections needed when anti-VEGF therapy was combined with topical bromfenac., Results: In total, ten studies evaluating bromfenac as an adjunct to anti-VEGF therapy were identified. Five studies were included in meta-analysis of the number of injections and five studies were included in the analysis of changes in central retinal thickness. A statistically significantly lower number of intravitreal injections (p = 0.005) was required when bromfenac was used as an adjunct to anti-VEGF therapy compared to anti-VEGF monotherapy with pro re nata regimen. At the same time, eyes receiving bromfenac as an adjunct to anti-VEGF therapy demonstrated non-inferior outcomes in central retinal thickness (p = 0.07). Except for one study which reported better visual outcomes with combined treatment, no difference in visual acuity or clinically significant adverse effects were reported., Conclusions: This literature review and meta-analysis showed that topical bromfenac can be considered as a safe adjunct to anti-VEGF therapy with a potential to reduce the treatment burden with anti-VEGF drugs requiring frequent injections without compromising improvement of central retinal thickness or visual acuity., (© 2024. The Author(s).)

Background: Rheumatoid arthritis (RA) is one of the most common forms of arthritis. Extracorporeal shockwave therapy (ESWT) has been identified as a viable alternative therapeutic approach in light of the present protracted clinical course of pharmacological treatment, and changes in levels of marker proteins in the blood samples of RA patients can be utilized to assess treatment outcomes., Methods: A randomized controlled trial was conducted involving forty patients diagnosed with rheumatoid arthritis (RA) who were assigned randomly to two groups. The first group received a combination of diclofenac and methotrexate (MTX) consisting of 25 mg of diclofenac administered thrice daily and 15 mg of MTX administered once weekly. Individual follow-up assessments were carried out after 7 and 14 days. Meanwhile, patients in the second group underwent two sessions of Extracorporeal Shockwave Therapy (ESWT), with a 7-day interval between sessions. Evaluations were conducted on day 7 and day 14. Patients who displayed pain control and stability were advised to continue the treatment, whereas those who had inflammation and discomfort were administered specific medications, and their progress was closely monitored until day 28. Blood samples were collected from both groups prior to treatment, after the first treatment, and after the second treatment. Four marker proteins (NRP-1, CELF-6, COX-2, and RGS-1) and two inflammatory cytokines (IL-6 and IL-17) were measured using western blot and RT-PCR techniques. A statistical analysis was conducted on the levels of specific proteins and inflammatory factors before and after treatment to evaluate its impact., Result: Both groups exhibited statistically significant differences in the serum level of target biomarkers before and after the intervention. However, the ESWT group demonstrated a more noticeable effect, while the diclofenac + MTX group exhibited a delayed anti-inflammatory effect compared to ESWT., Conclusion: Both treatments significantly improved joint function, relieved pain, and reduced inflammation in patients. However, ESWT demonstrated a more prominent clinical analgesic effect compared to the combination treatment of diclofenac and MTX. Furthermore, ESWT produced a more immediate and noteworthy anti-inflammatory impact by regulating NRP-1 expression, a trophic factor receptor that facilitates vascular endothelial cell migration and tissue repair through angiogenesis, and regulating RGS-1 to limit inflammatory signal transmission and immune cell activation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Mei Zhang et al.)

Objectives: The aim of this study was to understand profiles of topical Voltaren gel diclofenac (VGD) 2.32 and 1.16% consumers through analyzing prescription patterns and to characterize treatment satisfaction, functional impairment, and pain relief after over-the-counter (OTC) VGD use in Sweden under real-world conditions., Methods: This observational, real-world study conducted in Sweden had retrospective and prospective segments. The retrospective secondary data segment utilized 12-month diclofenac gel prescription data from the Swedish eHealth Agency (E-hälsomyndigheten). The prospective segment included electronic surveys completed at baseline and weeks 4 and 12 by adult consumers who purchased OTC VGD to treat their pain., Results: Secondary data analyses ( n = 12,145) showed that 56.7% of patients receiving diclofenac gel were females ≥70 years old. Most patients did not switch pain treatments; the mean time between diclofenac gel refills was about 2.5 months. From the surveys ( n = 264), VGD provided pain relief, indicated by improvement in 11-point pain numeric rating scale scores. Average pain severity at baseline was 5.8 - improving by a mean of 1.3 and 1.9 points at weeks 4 and 12, respectively. The majority of consumers reported improvement in daily functioning (i.e., health-related quality of life [HRQoL]), and most were at least somewhat satisfied with VGD treatment results., Conclusions: This real-world study provides important insights into the prescription patterns of diclofenac gel and the consumer experience with OTC VGD in Sweden. Patients rarely switched to other topical nonsteroidal anti-inflammatory drugs, and VGD consumers reported pain relief and improved HRQoL compared to baseline - resulting in treatment satisfaction., (© 2024 the author(s), published by De Gruyter.)

Osteoarthritis (OA) is a degenerative disease commonly seen in middle-aged and elderly people. Multiple cytokines are involved in the local tissue damage in OA. Currently, non-pharmacologic and surgical interventions are the main conventional approaches for the treatment of OA. In terms of pharmaceutical drug therapy, NSAIDs and acetaminophen are mainly used to treat OA. However, it is prone to various adverse reactions such as digestive tract ulcer, thromboembolism, prosthesis loosening, nerve injury and so on. With the in-depth study of OA, more and more novel topical drug delivery strategies and vehicles have been developed, which can make up for the shortcomings of traditional dosage forms, improve the bioavailability of drugs, and significantly reduce drug side effects. This review summarizes the immunopathogenesis, treatment guidelines, and progress and challenges of topical delivery technologies of OA, with some perspectives on the future pharmacological treatment of OA proposed., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Shentu et al.)

While neurosurgical interventions are frequently used in laboratory mice, refinement efforts to optimize analgesic management based on multimodal approaches appear to be rather limited. Therefore, we compared the efficacy and tolerability of combinations of the non-steroidal anti-inflammatory drug carprofen, a sustained-release formulation of the opioid buprenorphine, and the local anesthetic bupivacaine with carprofen monotherapy. Female and male C57BL/6J mice were subjected to isoflurane anesthesia and an intracranial electrode implant procedure. Given the multidimensional nature of postsurgical pain and distress, various physiological, behavioral, and biochemical parameters were applied for their assessment. The analysis revealed alterations in Neuro scores, home cage locomotion, body weight, nest building, mouse grimace scales, and fecal corticosterone metabolites. A composite measure scheme allowed the allocation of individual mice to severity classes. The comparison between groups failed to indicate the superiority of multimodal regimens over high-dose NSAID monotherapy. In conclusion, our findings confirmed the informative value of various parameters for assessment of pain and distress following neurosurgical procedures in mice. While all drug regimens were well tolerated in control mice, our data suggest that the total drug load should be carefully considered for perioperative management. Future studies would be of interest to assess potential synergies of drug combinations with lower doses of carprofen., (© 2024. The Author(s).)

Inflammation may contribute to postoperative cardiac complications and ketorolac, an anti-inflammatory agent inhibiting cyclooxygenase (COX), shows promise in enhancing cardiac graft patency by suppressing endothelial cell proliferation in animal studies. However, the safety of postoperative ketorolac use remains controversial. This study investigates the association between early ketorolac application and complications following cardiac surgery. Data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database fueled this retrospective cohort study. The primary outcome is a composite of mortality, pulmonary insufficiency, severe acute kidney injury (AKI), hemorrhage or hematoma, infection, cardiogenic shock, and cerebrovascular infarction postcardiac surgery. Propensity score matching (PSM; 1:1 match, caliper 0.2), multivariate logistic regression, interaction stratification analysis, pairwise algorithmic, and overlap weight model analyses were employed. Following inclusion and exclusion criteria, 7143 patients who underwent valvular surgery or coronary artery bypass grafting (CABG) were included. PSM created a balanced cohort of 3270 individuals (1635 in the ketorolac group). The matched cohort exhibited an 8.1% overall rate of postoperative complications, with a lower composite outcome rate in patients receiving ketorolac within 48 h of surgery compared with those without (PSM, OR 0.70 [95% CI, 0.54-0.90]). Consistent associations were observed in total cohort analyses, sensitivity, and subgroup analyses. Early ketorolac use within 48 h post-CABG or valvular procedures in adults is independently associated with a lower incidence of composite postoperative adverse events. Prospective trials are warranted to assess causality., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: The development of an efficient, multifunctional drug delivery system overcoming different obstacles generally associated with drug formulations, including the poor accumulation of the active principle in the target site and its sustained release for prolonged time., Methods: Our study proposes the development of a fluorinated poly(amidoamine) (PAMAM) carrier prodrug combining drug release boosted in alkaline environments with a possible implementation in 19 F MRI applications. In particular, we functionalized the terminal primary amines of PAMAM G2 and G4 through an ad hoc designed fluorinated ibuprofen-arginine Michael acceptor to obtain multifunctional ibuprofen-PAMAM-Arg conjugates., Results: These carriers demonstrated pH-dependent and sustained ibuprofen release for more than 5 days. This advantage was observed in both weak alkaline and physiological buffer solutions, allowing to overcome the limits associated to the burst release from similar fluorinated Arg-PAMAM dendrimers with ibuprofen physically encapsulated., Conclusion: These findings, coupled to the high biocompatibility of the system, suggest a potential synergistic biomedical application of our conjugates, serving as vehicles for drug delivery and as 19 F magnetic resonance imaging contrast agents., (© 2024. The Author(s).)

Background: In patients with a high recurrence risk after treatment for Dupuytren contracture (DC) by Collagenase Clostridium histolyticum (CCH), adjuvant medical therapy may improve the outcome. Non-steroidal anti-inflammatory drugs have been used in the treatment of similar fibroproliferative processes. The aim of this study was to investigate if adjuvant anti-inflammatory medication could improve the outcome of CCH treatment for DC. Methods: In a prospective double blinded randomised trial, the effect of adjuvant peroral celecoxib on the outcome of DC treated with CCH was investigated in 32 patients with a high fibrosis diathesis. Primary outcome was the increase in Total Passive Extension Deficit (TPED)/ray. Secondary outcomes were the TPED of the individual finger joints, Tubiana index, Disability of Arm, Shoulder and Hand score (DASH) and visual analogue scale (VAS) for pain and satisfaction. Results: A significantly greater improvement in the celecoxib group for TPED and metacarpophalangeal contracture was found. For the proximal interphalangeal joint, the effect was much less pronounced. The VAS for pain and satisfaction were better at 6 and 12 weeks in the celecoxib group. The other outcome parameters did not significantly differ between both groups. Conclusions: Adjuvant peroral administration of celecoxib might improve the gain in TPED after treatment with CCH in patients with DC and a high fibrosis diathesis, with a beneficial effect up to 24 months. Level of Evidence: Level II (Therapeutic).

Background: The average rate of patient dissatisfaction following total knee arthroplasty (TKA) is 10%. Multi-modal analgesia is the present standard of pain management after TKA. Studies show that with multi-modal analgesia, approximately 60% of patients experience severe knee pain following surgery, while around 30% experience moderate pain. To date, there is no literature available on targeted pain management using bone cement., Objectives: To investigate the feasibility of incorporating anti-inflammatory medications and identify the analgesic with the best release pharmacokinetics from bone cement for application in pain management., Methods: In an in-vitro study, 100 mg of five drugs (aceclofenac, diclofenac, naproxen, paracetamol and methyl prednisolone) were incorporated into bone cement (Palacos). Cement cubes holding each drug were made and allowed to harden for 30 min. Each drug-containing cube was placed in a beaker with saline for 72 h. Fractions of 10 ml were collected at 0, 6, 24, 48 and 72 h and analysed using high-pressure liquid chromatography to measure the percentage release of the drug from bone cement., Results: Naproxen showed superior elution from bone cement, with 10.9% at 24 h and 9.08% at 72 h. Paracetamol showed 4.9% at 24 h and 3.78% at 72 h, aceclofenac 0.2% at 24 h and 0.4% at 72 h, diclofenac 3.03% at 24 h and 1.99% at 72 h, and methylprednisolone 0.26% at 24 h and 0.32% at 72 h., Conclusions: Polymethylmethacrylate bone cement can elute analgesics in vitro. Among the five drugs studied, naproxen had the best release kinematics from polymethylmethacrylate bone cement. Analgesic eluting bone cement is a novel approach for targeted postoperative pain management in TKA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) regulate inflammation, which is associated with their role in preventing neurodegenerative diseases in epidemiological studies. It has sparked interest in their unconventional application for reducing neuroinflammation, opening up new avenues in biomedical research. However, given the pharmacological drawbacks of NSAIDs, the development of formulations with naturally antioxidant/anti-inflammatory dietary fatty acids has been demonstrated to be advantageous for the clinical translation of anti-inflammatory-based therapies. It includes improved blood-brain barrier (BBB) permeability and reduced toxicity. It permits us to speculate about the value of linoleic acid (LA)-isomers in preventing and treating neuroinflammatory diseases compared to NSAIDs. Our research delved into the impact of various factors, such as administration route, dosage, timing of intervention, and BBB permeability, on the efficacy of NSAIDs and LA-isomers in preclinical and clinical settings. We conducted a systematic comparison between NSAIDs and LA-isomers regarding their therapeutic effectiveness, BBB compatibility, and side effects. Additionally, we explored their underlying mechanisms in addressing neuroinflammation. Through our analysis, we've identified challenges and drawn conclusions that could propel advancements in treating neurodegenerative diseases and inform the development of future alternative therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Phenylbutazone (PBZ) is a widely used nonsteroidal anti-inflammatory drug for horses. However, because of its gastrointestinal side effects, its administration requires careful attention in veterinary practice. Malondialdehyde (MDA) is a serum biomarker associated with increased damage to the equine gastrointestinal system. This study investigated the hematological effects and alterations in the gastrointestinal tract and assessed serum MDA concentrations following repeated oral PBZ administration at clinical doses. Fourteen horses were randomly divided into control and treatment groups. All horses in the treatment group were administered 4.4 milligrams per kilogram of body weight of PBZ syrup orally twice a day for 7 days, whereas the control group received syrup as a placebo. The development of gastrointestinal side effects was investigated using gastroscopy, abdominal ultrasound, and fecal pH; serum MDA concentrations were assessed using a commercially available enzyme-linked immunosorbent assay kit. Data were compared between PBZ-treated and control horses before and after the treatment period. The treatment group exhibited decreased albumin and total protein concentrations. Moreover, this group exhibited a higher thickness of the right dorsal colon wall (p = 0.03) and had higher scores for squamous gastric ulcers (p = 0.01). Fecal pH was lower in the treatment group than in the control group after PBZ administration (p < 0.01). Although MDA concentrations were higher in the treatment group after PBZ administration, they did not differ significantly from those of the control group. This study highlighted the changes in hematological and gastrointestinal lesions resulting from PBZ administration in horses at clinical doses, even without clinical signs. However, MDA may not be an optimal biomarker for the early detection of gastrointestinal damage due to PBZ treatment in horses., (© 2024. The Author(s).)

The present study tested the hypothesis that ingesting 800 mg Ibuprofen prior to self-paced cycling at a fixed rating of perceived exertion (RPE) improves performance by attenuating the release of Interleukin (IL)-6 and its signalling molecules, whilst simultaneously modulating cortical activity and cerebral oxygenation to the brain. Eight healthy, recreationally active males ingested 800 mg Ibuprofen or a placebo ~ 1 h prior to performing fixed RPE cycling for 60 min in 35 °C and 60% relative humidity at an intensity of hard to very hard (RPE = 16) with intermittent maximal (RPE = 20) sprints every 10 min. Power output (PO), core and mean skin temperatures (T c , T sk ), respectively, and heart rate (HR) were measured continuously. Electroencephalography (EEG) recordings at the frontal (Fz), motor (Cz) and Parietal (Pz) areas (90 s) were collected every 5 min. IL-6, soluble glycoprotein receptor (sgp130) and IL-6 receptor (R) were collected at pre-, 30 min and immediately post-exercise. Mean PO, HR, T c and T sk , and RPE were not different between trials (P ≥ 0.33). At end-exercise, the change in IL-6, sgp130 and sIL-6R was not different between trials (P ≥ 0.12). The increase in α and β activity did not differ in any cortices between trials (P ≥ 0.07); however, there was a significant reduction in α/β activity in the Ibuprofen compared to placebo trials at all sites (P ≤ 0.05). Ingesting a maximal, over-the-counter dose of Ibuprofen prior to exercise in the heat does not attenuate the release of IL-6, nor improve performance, but may influence cortical activity evidenced by a greater reduction in α/β activity., (© 2024. The Author(s).)

Background: Managing rheumatic disease activity using pregnancy-compatible medications is essential for reducing adverse maternal and fetal outcomes. We characterized medication use and discontinuation before, during, and after pregnancy, among female patients with rheumatic diseases attending a targeted pregnancy and rheumatic diseases clinic., Methods: We conducted a cross-sectional medical record review of female patients with rheumatic diseases at a Canadian clinic between January 2017 and July 2020. Patients were categorized by pregnancy stage at their latest clinic visit: (1) preconception; (2) pregnant; (3) postpartum. We assessed use of conventional, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), prednisone, and nonsteroidal anti-inflammatory drugs across 6 perinatal windows: 24 and 12 months preconception, each pregnancy trimester, and 3 months postpartum. We reported adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for medication discontinuation in the first trimester and subsequent disease flare., Results: Of 230 included patients, 85 (37.0%), 12 (5.2%), and 133 (57.8%) were preconception, pregnant, and postpartum, respectively. Approximately half experienced at least 1 disease flare during each pregnancy stage (56.4% preconception, 58.1% during pregnancy, and 53.7% postpartum). Most used at least 1 DMARD throughout the perinatal period (82.6% preconception, 55.6% during pregnancy, and 45.1% postpartum). Overall, 25.5% discontinued at least 1 DMARD in the first trimester. DMARD discontinuation was associated with disease flare during pregnancy (aOR, 1.49; 95% CI, 0.55-4.03; p = 0.87) and postpartum (aOR, 3.09; 95% CI, 0.83-11.47; p = 0.09)., Conclusions: Patients receiving care at a pregnancy and rheumatic disease clinic show perinatal medication use patterns consistent with recent recommendations and clinical guidelines., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pain control and patient satisfaction after total knee arthroplasty (TKA) have room for improvement. While studies have reported better analgesic outcomes with antidepressants like duloxetine in patients who do not have central sensitivity (CS), we undertook this trial to determine the short and midterm analgesic role of low-dose duloxetine in patients who do not have CS., Methods: This prospective, double-blinded, randomized, placebo-controlled trial was conducted in 106 patients undergoing single-setting, bilateral TKA under spinal anesthesia. There were 2 matched groups, with one given 20 mg of duloxetine and the other given a placebo (similar in appearance and weight) from preoperative day 2 to postoperative day 28. Follow-ups were scheduled at 48-hours, 1-week, 2-weeks, 4-weeks, and 3-months. Pain was measured using a visual analogue scale at rest and visual analogue scale at mobilization (mVAS). Secondary measures included additional non-steroidal anti-inflammatory drug consumption, patient satisfaction, and safety profile., Results: The visual analogue scale at rest in the duloxetine group was better in the first 48 hours (6.38 ± 1.32 versus 7.02 ± 0.99; P = .017), 1-week (4.76 ± 1.24 versus 5.89 ± 1.06; P < .001), and 2-weeks (3.34 ± 1.19 versus 4.26 ± 1.02; P < .001) follow-up. The mVAS remained significantly higher in the duloxetine group in the first 48 hours (7.23 ± 1.12 versus 8.21 ± 0.69; P < .001), 1-week (5.83 ± 1.11 versus 6.82 ± 0.92; P < .001), and 2 weeks (3.70 ± 0.89 versus 4.60 ± 1.03; P < .001) follow-up. Both outcomes became comparable from 4-week follow-up onward. Patient satisfaction (8.44 ± 1.68 versus 7.17 ± 1.04; P < .001) and additional non-steroidal anti-inflammatory drug consumption (2,770 ± 533.05 versus 3,566.04 ± 464.54; P < .001) were better in the duloxetine group, with a comparable safety profile., Conclusions: In patients who did not have CS, persistent pain after bilateral TKA can be managed safely and successfully by a daily dose of 20 mg Duloxetine, improving patient satisfaction and analgesic consumption in the acute postoperative phase., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: Postoperative sore throat (POST) and hoarseness are common complications of tracheal intubation. This study aims to evaluate the efficacy of flurbiprofen administered through the subglottic port of tracheal tubes to prevent POST after cardiac surgery., Design: Single-center, prospective, randomized, double-blind, placebo-controlled trial., Setting: Tertiary Care Referral University Hospital (Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome)., Patients: Included 71 patients undergoing for elective cardiac surgery. Inclusion criteria were (a) age between 50 and 75 years, (b) NYHA class I or II, (c) surgery for myocardial revascularization or valve repair or replacement under cardiopulmonary bypass., Intervention: Patients were double blind randomized to receive flurbiprofen or saline in the subglottic port of the endotracheal tube (groups F and P). The solution was injected ten minutes after tracheal tube placement, ten minutes after ICU admission and ten minutes before tracheal tube removal., Measurements: The primary outcome was to assess the effect of topical flurbiprofen administered through the subglottic port of the tracheal tube to prevent post-operative sore throat (POST). The secondary outcomes were the presence of hoarseness safety and patient's subjective satisfaction with their recovery. We did not report any exploratory outcomes., Main Results: We analyzed 68 patients, 34 patients in each group. In group F, two patients complained of POST and hoarseness (5.9%), while all controls did. The two groups significantly differed in the severity scores (VAS and TPS for sore throat and HOAR for hoarseness) at all time points. In group P, patients reported mild to moderate symptoms that significantly improved or disappeared 36 h after tracheal tube removal. According to the multivariable model, hoarseness affected women less than men, in the control group (p = 0.002). None of the patients in either group reported any adverse effects., Conclusions: Repeated administration of flurbiprofen through the subglottic port of tracheal tubes reduced the incidence of sore throat and hoarseness after cardiac surgery without evidence of complications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin for 2-4 weeks with colchicine for 3 months for the treatment of acute pericarditis. In patients with HFrEF and/or CAD, the adverse effect profile of NSAIDs pose concern. While previous studies evaluated colchicine as adjunctive therapy, colchicine monotherapy has never been assessed. This study aims to compare the efficacy of colchicine monotherapy to NSAID monotherapy or combination therapy for the prevention of recurrent pericarditis in patients with HFrEF and/or CAD. Methods: This was a single health-system, retrospective, observational cohort study. Patients were 18 years or older, had a diagnosis of acute pericarditis and HFrEF and/or CAD, and were discharged on colchicine and/or NSAID therapy. Patients were excluded if they had an episode of pericarditis within the previous 12 months. The primary outcome was the incidence of pericarditis recurrence or documentation of incessant symptoms within 12 months of the index hospitalization. Results: Of the 77 patients included, 43 (55.8%) were treated with colchicine monotherapy, 7 (9.1%) were treated with NSAID monotherapy, and 27 (35.1%) were treated with combination therapy. Pericarditis recurrence or documentation of incessant symptoms occurred in 16.3% of patients treated with colchicine monotherapy, 28.6% of those treated with NSAID monotherapy, and 18.5% of those treated with combination therapy ( P = .740). Conclusion: In this study, no difference in the primary outcome was observed between groups. However, a prospective, randomized trial is needed to further elucidate the efficacy of colchicine monotherapy for the treatment of acute pericarditis in patients with HFrEF and/or CAD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The oral formulation design for colon-specific drug delivery brings some therapeutic benefits in the ulcerative colitis treatment. We recently reported the specific delivery of hemoglobin nanoparticles-conjugating 5-aminosalicylic acid (5-ASA-HbNPs) to the inflamed site. In the current study, the therapeutic effect of the 5-ASA-HbNPs formulation was confirmed in vivo. This evaluation of 5-ASA-HbNPs not only shows longer colonic retention time due to adhesive properties, also provides full support for it as compared with free 5-ASA. It was considered as a suitable bio-adhesive nanoparticle with mucoadhesive property to pass through the mucus layer and accumulate into the mucosa. In UC model mice, a two-fold decrease in the disease activity indexes and colon weight/length ratios was significantly observed in the group treated with 5-ASA-HbNPs. This group received one percent of the standard dosage of 5-ASA (50 μg/kg), while, a similar result was observed for a significant amount of free 5-ASA (5 mg/kg). Furthermore, microscopic images of histological sections of the extracted colons demonstrated that the 5-ASA-HbNPs and 5-ASA groups displayed instances of inflammatory damage within the colon. However, in comparison to the colitis group, the extent of this damage was relatively moderate, suggesting 5-ASA-HbNPs improved therapeutic efficacy with the lower dosage form., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC); however, clinical and environmental risk factors for pouchitis remain poorly understood. We explored the relationship between specific clinical factors and the incidence of pouchitis., Methods: We established a population-based cohort of all adult persons in Denmark undergoing proctocolectomy with IPAA for UC from 1996-2020. We used Cox proportional hazard modeling to assess the impact of antibiotic, nonsteroidal anti-inflammatory drug (NSAID) exposure, and appendectomy on diagnosis of acute pouchitis in the first 2 years after IPAA surgery., Results: Among 1616 eligible patients, 46% developed pouchitis in the first 2 years after IPAA. Antibiotic exposure in the 12 months before IPAA was associated with an increased risk of pouchitis (adjusted hazard ratio [aHR], 1.41; 95% confidence interval [CI], 1.22-1.64) after adjusting for anti-tumor necrosis factor alpha use and sex. Compared with persons without any antibiotic prescriptions in the 12 months before IPAA, the risk of pouchitis was increased in those with 1 or 2 courses of antibiotics in that period (aHR, 1.30; 95% CI, 1.11-1.52) and 3 or more courses (aHR, 1.77; 95% CI, 1.41-2.21). NSAID exposure in the 12 months before IPAA and appendectomy were not associated with risk of acute pouchitis (P = .201 and P = .865, respectively)., Conclusions: In this population-based cohort study, we demonstrated that antibiotic exposure in the 12 months before IPAA is associated with an increased risk of acute pouchitis. Future prospective studies may isolate specific microbial changes in at-risk patients to drive earlier interventions., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The safety reports arising currently on nimesulide are divulging the jeopardy of skin and subcutaneous tissue disorders (SSTDs)., Research Design and Methods: The global individual case safety reports on nimesulide-induced SSTDs available at VigiBase® were analyzed up to 31 March 2023. Disproportionality analyses viz. Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Information Component (IC) were performed to identify the quantitative signals., Results: Out of 33,983,649 de-duplicated cases available in the VigiBase ® , 1,664,134 (4.9%) were in pediatrics below 12 years of age. Among these, cases attributed to nimesulide were 251, of which 126 (50.2%) were on SSTDs. Among all the SSTDs reported for nimesulide, the serious reactions like urticaria [PRR = 2.3; lower bound (LB) ROR = 1.7; IC 025  = 0.6], Stevens-Johnson syndrome (SJS) [PRR = 28.3; LB ROR = 18.2; IC 025  = 3.2], angioedema [PRR = 7.5; LB ROR = 4.5; IC 025  = 1.7], and toxic epidermal necrolysis (TEN) [PRR = 27.4; LB ROR = 11.5; IC 025  = 1.5] were identified as potential signals. In comparison with non-SSTDs, SSTDs reported for nimesulide were significantly higher among children (2-11 years, 90.5%), from India (38.9%), and by the physician (60.3%)., Conclusions: Identifying the giant quantitate association between nimesulide and serious & life-threatening reactions like SJS and TEN, precautionary measures need to be taken by the regulatory authorities to prevent nimesulide-induced SSTDs among the pediatric population.

The aim of this study was to assess the effect of ibuprofen sustained release (SR) oral premedication on the efficacy of buccal infiltration (BI) with intraoperative and postoperative pain after single-visit root canal treatment. Sixty patients diagnosed with symptomatic irreversible pulpitis and apical periodontitis in mandibular molar were divided into two groups. Group SR received ibuprofen SR 800 mg and group PL received placebo capsule 1 h before 3.6 mL articaine BI injection. Pain was recorded using a modified visual analogue scale and postoperatively at intervals 6, 24 and 48 h. Group SR showed a significantly higher anaesthetic success rate (73.3%) compared to group PL (46.7%) (p < 0.05). Intraoperative and postoperative pain was significantly higher in group PL compared to group SR (p < 0.05). Premedication of ibuprofen SR improved the efficacy of primary BI in mandibular molars with symptomatic irreversible pulpitis and decreased postoperative pain at 6 and 48 h., (© 2024 Australian Society of Endodontology Inc.)

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice., (© 2024 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Most methodologically rigorous, ED-based, comparative effectiveness analgesic studies completed in the last two decades failed to find a clinically important difference between the comparators. We believe that many of these comparative effectiveness studies were biased towards the null hypothesis because some ED patients with intense pain will respond to relatively mild interventions. We hypothesized that including a run-in period would alter the results of an acute pain RCT., Methods: We conducted a sequential, multiple-assignment, randomized study. Adults with acute moderate/severe musculoskeletal pain were randomized (3:1 ratio) to run-in period or no run-in. We administered 650 mg acetaminophen to run-in participants. Those run-in patients who reported insufficient relief one-hour later were randomized (1:1 ratio) to ibuprofen 800mg PO or ketorolac 20mg PO as were all participants randomized to no run-in. The primary outcome was achieving a clinically important improvement, defined as improvement ≥1.3 on a 0-10 scale. We built a logistic regression model including run-in/no run-in, ketorolac/ibuprofen, age and sex., Results: Of 307 participants who received acetaminophen, 100 (32.6%) reported inadequate relief and were randomized to an NSAID. Of the 100 patients randomized to no run-in, 84/100 (84%) achieved the primary outcome versus 246/287 (86%) run-in participants (95% CI for difference = 2%:-7,10%). Among run-in participants who received an NSAID, 82/99(83%) achieved the primary outcome versus 84/100(84%) no run-in participants (p = 0.82). Among all ibuprofen participants, 44/49(90%) randomized to run-in and 42/50(84%) randomized to no run-in achieved the primary outcome. Among all ketorolac participants, 38/50(76%) randomized to run-in and 42/50 (84%) randomized to no run-in achieved the primary outcome. We observed the following results in a multivariable analysis: OR for ketorolac versus ibuprofen:0.60 (95% CI: 0.28, 1.28); OR for run-in versus no run-in:0.91(95% CI: 0.43, 1.93)., Conclusions: Among patients with acute musculoskeletal pain, using an acetaminophen first strategy did not alter pain outcomes., Competing Interests: Declaration of competing interest None of the authors have any competing financial or intellectual interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug-loaded porous membranes have been deemed to be effective physicochemical barriers to separate postoperative adhesion-prone tissues in tendon healing. However, cell viability and subsequent tissue regeneration might be severely interfered with the unrestricted release and the locally excessive concentration of anti-inflammatory drugs. Herein, we report a double-layered membrane with sustained and uni-directional drug delivery features to prevent peritendinous adhesion without hampering the healing outcome. A vortex-assisted electrospinning system in combination with ibuprofen (IBU)-in-water emulsion was utilized to fabricate IBU-loaded poly-ʟ-lactic-acid (PLLA) fiber bundle membrane (PFB-IBU) as the anti-adhesion layer. The resultant highly porous structure, oleophilic and hydrophobic nature of PLLA fibers enabled in situ loading of IBU with a concentration gradient across the membrane thickness. Aligned collagen nanofibers were further deposited at the low IBU concentration side of the membrane for regulating cell growth and achieving uni-directional release of IBU. Drug release kinetics showed that the release amount of IBU from the high concentration side reached 79.32% at 14 d, while it was only 0.35% at the collagen side. Therefore, fibroblast proliferation at the high concentration side was successfully inhibited without affecting the oriented growth of tendon-derived stem cells at the other side. In vivo evaluation of the rat Achilles adhesion model confirmed the successful peritendinous anti-adhesion of our double-layered membrane, in that the macrophage recruitment, the inflammatory factor secretion and the deposition of pathological adhesion markers such as α-SMA and COL-III were all inhibited, which greatly improved the peritendinous fibrosis and restored the motor function of tendon., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The close relationship between inflammatory processes and epileptic seizures is already known, although the exact pathophysiological mechanism is unclear. In this study, the anticonvulsant capacity of piroxicam, an anti-inflammatory drug, was evaluated. A rat pentylenetetrazole kindling model was used. Methods: Male Wistar rats, 8-9 weeks old, received piroxicam (0.15 and 0.30 mg/kg), diazepam (2 mg/kg) or saline for 14 days, and PTZ, on alternate days. Intraperitoneal was chosen as the route of administration. The intensity of epileptic seizures was assessed using a modified Racine scale. The open field test and object recognition analysis were performed at the beginning of the study to ensure the safety of the drugs used. At the end of the protocol, the animals were euthanized to measure the levels of inflammatory (TNF-a and IL-6) and anti-inflammatory (IL-10) cytokines in the cortex, hippocampus, and serum. Results: There were no changes in the open field test and object recognition analysis. Piroxicam was found to decrease Racine scale scores at both concentrations. The reported values for IL-6 levels remained steady in all structures, whereas the TNF-alpha level in the cortex was higher in animals treated with piroxicam than in the saline and diazepam subjects. Finally, animals treated with the anti-inflammatory drug presented reduced IL-10 levels in the cortex and hippocampus. onclusions: Using inflammation as a guiding principle, the anticonvulsant effect of PIRO could be associated with the hippocampal circuits, since this structure showed no increase in inflammatory cytokines.

Objectives: To quantify prevalence, harms, and NHS costs in England of problematic oral non-steroidal anti-inflammatory drug (NSAID) prescribing in high risk groups., Design: Population based cohort and economic modelling study., Setting: Economic models estimating patient harm associated with NSAID specific hazardous prescribing events, and cost to the English NHS, over a 10 year period, were combined with trends of hazardous prescribing event to estimate national levels of patient harm and NHS costs., Participants: Eligible participants were prescribed oral NSAIDs and were in five high risk groups: older adults (≥65 years) with no gastroprotection; people who concurrently took oral anticoagulants; or those with heart failure, chronic kidney disease, or a history of peptic ulcer., Main Outcome Measures: Prevalence of hazardous prescribing events, by each event and overall, discounted quality adjusted life years (QALYs) lost, and cost to the NHS in England of managing harm., Results: QALY losses and cost increases were observed for each hazardous prescribing event ( v no hazardous prescribing event). Mean QALYs per person were between 0.01 (95% credibility interval (CI) 0.01 to 0.02) lower with history of peptic ulcer, to 0.11 (0.04 to 0.19) lower with chronic kidney disease. Mean cost increases ranged from a non-statistically significant £14 (€17; $18) (95% CI -£71 to £98) in heart failure, to a statistically significant £1097 (£236 to £2542) in people concurrently taking anticoagulants. Prevalence of hazardous prescribing events per 1000 patients ranged from 0.11 in people who have had a peptic ulcer to 1.70 in older adults. Nationally, the most common hazardous prescribing event (older adults with no gastroprotection) resulted in 1929 (1416 to 2452) QALYs lost, costing £2.46m (£0.65m to £4.68m). The greatest impact was in people concurrently taking oral anticoagulants: 2143 (894 to 4073) QALYs lost, costing £25.41m (£5.25m to £60.01m). Over 10 years, total QALYs lost were estimated to be 6335 (4471 to 8658) and an NHS cost for England of £31.43m (£9.28m to £67.11m)., Conclusions: NSAIDs continue to be a source of avoidable harm and healthcare cost in these five high risk populations, especially in inducing an acute event in people with chronic condition and people taking oral anticoagulants., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: Funding from the NIHR; DMA reports research grants from NIHR, AbbVie, Almirall, Celgene, Eli Lilly, Janssen, Novartis, UCB, and the Leo Foundation. AC, EC, BG, DM, LP, and GR report research grants from NIHR. AC reports research grants from NIHR, UKRI, and Industrial Challenge Fund. AJA reports research grants from NIHR and was National Clinical Director for NHS England at the time of the study. RAE reports research grants from NIHR and Abbott., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

The goal of the present study was to prepare meloxicam (MX) entrapped hybrid particles (HPs) to enhance intestinal permeation and anti-inflammatory activity. MX-HPs were prepared by nanoprecipitation method using lipid, chitosan, poloxamer, and TPGS. The formulations (MX-HPs1, MX-HPs2, MX-HPs3) were evaluated for particle size, entrapment efficiency, and drug release to select the optimized composition and further evaluated for permeation study, stability study, morphology, interaction study, and anti-inflammatory activity by carrageenan-induced rat paw edema test. The prepared MX-HPs showed nano sized particles (198.5 ± 3.7 to 223.8 ± 2.1 nm) and PDI (<0.3), zeta potential (16.5 ± 2.7 to 29.1 ± 3.6 mV), and high entrapment efficiency (75.1 ± 4.7 to 88.5 ± 3.9%). The surface morphology was assessed by transmission electron microscopy and showed non-aggregated particles. Infra-red (IR) spectroscopy of pure MX as well as formulation revealed no drug-polymer interaction and X-ray diffraction confirmed the conversion of crystalline MX into amorphous form. The release study data revealed prolonged MX release for 24 h. The selected optimized hybrid particles (MX-HPs2) revealed a 2.3-fold improved enhancement ratio than free MX. The storage stability and gastrointestinal stability data demonstrated a stable formulation in SIF as well as SGF. The anti-inflammatory activity showed better therapeutic action than pure MX dispersion. From the study, it can be concluded that the prepared MX-HPs may be a promising delivery system for MX in treating inflammatory disorders., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Introduction: Rheumatoid arthritis (RA) is a chronic, autoimmune and inflammatory disease that mostly impacts the joints. Chronotherapeutics refers to a treatment method in which in-vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. Flurbiprofen is a non-steroidal anti-inflammatory drug, indicated for the relief of inflammation., Objectives: The aim of the present study was to develop & optimize the microsponges based of Flurbiprofen tablet for Chronotherapeutics for enhanced therapeutic effect., Methods: Microsponges were developed by Quasi Emulsion solvent diffusion method. Prepared microsponges were optimized in order to analyze the effects of independent variables like concentration of PVA (X1), Volume of Dichloromethane (X2) & stirring speed (X3) on the Entrapment Efficiency (Y1), Mean particle size (Y2) and Drug release at 8 hr (Y3) using box Behnken design. The optimized formulation was subjected to in vitro study and Comparison with marketed formulation. With release kinetics study., Result: The optimized formulation Batch (F-18) Show particle size of 49.12µm, entrapment efficiency of 87.46%, and drug release at 8 h 70.49%, which is under the acceptance criteria, which is more effective compared with Marketed tablet., Conclusion: The results showed that, as stirring speed increases, the particle size decreases and entrapment efficiency increases. While volume of dichloromethane increases, particle size decreases. Morphology was found to be porous and spherical. Optimized batch of Flurbiprofen microsponge was further formulated in future for invivo study and clinical trials.

Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The β-cyclodextrin (β-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by β-CD, due to the low binding constant between PX and β-CD (∼100 M -1 ). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between β-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (C max ) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiangjun Zhang reports financial support was provided by Natural Science Foundation Project of Chongqing. Xiangjun Zhang reports financial support was provided by Chongqing Municipal Education Commission Foundation. Yan Wang, Chao Yu and Xiangjun Zhang has patent pending to National Intellectual Property Administration，PRC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital., Methods: The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985 , CYP2C9*3 rs1057910 , CYP2C8*3 rs11572080 , CYP2C8*3 rs10509681 , PTGS-1 rs10306135 , PTGS-1 rs12353214 , and PTGS-2 rs20417 using real-time PCR., Results: In NSAIDs + patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30-22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15-8.46), and alcohol intake (OR=4.09, 95 % CI=1.05-15.87) increased odds of gastrointestinal damage. In NSAIDs + patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04-0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02-0.75) reduced the chance of upper gastrointestinal lesions., Conclusions: Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Mares enrolled in assisted reproductive technologies (ARTs) programs are often treated with non-steroidal anti-inflammatory drugs (NSAIDs), particularly phenylbutazone (Bute), due to chronic lameness. The current study was performed to determine the effect of Bute administration on the developmental competence of in vitro-matured equine oocytes subjected to Intracytoplasmic Sperm Injection (ICSI). In a Preliminary Study, immature cumulus-oocyte complexes (COCs) recovered by post-mortem ovary harvested from two healthy mares (n = 2) treated for 10 days with Bute (4.4 mg/kg, PO, BID), and four non-treated healthy mares (n = 4), were matured in vitro and subjected to Piezo-driven ICSI. Lower oocyte in vitro maturation [Bute: 25% (3/12) vs. Control: 61% (28/46)] and blastocyst rates [Bute: 0% (0/12) vs. Control: 18% (5/28)] were observed in the Bute-treated when compared to the Control mares (P < 0.05). In the Main Experiment, a group of healthy mares (n = 9) received a daily dose of Bute (4.4 mg/kg, orally, SID) for 10 days. A control group of mares (n = 10) was treated with an equal volume of placebo. Mares in both groups were subjected to ultrasound-guided transvaginal oocyte aspiration (TVA) on days 3, 33, and 77 following the last dose of Bute (PT). Recovered COCs from both mare groups were matured in vitro and subjected to Piezo-driven ICSI. By day-3 PT, oocyte in vitro maturation rate was similar between mare groups [Bute: 65% (36/55) vs. Control: 67% (78/116); P > 0.05], while oocyte recovery [Bute: 53% (55/103) vs. Control: 70% (116/166)], cleavage [Bute: 31% (11/36) vs. Control: 62% (48/78)] and blastocyst rates [Bute: [0%] (0/36) vs. Control: 28% (22/78)] were significantly different (P < 0.05). By day 33 PT and 77 PT, differences on oocyte recovery, in vitro maturation, cleavage, and blastocyst rates were not observed between mare groups. In summary, the administration of Bute for 10 consecutive days (4.4 mg/kg, PO, SID, or BID) is associated with a decrease in the ability of immature equine oocytes to undergo in vitro-maturation (Preliminary Study) and develop to the blastocyst stage following ICSI (Preliminary Study and Main Experiment). This negative effect appeared to be transient, as 30- and 77-days post-treatment, no differences on in vitro maturation, cleavage or blastocyst rates were observed., (Published by Elsevier Inc.)

Objective: To investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS)., Methods: Using the Korean National Health Insurance database, patients newly diagnosed with AS without prior CVD between 2010 and 2018 were included in this nationwide cohort study. The primary outcome was CVD, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Exposure to NSAIDs was evaluated using a time-varying approach. The dose of NSAIDs was considered in each exposure period. Cox proportional hazard regression was used to investigate the risk of CVD associated with NSAID use., Results: Of the 19 775 patients (mean age, 36 years; 75% were male), 19 706 received NSAID treatment. During follow-up period of 98 290 person-years, 1663 cases of CVD occurred including 1157 cases of ischaemic heart disease, 301 cases of stroke and 613 cases of congestive heart failure. Increasing dose of NSAIDs was associated with incident CVD after adjusting for confounders (adjusted HR (aHR) 1.10; 95% CI 1.08 to 1.13). Specifically, increasing dose of NSAIDs was associated with incident ischaemic heart disease (aHR 1.08; 95% CI 1.05 to 1.11), stroke (aHR 1.09; 95% CI 1.04 to 1.15) and congestive heart failure (aHR 1.12; 95% CI 1.08 to 1.16). The association between NSAID dose and higher CVD risk was consistent in different subgroups., Conclusion: In a real-world AS cohort, higher dose of NSAID treatment was associated with a higher risk of CVD, including ischaemic heart disease, stroke and congestive heart failure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Purpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin., Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro., Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (-30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 μM., Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Thiruchenthooran et al.)

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream-gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream-gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream-gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream-gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

Objective: This study was conducted to investigate the mechanisms of anaphylaxis in patients with osteoarthritis of the knee and hip after diclofenac etalhyaluronate [product name: JOYCLU® (JCL)] intra-articular injection and to determine the utility of tests to investigate the mechanism involved., Methods: In this observational study in Japan, patients aged ≥20 years with knee or hip osteoarthritis who received JCL intra-articular injection experienced anaphylactic symptoms considered related to JCL ('experienced patients') or did not experience allergic symptoms considered related to JCL ('non-experienced patients'). Basophil activation tests (BATs), specific immunoglobulin E (IgE) antibody testing by enzyme-linked immunosorbent assays (ELISAs) or immunochromatographic kit, and genome-wide association studies (GWASs) were conducted using patient blood and saliva., Results: Thirteen experienced patients and 14 non-experienced patients were tested. Seven experienced patients tested positive by BAT using diclofenac etalhyaluronate-containing test substances. Diclofenac-specific IgE antibodies were detected in four of seven BAT-positive patients but not in the non-experienced patients. Specific IgE antibody testing by immunochromatographic kit and genome-wide association study showed no clear results., Conclusions: These findings suggest that anaphylaxis occurs after JCL administration via an IgE-mediated mechanism and that diclofenac etalhyaluronate may be involved in this mechanism. BAT and diclofenac -specific IgE enzyme-linked immunosorbent assay may be useful tests for investigating the mechanisms of anaphylactic reactions after JCL administration., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)