Efficacy Of NSAIDs Research Articles

Topical nonsteroidal anti-inflammatory drugs for management of pain after PRK: systematic review and network meta-analysis.

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) for management of pain in patients after photorefractive keratectomy (PRK). Pain after PRK is a major concern for both patients and surgeons. Although evidence supports the use of NSAIDs postoperatively, no consensus exists regarding the preferred regimen. The study aimed to compare the efficacy and safety of different topical NSAIDs. This study was prospectively registered with PROSPERO (ID: CRD42023417651). A systematic search of electronic databases was performed, for randomized controlled trials reporting topical NSAIDs' outcomes of corneal re-epithelization, rescue analgesics intake, and pain in days 0 to 3 after PRK (postoperative days [PODs] 0 to 3). Studies were graded for risk of bias. Data were extracted, and standardized mean differences (SMDs) were evaluated in a network meta-analysis in accordance with the Cochrane's guidelines, to which a frequentist approach model was fitted. Transitivity was assessed using the net split method. Treatment effectiveness was ranked using forest plots based on comparison with placebo. P-scores (P) and league tables were used to examine combined direct and indirect comparisons. Of 1540 studies identified, 27 were included. These encompassed 2286 patients across 11 countries, evaluating 7 distinct topical NSAIDs. At POD0, ketorolac (P 0.764), flurbiprofen (P 0.763), and bromfenac (P 0.717) were the most efficient drugs overall and displayed significantly lower pain scores than placebo. Other than that, flurbiprofen held the highest rank for reported pain throughout, significantly outperforming placebo on POD1 (P 0.874, SMD -1.19, 95% CI -1.86 to -0.52), POD2 (P 0.882, SMD -1.05, 95% CI -1.82 to -0.27), and POD3 (P 0.939, SMD -1.14, 95% CI -2.1 to -0.18). Other NSAIDs were significantly better than placebo only on POD1 and POD0. Rescue analgesic intake analysis favored indomethacin (P 0.834, SMD -0.8, 95% CI -1.33 to -0.27), ketorolac, and diclofenac. Compared with placebo, re-epithelization was slowed to different significances with all NSAIDs but flurbiprofen (P 0.991, SMD -0.7, 95% CI -1.38 to -0.03). Flurbiprofen was favorable in pain scores on typically painful postoperative days and re-epithelization times. However, analgesics intake, a more objective outcome, suggested superiority of other NSAIDs. Inconsistencies may be explained by the small sample size. For clinical interpretation, NSAID effect sizes should be taken into consideration.

Effect of non-steroidal anti-inflammatory drugs on the management of postoperative pain after cardiac surgery: a multicenter, randomized, controlled, double-blind trial (KETOPAIN Study)

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are recommended for the management of acute postoperative pain as part of a multimodal strategy to reduce opioid use, relieve pain, and reduce chronic pain in non-cardiac surgery. However, significant concerns arise in cardiac surgery due to the potential adverse effects of NSAID including increased bleeding and acute kidney injury (AKI). We hypothesized that NSAIDs are effective against pain and safe in the early postoperative period following cardiac surgery, taking contraindications into account.MethodsThe KETOPAIN trial is a prospective, double blind, 1:1 ratio, versus placebo multicentric trial, randomizing 238 patients scheduled for cardiac surgery. Written consent will be obtained for all participants. The inclusion criterion is patients more than 18 years old undergoing for elective cardiac surgery under cardiopulmonary bypass (CPB). Patients will be allocated to the intervention (ketoprofen) group (n = 119) or the control (placebo) group (n = 119). In the intervention group, in addition to the standard treatment, patients will receive NSAIDs (ketoprofen) at a dose of 100 mg each 12 h 48 h after. The control group, in addition to the standard treatment, will receive a placebo of NSAIDs every 12 h for 48 h after surgery. An intention-to-treat analysis will be performed. The primary endpoint will be the intensity of acute postoperative pain at rest at 24 h from the end of surgery. Pain will be assessed using the numerous rating scale. The secondary endpoints will be postoperative pain on coughing during chest physiotherapy, postoperative pain until day 7, the pain trajectory between day 3 and day 7, cumulative opioid consumption within 48 h after surgery, nausea and vomiting, the occurrence of postoperative pulmonary complications within the first 7 days after surgery, neuropathic pain at 3 months, and quality of life at 3 months.DiscussionNSAIDs function as non-selective, reversible inhibitors of the cyclooxygenase enzyme and play a role in a multimodal pain management approach. While there are recommendations supporting the use of NSAIDs in major non-cardiac surgery, recent guidelines do not favor their use in cardiac surgery. However, this is based on low-quality evidence. Major concerns regarding NSAID use in cardiac surgery patients are potential increase in postoperative bleeding or AKI. However, few studies support the possible use of NSAIDs without the risk of bleeding and/or AKI. Also, in a recent French survey, many anesthesiologists reported using NSAIDs in cardiac surgery. To date, no large randomized study has been conducted to evaluate the efficacy of NSAIDs in the management of postoperative pain in cardiac surgery. The expected outcome of this study is an improvement in the management of acute postoperative pain in cardiac surgery with a multimodal strategy including the use of NSAIDs.Trial registrationClinicalTrials.gov NCT06381063. Registered on April 24, 2024.

Exploring potential neuroimaging biomarkers for the response to non-steroidal anti-inflammatory drugs in episodic migraine

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are considered first-line medications for acute migraine attacks. However, the response exhibits considerable variability among individuals. Thus, this study aimed to explore a machine learning model based on the percentage of amplitude oscillations (PerAF) and gray matter volume (GMV) to predict the response to NSAIDs in migraine treatment.MethodsPropensity score matching was adopted to match patients having migraine with response and nonresponse to NSAIDs, ensuring consistency in clinical characteristics and migraine-related features. Multimodal magnetic resonance imaging was employed to extract PerAF and GMV, followed by feature selection using the least absolute shrinkage and selection operator regression and recursive feature elimination algorithms. Multiple predictive models were constructed and the final model with the smallest predictive residuals was chosen. The model performance was evaluated using the area under the receiver operating characteristic (ROCAUC) curve, area under the precision-recall curve (PRAUC), balance accuracy (BACC), sensitivity, F1 score, positive predictive value (PPV), and negative predictive value (NPV). External validation was performed using a public database. Then, correlation analysis was performed between the neuroimaging predictors and clinical features in migraine.ResultsOne hundred eighteen patients with migraine (59 responders and 59 non-responders) were enrolled. Six features (PerAF of left insula and left transverse temporal gyrus; and GMV of right superior frontal gyrus, left postcentral gyrus, right postcentral gyrus, and left precuneus) were observed. The random forest model with the lowest predictive residuals was selected and model metrics (ROCAUC, PRAUC, BACC, sensitivity, F1 score, PPV, and NPV) in the training and testing groups were 0.982, 0.983, 0.927, 0.976, 0.930, 0.889, and 0.973; and 0.711, 0.648, 0.639, 0.667,0.649, 0.632, and 0.647, respectively. The model metrics of external validation were 0.631, 0.651, 0.611, 0.808, 0.656, 0.553, and 0.706. Additionally, a significant positive correlation was found between the GMV of the left precuneus and attack time in non-responders.ConclusionsOur findings suggest the potential of multimodal neuroimaging features in predicting the efficacy of NSAIDs in migraine treatment and provide novel insights into the neural mechanisms underlying migraine and its optimized treatment strategy.

Synthesis and evaluation of mutual prodrugs of some NSAIDs

The therapeutic efficacy of NSAIDs can be improved by reducing their gastrointestinal side effects by modifying their carboxyl group. Anti-inflammatory drugs Ibuprofen, Ketoprofen were chosen for the preparation of mutual prodrugs with paracetamol. The compounds were synthesized with the aim of achieving a synergistic effect and reducing the gastric irritation of anti-inflammatory drugs. Compounds were confirmed by characterization. The synthesis involved an esterification reaction between the carboxyl group of selected NSAIDs and the hydroxyl group of paracetamol. Mutual prodrugs were evaluated for hydrolysis study in acidic medium and phosphate buffer. Compounds were found to hydrolyze at a controlled rate in the environment, and thus this study found that a mutual prodrug approach can be effectively used to achieve the goals of enhancing the effectiveness of NSAIDs in two ways. First, by masking the carboxyl group of NSAIDs to reduce GI effects and achieve synergistic effects using paracetamol as a pro moiety. Both IP and KP prodrugs were retaining anti-inflammatory activity intact and exhibited much-reduced gastric irritant activity. Prodrug IP however, showed better activity and negligible ulcerogenic tendency than KP.

The Clinical Pharmacology and Therapeutic Evaluation of Non-Steroidal Anti-Inflammatory Drugs in Adult Horses.

This review firstly examines the underlying pathophysiology of pain and inflammation associated with orthopedic disease and endotoxemia. Then, it reviews the clinical pharmacology (pharmacokinetics and pharmacodynamics) of both conventional and non-conventional NSAIDs in the adult horse, and finally provides an overview of different modalities to evaluate the therapeutic efficacy of NSAIDs in research.

An interpretable machine-learning model for predicting the efficacy of nonsteroidal anti-inflammatory drugs for closing hemodynamically significant patent ductus arteriosus in preterm infants.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the closure of ductus arteriosus in premature infants. We aimed to develop and validate an interpretable machine-learning model for predicting the efficacy of NSAIDs for closing hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. We assessed 182 preterm infants ≤ 30 weeks of gestational age first treated with NSAIDs to close hsPDA. According to the treatment outcome, patients were divided into a "success" group and "failure" group. Variables for analysis were demographic features, clinical features, as well as laboratory and echocardiographic parameters within 72 h before medication use. We developed the machine-learning model using random forests. Model performance was assessed by the area under the receiver operating characteristic curve (AUC). Variable-importance and marginal-effect plots were constructed to explain the predictive model. The model was validated using an external cohort of two preterm infants who received ibuprofen (p.o.) to treat hsPDA. Eighty-three cases (45.6%) were in the success group and 99 (54.4%) in the failure group. Infants in the success group were associated with maternal chorioamnionitis (p = 0.002), multiple births (p = 0.007), gestational age at birth (p = 0.020), use of indometacin (p = 0.007), use of inotropic agents (p < 0.001), noninvasive ventilation (p = 0.001), plasma albumin level (p < 0.001), PDA size (p = 0.038) and Vmax (p = 0.013). Multivariable binary logistic regression analysis showed that maternal chorioamnionitis, multiple births, use of indomethacin, use of inotropic agents, plasma albumin level, and PDA size were independent risk factors influencing the efficacy of NSAIDs (p < 0.05). The AUC of the random forest model was 0.792. The top-three features contributing most to the model in the variable-importance plot were the plasma albumin level and platelet count 72 h before treatment and 24-h urine volume before treatment. In the external cohort, treatment succeeded in one case and failed in the other. The probabilities of success and failure predicted by the random forest model were 60.2% and 48.4%, respectively. Based on clinical, laboratory, and echocardiographic features before first-time NSAIDs treatment, we constructed an interpretable machine-learning model, which has a certain reference value for predicting the closure of hsPDA in premature infants under 30 weeks of gestational age.

MP53-05 RISK OF ACUTE KIDNEY INJURY AFTER LOWER URINARY TRACT RECONSTRUCTION WITH EARLY NSAID THERAPY: A PROPENSITY MATCHED RETROSPECTIVE ANALYSIS

You have accessJournal of UrologyCME1 Apr 2023MP53-05 RISK OF ACUTE KIDNEY INJURY AFTER LOWER URINARY TRACT RECONSTRUCTION WITH EARLY NSAID THERAPY: A PROPENSITY MATCHED RETROSPECTIVE ANALYSIS Darren Ha, Eliza D. Blanchette, Duncan T. Wilcox, Vijaya M. Vemulakonda, Daniel N. Wood, and Kyle O. Rove Darren HaDarren Ha More articles by this author , Eliza D. BlanchetteEliza D. Blanchette More articles by this author , Duncan T. WilcoxDuncan T. Wilcox More articles by this author , Vijaya M. VemulakondaVijaya M. Vemulakonda More articles by this author , Daniel N. WoodDaniel N. Wood More articles by this author , and Kyle O. RoveKyle O. Rove More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003301.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Response to the opioid epidemic led to increased use of postoperative, non-opioid analgesia. Some pediatric urologists do not routinely use NSAIDs for fear of causing acute kidney injury (AKI). While previous studies have demonstrated the safety and efficacy of NSAIDs in children, safety after lower urinary tract reconstruction has not been well characterized. Using the Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI (increase in creatinine ≥0.3 mg/dL or increase in creatinine ≥1.5× baseline or urine output <0.5 mL/kg/hr for 6 hours), we hypothesized there would be a difference in incidence of postoperative AKI between patients who did and did not receive NSAIDs after these operations. METHODS: Patients 2–18 years old who underwent lower urinary tract reconstruction (i.e., bladder augmentation and/or creation of a catheterizable channel) from 2009 to 2021 and had documented urine were reviewed. CKD and stage were calculated from creatinine and cystatin C within 6 months of surgery using the CKiD U25 equations. Patients who received NSAIDs were propensity matched on 19 characteristics in a 2:1 ratio with patients undergoing similar surgeries who did not receive NSAIDs in the operating room or in the first 6 hours postoperatively. The primary outcome was incidence of AKI during 48 hours after surgery. RESULTS: The unmatched cohorts included 260 patients. After propensity matching, there were no meaningful differences in most characteristics among 118 in the NSAID arm and 59 in the no NSAID arm. 54 CKD and 4 renal transplant patients were included. There was no difference in the incidence of postoperative AKI based on any KDIGO criteria (18.6% no NSAID vs 15.3% NSAID, p=0.71). Median postoperative opioids fell from 0.75 mg/kg in the no NSAID arm to 0.30 mg/kg morphine equivalents in the NSAID arm (p=0.02). Log-rank testing by Kaplan-Meier analysis demonstrated no difference in time to incidence of low urine output between the groups (p=0.38). In the whole population not stratified by NSAID use, no differences were seen in AKI between those with and without CKD (16.6% vs 16.4%). CONCLUSIONS: There was no difference in the incidence of postoperative AKI among patients who did and did not receive NSAIDs after lower urinary tract reconstruction. These results support that postoperative NSAIDs were an unlikely source of AKI and result in lower opioid usage, but also indicate a proportion of patients undergoing these operations may be susceptible to AKI, likely owing to underlying disease, longer operations, and fluid shifts. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e713 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Darren Ha More articles by this author Eliza D. Blanchette More articles by this author Duncan T. Wilcox More articles by this author Vijaya M. Vemulakonda More articles by this author Daniel N. Wood More articles by this author Kyle O. Rove More articles by this author Expand All Advertisement PDF downloadLoading ...

Efficacy of in-utero NSAID versus expectant management for fetal severe ebstein anomaly

Efficacy of in-utero NSAID versus expectant management for fetal severe ebstein anomaly

Non-Steroidal Anti-Inflammatory Drugs and Associated Toxicities in Horses.

Effective pain management in horses can be a challenge despite the understanding that appropriate analgesia improves animal welfare and increases treatment success. The administration of NSAID drugs, particularly phenylbutazone and flunixin, are common practice in equine veterinary patients. Known for their analgesic and anti-inflammatory properties, NSAIDs are used for the treatment of a variety of conditions in horses, from gastrointestinal to orthopedic pain. Despite extensive usage, NSAIDs have a narrow margin of safety and the body of literature documenting the efficacy and side effects of different NSAIDs is broad. The three main side effects associated with excessive or prolonged NSAID usage in horses include gastroduodenal ulceration, right dorsal colitis (RDC) and renal papillary necrosis. The use of cyclooxygenase-2 selective NSAIDS, such as firocoxib, are theoretically safer. The aim of this paper is to review the current literature on the use and efficacy of different NSAIDs, summarise the associated side effects of NSAID usage and evaluate the current state of knowledge for the diagnosis and treatment of such toxicities.

AINS : la prévention des complications

The efficacy of NSAIDs in many rheumatological indications, for analgesic and anti-inflammatory purposes, is no longer in question. However, their prescription may be hindered by co-morbidities that could be aggravated by these drugs, such as coronary artery disease, chronic renal failure or a history of bleeding gastric ulcers. This article provides an update on preventive measures to avoid these complications.

Efficacy of Tocilizumab vs. NSAIDs in the Treatment of Juvenile Rheumatoid Arthritis

Tocilizumab is a humanized monoclonal antibody that binds to IL-6 receptors, both the soluble receptor (sIL-6R) and the one located in the cell membrane. In this way it blocks the molecular complex of the receptor and prevents cytokine signaling. It is a drug which has recently been approved by the FDA, several studies recently carried out at international level (USA, Japan, Europe) have demonstrated the great efficacy of tocilizumab in the treatment of juvenile rheumatoid arthritis.

Efficacy of Tocilizumab vs. NSAIDs in the Treatment of Juvenile Rheumatoid Arthritis

Efficacy of Tocilizumab vs. NSAIDs in the Treatment of Juvenile Rheumatoid Arthritis

The Effect of a Local Injection of Flurbiprofen Ester Microspheres on Systemic Inflammatory Model Rats With a Closed Femoral Shaft Fracture.

Background: Periarticular injections with a combination of local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDs), and epinephrine are becoming increasingly popular in the perioperative analgesia of artificial joint replacement. However, data on the efficacy and safety of local injection NSAIDs are still scarce. The purpose of this study was to investigate the efficacy and safety of a local injection of Flurbiprofen Ester Lipid microspheres into the inflammatory model of femoral shaft closed fractures in rats. Methods: A systemic inflammatory model was induced in SD rats (60) by closed femoral shaft fracture; 12 non-fractured rats were used as the blank control group (group A). The systemic inflammation model of 60 rats was divided into 5 groups (12 in each group); Group B: intramuscular injectionof the same amount of normal saline at different time points as a negative control; Group C: intravenous injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group D: intramuscular injection of Flurbiprofen Ester microspheres (2.25 mg/kg) at different time points; Group E: intramuscular injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group F: intramuscular injection of Flurbiprofen Ester microspheres (9 mg/kg) at different time points. The behavioral test observed the behavior of the rats. Then, the inflammation factors of CRP, IL-6, COX-1, COX-2 and TNF-αby ELISA were recorded. Results: Through the behavioral test it could be found that the effect of the intramuscular and intravenous injections of Flurbiprofen Ester microspheres was similar. Fracture rats with a local injection of Flurbiprofen Ester microspheres showed lower inflammation levels measured by COX-1, CRP, and TNF-α compared with the control group. Pathological sections at 24, 48, and 96 h after surgery did not display any local muscle necrosis at the local injection site. These findings suggested that a Flurbiprofen Ester microsphere muscular injection exhibited a similar effect to an intravenous injection. Conclusion: The local injection of Flurbiprofen Ester microspheres significantly reduced the inflammatory response in fracture rats and did not increase the risk of muscle necrosis, suggesting its feasibility in local injection analgesia.

ESTIMATION OF TOLERANCE OF A DOMESTIC NON-STEROID ANTI-INFLAMMATORY DRUG IN THE POSTOPERATIVE PERIOD OF EXTRACTION OF CATARACTS

Summary. The article discusses the efficacy and tolerability of a non-steroidal anti-inflammatory domestic drug after cataract extraction, the severity of side effects of a non-steroidal anti-inflammatory drug.&#x0D; The aim of the study – optimization of methods of postoperative treatment of cataracts using the domestic non-steroidal anti-inflammatory Diclofenac drug, 0.1 % eye drops, produced by JV “Jurabek Laboratories” LLC.&#x0D; Materials and Methods. The study included patients who were at inpatient treatment at the Clinic No. 2 of the Tashkent Medical Academy. The study group included 60 people: 21 men and 39 women, the age of patients was 18–73 years. In two groups, we compared the efficacy and tolerability of domestic and foreign NSAIDs after cataract extraction.&#x0D; Results. The effectiveness of the complex treatment is confirmed by the reduction in the duration of relief of the main symptoms of inflammation in patients of both groups. Both drugs did not cause side effects and were well tolerated by patients. Tolerability of the treatment in the group receiving domestic NSAIDs was 93.4 %, in the group receiving foreign NSAIDs – 95.7 %.&#x0D; Conclusions. According to the results of our studies, it was proved that therapy after cataract extraction with the use of a domestic-made NSAID is not inferior in efficiency and tolerability to a foreign-made drug and can be used in the postoperative period of cataract.

Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery.

Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery.

The efficacy of nonsteroidal anti-inflammatories in the prevention of heterotopic ossification following elbow trauma surgery.

BackgroundHeterotopic ossification (HO) is common following surgery for elbow trauma and can have a significant impact on elbow function. The use of nonsteroidal anti-inflammatories (NSAIDs) for HO prophylaxis following total hip arthroplasty is well described, with the gold standard of indomethacin 25 mg tid for 6 weeks. However, there is sparse evidence relating to the elbow joint, particularly after elbow trauma surgery. We aim to investigate the efficacy of NSAIDs in the primary prevention of HO amongst all adult patients undergoing surgery for elbow trauma and identify risk factors for HO formation.MethodsA search of the Fiona Stanley Hospital electronic theater database for procedures undertaken for elbow trauma from January 2015 to June 2020 was performed. Electronic medical records and radiographs were reviewed to determine the incidence of HO, prescription of NSAIDs, biographical data, and complications.ResultsOne hundred and fifty-three patients were identified of which 78 patients received NSAIDs postoperatively, compared to 72 who did not. The prescribing history of the remaining 3 patients was unknown. In the NSAID group, the typical patient was prescribed 3-7 days of NSAIDs. Ten patients received a prophylactic course (4-6 weeks). The incidence of HO was similar in both groups (24% in those taking NSAIDs vs. 21% in those not taking NSAIDs). Of those specifically prescribed a prophylactic course, 50% developed HO and 50% did not. Statistical analysis demonstrated that patients with increased body mass index and high energy injuries were more likely to develop HO. Overall complications were low within the cohort. Only 1 patient, who was prescribed NSAIDs, suffered a fracture nonunion (1.3%).ConclusionNSAIDs did not affect the incidence of HO about the elbow following surgery for trauma amongst our cohort. There was no appreciable difference in the rates of HO amongst those prescribed NSAIDs and those who were not. Increased body mass index and high energy trauma were predictive for higher incidence of HO. Risks of NSAID therapy were low, with only 1 (1.3%) patient suffering a nonunion.

Efficacy of NSAIDs versus radiotherapy for heterotopic ossification prophylaxis following total hip arthroplasty in high-risk patients: a systematic review and meta-analysis

The aims of this systematic review were: (1) to investigate the prophylactic effect of radiotherapy (RT) and NSAIDs in high-risk patients following total hip arthroplasty (THA); and (2) to compare the efficacy of non-selective and COX-II selective NSAIDs in preventing post-THA HO, utilising a meta-analysis of randomised control studies. The PubMed, Embase, and Cochrane Databases were searched for articles regarding HO following THA in March 2019. Studies were included if they contained data regarding HO incidence after THA or contained data regarding HO prophylaxis comparison of NSAIDs and/or RT in terms of dosage or duration. 24 studies reported on populations that were not at high-risk for HO. These studies reported between 47.3% and 90.4% of their patient populations had no HO formation; between 2.8% and 52.7% had mild formation; and between 0.0% and 10.4% had severe formation. A total of 13 studies reported on populations at high-risk for HO. Studies analysing RT in high-risk patients reported between 28.6% and 97.4% of patients developed no HO formation; between 1.9% and 66.7% developed mild HO formation; and between 0.0% and 11.9% developed severe HO formation. Studies analysing NSAID treatment among high-risk populations reported between 76.6% and 88.9% had no HO formation; between 11.1% and 23.4% had mild HO formation, and between 0.0% and 1.8% had severe HO formation. 9 studies were identified as randomised control trials and subsequently used for meta-analysis. The relative risk for COX-II in developing any HO after THA was not significantly different compared to non-selective NSAIDs (RR 1.00; CI, 0.801-1.256; p = 0.489). NSAIDs prophylaxis for HO may have better efficacy than RT in high-risk patients following THA. Non-selective and COX-II selective NSAIDs have comparable efficacy in preventing HO. Factors such as medical comorbidities and side-effect profile should dictate the prophylaxis recommendation.

Efficacy of EGFR Inhibitors and NSAIDs Against Basal Bladder Cancers in a Rat Model: Daily vs. Weekly Dosing, Combining EGFR Inhibitors with Naproxen, and Effects on RNA Expression.

There are few effective treatments specifically aimed at basal bladder cancer. Female F344 rats administered N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) develop large invasive bladder cancers. We determined the efficacy of daily vs weekly dosing of EGFR inhibitors, determined the efficacy of naproxen combined with an EGFR inhibitor, and performed RNA analysis of bladder tumors treated for 5 days with EGFR inhibitors or NO-naproxen to identify pharmacodynamic biomarkers. Erlotinib (6 mg/Kg BW daily or 21 or 42 mg/Kg BW weekly), lapatinib (25 or 75 mg/Kg BW daily or 263 or 525 mg/Kg BW weekly) and/or naproxen (30 mg/Kg BW daily) were administered to OH-BBN-treated rats beginning 2-12 weeks post OH-BBN. Rats were sacrificed 28 weeks after the final OH-BBN treatment to determine the effects of the EGFR inhibitors + naproxen on bladder weights and tumor development. In a separate study, rats were treated with OH-BBN. When palpable tumors developed, rats were treated with erlotinib, lapatinib, gefitinib, or the NSAID NO-naproxen for 5 days. RNA analysis was performed on the tumors. Daily or weekly dosing of erlotinib or lapatinib and daily dosing of naproxen reduced large tumor formation up to 70%, while combining daily lapatinib and naproxen reduced tumors 100%. RNA Analysis: All EGFR inhibitors strongly reduced cell proliferation and chromosome replication pathways, while NO-naproxen altered the G protein receptor, oxygen homeostasis and immune function pathways. While daily and weekly dosing with EGFR inhibitors and naproxen were effective, combining lapatinib and naproxen yielded no tumors. This might encourage its clinical use in an adjuvant setting with superficial basal tumors, and perhaps even in a more advanced setting. Furthermore, RNA analysis identified specific pathways that might be potential pharmacodynamic biomarkers in clinical trials.

The non-steroidal anti-inflammatory drug salsalate provides safe and effective control of mucositis-unrelated pain during autologous and allogeneic hematopoietic stem cell transplantation.

Pain is a serious adverse event which frequently accompanies hematopoietic stem cell transplantation (HSCT). The safety and efficacy of NSAIDS during HSCT is currently unknown. Salsalate is a platelet-sparing NSAID with a favorable toxicity profile compared with other NSAIDS. We report the safety and efficacy of salsalate for different types of pain during SCT. We conducted a retrospective study of SCT recipients empirically treated with salsalate for > 48h. Pain scores were assessed using the verbal rating scale for pain. A subset analysis of patients who received > 7days of salsalate during periods of pancytopenia, mucositis, and other end-organ toxicities is included. Sixty-four patients, 42 auto- and 22 allografts, were identified. Reason for use: vertebral-related pain (30%), musculoskeletal (30%), and cytokine inflammatory pain syndromes (24%). Median dose 1500mg/day, number of treatment days = 5, started on day+5 post-HSCT. Pain resolved/improved to pain score < 4 in 76% and stable in 15%. Forty-four patients (28-auto and 16 allografts) received > 7-day salsalate. Median WBC and platelet nadir were < 0.1 and 10,000 cells/ml respectively. pain was improved or eradicated in 64% and stable in 32%. LFT elevation (n = 2), elevated serum creatinine (n = 2), and minor bleed (n = 5-nose, gums, and urine). Salsalate discontinuation (n = 6): ineffective (n = 1), the liver (n = 1), the kidney (n = 1), > 5 platelet transfusions (n = 1), and vomiting (n = 2). There was no treatment related mortality. Salsalate was well tolerated, safe, and beneficial for several different types of pain during HSCT.

Novel Molecular Mechanism of Aspirin and Celecoxib Targeting Mammalian Neuraminidase-1 Impedes Epidermal Growth Factor Receptor Signaling Axis and Induces Apoptosis in Pancreatic Cancer Cells.

BackgroundAspirin (acetylsalicylic acid) and celecoxib have been used as potential anti-cancer therapies. Aspirin exerts its therapeutic effect in both cyclooxygenase (COX)-dependent and -independent pathways to reduce tumor growth and disable tumorigenesis. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces factors that cause inflammation and pain. The question is whether aspirin and celecoxib have other molecular targets of equal or more therapeutic efficacy with significant anti-cancer preventive benefits.AimHere, we propose that aspirin and celecoxib exert their anti-cancer effects by targeting and inhibiting mammalian neuraminidase-1 (Neu-1). Neu-1 has been reported to regulate the activation of several receptor tyrosine kinases (RTKs) and TOLL-like receptors and their downstream signaling pathways. Neu-1 in complex with matrix metalloproteinase-9 (MMP-9) and G protein-coupled receptors (GPCRs) has been reported to be tethered to RTKs at the ectodomain.Materials and MethodsThe WST-1 cell viability assay, Caspase 3/7 assay, and Annexin V assay were used to evaluate the cell viability and detect apoptotic and necrotic cells following treatment in MiaPaCa-2, PANC-1 and the gemcitabine-resistant PANC-1 variant (PANC-1 GemR) cells. Microscopic imaging, lectin cytochemistry, and flow cytometry were used to detect levels of α-2,3 sialic acid. Epidermal growth factor (EGF)-stimulated live cell sialidase assays and neuraminidase assays were used to detect Neu-1 activity. Immunocytochemistry was used to detect levels of EGFR and phosphorylated EGFR (pEGFR) following treatment.ResultsFor the first time, aspirin and celecoxib were shown to significantly inhibit Neu-1 sialidase activity in a dose- and time-dependent manner following stimulation with EGF. Aspirin blocked Neu-1 desialylation of α-2,3-sialic acid expression following 30 min stimulation with EGF. Aspirin and celecoxib significantly and dose-dependently inhibited isolated neuraminidase (Clostridium perfringens) activity on fluorogenic substrate 2ʹ-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (4-MUNANA). Aspirin inhibited phosphorylation of the EGFR in EGF-stimulated cells. Aspirin dose- and time-dependently induced CellEvent caspase-3/7+ cells as well as apoptosis and necrosis on PANC-1 cells.ConclusionThese findings signify a novel multimodality mechanism(s) of action for aspirin and celecoxib, specifically targeting and inhibiting Neu-1 activity, regulating EGF-induced growth receptor activation and inducing apoptosis and necrosis in a dose- and time-dependent manner. Repurposing aspirin and celecoxib as anti-cancer agents may also upend other critical targets involved in multistage tumorigenesis regulated by mammalian neuraminidase-1.SignificanceThese findings may be the missing link connecting the anti-cancer efficacy of NSAIDs to the role of glycosylation in inflammation and tumorigenesis.