Nonsteroidal Anti-inflammatory Drugs Users Research Articles

Renal injury in NSAIDs: a real-world analysis based on the FAERS database.

This study aims to evaluate the reporting risk of renal injury associated with non-steroidal anti-inflammatory drugs (NSAIDs), with a particular focus on the reporting risk levels and onset times of different NSAIDs. A pharmacovigilance study was conducted using data from the FAERS database from January 2004 to December 2023. Reports of renal injury were identified, and signal detection was performed using reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) methods. The study compared the incidence, mortality rates, and onset times of renal injury across five NSAIDs. Among the 7436 cases of NSAID-associated renal injury analyzed, elderly patients are at an increased risk of renal injury associated with NSAID usage. Ibuprofen had the highest number of reports (3475 cases, 46.7%), while celecoxib had the lowest (542 cases, 7.3%). Ibuprofen showed the highest signal with renal injury (ROR 3.3, IC025 1.7), whereas celecoxib exhibited the lowest (ROR 1.4, IC025 0.4). Aspirin had the highest mortality rate associated with renal injury (18.7%), while ibuprofen had the lowest (3.8%). The median onset time for renal injury was 6days, with 79.3% of adverse events occurring within the first 30days of use. The study indicates that ibuprofen presents the highest signal of renal injury, while celecoxib shows the lowest signal. The likelihood of NSAID-associated renal injury is heightened in elderly patients, and all five studied NSAIDs are linked to an increased likelihood of acute renal injury. NSAID-related renal damage tends to occur early in the treatment process, potentially leading to serious consequences. Due to the inherent limitations of pharmacovigilance studies, certain findings require additional validation like cohort studies. Nonetheless, the potential for an increased risk of renal injury must be taken into account in patient care.

Non-steroidal anti-inflammatory drug use and inflammatory markers associated with gallbladder dysplasia: A case-control analysis within a series of patients undergoing cholecystectomy.

Inflammation has been associated with the development of gallbladder cancer (GBC). However, little is known about the associations of both, inflammation and the use of non-steroidal anti-inflammatory drugs (NSAIDs), with preneoplastic lesions. We analyzed the association of NSAIDs and gallbladder dysplasia in 82 patients with dysplasia and 1843 patients with gallstones among symptomatic patients from a high-risk population. We also analyzed associations for 33 circulating immune-related proteins in a subsample of all 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Biliary colic was reported among most cases (97.6%) and controls (83.9%). NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95%CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with sex- and age-adjusted ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline associated (OR: 0.74, 95%CI: 0.54-1.01) after adjusting the logistic regression model for sex, age, and NSAIDs. In conclusion, NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for symptomatic gallstones patients. The inverse association between immune-related markers and dysplasia requires additional research, ideally in prospective studies with asymptomatic participants, to understand the role of the inflammatory response in the natural history of GBC and to address the biological effect of NSAIDs.

Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7days before). The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

Self-Reported Gastrointestinal Symptoms Associated with NSAIDs and Caffeine Consumption in a Jordanian Subpopulation.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) and caffeine-containing beverages are widely consumed but their impact on gastrointestinal (GI) health requires further investigation. This cross-sectional study investigated the relationship between NSAIDs use, caffeinated drink consumption, and the prevalence of self-reported GI symptoms in a Jordanian subpopulation. Methods: An online survey was administered to 400 Jordanian individuals aged 18-65 years. Data on sociodemographics, NSAIDs use, caffeine consumption, peptic ulcer disease (PUD) history, and GI symptoms were collected. Contingency tables were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between exposures and outcomes. Results: The prevalence of self-reported PUD-related GI symptoms was 6.0%. NSAID users had higher odds of PUD (OR = 2.431) and related GI symptoms, including abdominal pain (OR = 4.688, p < 0.001) and discomfort (OR = 8.068, p < 0.001). Caffeine consumption was associated with self-reported burning stomach pain (OR = 14.104, p < 0.001), fullness (OR = 8.304, p = 0.010), and bloating (OR = 8.304, p = 0.010). Coffee, tea, soft drinks, and energy drinks were associated with increased odds of various GI symptoms (ORs 2.018-12.715, p < 0.05). Conclusions: NSAIDs use and caffeine consumption were independently associated with the increased prevalence of self-reported PUD and related GI symptoms. Despite the lack of adjustment for necessary confounders, our findings highlight the importance of considering the potential GI effects of NSAIDs and caffeine. Public health strategies promoting their safe use may help reduce the burden of GI disorders.

Diaphragm Disease of the Terminal Ileum: The Great Imitator.

The incidence of diaphragm disease has been soaring due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs).Diaphragm disease is characterized by diaphragm-like mucosal projections and annular constrictions that induce luminal narrowing and result in bowel obstruction.Physicians should get acquainted with diaphragm disease and include it in their differential diagnosis when approaching a patient with obstruction-like symptoms or non-specific and vague abdominal pain in the setting of chronic NSAIDs usage.

NSAID-induced Gastric Ulcer Disease: A Deleterious Connection.

Gastric ulcers induced by non-steroidal anti-inflammatory drug (NSAID) usage have become a common public health problem, and several studies have established chronic NSAID usage to be one of the risk factors for the pathogenesis of peptic ulcers in patients. This review includes numerous articles that link NSAID usage with peptic mucosal erosion, especially among patients under anticoagulant therapy or with other risk factors. Risk factors for NSAID-induced peptic ulcers are reviewed, in addition to pathogenesis, clinical signs, symptoms, diagnosis, prevention, and treatments. We also emphasize effective methods for the prevention and management of peptic ulcers among NSAID users. Such methods include the use of selective Cyclo-oxygenase (COX-2) inhibitors as an alternative to aspirin or other Cyclo-oxygenase (COX-1) inhibitors, or using the lowest dosage possible in patients with other comorbidities. We have conducted a thorough review of the literature on diagnostic tests and alternative medication that can be used in the management of NSAID toxicity-induced ulcers.

The Use of Tranexamic Acid for Primary Prophylaxis of Heterotopic Ossification Following Total Hip Arthroplasty

BackgroundHeterotopic ossification (HO) is a relatively common complication after total hip arthroplasty (THA) and can range from a radiographic observation only to severely disabling and requiring revision surgery. Prophylaxis is recommended for high-risk patients, though the ideal method and targeted population are open to debate. Tranexamic acid (TXA) is a medication increasingly being used to reduce blood loss associated with orthopaedic surgeries, including THA. MethodsA retrospective review of 357 patients undergoing THA from November 2020 through December 2023 was conducted. The patients were grouped based on whether they received intravenous TXA perioperatively or not, and their propensity score matched 2:1 TXA to no TXA on age, body mass index, sex, Charlson Comorbidity Index, and perioperative celecoxib use. Univariate and multivariate analyses were performed. ResultsAfter propensity score matching, the only significant differences between groups were American Society of Anesthesiologists (ASA) scores and preoperative celecoxib use between groups, as the TXA group had fewer patients who had an ASA of 3 or more (38.9 versus 58.5%, P < 0.001) and more patients who had taken celecoxib preoperatively (16.3 versus 5.9%, P = 0.010). Perioperatively, patients were more likely to undergo THA using the anterior approach (74.5 versus 57.6%, P = 0.002) and were more likely to receive postoperative celecoxib prescriptions (44.8 versus 31.4%, P = 0.021), but there was no difference in other nonsteroidal anti-inflammatory drug (NSAID) usage postoperatively. Postoperatively, patients who received TXA had a lower rate of HO on the last postoperative x-ray (20.1 versus 33.9%, P = 0.007). Multivariable logistic regression, to assess predictors of HO, found that patients who had TXA were 42% less likely to have visible HO (OR [odds ratio] = 0.58, P = 0.047), while holding surgical approach, American Society of Anesthesiologists score, preoperative and postoperative celecoxib use, and postoperative other nonsteroidal anti-inflammatory drug use constant. ConclusionsThe use of TXA in patients undergoing primary THA results in a decreased likelihood ofHO formation on postoperative x-rays.

Trends in Upper Gastrointestinal Bleeding in Children: The Impact of Helicobacter pylori Infection and Non-Steroidal Anti-Inflammatory Drug Use.

Upper gastrointestinal bleeding (UGIB) is a significant concern in children, contributing to 6-20% of cases in pediatric intensive care units. This study evaluates the roles of Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) usage in the etiology of UGIB in children, with a particular focus on trends observed during the COVID-19 pandemic. We conducted a retrospective analysis of 103 pediatric patients who underwent esophagogastroduodenoscopy (EGD) for UGIB between January 2015 and December 2023. Of these, 88 patients were included in the final analysis, where the source of bleeding was successfully identified. Hematemesis was the most common presentation, and the source of bleeding was identified in 85.43% of cases. The prevalence of H. pylori infection remained stable across the pre-pandemic (39.7%) and post-pandemic (36.7%) periods. However, NSAID usage increased nearly threefold during the pandemic, with 36.7% of post-pandemic UGIB cases associated with NSAID use, compared to 12.1% pre-pandemic. These findings underscore the significant roles of H. pylori and NSAID use in pediatric UGIB, with a notable increase in NSAID-related cases during the pandemic.

The role of aspirin in the prevention of pancreatic cancer: A nested case-control study in the UK Biobank

BackgroundAspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) usage has been associated with pancreatic ductal adenocarcinoma (PDAC) prevention, though epidemiological data have not reliably demonstrated this. The aim of this study is to identify if aspirin and other NSAIDs are effective in the primary prevention of PDAC in a large UK prospective cohort. MethodsA nested case-control study was conducted using the UK Biobank cohort. Incident PDAC cases (n = 1129 of whom 239 (21.2 %) were using aspirin) were age and sex-matched with cancer-free controls (n = 8822 of whom 1752 (19.9 %) were using aspirin). Conditional logistic regression models were used to generate odds ratios (ORs) and 95 % confidence intervals (CI) for risk of PDAC with and without regular use of aspirin, non-aspirin NSAIDs and all NSAIDs respectively. Exploratory analyses were carried out assessing interactions with diabetes mellitus (DM) as a condition with increased pancreatic cancer risk. ResultsRegular aspirin use at initial recruitment was independently associated with a decreased risk of PDAC (OR [95 % CI] = 0.80 [0.68–0.95] P = 0.01). Regular non-aspirin NSAID use was not associated with a risk reduction of PDAC (OR [95 % CI] = 1.01 [0.84–1.23] P = 0.88). Exploratory analyses showed that in those with DM; regular aspirin use reduced risk of PDAC (OR [95 % CI] = 0.60 [0.42–0.85] P = 0.004) compared to non-use. DiscussionRegular aspirin use is associated with a reduction in risk of PDAC. The reduced risk is more apparent in participants with DM.

A novel deep learning approach for optimizing preparation and usage of nonsteroidal anti-inflammatory drugs (NSAIDs) in spine care

Nonsteroidal anti-inflammatory drugs (NSAIDs) are essential for the management of pain and inflammation brought by illnesses of the spine. NSAIDs are essential in the treatment of inflammation and pain in a variety of spinal disorders. In order to relieve pain for patients and enhance their quality of life, NSAIDs should be used effectively. The effectiveness and safety of NSAIDs for spinal pain were assessed using a systematic review and meta-analysis. We gathered the patient data. The insufficient data is cleaned using tokenization and the data extraction employs Term Frequency-Inverse Document Frequency (TF-IDF). A Monarch Butterfly Optimization Dynamic Generative Adversarial Networks (MBO+DGAN) for the preparation and use of NSAIDs in spine care. Our studies show the possibility of the MBO+DGAN strategy to enhance the administration of NSAIDs in spine care, leading to improved clinical results, patient experiences and possibly lower healthcare costs. The MBO+DGAN assesses a method's effectiveness by evaluating its performance in terms of Accuracy (95%), Sensitivity (96%), Precision (97%) and Specificity (94%). The opportunity to use MBO+DGAN to improve how NSAIDs are created and utilized in the complex world of spine care. This technique offers an effective approach to enhance patient care and outcomes in the difficult field of spine healthcare by enabling customized treatment plans.

Drugs Effective for Nonsteroidal Anti-inflammatory Drugs or Aspirin-induced Small Bowel Injuries: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The frequency of small bowel (SB) injuries has increased due to the increased use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. This study was a systematic review and meta-analysis to compare drugs effective for SB injuries caused by NSAIDs or aspirin use. We searched MEDLINE, Embase, and Cochrane registries for randomized controlled trials through February 2023. The extracted data included changes in the number of erosions or ulcers in the jejunum or ileum observed through capsule endoscopy in patients taking NSAIDs or aspirin and administration of various mucoprotectants. We investigated the therapeutic or preventive efficacy of these drugs. The methodological bias was evaluated using Risk of Bias 2.0. Eighteen randomized controlled trials of drugs effective for NSAIDs or aspirin-induced SB injuries were included and analyzed. The agents used to treat or prevent SB injuries were rebamipide, misoprostol, geranylgeranylacetone, and probiotics. In the meta-analysis, the mucoprotectants that showed a significant effect in treating NSAID users, who developed SB injuries, were misoprostol (mean difference: -9.88; 95% CI: -13.26 to -6.50). Meanwhile, the mucoprotectant that can prevent SB injuries caused by NSAIDs or aspirin in the general population was rebamipide (mean difference: -1.85; 95% CI: -2.74 to -0.96). Misoprostol was effective in treating SB injuries caused by NSAIDs or aspirin (CRD42023410946).

Harmonizing ecology and society: an integrated analysis of vulture conservation in the Nilgiri Biosphere Reserve, India

The Nilgiri Biosphere Reserve (NBR) in southern India is home to several critically endangered vulture species. This study in Mudumalai Tiger Reserve and Sathyamangalam Tiger Reserve of NBR presents an integrated analysis of vulture conservation efforts focusing on harmonizing ecosystem preservation and community engagement. We assessed the current status of all four vulture species in the NBR using the road transect method, covering 2,040 km with 24 replications (January–December 2021). We undertook covert surveys in 82 veterinary pharmacies across four districts of Tamil Nadu to determine the availability of non-steroidal anti-inflammatory drugs (NSAIDs), considering the 100-km vulture safe zone that included vulture nesting and foraging areas. As practical conservation efforts require active local community participation, our assessments include the perception study of local communities in 20 villages (eight tribal and 12 non-tribal) near vulture habitats. We focused on NSAID usage, considering the impact of numerous socio-economic factors on vulture conservation efforts. We surveyed 540 respondents using detailed questionnaires for these evaluations. The study underlined the need for a comprehensive vulture management plan that balances ecological concerns with the well-being and means of subsistence of surrounding communities. This study is helpful for future conservation efforts in other areas with comparable problems at the nexus of ecology and society.

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database.

Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age. A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan's Longevity Improvement & Fair Evidence study. The cohort entry (t0) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category's odds ratio compared to non-users. Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44-0.96) for Continuous-users and 2.57 (1.73-3.81) for Irregular-users. Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age.

Perioperative non-opioid analgesia strategies after high tibial osteotomy: a systematic review of prospective studies.

Little is known about the optimal analgesia regimen after HTO. Thus, this study systematically reviewed the literature on clinical and patient-reported outcomes of pain management strategies for patients after HTO. A comprehensive search of the PubMed, Cochrane CENTRAL, and CINAHL databases was conducted from inception through September 2023. Studies were included if they evaluated pain reduction with analgesia strategies after HTO and were excluded if they did not report pain control outcomes. Five studies with 217 patients were included. Patients with a multimodal intraoperative injection cocktail to the knee, femoral nerve block (FNB), or adductor canal block (ACB) for HTO had significant improvement in visual analog scale (VAS) and numerical rating scale (NRS) scores in the first 12h postoperatively compared to controls. Patients on duloxetine had significantly lower NRS scores at 1, 7, and 14 days postoperatively and significantly lower nonsteroidal anti-inflammatory drug (NSAID) usage throughout the two-week postoperative period than the control group. Patients receiving an ACB had significantly lower opioid consumption than controls at 12h postoperative. In patients with an FNB or ACB, no significant difference in quadriceps strength or time to straight leg raise postoperatively was observed compared to controls. A multimodal periarticular injection cocktail, FNB, or an ACB effectively reduces pain on the first day after HTO, with an ACB able to reduce opioid consumption on the first postoperative day. Duloxetine combined with an ACB effectively decreases pain for two weeks postoperatively while reducing NSAID consumption in patients after HTO. IV.

Strategies to Improve the Transdermal Delivery of Poorly Water-Soluble Non-Steroidal Anti-Inflammatory Drugs.

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in incorporating the drugs into formulations suitable for application to skin and may limit transdermal permeation, particularly if the goal is therapeutic systemic drug concentrations. This review is an overview of the various strategies used to increase the solubility of poorly soluble NSAIDs and enhance their permeation through skin, such as the modification of the vehicle, the modification of or bypassing the barrier function of the skin, and using advanced nano-sized formulations. Furthermore, the simple yet highly versatile microemulsion system has been found to be a cost-effective and highly successful technology to deliver poorly water-soluble NSAIDs.

NSAID PRESCRIPTION SURVEY IN INTEGRATED TRADITIONAL AND WESTERN MEDICINE TREATMENT: ASSESSING GASTROINTESTINAL AND CARDIOVASCULAR RISKS

Introduction: Non-steroidal anti-inflammatory drug (NSAID) usage should be carefully considered based on gastrointestinal (GI) and cardiovascular (CV) risks. In light of restricted evidence, this study aims to assess the prescription of NSAIDs concerning the GI and CV risks in the integrated treatment of Traditional medicine (TM) and Western medicine (WM). Materials and method: A retrospective cross-sectional study was conducted on 393 medical records of inpatients using NSAIDs in 2022 at the Traditional Medicine Hospital of Ho Chi Minh City. GI and CV risks, as well as information regarding NSAID prescriptions, were recorded. A multivariable regression model was employed to identify factors associated with the prescription of NSAID groups. Results: NSAIDs were primarily prescribed for musculoskeletal and connective tissue disorders (87.28%). Approximately half of the cases exhibited moderate to high GI risk (47.59%), while for CV risk, there were 68.95% with moderate to very high risk. COX-2 inhibitors were the most commonly prescribed (94.66%), even when considering GI and CV risks separately. In the majority, NSAID prescriptions aligned with both risks according to American College of Gastroenterology (ACG) guidelines (73.79%). The prescription of NSAID groups was significantly influenced by patient gender, ailment type, and physician education (p&lt;0.05), but not by GI and CV risks (p&gt;0.05). Conclusion: Patients receiving NSAIDs in integrated TM and WM treatment often faced an increased GI and CV risk, with the majority adhering to ACG guidelines. However, GI and CV risks were not significantly considered for NSAID group selections. Multi-center studies should be conducted.

In-silico design, molecular docking, molecular dynamic simulations, Molecular mechanics with generalised Born and surface area solvation study, and pharmacokinetic prediction of novel diclofenac as anti-inflammatory compounds

The prostaglandins inside inflamed tissues are produced by cyclooxygenase-2 (COX-2), making it an important target for improving anti-inflammatory medications over a long period. Adverse effects have been related to the traditional usage of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation, mainly centered around gastrointestinal (GI) complications. The current research involves the creation of a virtual library of innovative molecules showing similar drug properties via a structure-based drug design. A library that includes five novel derivatives of Diclofenac was designed. Subsequently, molecular docking through the Glide module and determining the binding free energy implementing the Prime-MMGBSA module by the Schrödinger software package was used to identify compounds that showed marked specificity towards the COX-2 isoform. In addition, the ligands are subject to evaluation of their drug-like properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) characteristics using the QikProp module. Finally, molecular dynamics simulation has been calculated for the best molecule. The docking results indicated that all compounds own a predictive capability for specific binding to the COX-2 enzyme compared to the standard drug with a docking score range from -10.07 to -10.66 Kcal/mole, thus potentially overcoming the limitations imposed previously by the drugs currently used in clinical use. The ADMET analysis of the virtually active compounds demonstrated an acceptable drug-like profile and desirable pharmacokinetics properties. MM/GBSA calculation revealed that all the suggested compounds exhibited favorable free binding energies (-49.150 to - 60.185 Kcal/mole), indicating their strong potential to fit well into the COX-2 receptor. Finally, the MD simulation study revealed that compound 1 had perfect alignment with COX-2 receptor. The findings indicated that the compounds possess a predictive capability for specific binding to the COX-2 enzyme, thus potentially surmounting the restrictions imposed by the drugs currently employed in clinical use.

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

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. 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. 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 6h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1β 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. 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.

Abstract 3446: Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia

Abstract Background: Most gallbladder cancer (GBC) cases arise from the metaplasia-dysplasia-GBC sequence, and chronic inflammation has been associated with its development. The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of GBC; however, little is known about these associations with preneoplastic lesions. We thus aimed to study the associations of the use of NSAIDs and inflammatory proteins with gallbladder dysplasia, a precursor to GBC. Methods: Associations of NSAIDs and gallbladder dysplasia were evaluated in 1,925 Chilean cholecystectomy patients, 82 with dysplasia and 1,843 with gallstones but not dysplasia. In addition, we measured 33 circulating inflammatory proteins in a subsample of 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and associations of inflammatory proteins and gallbladder dysplasia were analyzed. Results: NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95% CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline-associated (OR: 0.74, 95%CI: 0.54-1.01) in the multivariable logistic regression model additionally adjusted for sex, age and NSAID use. Conclusion: NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for gallstones patients. Prospective studies are needed to understand the inverse association of immune-related markers and dysplasia, and to evaluate the biological effect of NSAIDs in GBC. Research supported by general funds from the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Office of Research on Women’s Health, National Institutes of Health. Citation Format: Lorena Rosa, Paz Cook, Ruth M. Pfeiffer, Troy J. Kemp, Allan Hildesheim, Burcin Pehlivanoglu, Volkan Adsay, Enrique Bellolio, Juan Carlos Araya, Ligia Pinto, Catterina Ferreccio, Gloria Aguayo, Eduardo Viñuela, Jill Koshiol. Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3446.

A clinical study on the risk and safety profiles of NSAIDs used for osteoporotic fractures in Chinese patients with rheumatoid arthritis

Purpose: To investigate the risk and safety profile of non-steroidal anti-inflammatory drugs (NSAIDs) for osteoporotic fractures in patients with rheumatoid arthritis (RA). &#x0D; Methods: 298 RA patients admitted to The First People's Hospital of Huzhou, Huzhou, China from August 2020 to September 2022, were investigated. Patients were assigned to groups based on drugs used viz: control group received anti-rheumatic drugs other than NSAIDs; corticosteroid group received dexamethasone, disease-modifying anti-rheumatic drugs (DMARDs) groups received sulfasalazine, NSAID group received either diclofenac or ibuprofen etc. Each group of patients received the respective treatment frequently for at least 3 years. The primary outcome in this study was the incidence of osteoporotic fracture resulting from fragile bone and deterioration of bone mass. &#x0D; Results: The incidence of osteoporotic fracture was highest in NSAID group (11.58 %) when compared to 5.44, 4.96, and 2.36 % in the corticosteroid, DMARD and control groups, respectively (p &lt; 0.05). This shows that users of NSAIDs had a 5-fold higher risk of osteoporotic fracture than patients in control group (OR = 1.26 (95 % CI: 1.22 - 1.81)) and 2-fold possibility of osteoporotic fracture when compared to corticosteroid users ((OR = 1.46 (95 % CI: 1.57 - 2.32)) and DMARD users (1.83 (95 % CI: 1.26 - 1.67)). &#x0D; Conclusion: Rheumatoid arthritis patients on NSAIDs such as celecoxib, diclofenac, ibuprofen, indomethacin, and oxaprozin are at risk of developing osteoporotic fracture. Therefore, NSAIDs must be used with proper counseling in RA patients to minimize the risk of osteoporotic fracture. In future, the study duration will need to be extended to determine the long-term effects and potential changes in bone properties.