Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.

Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Abnormal causal connectivity of anterior cingulate cortex-visual cortex circuit related to nonsteroidal anti-inflammatory drug efficacy in migraine.

The anterior cingulate cortex (ACC) and visual cortex are integral components of the neurophysiological mechanisms underlying migraine, yet the impact of altered connectivity patterns between these regions on migraine treatment remains unknown. To elucidate this issue, we investigated the abnormal causal connectivity between the ACC and visual cortex in patients with migraine without aura (MwoA), based on the resting-state functional magnetic resonance imaging data, and its predictive ability for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). The results revealed increased causal connectivity from the bilateral ACC to the lingual gyrus (LG) and decreased connectivity in the opposite direction in nonresponders compared with the responders. Moreover, compared with the healthy controls, nonresponders exhibited heightened causal connectivity from the ACC to the LG, right inferior occipital gyrus (IOG) and left superior occipital gyrus, while connectivity patterns from the LG and right IOG to the ACC were diminished. Based on the observed abnormal connectivity patterns, the support vector machine (SVM) models showed that the area under the receiver operator characteristic curves for the ACC to LG, LG to ACC and bidirectional models were 0.857, 0.898, and 0.939, respectively. These findings indicate that neuroimaging markers of abnormal causal connectivity in the ACC-visual cortex circuit may facilitate clinical decision-making regarding NSAIDs administration for migraine management.

Buprenorphine Versus Diclofenac for Pain Relief in Acute Pancreatitis: A Double-Blinded Randomized Controlled Trial.

BACKGROUND: Although both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are used for analgesia in acute pancreatitis (AP), the analgesic of choice is not known. We compared buprenorphine, an opioid, and diclofenac, an NSAID, for analgesia in AP. METHODS: In a double-blind randomized controlled trial, AP patients were randomized to receive intravenous diclofenac or intravenous buprenorphine. Fentanyl was used as rescue analgesia, delivered through a patient-controlled analgesia pump. Primary outcome was the difference in the dose of rescue fentanyl required. Secondary outcomes were the number of effective and ineffective demands of rescue fentanyl, pain-free interval, reduction in visual analogue scale (VAS) score, adverse events, and organ failure development. RESULTS: Twenty-four patients were randomized to diclofenac and 24 to buprenorphine. The 2 groups were matched at baseline. The total amount of rescue fentanyl required was significantly lower in the buprenorphine group:130 µg, interquartile range (IQR), 80-255 vs 520 µg, IQR, 380-1065 (P < .001). The number of total demands was 32 (IQR, 21-69) in the diclofenac arm vs 8 (IQR, 4-15) in the buprenorphine arm (P < .001). The buprenorphine group had more prolonged pain-free interval (20 vs 4 hours; P < .001), with greater reduction in the VAS score at 24, 48, and 72 hours compared with the diclofenac group. These findings were confirmed in the subgroup of moderately severe/severe pancreatitis. Adverse events profile was similar in the 2 groups. CONCLUSIONS: Compared with diclofenac, buprenorphine appears to be more effective and equally safe for pain management in AP patients, even in the subcohort of moderately severe or severe pancreatitis (Trial Registration number: CTRI/2020/07/026914).

Simultaneous determination of plasma protein binding of five C-glycosylflavones from TFDS by rapid equilibrium dialysis.

The total flavonoids of Desmodium styracifolium (TFDS) are flavonoid-rich extracts obtained from Desmodii Styracifolii Herba, which is approved for the treatment of urolithiasis in China. C-glycosylflavones including schaftoside, vicenin-1, vicenin-2, vicenin-3, and isovitexin are the main active constituents. In this study, the plasma protein binding of these compounds was determined for the first time in rat and human plasma by rapid equilibrium dialysis combined with HPLC-MS/MS method. The developed method was validated in terms of specificity, linearity, accuracy, precision, extraction effect, matrix effect, and stability. Schaftoside, vicenin-1, vicenin-2, and vicenin-3 exhibited moderate plasma protein binding, ranging from 56.6% to 61.5% in rat plasma and 55.0%-62.9% in human plasma. In comparison, isovitexin demonstrated a higher plasma protein binding in the range of 92.3-93.1% and 95.1-96.2% in rat and human plasma, respectively. Furthermore, the potential interactions mediated via plasma protein binding between isovitexin and nonsteroidal anti-inflammatory drugs (NSAIDs) were investigated by rapid equilibrium dialysis. No significant changes were observed, indicating a lower likelihood of interaction between TFDS and NSAIDs due to plasma protein binding in the treatment of urinary system disorders.

Pharmaceutical Residues in Edible Oysters along the Coasts of the East and South China Seas and Associated Health Risks to Humans and Wildlife.

The investigation of pharmaceuticals as emerging contaminants in marine biota has been insufficient. In this study, we examined the presence of 51 pharmaceuticals in edible oysters along the coasts of the East and South China Seas. Only nine pharmaceuticals were detected. The mean concentrations of all measured pharmaceuticals in oysters per site ranged from 0.804 to 15.1 ng g-1 of dry weight, with antihistamines being the most common. Brompheniramine and promethazine were identified in biota samples for the first time. Although no significant health risks to humans were identified through consumption of oysters, 100-1000 times higher health risks were observed for wildlife like water birds, seasnails, and starfishes. Specifically, sea snails that primarily feed on oysters were found to be at risk of exposure to ciprofloxacin, brompheniramine, and promethazine. These high risks could be attributed to the monotonous diet habits and relatively limited food sources of these organisms. Furthermore, taking chirality into consideration, chlorpheniramine in the oysters was enriched by the S-enantiomer, with a relative potency 1.1-1.3 times higher when chlorpheniramine was considered as a racemate. Overall, this study highlights the prevalence of antihistamines in seafood and underscores the importance of studying enantioselectivities of pharmaceuticals in health risk assessments.

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.

Nonsteroidal Anti-inflammatory Drugs for the Prevention of Post-endoscopic Retrograde Cholangiopancreatography Pancreatitis.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most frequent and severe complication following ERCP, elevating both patient suffering and healthcare costs, and posing challenges to the advancement of ERCP techniques. Empirical evidence supports the prophylactic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of PEP, especially in high-risk populations, as endorsed by both the American Society for Gastrointestinal Endoscopy (ASGE) and the European Society for Gastrointestinal Endoscopy (ESGE). However, the prophylactic efficacy of NSAIDs in average-risk individuals, alongside the ideal drug selection, dosing, and timing of NSAID administration, remains to be elucidated. Furthermore, the synergistic preventive potential of NSAIDs when integrated with other interventions, such as hydration, pancreatic stenting, somatostatin administration, sublingual nitrate application, and epinephrine, warrants further clarification. In this paper, we conduct an exhaustive review of the prophylactic effect and clinical administration of NSAIDs for PEP. We comprehensively synthesize findings from clinical trials investigating NSAIDs, both in monotherapy and combination regimens, for PEP prevention. Additionally, we scrutinize the current landscape of NSAID usage in clinical practice and evaluate their cost-effectiveness. Future research should concentrate on refining NSAID prophylaxis strategies for PEP in patients at different risk levels, while also enhancing adherence to clinical guidelines and alleviating the issue of NSAID cost inflation.

Medication-based profiling of older orthopedic patients: a multicenter cross-sectional study.

BACKGROUND: Managing medication use in older orthopedic patients is imperative to extend their healthy life expectancy in an aging society. However, the actual situation regarding polypharmacy, the intake of potentially inappropriate medications (PIMs), and fall risk-increasing drugs (FRIDs) among older orthopedic patients is not well characterized. This study aimed to investigate the medication-based profiles of older orthopedic patients to highlight the critical points of concern. METHODS: We retrospectively reviewed the clinical data of consecutive patients aged ≥ 65 years who underwent orthopedic surgery at two acute care hospitals between April 2020 and March 2021. The cutoff number of prescribed drugs for polypharmacy was set at 6. According to the specified guidelines, 19 categories of drugs were identified as PIMs, and 10 categories were classified as FRIDs. RESULTS: A total of 995 older patients with orthopedic surgery were assessed, of which 57.4% were diagnosed with polypharmacy, 66.0% were receiving PIMs, and 41.7% were receiving FRIDs. The prevalence of FRID intake did not significantly differ among patients with degenerative spinal disease (n = 316), degenerative disease of extremities (n = 331), and fractures (n = 272). Compared with patients with degenerative disease of the extremities, the multivariable-adjusted prevalence ratios (PRs) of polypharmacy and PIM intake were significantly higher in patients with degenerative spinal disease (1.26 [confidence intervals (CI): 1.11-1.44] and 1.12 [CI: 1.00-1.25]), respectively. Use of antiemetic drugs (adjusted PR, 13.36; 95% CI: 3.14-56.81) and nonsteroidal anti-inflammatory drugs (adjusted PR, 1.37; 95% CI: 1.05-1.78) was significantly higher in patients with degenerative spinal disease. Among patients with degenerative spinal disease, the prevalence of antiemetic drug intake was 8.7% in lumbar spinal patients and 0% in cervical spinal patients. CONCLUSIONS: More than half of the orthopedic patients in this study were affected by polypharmacy, and approximately two-thirds were prescribed some form of PIMs. Patients with degenerative spinal disease showed a significantly higher prevalence of polypharmacy and PIM use compared with other orthopedic diseases. Particular attention should be paid to the high frequency of antiemetic drugs and nonsteroidal anti-inflammatory drugs intake among patients with degenerative lumbar spine conditions.

A single, maximal dose of celecoxib, ibuprofen, or flurbiprofen does not reduce the muscle signalling response to plyometric exercise in young healthy adults.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) possess analgesic and anti-inflammatory properties by inhibiting cyclooxygenase (COX) enzymes. Conflicting evidence exists on whether NSAIDs influence signaling related to muscle adaptations and exercise with some research finding a reduction in muscle protein synthesis signaling via the AKT-mTOR pathway, changes in satellite cell signaling, reductions in muscle protein degradation, and reductions in cell proliferation. In this study, we determined if a single maximal dose of flurbiprofen (FLU), celecoxib (CEL), ibuprofen (IBU), or a placebo (PLA) affects the short-term muscle signaling responses to plyometric exercise. METHODS: This was a block randomized, double-masked, crossover design, where 12 participants performed four plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% 1RM. Two hours before exercise, participants consumed a single dose of celecoxib (CEL 200 mg), IBU (800 mg), FLU (100 mg) or PLA with food. Muscle biopsy samples were collected before and 3-h after exercise from the vastus lateralis. Data were analyzed using a repeated measures (RM) ANOVA, ANOVA, or a Friedman test. Significance was considered at p < 0.05. RESULTS: We found no treatment effects on the mRNA expression of PTSG1, PTSG2, MYC, TBP, RPLOP, MYOD1, Pax7, MYOG, Atrogin-1, or MURF1 (all, p > 0.05). We also found no treatment effects on AKT-mTOR signaling or MAPK signaling measured through the phosphorylation status of mTORS2441, mTORS2448, RPS6 235/236, RPS 240/244, 4EBP1, ERK1/2, p38 T180/182 normalized to their respective total abundance (all, p > 0.05). However, we did find a significant difference between MNK1 T197/202 in PLA compared to FLU (p < .05). CONCLUSION: A single, maximal dose of IBU, CEL, or FLU taken prior to exercise did not affect the signaling of muscle protein synthesis, protein degradation, or ribosome biogenesis three hours after a plyometric training bout.

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.

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.

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.

Preoperative versus postoperative nonsteroidal anti-inflammatory drugs in femoroacetabular impingement patients undergoing hip arthroscopy surgery: analgesic effect, joint function, patients' satisfaction, and quality of life.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic effects on femoroacetabular impingement (FAI) patients undergoing hip arthroscopy surgery (HAS). However, the influence of medication time on the analgesic effect of NSAIDs is uncertain. This study aimed to compare the analgesic effect, joint function, quality of life (QoL), and patients' satisfaction between preoperative and postoperative NSAIDs in these patients. METHODS: In this prospective, observational study, 165 FAI patients undergoing HAS with NSAIDs (celecoxib, meloxicam, and nimesulide) for analgesia were divided into preoperative (PRE-A) and postoperative analgesia (POST-A) groups according to their actual medication. RESULTS: The visual analog scale (VAS) pain scores on the 1st (P < 0.001) and 3rd (D3) (P = 0.015) days after the operation were lower in the PRE-A group versus the POST-A group but not preoperatively (P = 0.262) or on the 7th day after the operation (D7) (P = 0.302). The proportion of patients receiving rescue analgesia decreased in the PRE-A group versus POST-A group (P = 0.041). However, the modified Harris hip score (mHHS), proportion of patients with an mHHS ≥ 70, and EuroQol-5-dimensional score at preoperative, 1st month (M1), and 3rd month (M3) after the operation were similar between the groups (all P > 0.050). The VAS score on D7 was greater in the PRE-A group compared to the POST-A group (P = 0.014), but the scores at M1 and M3 and the satisfaction and very satisfaction rates at D7, M1, and M3 did not differ between the groups (all P > 0.050). Subgroup analysis revealed that the type of NSAID did not affect most outcomes. CONCLUSION: Preoperative NSAIDs elevate analgesic effect and patients' satisfaction, but not joint function or QoL compared to postoperative NSAIDs in FAI patients undergoing HAS.

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.

[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.

Aspirin in the Prevention of Colorectal Neoplasia.

High-quality evidence indicates that regular use of aspirin is effective in reducing the risk for precancerous colorectal neoplasia and colorectal cancer (CRC). This has led to US and international guidelines recommending aspirin for the primary prevention of CRC in specific populations. In this review, we summarize key questions that require addressing prior to broader adoption of aspirin-based chemoprevention, review recent evidence related to the benefits and harms of aspirin use among specific populations, and offer a rationale for precision prevention approaches. We specifically consider the mechanistic implications of evidence showing differences in aspirin's effects according to age, the potential role of modifiable mechanistic biomarkers for personalizing prevention, and emerging evidence that the gut microbiota may offer novel aspirin-associated preventive targets to reduce high-risk neoplasia.

Hypersensitivity to Ibuprofen: Real-Life Experience in Children with History of Suspected Immediate Reactions.

INTRODUCTION: Ibuprofen is the most common culprit drug causing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children. We aimed to evaluate the frequency, clinical characteristics, and risk factors of confirmed ibuprofen allergy in children presenting with a history of suspected immediate type ibuprofen-induced hypersensitivity reactions. METHODS: We evaluated 50 (35 M, 15 F) children with a median age of 7 years, who were referred to our clinic with suspected immediate ibuprofen hypersensitivity. Patients were subjected to a diagnostic work up including drug provocation tests (DPTs) with the culprit drug. Reactions were classified according to the European Academy of Allergy and Clinical Immunology Task Force recommendations for pediatric patients. Proven ibuprofen allergic patients underwent DPT to find a safe alternative drug. RESULTS: Ibuprofen allergy was confirmed in 34% (n: 17) of children; 9 patients were diagnosed by DPTs and 8 patients diagnosed based on their histories. Angioedema was the most common clinical manifestation (n: 30, 60%). Among patients with proven ibuprofen allergy, 7 of them were classified as cross-intolerant. Cross-intolerance reactions were further classified as NSAID-exacerbated cutaneous disease (n = 1) and NSAID-induced urticaria/angioedema/anaphylaxis (n = 6). As an alternative drug, paracetamol was safely tolerated, whereas 1 patient developed angioedema and urticaria with nimesulide. Older age and male gender were identified as independent risk factors for immediate-type ibuprofen allergy. CONCLUSION: DPTs should be performed to confirm or exclude ibuprofen allergy in children and to find safe alternative drugs. Male gender and older age are risk factors for ibuprofen allergy. NSAID-induced hypersensitivity reactions in the pediatric population cannot be well defined using the adult classification system.

Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China.

The Gutong Patch (GTP) is common in clinical practice for bone diseases. This study compared the efficacy and safety of GTP and nonsteroidal anti-inflammatory drugs (NSAIDs) for KOA patients from 35 medical centers assigned to GTP, selective COX-2 inhibitor (SCI), GTP + SCI, non-selective COX-2 inhibitor (NSCI), and GTP + NSCI groups. The visual analog scale (VAS) pain score, EuroQol-VAS, EuroQol 5D-3 L, time to articular pain relief / disappearance, and joint motion recovery were the efficacy assessments. Safety assessments included contact dermatitis, gastrointestinal disorders, etc. The p-value < 0.05 was considered statistically significant. After statistical analysis, the SCI and GTP + SCI groups showed better improvement of VAS than the GTP group; the time to articular pain relief in the NSCI group was shorter than that in GTP and SCI group; the time to joint motion recovery in the GTP + NSCI group was longer than that in the SCI group. Additionally, the improvement of the quality of life in all groups was significant after treatments. While the incidence of gastrointestinal adverse events in the NSAIDs group was higher than that in the GTP and GTP + NSAIDs groups. GTP and NSAIDs are effective for KOA patients, and GTP is more suitable for KOA patients with cardiovascular and gastrointestinal comorbidities. This study was approved by the Ethics Committee at Peking Union Medical College Hospital (HS-1766) and registered in the Chinese Clinical Trial Registry (ChiCTR2100046391).

Cross-reactivity between nonsteroidal anti-inflammatory drugs in fixed drug eruption: Two unusual cases and a literature review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.