A single extraction 96-well method for LC-MS/MS quantification of urinary eicosanoids, steroids and drugs.

Urinary eicosanoid concentrations reflect inflammatory processes in multiple diseases and have been used as biomarkers of disease as well as suggested for patient stratification in precision medicine. However, implementation of urinary eicosanoid profiling in large-scale analyses is restricted due to sample preparation limits. Here we demonstrate a single solid-phase extraction of 300 µL urine in 96-well-format for prostaglandins, thromboxanes, isoprostanes, cysteinyl-leukotriene E4 and the linoleic acid-derived dihydroxy-octadecenoic acids (9,10- and 12,13-DiHOME). A simultaneous screening protocol was also developed for cortisol/cortisone and 7 exogenous steroids as well as 3 cyclooxygenase inhibitors. Satisfactory performance for quantification of eicosanoids with an appropriate internal standard was demonstrated for intra-plate analyses (CV = 8.5-15.1%) as well as for inter-plate (n = 35) from multiple studies (CV = 22.1-34.9%). Storage stability was evaluated at - 20 °C, and polar tetranors evidenced a 50% decrease after 5 months, while the remaining eicosanoids evidenced no significant degradation. All eicosanoids were stable over 3.5-years in urine stored at - 80 °C. This method will facilitate the implementation of urinary eicosanoid quantification in large-scale screening.

Design, classification, and adverse effects of NSAIDs: A review on recent advancements.

Inflammation is a hallmark of many diseases, including cancer, neurodegenerative diseases like Alzheimer's, type II diabetes, rheumatoid arthritis, and asthma. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been a cornerstone in the management of various inflammatory, pain, and fever-related conditions. As a result, NSAIDs have found their applications in new therapeutic areas. NSAIDs are known to act by inhibiting the cyclooxygenase (COX) pathway. In recent years, new strategies have been proposed to counter inflammation and develop safer COX inhibitors. This review discusses the design of new COX inhibitors, the derivatization of conventional NSAIDs, and their biological applications. The review also presents an integrated classification of NSAIDs incorporating both traditional chemical-based and function-based approaches, including a brief overview of the NSAIDs of natural origins. Additionally, the review addresses adverse effects associated with different NSAIDs, including effects associated with cardiovascular, renal, and hepatic complications emphasizing the need for the development of new and safer COX inhibitors.

Identification of cyclooxygenase-II inhibitory saponins from fenugreek wastes: Insights from liquid chromatography-tandem mass spectrometry metabolomics, molecular networking, and molecular docking.

INTRODUCTION: This research explores sustainable applications for waste generated from fenugreek (Trigonella foenum-graecum), a plant with both nutritional and medicinal uses. The study specifically targets waste components as potential sources of nutrients and bioactive compounds. OBJECTIVES: The focus is to conduct detailed metabolic profiling of fenugreek waste, assess its anti-inflammatory properties by studying its cyclooxygenase (COX) inhibitory effect, and correlate this effect to the metabolite fingerprint. MATERIALS AND METHODS: Ethanolic extracts of fenugreek fruit pericarp and a combination of leaves and stems were subjected to untargeted metabolic profiling using liquid chromatography-mass spectrometry integrated with online database searches and molecular networking as an effective dereplication strategy. The study also scrutinized the COX inhibitory capabilities of these extracts and saponin-rich fractions prepared therefrom. Molecular docking was employed to investigate the specific interactions between the identified saponins and COX enzymes. RESULTS: The analysis led to the annotation of 81 metabolites, among which saponins were predominant. The saponin-rich fraction of the fruit pericarp extract displayed the strongest COX-II inhibitory activity in the in vitro inhibition assay (IC50 value of 81.64 ± 3.98 µg/mL). The molecular docking study supported the selectivity of the identified saponins towards COX-II. The two major identified saponins, namely, proto-yamogenin 3-O-[deoxyhexosyl (1 → 2)] [hexosyl (1 → 4)] hexoside 26-O-hexoside and trigofenoside A, were predicted to have the highest affinity to the COX-II receptor site. CONCLUSION: In the present study, we focused on the identification of COX-II inhibitory saponins in fenugreek waste through an integrated approach. The findings offer valuable insights into potential anti-inflammatory and cancer chemoprotective applications of fenugreek waste.

Experimental and Machine-Learning-Assisted Design of Pharmaceutically Acceptable Deep Eutectic Solvents for the Solubility Improvement of Non-Selective COX Inhibitors Ibuprofen and Ketoprofen.

Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.

Microbial Transformation of the Sesquiterpene Lactone, Vulgarin, by Aspergillus niger.

The biotransformation of vulgarin (1), an eudesmanolides-type sesquiterpene lactone obtained from Artemisia judaica, by the microorganism, Aspergillus niger, was carried out to give three more polar metabolites; 1-epi-tetrahydrovulgarin (1α,4α-dihydroxy-5αH,6,11ßH-eudesman-6,12-olide (2), 20% yield, 1α,4α-dihydroxyeudesm-2-en-5αH,6,11ßH-6,12-olide (3a), 10% yield, and C-1 epimeric mixture (3a, b), 4% yield, in a ratio of 4:1, 3a/3b. The structures of vulgarin and its metabolites were elucidated by 1 and 2D NMR spectroscopy in conjunction with HRESIMS. Metabolites (3a) and (3b) are epimers, and they are reported here for the first time as new metabolites obtained by biotransformation by selective reduction at C-1. Vulgarin and its metabolites were evaluated as anti-inflammatory agents using the human cyclooxygenase (COX) inhibitory assay. The obtained data showed that (1) exhibited a good preferential inhibitory activity towards COX-2 (IC50 = 07.21 ± 0.10) and had a moderate effect on COX-1 (IC50 = 11.32 ± 0.24). Meanwhile, its metabolite (3a) retained a selective inhibitory activity against COX-1 (IC50 = 15.70 ± 0.51). In conclusion, the results of this study revealed the necessity of the presence α, ß unsaturated carbonyl group in (1) for better COX-2 inhibitory activity. On the other hand, the selectivity of (1) as COX-1 inhibitor may be enhanced via the reduction of C-1 carbonyl group.

Design, synthesis and molecular docking studies of new azomethine derivatives as promising anti-inflammatory agents.

Herein, we synthesized a series of Ibuprofen-based 4a-k, quinoxaline-based 9a-f and pyridine-based 13a-h azomethine derivatives and studied their anti-inflammatory potency. The in-silico docking studies of the synthesized compounds 4a-k revealed better affinity for COX-2 as compared to COX-1 with best binding exhibited by 4a, 4d, and 4k.In vitro COX-1 and COX-2 inhibition assay performed on the azomethine derivatives further proved that synthesized compounds of series 4, 9 and 13 showed less inhibition of COX-1 enzyme than that of COX-2 enzyme. However, their SI values indicated that compounds had no COX-2 selectivity. The in-vivo screening of the selected compounds indicated compound 4d to be more potent exhibiting the best % inhibition of 70.70 ± 2.41, as compared to the standard NSAIDs. Based on the above observations, a well defined structure activity relationship analysis (SAR) has been described showcasing the importance of various functionalities for anti-inflammatory effects. Further, the azomethine derivatives have been found to be better superoxide radical scavengers with no significant DPPH activity. Due to their antioxidant properties, compounds were screened for their cytotoxicity against cervical cancer derived HeLa and breast cancer derived MCF-7 cell with the drug Paclitaxel as the standard. However, no significant cytotoxic effect was observed for the compounds. Also, the late apoptosis in cervical HeLa cancer cells did not show the expected results, as the compounds proved to be weakly cytotoxic. Thus, the major findings of the work demonstrates the Schiff bases to be promising anti-inflammatory agents compatible with NSAIDs, having moderate anti-oxidant properties with minimal cytotoxicity.

Efficacy of tramadol for postoperative pain management in dogs: systematic review and meta-analysis.

OBJECTIVE: To evaluate the evidence of analgesic efficacy of tramadol for the management of postoperative pain and the presence of associated adverse events in dogs. DATABASES USED: A comprehensive search using PubMed/MEDLINE, LILACS, Google Scholar and CAB databases with no restrictions on language and following a prespecified protocol was performed from June 2019 to July 2020. Included were randomized controlled trials (RCTs) performed in dogs that had undergone general anesthesia for any type of surgery. Two authors independently classified the studies, extracted data and assessed their risk of bias using Cochrane's tool. RevMan and GRADE methods were used to rate the certainty of evidence (CoE). CONCLUSIONS: Overall 26 RCTs involving 848 dogs were included. Tramadol administration probably results in a lower need for rescue analgesia versus no treatment or placebo [moderate CoE; relative risk (RR): 0.47; 95% confidence interval (CI): 0.26-0.85; I2 = 0%], and may result in a lower need for rescue analgesia versus buprenorphine (low CoE; RR: 0.50; 95% CI: 0.20-1.24), codeine (low CoE; RR: 0.75; 95% CI: 0.16-3.41) and nalbuphine (low CoE; RR: 0.05; 95% CI: 0.00-0.72). However, tramadol administration may result in an increased requirement for rescue analgesia versus methadone (low CoE; RR: 3.45; 95% CI: 0.66-18.08; I2 = 43%) and COX inhibitors (low CoE; RR: 2.27; 95% CI: 0.68-7.60; I2 = 45%). Compared with multimodal therapy, tramadol administration may make minimal to no difference in the requirement for rescue analgesia (low CoE; RR: 1.12; 95% CI: 0.48-2.60; I2 = 0%). Adverse events were inconsistently reported and the CoE was very low. The overall CoE of the analgesic efficacy of tramadol for postoperative pain management in dogs was low or very low, and the main reasons for downgrading the evidence were risk of bias and imprecision.

Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders.

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out.

Effects of COX inhibitors on responsiveness of the tracheal tract to acetylcholine and histamine and their relationship with LTC4 and PGE2 levels of bronchoalveolar lavage fluid in allergic Guinea pigs.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) intervene in the COX (cyclooxygenase) pathways which generate two important inflammation mediators, prostaglandins (PGs) and leukotriene (LTs). Contradictory claims regarding the effect of NSAIDs in asthmatic patients continues to be an issue. The present study investigated the effects of COX inhibitors on the responsiveness of the tracheal tract and on the levels of LTC4 and PGE2 in cells of the bronchoalveolar lavage fluid in an allergic guinea pig model.Materials and Methods: Adult male Dunkin-Hartley guinea pigs (250 - 300 g) were divided into seven groups of six animals each. Four COX inhibitors, aspirin (200 mg/kg and 20 mg/kg), indomethacin (10 mg/kg), ketoprofen (10 mg/kg), and celecoxib (25 mg/kg), were given orally on day 17 to allergy induced guinea pigs at 0, 12, and 24 h before ovalbumin challenge on day 18. PGF2 and LT4 were measured in the bronchoalveolar lavage fluid as well as inflammatory cell count and total protein. Tracheal responsiveness to acetylcholine (Ach) and histamine (His) also was evaluated.Results: An augment in the response of the trachea to Ach and His, as well as overt allergenic signs including short breath, wheezing and sneezing, was observed. The most significant increase in tracheal hyper-responsiveness was observed in the ketoprofen-treated group with similar but less pronounced changes observed in the indomethacin-treated group. Although some variables increased with the aspirin and celecoxib treatments, overall the tracheal sensitivity was reduced. Inflammatory cells including eosinophils and neutrophils corresponded to the changes observed for each treatment group.Conclusion: Ketoprofen and indomethacin increased the tracheal sensibility to Ach and His; therefore, their administration is not recommended in patients susceptible to allergy.

Synthesis and biological properties of aryl methyl sulfones.

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 µM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 µM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.

Prostanoids in the pathophysiology of human coronary artery.

Coronary artery disease is one of the leading causes of death in wordwide. There is growing evidence that prostanoids are involved in the physiology and pathophysiology of the human coronary artery by controlling vascular tone, remodelling of the vascular wall or angiogenesis. In this review, the production of prostanoids and the expression of prostanoid receptors in human coronary artery in health or disease are described. In addition, the interactions between sex hormones and prostanoids, their participations in the development of coronary artery diseases have been addressed. Globally, most of the studies performed in human coronary artery preparations have shown that prostacyclin (PGI2) has beneficial effects by inducing vasodilatation and promoting angiogenesis while reverse effects are confirmed by thromboxane A2 (TxA2). More studies are needed to determine the roles of the other prostanoids (PGE2, PGD2 and PGF2α) in vascular functions of the human coronary artery. Finally, in addition to the in vitro data about the human coronary artery, myocardial infarction induced by cyclooxygenase-2 (COX-2) inhibitor and the protective effects of aspirin after coronary artery bypass surgery suggest that prostanoids are key mediators in coronary homeostasis.

The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection.

BACKGROUND: Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed immune modulating therapies have been suggested as adjunctive treatment to TB antibiotics. Upregulated cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling pathway may cause a dysfunctional immune response that favors survival and replication of Mycobacterium tuberculosis (Mtb). METHODS: Blood samples were obtained from patients with latent TB (n = 9) and active TB (n = 33) before initiation of anti-TB chemotherapy. COX-2 expression in monocytes and ESAT-6 and Ag85 specific T cell cytokine responses (TNF-α, IFN-γ, IL-2), proliferation (carboxyfluorescein succinimidyl ester staining) and regulation (FOXP3+ T regulatory cells) were analysed by flow cytometry and the in vitro effects of the COX-1/2 inhibitor indomethacin were measured. RESULTS: We demonstrate that indomethacin significantly down-regulates the fraction of Mtb specific FOXP3+ T regulatory cells (ESAT-6; p = 0.004 and Ag85; p < 0.001) with a concomitant reduction of Mtb specific cytokine responses and T cell proliferation in active TB. Although active TB tend to have higher levels, there are no significant differences in COX-2 expression between unstimulated monocytes from patients with active TB compared to latent infection. Monocytes in both TB groups respond with a significant upregulation of COX-2 after in vitro stimulation. CONCLUSIONS: Taken together, our in vitro data indicate a modulation of the Th1 effector and T regulatory cells in Mtb infection in response to the COX-1/2 inhibitor indomethacin. The potential role as adjunctive host-directed therapy in TB disease should be further evaluated in both animal studies and in human clinical trials.

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities.

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC50s of 0.75-70.50µM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.

Cyclooxygeanse-2 promotes metastasis in osteosarcoma.

Cyclooxygenase-2 (COX-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, is associated with carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumors and resistance to apoptosis. COX-2 is also involved in metastasis and poor prognosis of cancer. Osteosarcoma with COX-2 positivity is from 67 to 92 %. COX-2-positive rate in metastatic lesions was greater than that of biopsy and/or resected samples of the primary site in osteosarcoma. And, what role does COX-2 play in osteosarcoma metastasis? Genetic studies support a cause-effect connection between COX-2 and tumorigenesis. COX-2 expression had a poor prognosis with regard to metastasis, and patients with increased COX-2 expression in lung metastases died of the disease. COX-2 expression has also been established as a marker in human osteosarcoma, and COX-2 inhibition has been suggested as a possible way of improving therapeutic outcome. In addition, COX-inhibitors inhibit the tumor initiation, matrix metalloproteinases (MMPs), cell differentiation and T cell proliferation and suppression of the antitumor activity of natural killer cells and macrophages, angiogenic mechanism. Therefore, we can exert the COX-inhibitors to potentialize the effects of chemotherapeutic agents, and reverse the metastasis in osteosarcoma to facilitate the patient who may benefit from addition of COX-inhibitors to standard cytotoxic therapy.

Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity.

Cyclooxygenase-2 (COX-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, is associated with inflammatory diseases and carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumors and resistance to apoptosis. Meanwhile, COX-2 contributes to immune evasion and resistance to cancer immunotherapy, which plays a crucial role in the innate and adaptive immune response. The activity of COX-2-PGE2-EP signal pathway can suppress Dendritic cells (DCs), natural killer (NK), T cells, type-1 immunity excluding type-2 immunity which promote tumor immune evasion. COX-2 and the prostaglandin cascade play important roles in the "inflammogenesis of cancer". In addition, COX-inhibitors can inhibit tumor immune evasion. Therefore, we can exert the COX-inhibitors to facilitate the patients to benefit from addition of COX-inhibitors to standard cytotoxic therapy.

The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression.

BACKGROUND: A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells. METHODS: The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR. RESULTS: The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are significantly more sensitive to treatment with ATRA alone than Daoy cells. CONCLUSIONS: The obtained results on medulloblastoma cell lines are in accordance with our previous findings on neuroblastoma cells and confirm our hypothesis concerning the common mechanism of the enhancement of ATRA-induced cell differentiation in various types of pediatric solid tumors.

Drug-Induced Anaphylaxis: National Database Analysis.

(1) Background: National health system databases represent an important source of information about the epidemiology of adverse drug reactions including drug-induced allergy and anaphylaxis. Analysis of such databases may enhance the knowledge of healthcare professionals regarding the problem of drug-induced anaphylaxis. (2) Methods: A retrospective descriptive analysis was carried out of spontaneous reports (SRs) with data on drug-induced anaphylaxis (SRsAs) extracted from the Russian National Pharmacovigilance database (analyzed period 2 April 2019-21 June 2023). The percentage of SRsAs among SRs of drug-induced allergy (SRsDIAs) was calculated, as well as of pediatric, elderly, and fatal SrsAs. Drugs involved in anaphylaxis were assessed among total SRsAs, pediatric, and elderly SRsAs, and among fatal SRsAs. Demographic parameters of patients were assessed. (3) Results: SRsAs were reported in 8.3% of SRsDIAs (2304/27,727), the mean age of patients was 48.2 ± 15.8 years, and females accounted for 53.2% of cases. The main causative groups of drugs were antibacterials (ABs) for systemic use (44.6%), local anesthetics (20.0%), and cyclooxygenase (COX) inhibitors (10.1%). Fatal SRsAs were reported in 9.5% (218/2304) of cases, the mean age of patients was 48.0 ± 16.7 years, and females accounted for 56.4% of cases. Pediatric SRsAs accounted for 3.9% of pediatric SRsDIAs and 5.8% of all SRsAs, with a mean age of 11.8 ± 4.5 years, and females acccounted for 51.9% of cases. Elderly SRsAs accounted for 2% of elderly SRsDIAs and 2.8% of all SRsAs, and the mean age was 73.0 ± 5.3 years, and females accounted for 43.5% of cases. ABs caused 40% of SRsAs in the elderly, 42.9% in children, and 50% of fatal SRsAs. (4) Conclusions: Our study revealed a relatively high proportion of anaphylaxis among SRs of drug-induced allergy. ABs were the most prevalent causative agents, especially in fatal SRsAs.

Exploring new imines as anti-inflammatory COX and 5-LOX inhibitors with an improved pharmacokinetic profile.

Background: Dual COX/5-LOX inhibition is a bright strategy for developing new potent and safe anti-inflammatory agents. Methods: New imines were synthesized and evaluated for their anti-inflammatory activity. The most active compounds were further investigated for their safety profile. Their molecular docking and physicochemical parameters were assessed. A new LC-MS/MS method was developed for the quantification of compound 4d in rat plasma. Results: Synthesized compounds were found to have anti-inflammatory activity (77-88% edema inhibition). In addition, 4d, 5m and 7d showed analgesic activity (92.50, 95.71 and 96.28% protection, respectively). 4d showed dual COX-2/5-LOX activity. Molecular docking expected the binding pattern of compounds in COX-1, COX-2 and 5-LOX active sites. The in vivo pharmacokinetic parameters of compound 4d were also obtained.

Insight on novel oxindole conjugates adopting different anti-inflammatory investigations and quantitative evaluation.

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 µM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.

[Box: see text].

The effects of cyclooxygenase and nitric oxide synthase inhibition on cardiodynamic parameters and coronary flow in isolated rat hearts.

BACKGROUND: Despite the widespread clinical use of cyclooxygenase (COX) inhibitors, dilemmas regarding the potential impact of these drugs on the cardiovascular system persist. OBJECTIVE: To estimate the effects of different COX inhibitors (meloxicam, acetylsalicylic acid [ASA] and SC-560) on cardiac function and coronary flow in isolated rat hearts, with special focus on the L-arginine/nitric oxide system. METHODS: The hearts of eight-week-old male Wistar albino rats (n=72; 12 rats per group; body mass 180 g to 200 g) were retrogradely perfused according to the Langendorff technique at gradually increased perfusion pressure (40 cmH2O to 120 cmH2O). After control experiments, the hearts were perfused with the following drugs: 100 µM ASA, alone or in combination with 30 µM N(ω)-nitro-L-arginine monomethyl ester (L-NAME), 0.3 µM meloxicam with or without 30 µM L-NAME, 3 µM meloxicam with or without 30 µM L-NAME, 30 µM L-NAME and 0.25 µM SC-560. In the control and experimental groups, the following parameters of heart function were continuously recorded: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate and mean blood pressure. Coronary flow was measured flowmetrically. The amount of released NO2 (-) was determined spectrophotometrically in coronary venous effluent. RESULTS: While meloxicam and SC-560 were found to have an adverse influence on cardiac function and coronary perfusion, ASA did not negatively affect the intact model of the heart. CONCLUSION: It appeared that interaction between COX and the L-arginine/nitric oxide system truly exists in coronary circulation and may explain the causes of the observed effects.