Target-guided isolation and purification of cyclooxygenase-2 inhibitors from Meconopsis integrifolia (Maxim.) Franch. by high-speed counter-current chromatography combined with ultrafiltration liquid chromatography.

Meconopsis integrifolia (Maxim.) Franch. is used extensively in traditional Tibetan medicine for its potent anti-inflammatory properties. In this study, six cyclooxygenase-2 (COX-2) inhibitors were purified from M. integrifolia using high-speed counter-current chromatography guided by ultrafiltration liquid chromatography (ultrafiltration-LC). First, ultrafiltration-LC was performed to profile the COX-2 inhibitors in M. integrifolia. The reflux extraction conditions were further optimized using response surface methodology, and the results showed that the targeted COX-2 inhibitors could be well enriched under the optimized extraction conditions. Then the six target COX-2 inhibitors were separated by high-speed countercurrent chromatography with a solvent system composed of ethyl acetate/n-butanol/water (4:1:4, v/v/v. Finally, the six COX-2 inhibitors, including 21.2 mg of 8-hydroxyluteolin 7-sophoroside, 29.6 mg of 8-hydroxyluteolin 7-[6'''-acetylallosyl-(1→2)-glucoside], 42.5 mg of Sinocrassoside D3, 54.1 mg of Hypolaetin 7-[6'''-acetylallosyll-(l→2)-3''-acetylglucoside, 30.6 mg of Hypolaetin 7-[6'''-acetylallosyll-(l→2)-6''-acetylglucoside and 17.8 mg of Hypolaetin were obtained from 500 mg of sample. Their structures were elucidated by 1 H-NMR spectroscopy. This study reveals that ultrafiltration-LC combined with high-speed counter-current chromatography is a robust and efficient strategy for target-guided isolation and purification of bioactive molecules. It also enhances the scientific understanding of the anti-inflammatory properties of M. integrifolia but also paves the way for its further medicinal applications.

Etoricoxib Coated Tablets: Bioequivalence Assessment between Two Formulations Administered under Fasting Conditions.

Etoricoxib is a non-steroidal anti-inflammatory drug with high selectivity for cyclooxygenase 2 (COX-2), exerting a pronounced anti-inflammatory effect with fewer adverse events when compared to COX-1 inhibitors. The present study aimed to evaluate the bioequivalence between two etoricoxib-coated tablet formulations to meet regulatory requirements for a branded generic product registration in Brazil. A crossover study with an open-label, randomized design and a single-dose regimen with two treatments and two periods was conducted on healthy Brazilians of both genders. Subjects randomly received a single dose of a 90 mg etoricoxib coated tablet of test product Xumer® 90 mg (Adium S.A.) and the reference product Arcoxia® 90 mg (Merck Sharp & Dohme Farmacêutica Ltda.) under fasting conditions separated by a 14-day period. Blood samples were collected sequentially for up to 96 h following drug administration, and the concentrations of etoricoxib in plasma were determined using a validated UPLC-MS/MS method. Pharmacokinetic parameters were computed utilizing non-compartmental analysis methods. A total of 32 healthy subjects were enrolled, and 25 subjects completed the study. Geometric mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-inf were 103.98% (95.63-113.06), 96.82% (91.82-102.09), and 95.79% (90.70-101.16), respectively. In accordance with regulatory standards, the test formulation (Xumer® 90 mg) has been deemed bioequivalent to the reference product (Arcoxia® 90 mg). As a result, these formulations can be considered interchangeable in clinical practice, with both proving to be safe and well-tolerated. The need for in vivo testing for the Xumer® 60 mg strength was waived due to the proportional similarity of the formulations and the similar in vitro dissolution profiles observed across the various strengths.

Pyridazine derivatives as selective COX-2 inhibitors: A review on recent updates.

Selective cyclooxygenase (COX)-2 inhibitors have several advantages over nonselective COX inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]), including the absence of adverse effects (renal and hepatic disorders) associated with the long-term use of standard NSAIDs, as well as an improved gastrointestinal profile. The pyridazine nucleus is regarded as a promising scaffold for the development of powerful COX-2 inhibitors, particularly when selectively functionalized. This article summarizes some methods for the synthesis of pyridazine derivatives. Furthermore, it covers all of the pyridazine derivatives that have appeared as selective COX-2 inhibitors, making it useful as a reference for the rational design of novel selective COX-2 inhibitors.

[Selective cyclooxygenase-2 inhibitor hypersensitivity]. / Hipersensibilidad selectiva a inhibidores de la ciclooxigenasa-2.

BACKGROUND: The cyclooxygenase-2 inhibitors are usually recommended as a safe alternative in patients with multiple hypersensitivity to non-steroidal antiinflammatory drugs. Nevertheless, both immediate and delayed hypersensitivity reactions have been described, and the possibility of cross-reactivity with sulphonamides. CASE REPORT: A 66-year-old patient who, after taking a celecoxib tablet, presented with latency of several hours a skin reaction. Previously, he had presented a minor reaction during treatment with etoricoxib without establishing the correlation at that time. The patient underwent an allergological study by means of skin tests with negative results and an oral challenged test with etoricoxib with positive results. Tolerance to sulfonamides was proven. CONCLUSIONS: We present a singular case of a cross-reactivity skin reaction to etoricoxib and celecoxib, suggesting the need to perform challenge tests to confirm the tolerance or not of each drug before allowing their use. On the contrary, trimethropim/sulfamethoxazole could be safely used in our patients, if needed.

INTRODUCCIÓN: Los inhibidores de la ciclooxigenasa-2 suelen indicarse en pacientes con hipersensibilidad múltiple a los antiinflamatorios no esteroides. Sin embargo, se han descrito reacciones de hipersensibilidad inmediata y retardada, además de posible reactividad cruzada con sulfonamidas. REPORTE DE CASO: Paciente masculino de 66 años, que acudió al servicio de Alergia por una reacción cutánea, luego de haber consumido un comprimido de celecoxib. Previamente, durante el tratamiento con etoricoxib, tuvo una reacción menor, sin establecer la correlación farmacológica. Se realizaron pruebas cutáneas (intraepidérmicas y epicutáneas), con resultados negativos, y un examen de exposición oral controlada con etoricoxib, con resultado positivo. Se comprobó la tolerancia a las sulfamidas. CONCLUSIONES: El caso de reacción cutánea, mediante reactividad cruzada, entre etoricoxib y celecoxib expuesto en este artículo sugiere la necesidad de realizar pruebas de provocación para confirmar la tolerancia de cada fármaco antes de su prescripción. Por el contrario, trimetropim-sulfametoxazol pueden indicarse con seguridad, si fuese necesario.

Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity.

Purpose: Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity. Materials and Methods: We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment. Results: A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity. Conclusion: These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Modeling and optimization of the protocol of complex chromatography separation of cyclooxygenase-2 inhibitors from Ganoderma lucidum spore.

INTRODUCTION: The spores of the medicinal fungus Ganoderma lucidum possess hepatoprotective properties. The main components, triterpenes, are particularly beneficial, making the screening and preparation of active triterpenes from Ganoderma lucidum significant. OBJECTIVES: We aimed to screen and verify cyclooxygenase-2 inhibitors from G. lucidum spores, establish a rapid online hyphenated technique for the preparation of active ingredients, and analyze the structures of the active ingredients. METHODS: Ultrafiltration LC combined with an enzyme inhibition assay and molecular docking was employed to screen and evaluate cyclooxygenase-2 ligands, which were prepared by pressurized liquid extraction coupled online with countercurrent chromatography and semi-preparative LC. The structures of the compounds were identified by nuclear magnetic resonance spectroscopy. RESULTS: Six cyclooxygenase-2 inhibitors, namely, ganoderic acids I, C2 , G, B, and A and ganoderenic acid A, were screened and evaluated. They were prepared using the online hyphenated technique, following which their structures were identified. CONCLUSION: This study provides opportunities for the discovery and development of new therapeutic drugs from other natural resources, as the present instrumental setup achieved efficient and systematic extraction and isolation of natural products compared with reference separation methods, thus exhibiting significant potential for industrial applications.

Design, synthesis, modeling studies and biological evaluation of pyrazole derivatives linked to oxime and nitrate moieties as nitric oxide donor selective COX-2 and aromatase inhibitors with dual anti-inflammatory and anti-neoplastic activities.

Two new series of pyrazole derivatives 10a-f and 11a-f with selective COX-2 inhibition pharmacophore and oxime/nitrate moieties as NO donor moiety were designed, synthesized and tested for anti-inflammatory, cytotoxic activities and NO release. Compounds 10c, 11a, 11e were more selective for COX-2 isozyme (S.I. = 25.95, 22.52 and 21.54 respectively) in comparison to celecoxib (S.I. = 21.41). Regarding anti-cancer activity, all synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compounds 10c, 11a, 11e were found to be the most potent inhibitors on breast, ovarian and melanoma cell lines (MCF-7, IGROV1 and SK-MEL-5), compound 11a causing 79 % inhibition in case of MCF-7, 78.80 % inhibition in case of SK-MEL-5 and unexpected cell growth -26.22 % inhibition in case of IGROV1 (IC50 = 3.12, 4.28, 4.13 µM respectively). On the other hand, compounds 10c and 11e showed lower inhibition on the same cell lines with IC50 = 3.58, 4.58, 4.28 µM respectively for 10c, IC50 = 3.43, 4.73, 4.43 µM respectively for 11e. Furthermore, DNA-flow cytometric analysis showed that compound 11a induces cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The pyrazole derivative with internal oxime 11a was the most potent compound against most used cell lines especially MCF-7, IGROV1 and SK-MEL-5 (IC50 = 3.12, 4.28, 4.13 µM respectively) with 4.82-fold selectivity towards MCF-7 than F180 fibroblasts. Moreover, oxime derivative 11a showed potent aromatase inhibitory activity (IC50 16.50 µM) when compared with reference compound letrozole (IC50 15.60 µM). All compounds 10a-f and 11a-f released NO in a slow rate (0.73-3.88 %) and the six derivatives 10c, 10e, 11a, 11b, 11c and 11e were the highest NO releasers (3.88, 2.15, 3.27, 2.27, 2.55 and 3.74 % respectively). Herein structure based and ligand based studies were implemented to under stand and evaluate the compounds activity for further in vivo and preclinical studies. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding aromatase enzyme inhibition, docking was carried out with ID: 1 M17. The internal oxime series was more active as anticancer because of their ability to form extra HBs with receptor cleft.

Significance of Pulmonary Endothelial Injury and the Role of Cyclooxygenase-2 and Prostanoid Signaling.

The endothelium plays a key role in the dynamic balance of hemodynamic, humoral and inflammatory processes in the human body. Its central importance and the resulting therapeutic concepts are the subject of ongoing research efforts and form the basis for the treatment of numerous diseases. The pulmonary endothelium is an essential component for the gas exchange in humans. Pulmonary endothelial dysfunction has serious consequences for the oxygenation and the gas exchange in humans with the potential of consecutive multiple organ failure. Therefore, in this review, the dysfunction of the pulmonary endothel due to viral, bacterial, and fungal infections, ventilator-related injury, and aspiration is presented in a medical context. Selected aspects of the interaction of endothelial cells with primarily alveolar macrophages are reviewed in more detail. Elucidation of underlying causes and mechanisms of damage and repair may lead to new therapeutic approaches. Specific emphasis is placed on the processes leading to the induction of cyclooxygenase-2 and downstream prostanoid-based signaling pathways associated with this enzyme.

Possible synergic action of non-steroidal anti-inflammatory drugs and glucosamine sulfate for the treatment of knee osteoarthritis: a scoping review.

BACKGROUND: Several studies have reported that glucosamine sulfate (GS) can improve knee osteoarthritis (OA) symptomatology. In parallel, the disease-modifying effects of non-steroidal anti-inflammatory drugs (NSAIDs) in knee OA have also been investigated. However, limited literature has reported the combined effect of GS and NSAIDs. The aim of this scoping review is to describe the scope and volume of the literature investigating the potential benefits and synergistic effect of a combination of GS and NSAIDs in patients with knee OA. METHODS: PubMed and Embase were searched for studies published from inception through April 2022, evaluating the effects of the combination of GS and NSAIDs in OA patients, versus either treatment alone. Data are reported narratively. RESULTS: Five studies were included in this review; 4 were randomized control trials and one was a prospective observational study. The duration of combination treatment was 6 to 12 weeks. The combination was compared to celecoxib in 2 studies, meloxicam in 1, etoricoxib in 1, and a conventional NSAID in 1 (ibuprofen or piroxicam). All 5 studies reported that in patients with knee OA, the combination of GS plus NSAID yielded a significantly greater benefit than single-agent therapy, in terms of outcomes including pain reduction, function, joint stiffness, and markers of inflammatory activity and cartilage degradation. CONCLUSION: The 5 studies included in this scoping review all report a significantly greater clinical benefit with a combination of GS plus NSAID compared to either treatment alone. The evidence supports efficacy in reducing pain, improving function, and possibly regulating joint damage. However, further randomized trials with larger sample sizes are warranted to confirm these findings.

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells.

COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.

Investigation of Radiotracer Metabolic Stability In Vitro with CYP-Overexpressing Hepatoma Cell Lines.

The characterization of novel radiotracers toward their metabolic stability is an essential part of their development. While in vitro methods such as liver microsome assays or ex vivo blood or tissue samples provide information on overall stability, little or no information is obtained on cytochrome P450 (CYP) enzyme and isoform-specific contribution to the metabolic fate of individual radiotracers. Herein, we investigated recently established CYP-overexpressing hepatoblastoma cell lines (HepG2) for their suitability to study the metabolic stability of radiotracers in general and to gain insight into CYP isoform specificity. Wildtype HepG2 and CYP1A2-, CYP2C19-, and CYP3A4-overexpressing HepG2 cells were incubated with radiotracers, and metabolic turnover was analyzed. The optimized protocol, covering cell seeding in 96-well plates and analysis of supernatant by radio thin-layer-chromatography for higher throughput, was transferred to the evaluation of three 18F-labeled celecoxib-derived cyclooxygenase-2 inhibitors (coxibs). These investigations revealed time-dependent degradation of the intact radiotracers, as well as CYP isoform- and substrate-specific differences in their metabolic profiles. HepG2 CYP2C19 proved to be the cell line showing the highest metabolic turnover for each radiotracer studied here. Comparison with human and murine liver microsome assays showed good agreement with the human metabolite profile obtained by the HepG2 cell lines. Therefore, CYP-overexpressing HepG2 cells provide a good complement for assessing the metabolic stability of radiotracers and allow the analysis of the CYP isoform-specific contribution to the overall radiotracer metabolism.

Dexmedetomidine and LPS co-treatment attenuates inflammatory response on WISH cells via inhibition of p38/NF-κB signaling pathway.

Background: Inflammatory dental diseases that occur during pregnancy can cause preterm labor and/or intrauterine growth restriction. Therefore, proactive treatment of dental diseases is necessary during pregnancy. Dexmedetomidine (DEX) is a widely used sedative in the dental field, but research on the effect of DEX on pregnancy is currently insufficient. In this study, we investigated the effects of co-treatment with DEX and lipopolysaccharide (LPS) on inflammatory responses in human amnion-derived WISH cells. Methods: Human amnion-derived WISH cells were treated with 0.001, 0.01, 0.1, and 1 µg/mL DEX with 1 µg/mL LPS for 24 h. Cytotoxicity of WISH cells was evaluated by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), p38, and nuclear factor kappa B (NF-κB) was examined by western blot analysis. The mRNA expression of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α was analyzed by real-time quantitative polymerase chain reaction. Results: Co-treatment with DEX and LPS showed no cytotoxicity in the WISH cells. The mRNA expression of IL-1ß and TNF-α decreased after co-treatment with DEX and LPS. DEX and LPS co-treatment decreased the protein expression of COX-2, PGE2, phospho-p38, and phospho-NF-κB in WISH cells. Conclusion: Co-treatment with DEX and LPS suppressed the expression of COX-2 and PGE2, as well as pro-inflammatory cytokines such as IL-1ß and TNF-α in WISH cells. In addition, the anti-inflammatory effect of DEX and LPS co-treatment was mediated by the inhibition of p38/NF-κB activation.

Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models.

BACKGROUND/AIMS: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. METHODS: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. RESULTS: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-ß signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. CONCLUSION: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

Natural Cyclooxygenase-2 Inhibitors Synergize With Butyrate to Augment Chicken Host Defense Peptide Gene Expression.

Enhancing the synthesis of microbicidal and immunomodulatory host defense peptides (HDP) is a promising host-directed antimicrobial strategy to combat a growing threat of antimicrobial resistance. Here we investigated the effect of several natural cyclooxygenase-2 (COX-2) inhibitors on chicken HDP gene regulation. Our results indicated that phenolic COX-2 inhibitors such as quercetin, resveratrol, epigallocatechin gallate, anacardic acid, and garcinol enhanced HDP gene expression in chicken HTC macrophage cell line and peripheral blood mononuclear cells (PBMCs). Moreover, these natural COX-2 inhibitors showed a strong synergy with butyrate in augmenting the expressions of multiple HDP genes in HTC cells and PBMCs. Additionally, quercetin and butyrate synergistically promoted the expressions of mucin-2 and claudin-1, two major genes involved in barrier function, while suppressing lipopolysaccharide-triggered interleukin-1ß expression in HTC macrophages. Mechanistically, we revealed that NF-κB, p38 mitogen-activated protein kinase, and cyclic adenosine monophosphate signaling pathways were all involved in the avian ß-defensin 9 gene induction, but histone H4 was not hyperacetylated in response to a combination of butyrate and quercetin. Because of their HDP-inducing, barrier-protective, and antiinflammatory activities, these natural COX-2 inhibitors, when combined with butyrate, may be developed as novel host-directed antimicrobial therapeutics.

Bioactivity-guided isolation of cyclooxygenase-2 inhibitors from Saussurea obvallata (DC.) Edgew. Using affinity solid phase extraction assay.

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea obvallata (DC.) Edgew. is a traditional Tibetan medicine used for the treatment of inflammation-related diseases, but the scientific validation was very limited. AIM OF THE STUDY: This study aimed to rapid screen and targeted isolate cyclooxygenase-2 (COX-2) inhibitors from S. obvallata extract. MATERIALS AND METHODS: An efficient ligand-fishing method based on affinity solid phase extraction (A-SPE) combining with HPLC was developed. The identified COX-2 inhibitors were separated using preparative liquid chromatography. In vitro COX-2 inhibition assays were employed to confirm the inhibitory activities of the isolated compounds. In addition, the effect of the isolated compounds on the production of prostaglandin E2 (PGE2) and the expression of COX-2 in LPS-induced RAW 264.7 were evaluated. RESULTS: A total of four phenylpropanoids, isolariciresinol, syringaresinol, pinoresinol and balanophonin were targeted isolated as COX-2 inhibitors with IC50 values of 36.4 ± 2.6 µM, 23.1 ± 1.8 µM, 3.6 ± 0.3 µM and 12.1 ± 0.9 µM, respectively. The isolated compounds significantly inhibited LPS-induced NO production in a dose-dependent manner. And, the results of the inhibitory effect on the release of PGE2 and the expression of COX-2 in LPS-induced macrophages were consistent with A-SPE analysis. CONCLUSION: The present work demonstrated that the developed A-SPE-HPLC method could successfully targeted isolated COX-2 inhibitors from S. obvallata extract. And, the isolation results indicated that the therapeutic effect of S. obvallata on inflammation-related diseases was partly based on the COX-2 active ingredients.

Celecoxib-induced drug fever: A rare case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Drug fever is frequently misdiagnosed, especially during concurrent infection. Celecoxib causes various adverse effects; however, celecoxib-induced drug fever is rarely reported. CASE SUMMARY: A 32-year-old man presented with pyrexia after 17 days of celecoxib therapy, which was reintroduced following 3-day total drug cessation. His fever recurred after this unsuspected rechallenge, which aided in the ultimate identification of the offending drug. A Naranjo Score of 8 led us to infer that drug fever was "probably" caused by celecoxib. WHAT IS NEW AND CONCLUSION: This is the first report of celecoxib-induced drug fever, aimed at assisting its diagnosis, particularly with rarely suspected causative drugs.

Effects of preoperative administration of parecoxib sodium on stress reaction and postoperative nausea and vomiting score in patients undergoing laparoscopic cholecystectomy / 中国基层医药

Objective:To investigate the effects of preoperative administration of parecoxib sodium on stress reaction and postoperative nausea and vomiting score in patients undergoing laparoscopic cholecystectomy.Methods:A total of 112 patients undergoing laparoscopic cholecystectomy in Lishui City People's Hospital from January 2020 to January 2021 were included in this study. They were randomly divided into observation group and control group, with 56 patients per group. The observation group was intravenously administered 40 mg parecoxib sodium 30 minutes before surgery, and the control group was identically administered equal amount of 0.9% sodium chloride injection. At 1, 6, 12 and 24 hours after surgery, Visual Analogue Scale (VAS) score, cortisol and adrenocorticotropic hormone levels and postoperative nausea and vomiting score were compared between the two groups.Results:At 1, 6 and 12 hours after surgery, VAS score in the observation group was (3.23 ± 0.85) points, (2.44 ± 0.76) points, (2.37 ± 0.69) points, respectively, which were significantly lower than (4.06 ± 1.12) points, (3.24 ± 0.95) points, (3.10 ± 1.07) points in the control group ( t = 4.41, 4.92, 4.29, all P < 0.001). At 1, 6, 12 and 24 hours after surgery, cortisol level in the observation group was (287.79 ± 35.46) ng/L, (303.55 ± 34.77) ng/L, (368.58 ± 31.22) ng/L, (397.16 ± 32.60) ng/L, respectively, which were significantly lower than (337.64 ± 39.52) ng/L, (364.18 ± 36.90) ng/L, (405.56 ± 37.29) ng/L, (455.51 ± 37.81) ng/L in the control group ( t = 7.02, 8.94, 5.69, 8.74, all P < 0.05). At 1, 6, 12 and 24 hours after surgery, adrenocorticotropic hormone level in the observation group was (59.25 ± 7.63) ng/L, (65.27 ± 8.23) ng/L, (72.29 ± 7.49) ng/L, (83.63 ± 8.57) ng/L, which were significantly lower than (64.48 ± 8.06) ng/L, (71.44 ± 8.59) ng/L, (79.79 ± 8.15) ng/L, (90.08 ± 8.26) ng/L in the control group ( t = 3.52, 3.88, 5.07, 4.05, all P < 0.05). Within 24 hours after surgery, the incidence of postoperative nausea and vomiting in the observation group was significantly lower than that in the control group [12.50% (7/56) vs. 28.57% (16/56), χ2 = 4.43, P < 0.05). Within 2 hours, 2-6 hours, and > 6-24 hours, postoperative nausea and vomiting score in the observation group was (1.31 ± 0.26) points, (1.43 ± 0.32) points, and (1.46 ± 0.41) points, respectively, which was significantly lower than (1.67 ± 0.41) points, (1.83 ± 0.39) points, (1.88 ± 0.44) points in the control group ( t = 2.12, 2.37, 2.14, all P < 0.05). Conclusion:Preoperative administration of parecoxib sodium exhibits a good postoperative analgesic effect in patients undergoing laparoscopic cholecystectomy. It can effectively reduce postoperative stress reactions, decrease the incidence of postoperative nausea and vomiting, and lower the severity of postoperative nausea and vomiting, and thereby can be widely used in clinical practice.

Efficacy and safety of cyclooxygenase 2 inhibitors for desmoid tumor management: a systematic review.

The efficacy and safety of cyclooxygenase 2 (COX2) inhibitors for the treatment of desmoid-type fibromatosis (DF) are unclear. Therefore, we systematically reviewed related literature to assess the efficacy and safety of COX2 inhibitors for DF treatment. We searched pertinent literature between January 1999 and August 2017 to identify relevant studies using the keywords "Fibromatosis, aggressive" and "Cyclooxygenase inhibitors." Thereafter, we screened and determined the quality of the studies using the Grading of Recommendations Assessment, Development, and Evaluation system and extracted the article data. The critical outcomes selected were the efficacy and adverse effects of COX2 inhibitors. Efficacy was evaluated in terms of clinical benefit when patients showed complete response, partial response, and stable disease. Thirty-one articles were identified from the database search, and one was identified through the reviewers' manual search. Finally, we retrieved six studies, including three case reports, comprising 89 patients after the first and second screenings. Fifty-three patients were excluded because three studies were reported from the same institution; hence, in total, 36 patients were included. Clinical benefit was noted in 64% of the patients. Three adverse effects were identified from the records of the six extracted studies. The strategy of watchful waiting using COX2 inhibitors with few side effects is weakly recommended for DF, especially DF patients with pain.

Targeted Separation of COX-2 Inhibitor from Pterocephalus hookeri Using Preparative High-Performance Liquid Chromatography Directed by the Affinity Solid-Phase Extraction HPLC System.

Pterocephalus hookeri, as a kind of popular traditional Tibetan medicine, is reputed to treat inflammatory related diseases. In the present work, a cyclooxygenase-2 functionalized affinity solid-phase extraction HPLC system was developed and combined with preparative-HPLC for rapidly screening and separating cyclooxygenase-2 ligand from P. hookeri extracts. Firstly, ligands of cyclooxygenase-2 were screened from extracts by affinity solid-phase extraction HPLC system. Then directed by the screening results, the recognized potential active compounds were targeted separated. As a result, the major cyclooxygenase-2 inhibitor of P. hookeri was obtained with a purity of >95%, which was identified as sylvestroside I. To test the accuracy of this method, the anti-inflammatory activity of sylvestroside I was inspected in lipopolysaccharide-induced RAW 264.7 cells. The results show that sylvestroside I significantly suppressed the release of prostaglandin E2 with dose-dependent, which was in good agreement with the screening result of the affinity solid-phase method. This method of integration of screening and targeted separation proved to be very efficient for the recognition and isolation of cyclooxygenase-2 inhibitors from natural products.

Comparison of celecoxib and acetaminophen for pain relief in pediatric day case tonsillectomy: A randomized double-blind study.

OBJECTIVE: Post-tonsillectomy pain is a common morbidity in children. The aim of this study was to compare the efficacy of celecoxib with acetaminophen on pain relief in pediatric day-case tonsillectomy. METHODS: We compared the analgesic effect of celecoxib (99 patients) with acetaminophen (100 patients) for the management of post-tonsillectomy pain. Post-tonsillectomy pain score was evaluated three times a day for 7 days. In addition, the incidence of post-tonsillectomy bleeding and the rate of patients who returned to regular diet were evaluated. RESULTS: In the first day, we observed lower mean pain score in the celecoxib group, than the acetaminophen group (P = 0.013). The overall pain score in other days was not significantly different between the two groups. In the celecoxib group, more patients resumed regular amount of oral intake within the first 3 days. Also, the rate of post-tonsillectomy bleeding in the two groups was not statistically different. CONCLUSION: We recommend celecoxib as a more suitable choice than acetaminophen for post-tonsillectomy pain management in the first day and resuming regular diet within 3 days.Level of Evidence: 1b.