Use Of COX-2 Inhibitors Research Articles

Immunohistochemical Investigation of Cyclooxygenase-2 Expression in Rabbit Uterine Adenocarcinoma and the Potential Use of COX-2 Inhibitors in Cancer Therapy

Cyclooxygenase-2 (COX-2) is overexpressed in many human and animal cancers. Selective COX-2 inhibitors have shown antitumoral effects in tumors with a high expression of COX-2. This study evaluates (1) the expression of COX-2 in rabbit uterine adenocarcinomas, (2) the correlation between immunophenotypic expression and histopathological changes, and (3) the post-surgery response to therapy with COX-2 inhibitors. Forty rabbit uteri were divided into three groups: neoplastic, hyperplastic, and normal endometrium. A histological and immunohistochemical score was applied to investigate the tumor’s grade and the COX-2 expression. By histological evaluation, 30 cases of endometrial adenocarcinoma, 5 cases of endometrial hyperplasia and 5 normal endometria were found. Of the six cases of endometrial adenocarcinoma with follow-up available, four received a post-surgical treatment with meloxicam and two were treated by surgery alone. The survival time of the animals treated with meloxicam was longer than that observed in the untreated animals. A statistically significant difference in COX-2 IHS was observed between non-neoplastic endometrium and adenocarcinoma. The progressive increase in COX-2 expression from normal epithelium to carcinoma suggests that upregulation of COX-2 expression may play a role in tumor initiation and progression. Our findings suggest the possible use of COX-2 inhibitors in treating uterine adenocarcinoma in rabbits. Further study will be needed to confirm this hypothesis.

Physicians’ attitudes toward gastroprotective strategies for nonsteroidal anti-inflammatory drug prescription

Introduction There is a paucity of information regarding providers’ attitudes toward gastric-protective strategies with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs). We aimed to assess gastric-protective strategies used upon prescribing NSAIDs and providers’ awareness of societal guidelines for preventing NSAID-induced gastric complications. Methods A standardized 10-item questionnaire was sent to all orthopedic providers in North Carolina and South Carolina. The survey design and refinement were based on a literature review, item generation, and small and large focus group discussions. Results Forty-two orthopedists responded to the survey (response rate 16%). The most frequently used NSAIDs were meloxicam (79%), naproxen (69%), and ibuprofen (64%). NSAIDs were most commonly prescribed on an as-needed basis (52%), followed by <3 months (43%). The most common indications were degenerative arthritis (95%) and herniated disk (45%). Gastrointestinal adverse effects of NSAIDs were managed by discontinuing NSAID therapy (73%) or switching to a cyclooxygenase-2 (COX-2) inhibitor (40%). A small proportion were managed by referring to another physician (36%). Some clinicians prescribed gastric prophylaxis for patients at high risk for NSAID-induced gastric complications (24%). The academic setting was significantly associated with gastric prophylaxis and frequent assessment for NSAID-induced gastric adverse events. Providers with >20 years of experience showed similar trends. In low-risk patients, compliance with gastroprotective prophylaxis prescription was low (5%). Most providers were unaware of the societal guidelines for NSAID-induced gastric complications or the preventive strategies. Conclusion Prescription of gastric-protective medications with concurrent NSAID therapy is relatively low among orthopedists. Academic setting and higher years of experience showed a significant trend toward more gastric-protective medication prescription, COX-2 inhibitor use, and frequent assessments for gastric adverse events when prescribing NSAID therapy. Provider education on the latest societal guidelines and computer-based alerts can increase compliance and assessment for NSAID-induced gastric complications and preventive strategies.

Some Aspects and Convergence of Human and Veterinary Drug Repositioning.

Drug innovation traditionally follows a de novo approach with new molecules through a complex preclinical and clinical pathway. In addition to this strategy, drug repositioning has also become an important complementary approach, which can be shorter, cheaper, and less risky. This review provides an overview of drug innovation in both human and veterinary medicine, with a focus on drug repositioning. The evolution of drug repositioning and the effectiveness of this approach are presented, including the growing role of data science and computational modeling methods in identifying drugs with potential for repositioning. Certain business aspects of drug innovation, especially the relevant factors of market exclusivity, are also discussed. Despite the promising potential of drug repositioning for innovation, it remains underutilized, especially in veterinary applications. To change this landscape for mutual benefits of human and veterinary drug innovation, further exploitation of the potency of drug repositioning is necessary through closer cooperation between all stakeholders, academia, industry, pharmaceutical authorities, and innovation policy makers, and the integration of human and veterinary repositioning into a unified innovation space. For this purpose, the establishment of the conceptually new "One Health Drug Repositioning Platform" is proposed. Oncology is one of the disease areas where this platform can significantly support the development of new drugs for human and dog (or other companion animals) anticancer therapies. As an example of the utilization of human and veterinary drugs for veterinary repositioning, the use of COX inhibitors to treat dog cancers is reviewed.

Investigating the impact of the inflammatory immune microenvironment and steroids or COX-2 inhibitors usage on immunotherapy in advanced esophageal squamous cell carcinoma (ESCC): a propensity score matched analysis.

The research aimed to evaluate the connection between pre-treatment inflammatory biomarkers and clinical results in advanced esophageal squamous cell carcinoma (ESCC) receiving immune checkpoint inhibitors. Between 2019 and 2022, we analyzed 354 individuals diagnosed with metastatic ESCC who underwent immunotherapy. The study sought to evaluate the impact of specific inflammatory biomarkers (Neutrophil/Lymphocyte Ratio (NLR), C-reactive protein to albumin ratio (CRP/ALB) and Glasgow Prognostic Score (GPS), Cyclooxygenase-2 (COX-2) inhibitors or steroids usage on the effectiveness and survival outcomes of immunotherapy in advanced ESCC. The research utilized Kaplan‒Meier and Cox regression models alongside propensity score matching for analysis. The findings revealed that elevated pre-treatment NLR (11.0 vs. 14.6months, p = 0.021) and CRP/ALB (11.4 vs. 14.6months, p = 0.022) levels were significantly associated with poorer overall survival (OS) outcomes, while the use of steroids did not show a significant difference in OS (15.5 vs. 15.4months, p = 0.685) between groups. Similarly, no notable disparity in OS was observed between patients treated withCOX-2 inhibitors and those who were not (13.8 vs. 11.0months, p = 0.054). Lower levels of NLR and CRP/ALB prior to treatment were linked to better effectiveness and OS in immunotherapy for advanced ESCC. The study did not identify a significant relationship between OS in patients with esophageal cancer and the use of either steroids or COX-2 inhibitors.

Evaluation of systemic medications associated with diabetic retinopathy: a nested case–control study from the UK Biobank

AimsThis study aims to investigate the associations between commonly used systemic medications and diabetic retinopathy (DR).MethodsIndividuals with linked primary care prescription data from the UK Biobank were included. Cases were...

Contribution of non-steroidal anti-inflammatory drugs to breast cancer treatment: In vitro and in vivo studies.

Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been described in breast, urinary, colorectal, prostate, and lung cancers as being involved in tumor initiation, promotion, progression, angiogenesis, and immunosuppression. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for several medical conditions to not only decrease pain and fever but also reduce inflammation by inhibiting COX and its product synthesis. To date, significant efforts have been made to better understand and clarify the interplay between cancer development, inflammation, and NSAIDs with a view toward addressing their potential for cancer management. This review provides readers with an overview of the potential use of NSAIDs and selective COX-2 inhibitors for breast cancer treatment, highlighting pre-clinical in vitro and in vivo studies employed to evaluate the efficacy of NSAIDs and their use in combination with other antineoplastic drugs.

Abstract 1415: Reduction in photoimmunotherapy-induced edema with COX-2 inhibition: Combatting clinically relevant adverse events without compromising efficacy

Abstract ASP-1929 photoimmunotherapy (PIT), an investigational drug-device combination, consists of an epithelial growth factor receptor (EGFR)-targeting drug, cetuximab, conjugated to a light-activatable dye, IRDye® 700DX, and a laser light. Localized illumination results in rapid and selective tumor necrosis in the preclinical setting, and early clinical studies demonstrate a manageable safety profile in patients with head and neck squamous cell carcinoma. In the ongoing clinical trials, however, edema is a commonly reported adverse event and laryngeal edema, requiring prophylactic tracheostomy, has been noted in some patients. Thus, a critical need exists to provide clinicians with tools to manage ASP-1929 PIT-associated edema to ensure optimal patient outcome. To evaluate edema following cancer-targeted PIT, we developed a mouse tumor model and used it to characterize the mechanism of edema development and evaluate various methods for edema reduction. Briefly, cohorts of mice bearing syngeneic LL/2 tumors engineered to express Ephrin A2 (EphA2) were administered an anti-EphA2 antibody conjugated to IR700 (conjugate) or saline control. Light was applied 24h following administration and edema was measured by caliper. In control mice, light alone did not generate edema; however, mice treated with conjugate plus light showed a light-dose dependent increase in edema volume which peaked at 6h post light delivery. We next evaluated a series of inflammatory cytokines and immune cell populations in the blood and tumor region at the onset (2h), peak (6h), and resolution (24h) of PIT-induced edema. We found a striking increase in neutrophils (500-fold greater than control mice, n=10, p&amp;lt;0.0001) in the blood at the peak of edema formation coinciding with a significant increase in IL-6 (n=5, p&amp;lt;0.001) and IL-10 (n=5, p&amp;lt;0.05), indicating the onset of a heightened inflammatory response. To combat the edema formation, we next evaluated the effect of various anti-inflammatory drugs commonly used in the clinical setting. Cohorts of mice were administered conjugate plus light in the presence or absence of steroids or the selective COX-2 inhibitor meloxicam. Results show there is no reduction in edema by steroids regardless of timing of administration. Conversely, the addition of meloxicam resulted in a significant reduction in edema at all time points and light doses evaluated: 40-50% reduction at both 2h and 6h post-PIT when administered prophylactically and 25% reduction at 6h post-PIT when administered post-light (all settings, n=10, p&amp;lt;0.0001). Importantly, we found the reduction in edema with meloxicam was not associated with a loss of therapeutic benefit based on measurement of tumor growth. In conclusion, the use of COX-2 inhibitors may be directly translated to the clinic for the benefit of patients receiving ASP-1929 PIT and should undergo further evaluation. Citation Format: Gina Ma, Myra Gordon, Jason Lapetoda, Abram Lozano, Christopher M. Amantea, Takuya Osada, Amy H. Thorne. Reduction in photoimmunotherapy-induced edema with COX-2 inhibition: Combatting clinically relevant adverse events without compromising efficacy [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 1415.

COX2 Inhibitor Use and Type 2 Diabetes Treatment Intensification: a Registry-based Cohort Study

AimThis study examined the association between cyclooxygenase-2 inhibitor (COX2i) use and diabetes progression in people with type 2 diabetes. MethodsWe conducted a nation-wide cohort study using an Australian diabetes registry linked to medication dispensing data. We assessed time to diabetes treatment intensification among new users of COX2i compared to mild opioids. Inverse probability of treatment-weighted Cox regression models were used to adjust for age, sex, time since diabetes diagnosis, comorbidities, and socio-economic disadvantage. We conducted several sensitivity analyses, including per-protocol analyses and comparing use of any NSAID to mild opioids. ResultsThere were 8,071 new users of COX2i and 7,623 of mild opioid with 4,168 diabetes treatment intensifications over a median follow-up of 1.6 years. Use of COX2i was associated with decreased risk of treatment intensification when compared to mild opioid (HR 0.91, 95%CI 0.85-0.96). The results were not significant in the per-protocol analyses. Use of any NSAID was associated with a lower risk of treatment intensification compared to mild opioid (HR 0.90, 95%CI 0.85-0.96). ConclusionsTreatment with COX2i may be associated with a modest decreased risk of diabetes treatment intensification compared to mild opioids. Future clinical studies are required to confirm whether COX2 inhibition has clinically significant benefits for glycaemic control.

COX-2/sEH-Mediated Macrophage Activation Is a Target for Pulmonary Protection in Mouse Models of Chronic Obstructive Pulmonary Disease

Effective inhibition of macrophage activation is critical for resolving inflammation and restoring pulmonary function in patients with chronic obstructive pulmonary disease (COPD). In this study, we identified the dual-enhanced cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD and in macrophages exposed to cigarette smoke extract. Pharmacological reduction of the COX-2 and sEH by 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) effectively prevented macrophage activation, downregulated inflammation-related genes, and reduced lung injury, thereby improving respiratory function in a mouse model of COPD induced by cigarette smoke and lipopolysaccharide. Mechanistically, enhanced COX-2/sEH triggered the activation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, leading to the cleavage of pro-IL-1β into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic drug for the treatment of COPD.

Non-steroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors Do Not Affect Healing After Rotator Cuff Repair: A Systematic Review and Meta-analysis

To determine whether non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors affect healing rate, functional outcomes, and patient satisfaction after rotator cuff repair. Medline, EMBASE, PsychINFO and the Cochrane Library were searched for randomized controlled trials (RCTs) investigating the use of NSAIDs and COX-2 inhibitors after arthroscopic rotator cuff repair. Primary outcomes included healing and retear rate, determined by radiological imaging. Secondary outcomes included shoulder-specific outcome measures and the visual analog scale (VAS). Risk of bias was graded using the Cochrane risk-of-bias v2.0 tool. The GRADE framework was used to assess certainty of findings. Seven RCTs with a total of 507 patients were included (298 randomized to NSAID/COX-2 vs 209 randomized to control). NSAIDs use did not yield a difference in retear rate (P= .77). NSAIDs were shown to significantly reduce pain in the perioperative period (P= .01); however, no significant difference was present at a minimum of 6 months (P= .11). COX-2 inhibitors did not significantly reduce pain (P= .15). Quantitative analysis of ASES and UCLA scores showed NSAIDs significantly improved functional outcomes versus control (P= .004). COX-2 inhibitors did not significantly improve functional outcomes (P= .15). Two trials were deemed "low" risk of bias, four trials were graded to have "some concerns", and one trial was graded to have "high" risk of bias. Retear rate and functional PROMs were deemed to have "low" certainty. VAS pain scale was graded to have "moderate" certainty. This systematic review and meta-analysis indicates that NSAIDs do not affect healing rate after arthroscopic rotator cuff repair, but they do significantly improve postoperative pain and functional outcomes. No significant difference was seen in pain or functional outcomes with the use of COX-2 inhibitors. Level I, meta-analysis of randomized controlled trials.

Selective COX-2 Inhibitor Is Beneficial in Suppressing Chronic Postsurgical Pain in Esophageal Cancer Patients and May Prolong Patient Survival

Introduction: Chronic postsurgical pain (CPSP) is a common complication after surgical procedures. Radical resection of esophageal cancer is a complex procedure, one of the most extensive and traumatic surgical procedures in oncological surgery, and the incidence of postoperative chronic pain is high, seriously affecting patients’ postoperative recovery. Therefore, this study aimed to investigate the incidence of CPSP in patients with esophageal cancer and to analyze the risk factors associated with its occurrence in order to provide certain prevention and treatment ideas for clinical prevention and reduction of CPSP. Methods: Patients with radical esophageal cancer resection were selected as the study subjects, and the clinical data regarding to patients’ preoperative comorbidities, ASA grading, surgical method, use of selective COX-2 inhibitors, postoperative analgesic pump use, and patients’ postoperative tumor recurrence time were collected. The differences in clinical data between the CPSP group and no-CPSP group were compared to analyze the risk factors for the occurrence of CPSP. Results: A total of 262 patients were included; 57 (21.76%) developed CPSP, and there were statistical differences between the two groups in terms of selective COX-2 inhibitor and postoperative analgesic pump use rates and surgical modality (p < 0.05), and logistic regression analysis showed that age and length of surgery increased the risk of CPSP, perioperative selective COX-2 inhibitor use decreased the risk of CPSP occurrence (p < 0.05), the extent of tumor infiltration and regional lymph node metastasis were risk factors for shortening tumor-free survival (TFS), and age and use of selective COX-2 inhibitor were influential factors for prolonging TFS (p < 0.05). Conclusion: Patients with esophageal cancer have a high incidence of postoperative chronic pain, with youth and length of surgery being risk factors for CPSP, and perioperative pain management with selective COX-2 inhibitors can reduce the incidence of CPSP and is associated with prolonged TFS.

Non-steroidal anti-inflammatory drugs and risk of pulmonary embolism in patients with inflammatory joint disease-results from the nationwide Norwegian Cardio-rheuma registry.

Patients with inflammatory joint diseases (IJD), including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) have increased rates of pulmonary embolism (PE). Non-steroidal anti-inflammatory drugs (NSAIDs) use is associated with PE in the general population. Our aim was to evaluate the association between NSAIDs use and PE in IJD patients. Using individual-level registry data from the whole Norwegian population, including data from the Norwegian Patient Registry and the Norwegian Prescription Database, we: (1) evaluated PE risk in IJD compared to non-IJD individuals, (2) applied the self-controlled case series method to evaluate if PE risks were associated with use of traditional NSAIDs (tNSAIDs) and selective cox-2 inhibitors (coxibs). After a one-year wash-out period, we followed 4660475 adults, including 74001 with IJD (RA: 39 050, PsA: 20803, and axSpA: 18591) for a median of 9.0 years. Crude PE incidence rates per 1000 patient years were 2.02 in IJD and 1.01 in non-IJD individuals. Age and sex adjusted hazard ratios for PE events were 1.57 for IJD patients compared to non-IJD. Incidence rate ratios (IRR) [95% confidence interval (CI)] for PE during tNSAIDs use were 0.78 (0.64-0.94, P=0.010) in IJD and 1.68 (1.61-1.76, P<0.001) in non-IJD. IRR (95% CI) for PE during coxibs use was 1.75 (1.10-2.79, P=0.018) in IJD and 2.80 (2.47-3.18, P<0.001) for non-IJD. Pulmonary embolism rates appeared to be higher in IJD than among non-IJD subjects in our study. Traditional NSAIDs may protect against PE in IJD patients, while coxibs may associated with increased PE risk.

COX inhibitor use during definitive radiotherapy is associated with worse hearing preservation in patients with vestibular schwannoma.

Patients with vestibular schwannoma undergoing definitive radiotherapy commonly experience hearing loss due to tumor and treatment effects; however, there is limited data evaluating concurrent medication use and other clinicopathologic factors associated with hearing preservation during and after radiotherapy. We performed a retrospective cohort study reviewing consecutive patients from 2004 to 2019 treated with radiotherapy for vestibular schwannoma at our institution. Ninety four patients with concurrent medications, baseline audiograms, and post-radiotherapy audiograms available were evaluable. We performed chi-squared analyses of the frequency of various clinicopathologic factors and t-tests evaluating the degree of hearing loss based on audiograms. At a median follow-up of 35.7months (mean: 46.5months), the baseline pure-tone average (PTA) of the ipsilateral ear worsened from 38.4 to 59.5dB following completion of radiotherapy (difference: 21.1, 95% CI 17.8-24.4dB, p < 0.001). 36 patients (38.3%) reported regular use of cyclooxygenase (COX) inhibitors (including acetaminophen and NSAIDs) during radiotherapy. The mean increase in PTA was significantly higher for patients taking COX inhibitors (25.8dB vs 18.1dB, p = 0.024) in the ipsilateral ear but not for the contralateral side. COX inhibitor use remained independently associated with worse PTA in the multivariate analysis. COX inhibitor use during definitive radiotherapy is associated with worse hearing loss in the affected ear but not for the contralateral side. This suggests the ototoxic effects of COX inhibitors may influence the effects of radiotherapy. These results could have clinical implications and warrant further investigation.

Evaluation of cyclooxygenase-2, P53, vascular endothelial growth factor, and nitric oxide synthase-2 in angiogenesis and growth of tobacco-related malignancies

Objectives: In India, tobacco consumption is responsible for half of all the cancers in men and a quarter in women. The present study focuses on the expression of cyclooxygenase-2 (COX-2), P53, vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS) and their relationship with the growth and angiogenesis of tobacco-related malignancies of the oral cavity, esophagus, lungs, and stomach. It further evaluates the carcinogenic action of nicotine and examines whether COX-2 and NOS-2 overexpression is responsible for tumor growth and associated angiogenic VEGF expression via its receptor. Materials and Methods: A cross-sectional study on 140 biopsies, resected specimens of cancer of oral cavity, esophagus, stomach, and lungs, was done. Immunohistochemical evaluation for p53, COX-2, VEGF, and inducible NOS was done. Relevant statistical analysis was applied for the significance of the findings. Statistical Analysis: Relevant statistical analysis was done using SPSS, chi-square and Fisher's exact tests were applied for the significance of the findings. A p-value of &lt; 0.05 was considered as significant value. Results: Immunohistochemical evaluation of pattern of expression of COX-2, NOS-2, VEGF, and p53 was done in both tobacco- and nontobacco-associated cases. The results of the present study revealed an upregulation of COX-2, NOS-2, VEGF, and p53 in all the malignancies. Conclusion: The present results indicated that p53 protein accumulation and increased expression of COX-2, NOS-2, and VEGF might be responsible for carcinogenesis and tumor aggressiveness by enhancing angiogenesis. A possible significant effect of nicotine on COX-2 and P53 expression in tumorigenesis is revealed. These data might have important implications for the therapeutic use of COX-2, NOS-2, and VEGF inhibitors as well as of p53 gene therapy in future anticancer therapeutic strategies in tobacco-related malignancies.

Clinical Use of COX-2 Inhibitors Containing Quinoline Heterocycle as a Selective Therapeutic Agents for Complementary Medicine

Clinical Use of COX-2 Inhibitors Containing Quinoline Heterocycle as a Selective Therapeutic Agents for Complementary Medicine

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders.

The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE2-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE2, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE2 participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE2. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE2 upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE2 have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.

PDE5 inhibitors and gastric mucosa: implications for the management of peptic ulcer disease.

Peptic ulcer disease (PUD) continues to be a cause of significant morbidity and mortality worldwide. Almost two-thirds of PUD cases are asymptomatic. In symptomatic patients, epigastric pain is the most common presenting symptom of PUD, which is manifested by nausea, abdominal fullness, bloating, and dyspepsia. Most PUD cases are associated with the use of COX inhibitors or Helicobacter pylori infection, or both. The traditional management of PUD includes the use of proton pump inhibitors to reduce the gastric acid secretion and antibacterial drugs to combat H. pylori. Timely diagnosis and treatment of PUD are vital to reduce the risk of associated morbidity and mortality, as is prevention of PUD among patients at high risk, including COX inhibitors users and those infected with H. pylori. PDE5 inhibitors have been used for the management of erectile dysfunction and pulmonary hypertension for decades. In recent years, studies have mentioned tremendous pleiotropic effects of PDE5 inhibitors on gastrointestinal, urogenital, musculoskeletal, reproductive, cutaneous, and neurologic disorders. Recent data shows that PDE5 inhibition augments gastric mucosa protection, and here, we review the most recent findings regarding the use of PDE5 inhibitors for the prevention and management of PUD.

Nonsteroidal Anti-inflammatory Drugs in the Acute Post-operative Period Are Associated With an Increased Incidence of Pseudarthrosis, Hardware Failure, and Revision Surgery Following Single-level Spinal Fusion.

Retrospective study. Research has shown that the use of NSAIDs and COX-2 inhibitors increases the risk of pseudoarthrosis following spinal fusion surgery. Pseudoarthrosis can lead to complications such as chronic pain and the need for additional surgeries. The purpose of this study was to examine the relationship between NSAID and COX-2 inhibitor use and pseudarthrosis, hardware complications, and revision surgeries in patients undergoing posterior spinal instrumentation and fusion. We queried the PearlDiver database using CPT and ICD-10 codes to identify patients between the ages of 50 and 85 who underwent posterior spinal instrumentation between 2016 and 2019 and experienced pseudarthrosis, hardware failure, or revision surgery. Information regarding age, Charlson Comorbidity Index, tobacco use, osteoporosis, and obesity were extracted from the database along with COX-2 or NSAID use during the first 6-week post-surgery period. Logistic regression was used to identify associations while adjusting for confounders. There were 178,758 patients included in the cohort; 9,586 experienced pseudarthrosis (5.36%), 2828 (1.58%) experienced hardware failure, and 10,457 (5.85%) patients underwent revision fusion surgery. Of these patients 23,602 (13.2%) filled NSAID and 5278 (2.95%) filled COX-2 prescriptions. A significantly higher proportion of patients using NSAIDs experienced pseudarthrosis, hardware failure, and revision surgery compared to patients not taking NSAIDs. COX-2 inhibitors were also associated with a significantly higher rate of pseudarthrosis, hardware failure, and revision surgery. Postoperative ketorolac use was not associated with these complications. Regression models demonstrated that both NSAIDs and COX-2 inhibitors were associated with statistically higher pseudarthrosis, hardware failure, and revision surgery rates. Both NSAID and COX-2 inhibitor use in the early post-surgical period may be associated with increased rates of pseudarthrosis, hardware failure, and revision surgery in patients undergoing posterior spinal instrumentation and fusion.

Increased Risk of Stiffness following Total Knee Arthroplasty with Direct Oral Anticoagulants and Avoidance of Selective COX-2 Inhibitors

Background Database studies demonstrate a strong association between use of direct oral anticoagulant (DOAC) medications and stiffness following total knee arthroplasty (TKA). The goal of this study was to evaluate whether the risk of stiffness in patients receiving a DOAC was affected by concomitant use or avoidance of a selective COX-2 inhibitor, when compared to a control group of patients receiving aspirin. Methods Consecutive primary TKA’s performed at a single institution between January 2014 - September 2019 were retrospectively reviewed. During this period, a risk-stratification algorithm for prophylaxis against venous thromboembolism (VTE) was used, with DOACs selected for patients at elevated VTE risk and aspirin for the remainder. Patients who required manipulation under anesthesia (MUA) within six months of index TKA were identified. Arc of motion (AOM) data at 6-weeks, 3-months, and 1-year was collected. Patients were divided into 3 groups based on postoperative medications prescribed: (a) Aspirin, (b) DOAC alone, and (c) DOAC + NSAID. Categorical variables were analyzed using Fisher’s Exact Tests and Pearson’s Chi-Square, while continuous variables were analyzed using Student’s T-test. Multivariate logistic regression was used to assess MUA risk while controlling for demographic differences. Results Forty patients underwent MUA from a population of 1,358 TKAs (2.9%). There was a significantly increased risk of MUA in patients where DOACs were used and concomitant NSAIDs were avoided when compared to the control group of patients receiving aspirin (5.4% vs 2.7%, OR 3.17; p = 0.029). This increased risk was not present when DOACs were used concomitantly with NSAIDs (3.1% vs 2.7%, OR 1.30; p = 0.573). In addition, less consistent AOM was achieved at 1-year postoperatively in the DOAC alone group compared to the control group of patients receiving aspirin (p=0.034). Conclusions Compared to aspirin anticoagulation, patients receiving DOACs without concomitant NSAIDs were more likely to develop postoperative stiffness requiring MUA and achieved less predictable AOM. The addition of selective COX-2 inhibitors may mitigate some risk of stiffness following primary TKA when anticoagulation with DOACs is necessary.

An Investigation of Insulin Resistance and Cachexia Relation in Patients with Metastatic Gastrointestinal Malignancies

Background: Insulin resistance has been suggested as one of the known metabolic disorders during cachexia. This study hypothesized that cachexia in cancer patients might be related to insulin resistance as early as cachexia development.&#x0D; Methods: This study was performed on 46 patients with metastatic gastrointestinal cancer. Anthropometric characteristics and biochemical markers were assessed at baseline, second and third month. Insulin resistance was assessed using the homeostasis model assessment-estimated insulin resistance (HOMA IR) method. SFQ-36 questions were used to assess the patients' quality of life at baseline, second and third months.&#x0D; Results: Anthropometric characteristic was significantly associated between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol (P-value = 0.93), albumin (P-value: 0.82), and serum creatinine (P-value = 0.88) in pre-cachectic patients decreased over three months. There was an increasing trend of insulin resistance between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol had an upward trend with a significant relation in cachectic patients [(P-value = 0.00), (P-value = 0.03), (P-value = 0.01)]. We detected a decreasing trend of insulin resistance between cachectic and non-cachectic patients from second to third month (P-value = 0.04). SFQ evaluation had no significant relation with cachectic status.&#x0D; Conclusion: Previous studies showed that the use of NSAIDs, progesterone’s, corticosteroids, COX-2 inhibitors, anabolic agents and drugs targeting inflammatory cytokines may be beneficial for improving of symptoms of cachexia. Significant relation between anthropometric variables with pre-cachexia and cachectic conditions was concluded. Patients' outcome and its relation with insulin resistance demonstrated a significant relation between the cachectic and non-cachectic patients in the third month. We also detected the increased serum cholesterol level in cachectic patients, moreover, higher cholesterol levels in expired cachectic patients than in the living.