Chondrotoxicity of Intra-Articular Injection Treatment: A Scoping Review.

The purpose of this scoping review was to identify possible chondrotoxic effects caused by drugs usually used for intra-articular injections. PubMed, Scopus, Web of Science and Cochrane were searched. Inclusion criteria required randomized controlled trials written in English that evaluate the toxic effect that damages the cartilage. The literature search resulted in 185 unique articles. 133 full-text articles were screened for inclusion, of which 65 were included. Corticosteroids, with the exception of triamcinolone, along with local anaesthetics, potentially excluding ropivacaine and liposomal bupivacaine, and nonsteroidal anti-inflammatory drugs, exhibited insufficient safety profiles to warrant casual use in clinical settings. Hyaluronic acid, on the other hand, appears to demonstrate safety while also mitigating risks associated with concurrent compounds, thereby facilitating therapeutic combinations. Additionally, there remains a paucity of data regarding platelet-rich plasma, necessitating further evaluation of its potential efficacy and safety. Overall, it seems that results are significantly influenced by the dosage and frequency of injections administered, observed in both human and animal studies.

Clinical efficacy of Osteoking in knee osteoarthritis therapy: a prospective, multicenter, non-randomized controlled study in China.

Background: Osteoking has been extensively used for the treatment of knee osteoarthritis (KOA). However, it is lack of high-quality evidence on the clinical efficacy of Osteoking against KOA and the comparison with that of nonsteroidal anti-inflammatory drugs (NSAIDs). Aims: To evaluate the efficacy and safety of Osteoking in treating KOA. Methods: In the current study, a total of 501 subjects were recruited from 20 medical centers, and were divided into the Osteoking treatment group (n = 428) and the NSAIDs treatment group (n = 73). The Propensity Score Matching method was used to balance baseline data of different groups. Then, the therapeutic effects of Osteoking and NSAIDs against KOA were evaluated using VAS score, WOMAC score, EQ-5D-3L and EQ-VAS, while the safety of the two treatment were both assessed based on dry mouth, dizziness, diarrhea, etc. Results: After 8 weeks of treatment, the Osteoking group was compared with the NSAIDs group, the VAS score [2.00 (1.00, 3.00) vs. 3.00 (2.00, 4.00)], WOMAC pain score [10.00 (8.00, 13.00) vs. 11.00 (8.00, 16.00) ], WOMAC physical function score [32.00 (23.00, 39.00) vs. 39.07 ± 16.45], WOMAC total score [44.00 (31.00, 55.00) vs. 53.31 ± 22.47) ], EQ-5D-3L score [0.91 (0.73, 0.91) vs. 0.73 (0.63, 0.83) ] and EQ-VAS score [80.00 (79.00, 90.00) vs. 80.00 (70.00, 84.00) ] were improved by the treatment of Osteoking for 8 weeks more effectively than that by the treatment of NSAIDs. After 8 weeks of treatment with Osteoking, the VAS scores of KOA patients with the treatment of Osteoking for 8 weeks were reduced from 6.00 (5.00, 7.00) to 2.00 (1.00, 3.00) (p < 0.05), which was better than those with the treatment of NSAIDs starting from 2 weeks during this clinical observation. Importantly, further subgroup analysis revealed that the treatment of Osteoking was more suitable for alleviating various clinical symptoms of KOA patients over 65 years old, with female, KL II-III grade and VAS 4-7 scores, while the clinical efficacy of NSAIDs was better in KOA patients under 65 years old and with VAS 8-10 scores. Of note, there were no differences in adverse events and adverse reactions between the treatment groups of the two drugs. Conclusion: Osteoking may exert a satisfying efficacy in relieving joint pain and improving life quality of KOA patients without any adverse reactions, especially for patients with KL II-III grades and VAS 4-7 scores. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=55387, Identifier ChiCTR2000034475.

Fabrication of sea urchin shaped polyaniline-modified magnetic microporous organic network for efficient extraction of non-steroidal anti-inflammatory drugs from animal-derived food samples.

In this work, a novel polyaniline-modified magnetic microporous organic network (MMON-PANI) composite was fabricated for effective magnetic solid phase extraction (MSPE) of five typical nonsteroidal anti-inflammatory drugs (NSAIDs) from animal-derived food samples before high performance liquid chromatography (HPLC) detection. The core-shell sea urchin shaped MMON-PANI integrates the merits of Fe3O4, MON, and PANI, exhibiting large specific surface area, rapid magnetic responsiveness, good stability, and multiple binding sites to NSAIDs. Convenient and effective extraction of trace NSAIDs from chicken, beef and pork samples is realized on MMON-PANI via the synergetic π-π, hydrogen bonding, hydrophobic, and electrostatic interactions. Under optimal conditions, the MMON-PANI-MSPE-HPLC-UV method exhibits wide linear ranges (0.2-1000 µg L-1), low limits of detection (0.07-1.7 µg L-1), good precisions (intraday and inter-day RSDs < 5.4 %, n = 3), large enrichment factors (98.6-99.9), and less adsorbent consumption (3 mg). The extraction mechanism and selectivity of MMON-PANI are also evaluated in detail. This work proves the incorporation of PANI onto MMON is an efficient way to promote NSAIDs enrichment and provides a new strategy to synthesize multifunctional MON-based composites in sample pretreatment.

Preparation of cationic microporous organic network for efficient solid-phase extraction of nonsteroidal anti-inflammatory drugs from environmental water and milk samples.

The overuse of nonsteroidal anti-inflammatory drugs (NSAIDs) poses many serious environmental and food safety concerns. Development of effective and sensitive sample pretreatment method for monitoring trace NSAIDs from complex samples is of great significance. Depending on the ionic and aromatic structures of NSAIDs, a cationic microporous organic network (MON) named TEPM-BBDC with large specific surface area, good solvent and thermal stabilities, and numerous interaction sites was designed and prepared for efficient solid-phase extraction (SPE) of four typical NSAIDs (flurbiprofen, ketoprofen, naproxen, and diclofenac sodium) from environmental water and milk samples. By anchoring the ionic groups in the conjugated MON frameworks, the prepared TEPM-BBDC offered good extraction for NSAIDs based on the π-π, hydrophobic, ion exchange, and electrostatic interactions. Under the optimal extraction conditions (initial concentration of each NSAID: 200 g L-1; sample volume: 50 mL; desorption solvent: 1.5 mL of MeOH + 1 % NH3·H2O; sample loading rate: 5 mL min-1; NaCl concentration: 0 mmol L-1; pH = 5), the proposed TEPM-BBDC-SPE-HPLC-UV method owned wide linear range (0.50-1000 g L-1), low limits of detection (0.10-0.40 g L-1), large enrichment factors (92.2-99.2), good precisions (intra-day and inter-day, RSD% = 1.3-7.8 %, n = 6) and reproducibility (column-to-column, RSD% = 8.0 %, n = 3). The developed method also exhibited good recoveries (83.6-113.4 %) for the determination of NSAIDs in river water, lake water and milk samples. This work not only revealed the potential of TEPM-BBDC for SPE of ionic NSAIDs in complex samples, but also highlighted the prospect of ionic MONs in sample pretreatment.

Nonsteroidal anti-inflammatory drug-induced small bowel strictures (diaphragm disease) - an under-recognized cause of small bowel obstruction.

BACKGROUND: Small bowel obstruction is a major source of morbidity and mortality that carries a significant economic burden. Recurrent small bowel obstruction may be secondary to circumferential strictures (small bowel diaphragm disease), an under-recognized entity secondary to long-term nonsteroidal anti-inflammatory drug (NSAID) use. We aimed to describe the sensitivity of preoperative computed tomography (CT) enterography in patients with surgically treated small bowel diaphragm disease. METHODS: We retrospectively reviewed adult patients who underwent elective small bowel resection for small bowel obstruction performed by a single minimally invasive surgeon between 2010 and 2023. Patient history, radiographic, endoscopic, operative, and pathology reports were reviewed for reference to NSAID use, small bowel strictures, diaphragms, and enteropathy. Exclusion criteria were prior radiation, inflammatory bowel disease, malignancy, adhesive disease, and anastomotic strictures. RESULTS: A total of 225 patients were identified, 22 (10%) of whom met the inclusion criteria. The mean age was 60.7 years (range 29-78), with 15 women (68%). All patients underwent minimally invasive small bowel resection for obstruction with histopathologic evidence of stricture without evidence of transmural inflammation, granuloma, or dysplasia and confirmed NSAID use (n = 22, 100%). Anemia was present in 36% (n = 8). Preoperative CT or magnetic resonance (MR) enterography was performed in 18 patients (82%), of which stricturing was reported in 13 (72%). Intraoperatively, palpation identified strictures in all patients. CONCLUSION: NSAID-induced small bowel injury is an under-recognized condition that, in severe cases, can present as small bowel obstruction. Surgeons should consider diaphragm disease in patients with obstruction and NSAID use, in which preoperative CT or MR enterography may be useful but cannot rule out disease.

[Current challenges for therapy of comorbid patients: a new look at celecoxib. A review].

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for a wide range of diseases is increasing, in part due to an increasing elderly population. Elderly patients are more vulnerable to adverse drug reactions, including side effects and adverse effects of drug-drug interactions, often occurring in this category of patients due to multimorbidity and polypharmacy. One of the most popular NSAIDs in the world is celecoxib. It is a selective cyclooxygenase (COX)-2 inhibitor with 375 times more COX-2 inhibitory activity than COX-1. As a result, celecoxib has a better gastrointestinal tract safety profile than non-selective NSAIDs. Gastrointestinal tolerance is an essential factor that physicians should consider when selecting NSAIDs for elderly patients. Celecoxib can be used in a wide range of diseases of the musculoskeletal system and rheumatological diseases, for the treatment of acute pain in women with primary dysmenorrhea, etc. It is also increasingly used as part of a multimodal perioperative analgesia regimen. There is strong evidence that COX-2 is actively involved in the pathogenesis of ischemic brain damage, as well as in the development and progression of neurodegenerative diseases, such as Alzheimer's disease. NSAIDs are first-line therapy in the treatment of acute migraine attacks. Celecoxib is well tolerated in patients with risk factors for NSAID-associated nephropathy. It does not decrease the glomerular filtration rate in elderly patients and patients with chronic renal failure. Many meta-analyses and epidemiological studies have not confirmed the increased risk of cardiovascular events reported in previous clinical studies and have not shown an increased risk of cardiovascular events with celecoxib, irrespective of dose. COX-2 activation is one of the key factors contributing to obesity-related inflammation. Specific inhibition of COX-2 by celecoxib increases insulin sensitivity in overweight or obese patients. Combination therapies may be a promising new area of treatment for obesity and diabetes.

NSAID medication mediates the causal effect of genetically predicted major depressive disorder on falls: Evidence from a Mendelian randomization study.

BACKGROUND: Increasing evidence supports that depression including major depressive disorder (MDD) is associated with an increased risk of falls. However, some studies suggest no association between MDD and falls. Therefore, the specific causal relationship whereby MDD affects the risk of falls remains elusive, and the potential mediators are unclear. METHODS: Summary-level data for MDD and falls were collected from the Genome-wide association studies (GWAS) in this study. Mendelian randomization (MR) and multivariable MR (MVMR) analyses were performed to evaluate the causal associations between MDD and falls. A Two-step MR analysis was employed to analyze the mediating effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the causal association between MDD and the risk of falls. RESULTS: Using the inverse-variance weighted (IVW) method, genetically predicted MDD was associated with an increased risk of falls (ß = 0.15, SE = 0.034; P = 1.61E-5). MVMR and two-step MR analyses demonstrated that MDD was a causal determinant of increased falls independent of body mass index (BMI), smoking initiation, and alcohol consumption and that this causal relationship was mediated by NSAID medication. LIMITATIONS: Extracted GWAS summary statistics are from European ancestry. Stratified analyses by sex and age were not included in our study. Therefore, it is unclear whether the results are the same for other ethnic groups, genders, and ages. CONCLUSIONS: Our results demonstrate that MDD is independently associated with an increased risk of falls, in which NSAIDs mediate the association. This study suggests that avoiding the use of NSAIDs may reduce the risk of falls in patients diagnosed with MDD.

Prolonged administration of oral phenylbutazone and firocoxib in horses has no impact on selected cytokine and growth factor concentrations in platelet-rich plasma and autologous protein solution.

OBJECTIVE: To determine the effects of prolonged administration of the oral NSAIDs phenylbutazone and firocoxib on concentrations of cytokines and growth factors in platelet-rich plasma (PRP) and autologous protein solution (APS). ANIMALS: 6 adult University owned horses. METHODS: Horses were randomized to receive phenylbutazone (1 g, orally, q 12 h) or firocoxib (57 mg, orally, q 24 h) for 6 days. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before the administration of NSAIDs and at 7 days (1 day following cessation of NSAIDs). Horses underwent a two-week washout period, during which blood was obtained at 14 days and 21 days. The protocol was repeated with a crossover design. PRP and APS were analyzed for concentrations of platelets, leukocytes, and several cytokines (IL-1ß, IL-10, IL-6, IL-8, and tumor necrosis factor-α) and growth factors (PDGF, FGF-2, and TGF-ß1) using immunoassays. Plasma was evaluated for drug concentrations. RESULTS: No significant differences existed in concentrations of growth factors and cytokines before or after prolonged administration of NSAIDs. There were significant differences in concentrations of leukocytes and platelets in PRP compared to APS, with higher concentrations of leukocytes at the day 7 time point (T) in APS (phenylbutazone) and in concentrations of platelets in APS at T0 (firocoxib) and in APS at T7 (phenylbutazone). CLINICAL RELEVANCE: Veterinarians can recommend the administration of these oral NSAIDs prior to obtaining blood for PRP and APS provided a single-day washout period is instituted.

Aspirin as a chemopreventive agent for cutaneous melanoma: a literature review.

Rising melanoma rates have spurred interest in preventive strategies. Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, show potential in reducing cancer risks. NSAIDs act on cyclooxygenase (COX) enzymes, impacting COX-2 associated with inflammation and cancer progression. This paper explores aspirin's role in cutaneous melanoma prevention, elucidating its mechanisms and acknowledging varying literature outcomes. Rather than providing conclusive recommendations, the review emphasizes the influence of individual factors, contributing to the ongoing dialogue on aspirin's complexities in melanoma prevention. A PubMed search using "Aspirin" AND "Cutaneous melanoma" yielded relevant English-language, peer-reviewed studies. Selection criteria focused exclusively on skin cancers, specifically cutaneous melanoma. Exclusions included studies covering various cancers, some non-dermatologic, and those not evaluating aspirin use independently but in conjunction with NSAIDs. The potential chemopreventive effects of aspirin and NSAIDs against melanoma have gained attention due to their association with a reduced risk of various cancers including gastric, colorectal, and breast. By inhibiting COX enzymes and the NF-κB pathway, these agents theoretically slow malignant cell activities, presenting a prospect for cancer prevention. Aspirin exhibits noteworthy effects, depleting growth-stimulating hormones, generating reactive oxygen species harmful to cancerous cells, and inhibiting COX-2 linked to cancer progression. Limited literature suggests survival benefits with aspirin use in stage II and III melanoma, possibly due to slowing disease progression, evident in smaller Breslow depths. Gender-specific responses to aspirin are notable, with some studies reporting a stronger chemopreventive correlation in females. It's crucial to note that geographic disparities, demographic cohorts, and individual-specific factors are confounding variables that may contribute to conflicting findings regarding aspirin's impact on melanoma. The association between aspirin use and melanoma risk is complex, with conflicting findings across diverse populations. Although it appears that more studies suggest a protective role for aspirin rather than not, evidence lacks consistency. Factors such as gender, geography, race, sun exposure, and health conditions play a role in shaping these varied outcomes, necessitating large-scale, prospective studies research and standardized parameters for more conclusive insights that may help guide tailored clinical strategies for melanoma prevention.

How to Define and Manage Low-Risk Drug Allergy Labels.

Risk stratification in drug allergy implies that specific risk categories (eg, low, moderate, and high) classify historical drug hypersensitivity reactions. These risk categories can be based on reaction phenotypic characteristics, the timing of the reaction and evaluation, the required reaction management, and individual characteristics. Although a multitude of frameworks have been described in the literature, particularly for penicillin allergy labels, there has yet to be a global consensus, and approaches continue to vary between allergy centers. Immune-mediated drug allergies can sometimes be confirmed using skin testing, but a negative drug challenge is required to demonstrate tolerance and remove the allergy from the electronic health record ("delabel" the allergy). Even for quintessential IgE-mediated drug allergy, penicillin allergy, recent data reveal that a direct oral challenge, without prior skin testing, is an appropriate diagnostic strategy in those who are considered low-risk. Drug allergy pathogenesis and clinical manifestations may vary depending on the culprit drug, and as such, the optimal approach should be based on risk stratification that considers individual patient and reaction characteristics, the likely hypersensitivity reaction phenotype, the drug class, and the patient's clinical needs. This article will describe low-risk drug allergy labels, focusing on ß-lactam and sulfonamide antibiotics, nonsteroidal anti-inflammatory drugs, iodinated contrast media, and common chemotherapeutics. This review will also address practical management approaches using currently available risk stratification and clinical decision tools.

Effects of Ibuprofen and Diclofenac Pre-Treatment on Viability and Apoptosis Processes in Human Dental Pulp Stem Cells.

Background and Objectives: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. Materials and Methods: We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro, as well as their effects on the expression of angiogenic growth factors (VEGFA and HGF) and selected genes in apoptosis signalling pathways (BAX, BAK, CASP3, CASP9, and BCL2). Results: Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Conclusions: Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.

A Case of Ketorolac-Induced Aseptic Meningitis.

Drug-induced aseptic meningitis is a rare condition that occurs because of an adverse reaction to medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Unlike bacterial or viral meningitis, aseptic meningitis is not caused by an infection, but rather by an inflammatory response. This condition creates a challenge since patients with aseptic meningitis often present with classic clinical meningeal symptoms, including fever, headache, and neck stiffness. We present a case of a patient with NSAID-induced aseptic meningitis and highlight the importance for healthcare providers to have a high index of suspicion for drug-induced aseptic meningitis in patients presenting with symptoms of meningitis with negative cerebrospinal fluid analysis and culture.

Effect of pulsed radiofrequency to the suprascapular nerve (SSN) in treating frozen shoulder pain: A randomised controlled trial.

BACKGROUND: Treatment for frozen shoulder (FS) focuses on pain control and restoring movement and strength through physical therapy. We aimed to evaluate the efficacy of pulsed radiofrequency (PRF) lesioning of the suprascapular nerve for the treatment of FS pain. METHODS: Forty patients with FS were enrolled and randomly assigned into the intervention group (n = 20) that received PRF and a control group (n = 20) which received medical treatment (NSAIDs). Patients were followed-up for a total of three months. The primary outcome was the pain intensity, measured by the Numeric Pain Rating Scale (NRS). The secondary outcomes included shoulder range of motion (ROM) evaluation measured by simple shoulder test (SST); Likert-type-based patient satisfaction scale; and any adverse events (AEs) throughout the treatment period. All results were measured at baseline, at the end of one week, four weeks and 12 weeks after treatment. RESULTS: At 12 weeks post-procedure, the intervention group significantly improved their pain (NRS dropped to 2.80 ± 0.5) and there was significant improvement in range of motion (SST from 6.55% ± 2.0% to 76.50% ± 6.5) compared to control group. CONCLUSIONS: PRF lesioning of the SSN is a fast and effective modality in treating frozen shoulder pain and improving ROM for three months.

Update in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Of all the possible complications associated with endoscopic retrograde cholangiopancreatography (ERCP), acute pancreatitis undoubtedly represents the heaviest burden for patients and healthcare professionals. The overall incidence, ranging from 3.5% to around 10%, and annual estimated costs exceeding $150 million in the USA should signal caution for everyone carrying out ERCP. In-depth knowledge of the risk factors and the pharmacological and endoscopic treatment options is required to avoid this adverse event. In this review, we evaluate the relevant data published in the literature since the appearance of the latest recommendations of the leading gastroenterological societies. Thus, we intend to provide a comprehensive and up-to-date overview of the factors to consider and possible interventions applicable before and after the intervention to prevent the development of post-ERCP pancreatitis.

Pompon mum-like ionic covalent organic framework nanocomposites for efficient solid-phase extraction of nonsteroidal anti-inflammatory drugs.

Molecularly imprinted ionic covalent organic framework nanocomposites (MI-IC-COF@SnO2) were prepared as potential adsorbents for the enhanced adsorption of nonsteroidal anti-inflammatory drugs (NSAIDs) from aqueous solution. The resulting material exhibited a pompon mum-like structure, featuring a large surface area, and well-defined mesopores. The presence of uniform positive ions within the three-dimensional skeleton of MI-IC-COF@SnO2 facilitated a rapid adsorption rate and high adsorption capacity for target analytes. Thermodynamic fitting revealed the adsorption process of NSAIDs to be feasible, endothermic, and spontaneous. Additionally, the adsorbent material exhibited respectable selectivity, as evidenced by imprinting factor values ranging from 2.8 to 6.7. Utilizing MI-IC-COF@SnO2 as the sorbent, a solid-phase extraction method coupled with high-performance liquid chromatography-ultraviolet detection (SPE-HPLC-UV) was developed and optimized. The proposed method demonstrated good linear range with determination coefficients of 0.998-0.999, and low limit of detection (0.18-1.35 µg L-1). Recoveries of NSAIDs in urine and river water samples were 78.1 %-106.1 %, with relative standard deviations lower than 12.5 %. This rapid and sensitive method enables the determination of NSAIDs at trace levels in complex matrices, providing reliable and reproducible results.

Available Therapeutic Options for Corneal Neovascularization: A Review.

Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-ß) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-ß-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.

Neutrophil extracellular trap formation and its implications in nonsteroidal anti-inflammatory drug-induced small intestinal injury.

BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. METHODS: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. RESULTS: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1ß and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. CONCLUSION: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.

The impact of perioperative nonsteroidal anti-inflammatory drugs on the postoperative outcomes of spinal surgery: a meta-analysis of 23 randomized controlled trials.

In recent years, nonsteroidal anti-inflammatory drug (NSAIDs), which are considered to affect the prognosis of spinal surgery, have been widely used in perioperative analgesia in spinal surgery, but the relationship between these two factors remains unclear. The purpose of this study was to explore the effect of perioperative use of NSAIDs on the prognosis of patients treated with spinal surgery. We systematically searched PubMed, Embase, and Cochrane Library for relevant articles published on or before July 14, 2023. We used a random-effect model for the meta-analysis to calculate the standardized mean difference (SMD) with a 95% confidence interval (CI). Sensitivity analyses were conducted to analyze stability. A total of 23 randomized clinical trials including 1457 participants met the inclusion criteria. Meta-analysis showed that NSAIDs were significantly associated with postoperative morphine use (mg) (SMD = -0.90, 95% CI -1.12 to -0.68) and postoperative pain (SMD = -0.71, 95% CI -0.85 to -0.58). These results were further confirmed by the trim-and-fill procedure and leave-one-out sensitivity analyses. The current study shows that perioperative use of NSAIDs appears to be an important factor in reducing postoperative pain and morphine use in patients undergoing spinal surgery. However, well-designed, high-quality randomized controlled trials (RCTs) are still required.

Novel drug-drug salt crystals of metformin with ibuprofen or naproxen: Improved solubility, dissolution rate, and synergistic antinociceptive effects.

As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals.