Selective Cyclooxygenase-2 Inhibitor Research Articles

Does Celecoxib Prescription for Pain Management Affect Post-tonsillectomy Hemorrhage Requiring Surgery? A Retrospective Observational Cohort Study.

Adenotonsillectomy and tonsillectomy (referred to as tonsillectomy hereafter) are common pediatric surgeries. Postoperative complications include hemorrhage requiring surgery (2 to 3% of cases) and pain. Although nonsteroidal anti-inflammatory drugs are commonly administered for postsurgical pain, controversy exists regarding bleeding risk with cyclooxygenase-1 inhibition and associated platelet dysfunction. Preliminary evidence suggests selective cyclooxygenase-2 inhibitors, for example celecoxib, effectively manage pain without adverse events including bleeding. Given the paucity of data for routine celecoxib use after tonsillectomy, this study was designed to investigate the association between postoperative celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery using chart-review data from the Children's Hospital of Eastern Ontario. After ethics approval, a retrospective single-center observational cohort study was performed in children less than 18 yr of age undergoing tonsillectomy from January 2007 to December 2017. Cases of adenoidectomy alone were excluded due to low bleed rates. The primary outcome was the proportion of patients with post-tonsillectomy hemorrhage requiring surgery. The association between a celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery was estimated using inverse probability of treatment weighting based on propensity scores and using generalized estimating equations to accommodate clustering by surgeon. An initial patient cohort of 6,468 was identified, and 5,846 children with complete data were included in analyses. Median (interquartile range) age was 6.10 (4.40, 9.00) yr, and 46% were female. In the cohort, 28.1% (n = 1,644) were prescribed celecoxib. Among the 4,996 tonsillectomy patients, 1.7% (n = 86) experienced post-tonsillectomy hemorrhage requiring surgery. The proportion with post-tonsillectomy hemorrhage requiring surgery among patients who had a tonsillectomy and were or were not prescribed celecoxib was 1.94% (30 of 1,548; 95% CI, 1.36 to 2.75) and 1.62% (56 of 3,448; 95% CI, 1.25 to 2.10), respectively. Modeling did not identify an association between celecoxib prescription and increased odds of post-tonsillectomy hemorrhage requiring surgery (odds ratio = 1.4; 95% CI, 0.85 to 2.31; P = 0.20). Celecoxib does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery, after adjusting for covariates. This large pediatric cohort study of celecoxib administered after tonsillectomy provides compelling evidence for safety but requires confirmation with a multisite randomized controlled trial.

Selection of NSAIDs for rational pharmacotherapy of chronic musculoskeletal pain: a clinical pharmacologist's perspective

Chronic musculoskeletal pain (CMSP) is one of the most common pathological conditions that limits patients' physical activity and reduces their quality of life. The analgesic and anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) make them the basis of pharmacotherapy for patients with chronic conditions affecting various parts of the musculoskeletal system. The main target of NSAIDs, cyclooxygenase (COX), exists in the form of two main isoforms, COX-1 and COX-2, the inhibition of each of which leads to a cascade of reactions at the cellular and tissue level that can cause both targeted pharmacological effects and side effects. The diversity of the chemical structures of NSAIDs leads to differences in their pharmacodynamic and pharmacokinetic parameters and correspondingly to differences in their efficacy and safety profile. Selective COX-2 inhibitors, coxibs, have shown an increased risk of cardiovascular side effects, which has led to significant restrictions on their use. Cardiotoxicity is not as pronounced with the non-selective COX inhibitors, but the range of their side effects is extremely wide. These side effects are dose-dependent and are characteristic, first of all, of systemic NSAIDs.The combination of systemic and topical NSAIDs makes it possible to reduce the dose of the former and improve the safety profile of anti-inflammatory therapy. Among the non-selective COX inhibitors with a satisfactory safety profile and high anti-inflammatory activity, the group of oxicams and especially tenoxicam should be emphasised, which are characterised by a maximum duration of action, which is an advantage in the treatment of patients with CMSP. This review addresses the issues of rational selection of NSAIDs based on comparative data on pharmacodynamics, pharmacokinetics and clinical trial results.

Fenamates and ibuprofen as foundational components in the synthesis of innovative, targeted COX-2 anti-inflammatory drugs, undergoing thorough biopharmacological assessments and in-silico computational studies

Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 μM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.

Enhanced potent immunosuppression of intracellular adipose tissue-derived stem cell extract by priming with three-dimensional spheroid formation

Immunomodulatory properties of mesenchymal stem cells are widely studied, supporting the use of MSCs as cell-based therapy in immunological diseases. This study aims to generate cell-free MSC extract and improves their immunomodulatory potential. Intracellular extracts were prepared from adipose-derived stem cells (ADSC) spheroid via a freeze-thawing method. The immunomodulatory capacities of ADSC spheroid extracts were investigated in vitro, including lymphocyte proliferation, T regulatory cell expansion, and macrophage assays. A comparative study was conducted with ADSC monolayer extract. The key immunomodulatory mediators presented in ADSC extract were identified. The results revealed that ADSC spheroid extract could suppress lymphocyte activation while enhancing T regulatory cell expansion. Immunomodulatory molecules such as COX-2, TSG-6, and TGF-β1 were upregulated in ADSC priming via spheroid culture. Selective inhibition of COX-2 abrogates the effect of ADSC extract on inducing T regulatory cell expansion. Thus, ADSC spheroid extract gains high efficacy in regulating the immune responses which are associated in part by COX-2 generation. Furthermore, ADSC spheroid extract possessed a potent anti-inflammation by manipulation of TNF-α production from LPS-activated macrophage. Our current study has highlighted the opportunity of using cell-free extracts from adipose tissue-derived mesenchymal stem cells spheroid as novel immunomodulators for the treatment of immunological-associated diseases.

Synthesis and anti-HCV activity of novel 5-arylmethylene-1,3-thiazolidin-4-one derivatives via suppression of NS5B polymerase and COX-2

Hepatitis C (HCV) is a viral infection that leads to forms of acute and chronic liver disease, including cirrhosis (scarring of the liver) and liver cancer. The World Health Organization (WHO) estimated in 2019 that approximately 290,000 people died from hepatitis C (mostly from cirrhosis and hepatocellular carcinoma). Direct-acting antiviral drugs (DAAs) can cure more than 95% of individuals with hepatitis C infection, while research on the discovery of new antiviral agents is still ongoing. The Hepatitis C virus (HCV) can cause various biochemical changes in liver cells, and some of these changes are associated with the COX-2 enzyme. The identification of its role in promoting growth in liver cells as well as its involvement in various cancer types, including hepatocellular carcinoma, has made COX-2 an important target in the development of new agents effective against HCV. In this study, thirty-six new 5-arylmethylene-2-imino-1,3-thiazolidin-4-one derivatives (5a-s, 6a-s) were synthesized through Knoevenagel condensation of 2-[(4-substitutedpyridin-2-yl)imino]-1,3-thiazolidin-4-one derivatives with various aldehydes. Structures of the synthesized compounds were elucidated by the use of spectral and chromatographic techniques, besides elemental analyses. Four compounds were selected for further studies as they were found to suppress the NS5B protein with anti-HCV activity using the Western Blotting method. The selected compounds 5o, 6m, 6r, and 6s inhibited HCV with EC50 values of 8.0 ± 0.2 µM, 13.9 ± 0.45, 9.2 ± 0.2 µM, and 12.1 ± 0.1 µM, respectively. It was determined that these compounds reduced HCV-induced COX-2 promoter activity in Ava5 cells compared to Huh7 cells. The antiviral effects of the compounds were also investigated on DENV, closely related to HCV due to sharing certain biological, structural, and mechanical properties throughout their life cycles. However, no significant effect was observed in the preliminary screening study, indicating the compounds' specificity for HCV. Considering the relationship between HCV, DENV, and COX-2, the compounds' COX-1 and COX-2 enzyme inhibition potentials were investigated both in vitro and in silico. Compounds 6d, 6e, 6f, and 6m, which exhibited high selective COX-2 inhibition, were discussed for their interactions with the active site. Our study revealed that our target compounds suppressed COX-2 both at the protein level and through enzyme inhibition, thus providing promising findings for the discovery of new anti-HCV effective COX-2 inhibitors.

Quantification of Etoricoxib in Low Plasma Volume by UPLC-PDA and Application to Preclinical Pharmacokinetic Study.

An ultra-performance liquid chromatography with photodiode array (UPLC-PDA) UV detection method was developed here for the first time for simple, rapid, selective and sensitive quantification of the commonly prescribed selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib in low plasma volumes (50 μL). The method includes protein precipitation followed by liquid-liquid extraction, evaporation and reconstitution. A gradient mobile phase of 75:25 going to 55:45 (v/v) water:acetonitrile (1 mL/min flow rate) was applied. Total run time was 8 min, representing a significant improvement relative to previous reports. Excellent linearity (r2 = 1) was obtained over a wide (0.1-12 µg/mL) etoricoxib concentration range. Short retention times for etoricoxib (4.9 min) and the internal standard trazodone (6.4 min), as well as high stability, recovery, accuracy, precision and reproducibility, and low etoricoxib LOD (20 ng/mL) and LOQ (100 ng/mL), were achieved. Finally, the method was successfully applied to a pharmacokinetic study (single 20 mg/kg orally administered etoricoxib mini-capsule) in rats. In conclusion, the advantages demonstrated in this work make this analytical method both time- and cost-efficient for drug monitoring in pre-clinical/clinical settings.

Design, Synthesis, In Silico Study and Anti-Inflammatory Evaluation of New Ketoprofen Thiourea Derivatives

The In the current study, six new derivatives of ketoprofen thiourea were designed and synthesized In order to enhance COX-2 enzyme selectivity. The chemical structures of these derivatives were confirmed by spectral analysis. The anti-inflammatory activities of these derivatives was investigated insilico and in vivo. The results revealed that compound B4 were the most active. The new derivatives also showed drug-likeness and gastric absorption as predicted by computational methods. These results above indicated that the synthesized compounds deserve additional investigation as potential selective COX-2 inhibitors.

Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors.

Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Comparative disposition kinetics of oral deracoxib in sheep and goats.

This study investigates the pharmacokinetics (PK) of deracoxib (DX), a selective COX-2 inhibitor, in sheep and goats following a single oral dose. DX, approved for dogs, holds potential as an alternative NSAID in small ruminants, particularly in light of heightened concern regarding abomasal ulceration. The study employed an oral administration of DX at a dose of 150 mg/head (sheep and goats), and plasma concentrations were determined after validating a high-performance liquid chromatography method, coupled to a UV detector. The PK parameters, including maximum plasma concentration (Cmax), time to reach Cmax (Tmax), elimination half-life (t1/2), and area under the curve (AUC), were evaluated through non-compartmental analysis. Results showed detectable DX in plasma up to 48 h, with no observed adverse effects. No significant differences in any PK parameters were noted between sheep and goats. Notably, t1/2 values were relatively long, at 16.66 h for sheep and 22.86 h for goats. Despite the fact that both species exhibited comparable drug exposure, high individual variability was noted within each species, suggesting to take into account individual variations in response to DX treatment, rather than species-specific considerations. Additional research involving pharmacodynamics and multiple-dose studies is warranted to comprehensively assess the profile of DX in these species.

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<0.0001) in the blood at the peak of edema formation coinciding with a significant increase in IL-6 (n=5, p<0.001) and IL-10 (n=5, p<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<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.

Abstract 182: Cyclooxygenase-2 blockade is crucial to restore natural killer cell activity before anti-CTLA-4 therapy against high-grade serous ovarian cancer

Abstract Objective: Here our goal was to evaluate the impact of the immunosuppressive enzyme cyclooxygenase-2 (COX-2) expression on the immune effector capacity against high-grade serous ovarian cancer (HGSOC) tumor cells through bioinformatic tools and in vitro validation. Methods: We performed an integrated bioinformatics analysis from transcriptomic data based on RNAseq (TCGA-OV, n=368; Australian cohort AOCS, n=80) and RNA microarrays (GSE26193, n=62; GSE30161, n=45). We estimated the proportion and characteristics of immune cells employing Gene Set Variation Analysis (GSVA), MIXTURE and Ecotyper cell deconvolution algorithms. Survival curves and Cox-regression models were built up according to known risk factors and immune scores predicted by in-silico analysis. Afterward, we validated these results using flow cytometry and cytotoxicity assays on circulating NK cells collected from advanced HGSOC patients treated at our institution (n=5). After three days of incubation, isolated NK cell cultures were stimulated with three pulses of a selective COX-2 inhibitor (celecoxib) or MOCK, daily. An anti-CTLA-4 monoclonal antibody (ipilimumab) or MOCK was added at the third pulse. Two ovarian cancer cell lines (SKOV3 and HeyA8) were treated similarly. Next, NK cells were co-cultured with SKOV3 or HeyA8 and cytotoxicity on these cells was examined using lactate dehydrogenase (LDH) cell viability assay. Results: Transcriptomic data evidenced a non-linear relationship between COX-2 gene, PTGS2, and CTLA4 in advanced stages of HGSOC. Hence, PTGS2/CTLA4 ratio allows us to investigate how COX-2 influences changes in the immune profile of these patients. Based on bioinformatics, a high PTGS2/CTLA4 ratio determines particularly dysfunctional NK cell states, along with the reduction of NK gene score associated with infiltration, cytotoxicity, and survival in HGSOC. Additionally, selective COX-2 blockade improves NK cell cytotoxicity against HGSOC cell lines independently of the CTLA-4 signaling. In fact, ipilimumab effect was almost absent in those cases with high COX2 activity. Interestingly, previous treatment with celecoxib on NK cells mainly explains the difference in cytotoxicity (p= 0.0253, two-way ANOVA test with Tukey’s multiple comparisons). Conclusions: This work represents the first evidence of the influence of COX-2 on NK cell function as a crucial factor for the efficacy of anti-CTLA-4 therapy in HGSOC patients who exhibited high tumoral levels of CTLA-4. HGSOC patients present dysfunctional circulating NK cells preferentially due to the strong CO-2 expression. Last, we emphasize the modulation of chronic inflammation to direct an immune pattern with greater antitumor capacity in HGSOC. (Funding: Fondecyt 1201083 and FONDAP 152220002 [MAC], CONICYT/Doctorado Nacional 2019-Folio 21190421 [FGV], CONICYT FONDAP 15130011 [MAC, IW]). Citation Format: Fernan Gomez-Valenzuela, Ignacio Wichmann, Felipe Suárez, Sumie Kato, Enrique Ossandón, Marcela Hermoso, Elmer Fernández, Mauricio A. Cuello. Cyclooxygenase-2 blockade is crucial to restore natural killer cell activity before anti-CTLA-4 therapy against high-grade serous ovarian cancer [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 182.

Cardioprotective role of royal jelly in the prevention of celecoxib-mediated cardiotoxicity in adult male albino rats

BackgroundCelecoxib, a cyclooxygenase-2 selective inhibitor non-steroidal anti-inflammatory drugs, is used for the management of short- and long-term pain as well as in other inflammatory conditions. Unfortunately, its chronic use is highly associated with serious abnormal cardiovascular events. The current study was designed to explore the effect of long-term administration of celecoxib on the cardiac tissues of male albino rats. The study also examined the alleged cardioprotective effect of royal jelly.MethodsThirty, male albino rats were randomly divided into 3 equal groups; 10 each: (1) rats served as the control group and received no drug; (2) rats received celecoxib (50 mg/kg/day, orally), for 30 consecutive days; (3) rats received celecoxib (50 mg/kg/day, orally) plus royal jelly (300 mg/kg/day, orally) for 30 consecutive days. Sera were collected to assay cardiac enzymes and oxidant/antioxidant status. Rats were euthanatized and cardiac tissues were dissected for quantitative estimation of apoptotic genes (Bax) and anti-apoptotic gene (Bcl-2).ResultsLong-term celecoxib administration caused cardiotoxicity in male albino rats as manifested by significant elevation of serum levels of creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH), with ameliorative effects of royal jelly against celecoxib-induced cardiotoxicity as manifested by significantly decrease in serum CPK, CK-MB, and LDH levels. It also showed a significant decrease in the oxidative stress indicator malondialdehyde (MDA) levels and the bax gene. Additionally, it demonstrated significant increases in the bcl-2 gene and superoxide dismutase (SOD) levels, which contribute to its therapeutic effects against celecoxib-induced cardiotoxicity.ConclusionLong-term celecoxib administration caused cardiotoxicity in male albino rats with protective effect of royal jelly being given together. It could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib.Trial registrationNot applicable.

Design, Synthesis, and Biological Evaluation of Novel Phenoxy Acetic Acid Derivatives as Selective COX-2 Inhibitors Coupled with Comprehensive Bio-Pharmacological Inquiry, Histopathological Profiling, and Toxicological Scrutiny.

COX-2 plays a key role in converting arachidonic acid into prostaglandins. This makes it a significant target for treating inflammation. Selective COX-2 inhibitors have marked a new phase in inflammatory treatment, providing significant effectiveness while reducing negative side effects. Herein, we aimed at the design and synthesis of new anti-inflammatory agents 5a-f, 7a-b, 10a-f, and 13a-b with expected selective inhibition for COX-2. Compounds 5d-f, 7b, and 10c-f showed significant COX-2 inhibition with IC50 in the range of 0.06-0.09 μM, indicating powerful pharmacological potential. In light of this, eight compounds were selected for further testing in vivo to assess their selectivity toward COX-1/COX-2 enzymes with the ability to reduce paw thickness. Compounds 5f and 7b showed significant anti-inflammatory effects without causing stomach ulcers, as they showed significant in vivo inhibition for paw thickness at 63.35% and 46.51%, as well as paw weight at 68.26% and 64.84%. Additionally, the tested compounds lowered TNF-α by 61.04% and 64.88%, as well as PGE-2 by 60.58% and 57.07%, respectively. Furthermore, these potent compounds were thoroughly analyzed for their pain-relieving effects, histological changes, and toxicological properties. Assessing renal and stomach function, as well as measuring liver enzymes AST and ALT, together with kidney indicators creatinine and urea, offered valuable information on their safety profiles. Molecular modeling studies explain the complex ways in which the strong interacts with the COX-2 enzyme. This comprehensive strategy emphasizes the therapeutic potential and safety profiling of these new analogues for managing inflammation.

Pharmacodynamic and Pharmacokinetic Comparison between Selective and Non-selective COX-2 Inhibitors in Mice

Pharmacodynamic and Pharmacokinetic Comparison between Selective and Non-selective COX-2 Inhibitors in Mice

Modification of 4-(4-chlorothiophen-2-yl)thiazol-2-amine derivatives for the treatment of analgesia and inflammation: synthesis and in vitro, in vivo, and in silico studies.

Inflammation is a protective response to a variety of infectious agents. To develop a new anti-inflammatory drug, we explored a pharmacologically important thiazole scaffold in this study. In a multi-step synthetic approach, we synthesized seven new thiazole derivatives (5a-5g). Initially, we examined the in vitro anti-inflammatory potentials of our compounds using COX-1, COX-2, and 5-LOX enzyme assays. After in vitro confirmation, the potential compounds were subjected to in vivo analgesic and anti-inflammatory studies. The hot plate method was used for analgesia, and carrageenan-induced inflammation was also assayed. Overall, all our compounds proved to be potent inhibitors of COX-2 compared to celecoxib (IC50 0.05μM), exhibiting IC50 values in the range of 0.76-9.01μM .Compounds 5b, 5d, and 5e were dominant and selective COX-2 inhibitors with the lowest IC50 values and selectivity index (SI) values of 42, 112, and 124, respectively. Similarly, in the COX-1 assay, our compounds were relatively less potent but still encouraging. Standard aspirin exhibited an IC50 value of 15.32μM. In the 5-LOX results, once again, compounds 5d and 5e were dominant with IC50 values of 23.08 and 38.46μM, respectively. Standard zileuton exhibited an IC50 value of 11.00μM. Based on the COX/LOX and SI potencies, the compounds 5d and 5e were subjected to in vivo analgesic and anti-inflammatory studies. Compounds 5d and 5e at concentrations of 5, 10, and 20mg/kg body weight were significant in animal models. Furthermore, we explored the potential role of compounds 5d and 5e in various phlogistic agents. Similarly, both compounds 5d and 5e were also significantly potent in the anti-nociceptive assay. The molecular docking interactions of these two compounds with the target proteins of COX and LOX further strengthened their potential for use in COX/LOX pathway inhibitions.

Safety of partial selective COX-2 inhibitors in patients with cross-reactive NSAID hypersensitivity and factors affecting safety

Aims: Partial selective COX-2 inhibitors, such as nimesulide, or meloxicam are tolerated by the majority of the patients with cross-reactive NSAID hypersensitivity. This study aimed to obtain more information about the safety of partial selective COX-2 inhibitors; nimesulide and meloxicam in non-immunologic type, cross-reactive NSAID hypersensitivity and to detect risk factors for intolerance to these drugs.
 Methods: This is a retrospective study of patients with suggestive of cross-reactive NSAID hypersensitivity who admitted to our clinic over a period of 10 years. Patients who had a reliable history of immediate type NSAIDs hypersensitivity with at least 2 chemically unrelated class and/or positive ASA provocation test and who underwent alternative drug provocation test with partial selective COX-2 inhibitors (nimesulide and/or meloxicam) were included to study. Patients’ demographics, comorbidities, atopy status, duration of NSAID hypersensitivity, total number of reactions, reaction grades, clinical phenotypes, pulmonary function test parameters and results of alternative drug provocation test results are recorded. Patients with and without reactions during alternative provocation tests with nimesulide and/or meloxicam were compared in terms of these data. 
 Results: A total of 560 patients were included in the study, 378 (67.5%) of them were female. Allergic comorbidities were detected in 394 (72.6%) patients. Asthma, other drug allergies and nasal polyp were the most common comorbidities. Alternative drug provocation test positivity with nimesulide and/or meloxicam was detected in 50 of 560 (8.9%) patients. Provocation test positivity was 33/541 (6.1%) with nimesulide, 30/517 (5.8%) with meloxicam and 13/498 (2.3%) with both nimesulide and meloxicam. Duration of NSAID hypersensitivity was shorter and allergic comorbidities, asthma, nasal polyp and the coexistence of asthma and nasal polyp were more common in patients with a positive provocation test.
 Conclusion: The partial selective COX-2 inhibitors nimesulide and meloxicam are well tolerated alternatives in patients with cross-reactive NSAID hypersensitivity. Hypersensitivity to these drugs is significantly higher in patients with asthma and/or nasal polyp than other group of cross-reactive NSAID hypersensitive patients and also in patients with a shorter duration of NSAID hypersensitivity.

Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition

COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC50 = 1.53 μM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.

Nationwide Etoricoxib Injection Clinical Experience (NICE): Real-World Evidence in Indian Patients.

Introduction Pain is a major health issue globally. Etoricoxib, a highly selective COX-2 inhibitor, given orally, has been found to be efficacious and safe in the management of acute and chronic pain. Oral etoricoxib has been extensively studied; however, there is a lack of research exploring the use of etoricoxib via alternative routes, specifically intramuscular (IM) injection. This study aimed to evaluate the effectiveness and safety of an innovative and novel formulation of IM etoricoxib injection 90 mg/mL in the management of patients with acute pain in India. Method This was a real-world, multicenter, retrospective, observational study to investigate the effectiveness and safety of IM etoricoxib injection in the management of patients with acute pain in India (outpatient setting). The clinical data of 383 patients from 42 centers across India were collected from November 2022 to April 2023. Following approval from the site investigator, comprehensive patient-level information encompassing demographic and clinical variables as well as comorbidities was collected and entered into a case report form. Approval from the Independent Ethics Committee (IEC) and Institutional Review Board (IRB) was sought. The safety and effectiveness at 30 minutes and 60 minutes of IM etoricoxib injection were then analyzed. Results Among the studied patients, etoricoxib was used for the management of knee arthritis, fracture, post-traumatic pain, postoperative cases, acute back pain, back injury, torn ligament, and muscle strain and sprain. Of 383 patients, 98.17% had moderate-to-severe pain at baseline on the visual analogue scale (VAS) (0 being no pain and 10 being severe unbearable pain). The percentage of patients with severe pain reduced to only 6.78% and 4.17% at 30 minutes and 60 minutes, respectively. The improvement in the VAS score was statistically significant from baseline to 30 minutes and 60 minutes, and at 60 minutes compared to 30 minutes (p < 0.0001). More than half the patients (56.91%) had no pain at the site of the injection. Most of the doctors (70.23%) opined that the IM etoricoxib injection was better than their currently used NSAID injections for pain relief. Only 12.79% of patients required rescue analgesia post-IM etoricoxib injection. IM etoricoxib injection was well tolerated as 98.69% of the patients did not experience or report any adverse events post-IM injection. Conclusion This real-world, multicenter, retrospective, observational study across India demonstrated that the innovative and novel formulation of etoricoxib (90 mg/mL IM injection) was effective and well-tolerated in the management of acute pain. Overall, this study provides valuable insights into the real-world effectiveness and safety of IM etoricoxib injections, suggesting it could be a promising therapy for the management of acute pain for optimal patient benefit.

Dual COX-2 and 15-LOX inhibition study of novel 4-arylidine-2-mercapto-1-phenyl-1H-imidazolidin-5(4H)-ones: Design, synthesis, docking, and anti-inflammatory activity.

Novel arylidene-5(4H)-imidazolone derivatives 4a-r were designed and evaluated as multidrug-directed ligands, that is, inflammatory, proinflammatory mediators, and reactive oxygen species (ROS) inhibitors. All of the tested compounds showed cyclooxygenase (COX)-1 inhibitory effect more than celecoxib and less than indomethacin and also demonstrated an improved inhibitory activity against 15-lipoxygenase (15-LOX). Compounds 4f, 4l, and 4p exhibited COX-2 selectivity comparable to that of celecoxib, while 4k was the most selective COX-2 inhibitor. Interestingly, the screened results showed that compound 4k exhibited a superior inhibition effect against 15-LOX and was found to be the most selective COX-2 inhibitor over celecoxib, whereas compound 4f showed promising COX-2 and 15-LOX inhibitory activities besides its inhibitory effect against ROS production and its lowering effect of both tumor necrosis factor-α and interleukin-6 levels by ∼80%. Moreover, compound 4f attenuated the lipopolysaccharide-mediated increase in NF-κB activation in RAW 264.7 macrophages. The preferred binding affinity of these molecules was confirmed by docking studies. We conclude that arylidene-5(4H)-imidazolone scaffolds provide promising hits for developing new synthons with anti-inflammatory and antioxidant activities.

Sulfadiazine Exerts Potential Anticancer Effect in HepG2 and MCF7 Cells by Inhibiting TNFα, IL1b, COX-1, COX-2, 5-LOX Gene Expression: Evidence from In Vitro and Computational Studies.

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.