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Inflammation is an essential body immune system response against various infections and tissue injuries and maintains normal homeostasis. Alterations in inflammatory responses lead to multiple disorders like heart diseases, obesity, diabetes, cancer, stroke, and neurodegenerative disorders. Cyclooxygenases (COXs), the enzymes, exist in two isoforms (COX‐1 and COX‐2) that catalyze the rate‐determining step of prostaglandin biogenesis and play a significant role in inflammation. COX‐2 inhibitors, although effective anti‐inflammatory agents are considered to be highly unsafe for long‐term usage due to their possible side and adversative effects. Recently, fused‐thienopyrimidines have emerged as a privileged scaffold with excellent anti‐inflammatory potential. In the present review, we have emphasized the recent developments in the design and synthetic strategies of fused‐thienopyrimidine derivatives and their detailed structure‐activity‐relationship (SAR) studies. The primary goal of this review is to provide restructuring knowledge about this template, which could prove beneficial and valuable for chemists working in the anti‐inflammatory area. [ABSTRACT FROM AUTHOR]

Acacia nilotica L., also known as babul, belonging to the Fabaceae family and the Acacia genus, is typically used for ornamental purposes and also as a medicinal plant found in tropical and subtropical areas. This plant is a rich source of bioactive compounds. The current study aimed to elucidate the hypoglycemic, anti‐inflammatory, and neuroprotective potential of A. nilotica's crude methanolic extract. The results of the in vitro antidiabetic assay revealed that methanolic extract of A. nilotica inhibited the enzyme α‐glucosidase (IC50: 33 μg mL−1) and α‐amylase (IC50: 17 μg mL−1) in a dose‐dependent manner. While in the anticholinesterase enzyme inhibitory assay, maximum inhibition was shown by the extract against acetylcholinesterase (AChE) (637.01 μg mL−1) and butyrylcholinesterase (BChE) (491.98 μg mL−1), with the highest percent inhibition of 67.54% and 71.50% at 1000 μg mL−1, respectively. This inhibitory potential was lower as compared to the standard drug Galantamine that exhibited 82.43 and 89.50% inhibition at the same concentration, respectively. Moreover, the methanolic extract of A. nilotica also significantly inhibited the activities of cyclooxygenase 2 (COX‐2) and 5‐lipoxygenase (5‐LOX) in a concentration‐dependent manner. The percent inhibitory activity of 5‐LOX and COX‐2 ranged from 42.47% to 71.53% and 43.48% to 75.22%, respectively. Furthermore, in silico, in vivo, and clinical investigations must be planned to validate the above‐stated bioactivities of A. nilotica. [ABSTRACT FROM AUTHOR]

Background Tramadol (TRM) and celecoxib (CLX) form a novel mixture that helps relieve acute pain when other painkillers have no action. It is also reported that these drugs, TRM and CLX, are used to control COVID-19 symptoms. Objective The current work highlights three important pillars of modern pharmaceutical analysis, which are as follows; impurity profiling, greenness/whiteness studies and simplicity accompanied by sensitivity. Since 4-methyl acetophenone inhibits the human carbonyl reductase enzyme (type I) and since this compound may pose a health risk, it is crucial to regulate its concentration in all dosage forms of CLX. Methods Two simple and green spectrophotometric methods were developed, namely third derivative (D3) and Fourier self- deconvulation (FSD), for resolving severely overlapped spectra of TRM and CLX in the presence of 4-methyl acetophenone (4-MAP) as a process-related impurity in their novel tablet combination. Results The two approaches showed acceptable linearity with an excellent correlation coefficient. In both methods, TRM was measured when CLX and 4-methyl acetophenone were zero-crossing. The same procedure was applied for measuring CLX and its process-related impurity 4-MAP. Conclusion The methodologies developed were thoroughly validated in compliance with ICH (International Council on Harmonisation) guidelines. Student t - and F -tests revealed no statistically significant variation among the current methods and the reported method. Highlights No spectrophotometric methods have been published previously for the simultaneous analysis of TRM and CLX along with 4-MAP. As a result, the newly developed spectrophotometric approaches have great relevance and originality in the field of pharmaceutical analysis. [ABSTRACT FROM AUTHOR]

A novel class of benzimidazole–thiazole products have been designed as potential inhibitors of cyclooxygenase, and the synthesized compound structures were verified using instrumental analysis techniques. The in vitro inhibitory effect on COX-1 was dose-dependent, with a significant reduction in effectiveness at lower concentrations. Among the compounds (7b) (IC50 0.297 μM) (7c) (IC50 0.311 μM) (8b) (IC50 0.279 μM) and (8c) (IC50 0.215 μM), which are the most active compounds, IC50 values were close to celecoxib (IC50 0.132 μM) against COX-2. Molecular docking studies were carried out on compounds against COX-2 using Glide XP. The compounds 7b, 7c, 8b, and 8c demonstrated significant docking scores of −8.927 kcal mol−1, −8.578 kcal mol−1, −8.485 kcal mol−1, and −8.899 kcal mol−1, respectively, which suggest a promising interaction with the COX-2 enzyme. Moreover, molecular dynamics simulations of 100 ns duration were performed with COX-2 and active compound complexes using Gromacs. The dynamic simulation results support the findings from the molecular docking studies and suggest that compounds 7b, 7c, 8b, and 8c may have the potential to act as potent and selective COX-2 inhibitors. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. Case Report: A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. Conclusions: Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects. [ABSTRACT FROM AUTHOR]

A series of Mn(II), Fe(III), and Co(II), complexes with two ligands derived from 2-aminopyridine, 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (L1) and 2-{[3-(trifluoromethyl)phenyl]-amino}-3-pyridinecarboxylic acid (L2), was prepared and characterized using elemental analysis, molar conductance, TG measurements, IR, UV-Vis, ESR, and magnetic measurements. The coordination mode of L1 and L2 ligands was evaluated and the different geometries around the metals were determined. A complementary computational study using density functional theory (DFT) calculations was carried out to optimize the structures of the metal complexes and to confirm the proposed geometries. Using the same theoretical method, the investigation of the frontier molecular orbitals (FMOs) was used to predict the stability/reactivity of the complexes. The study of the complexation in solution allowed the determination of the stability constants of the complexes confirming their stability in solution. The distribution of the species involving Co(II) over the whole pH-range was also studied. The electrochemical behavior of the ligands and their metal complexes was determined by cyclic voltammetry which revealed irreversible redox processes for all the compounds. The study of the biological activities of the synthesized compounds indicates that the metal complexes displayed enhanced antioxidant and antibacterial properties. Molecular docking results of the Co–L1 complex with bacterial DHPS confirmed that the metal-based compound could efficiently inhibit bacterial growth while the interactions with cyclooxygenase (COX-1 and COX-2) revealed that the compound could act as efficient anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

This correction notice from the Journal of Neuroinflammation addresses an error in the magnification of Figure 7 in an article titled "Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice." The magnifications of panels B and C were switched, and the revised Figure 7 is provided in the correction. The figure shows histological examination of brain sections after 24 hours, demonstrating brain tissue injury and inflammatory cell infiltration in TBI mice and TBZ-treated mice. ATB-346 treatment reduced the degree of brain injury and inflammatory cell infiltration. The correction is authored by Michela Campolo, Emanuela Esposito, Akbar Ahmad, Rosanna Di Paola, Irene Paterniti, Marika Cordaro, Giuseppe Bruschetta, John L. Wallace, and Salvatore Cuzzocrea. [Extracted from the article]

Genus Salsola (family Amaranthaceae) is one of the most prevailing genera in Saudi Arabia. Although several species were reported for their traditional uses, the majority of Salsola species still need to be phytochemically and biologically explored. The current study presents the GC-MS profiling as well as an in vitro investigation of the bioactivities of the n-hexane extracts from the five Salsola species: Salsola arabica, S. cyclophylla, S. imbricata, S. incanescens and S. villosa. Additionally, the compounds identified in the most active extracts were screened for their interaction with the active sites of cyclooxygenase enzyme isoforms (COX-1 and COX-2). GC-MS analysis of the n-hexane extracts from the five species resulted in the identification of 67 constituents. Oleic acid (75.57%), 1-octadecene (14.46%), cinnamaldehyde α-hexyl (57.15%), octacosyl heptafluorobutyrate (25.36%) and hexadecanoic acid methyl ester (26.15%) represent the major constituents in S. arabica, S. cyclophylla, S. imbricata, S. inscanescence and S. villosa, respectively. Results of bioactivity testing highlighted S. villosa as having the highest anti-oxidant activity (IC50 0.99 ± 0.05 mg/mL), which was closely followed by S. cyclophylla (IC50 1.36 ± 0.06 mg/mL) compared to the IC50 of 0.16 ± 0.01 mg/mL recorded by ascorbic acid. S. villosa was further noted for having the strongest COX-2 inhibitory activity (IC50 4.6 ± 0.13 µg/mL) among the tested extracts followed by S. arabica (IC50 13.1 ± 0.37 µg/mL) and S. cyclophylla (IC50 20.1 ± 0.57 µg/mL). On the other hand, S. imbricata extract displayed the most characteristic inhibition activity against COX-1 (IC50 10.2 ± 0.52 µg/mL), which was non-significant from the standard drug celecoxib. Based upon bioactivity results, the phytoconstituents identified in S. villosa and S. imbricata extracts were investigated for their capability to interact with the active sites of both cyclooxygenase enzyme isoforms adopting molecular docking. Results indicated the possibility to incorporate the compounds to active sites of the enzymes where some of them bind with their polar end into the cavity beyond Arg120 and their aliphatic chain oriented to the catalytically important Tyr385 similar to the natural substrate arachidonic acid, indicating that they could be promising candidates for the future development of selective COX inhibitors. [ABSTRACT FROM AUTHOR]

The two most significant as well as historically important non-steroidal and anti-inflammatory medications (NSAIDs), aspirin and ibuprofen, are frequently used to treat fever, pain, and inflammation. By blocking the activity of cyclooxygenase (COX), it can prevent the production of prostaglandin. In an effort to examine the physiochemical and biological properties of some heterocyclic amide derivatives and quantum mechanical computations have been used to analyze the compounds. To clarify the thermochemical, molecular orbital, and equilibrium geometrical features in the gas phase, density functional theory (DFT) with the B3LYP/6-31G basis set has been used. Binding affinities and modes of heterocyclic amide analogs have been investigated on human cyclooxygenase (COX-1 and COX-2) proteins (6Y3C and 5F19) using molecular docking as well as nonbonding interactions. Results from geometry and thermochemical analysis support the chemical sustainability of all the structures. Most of the compounds exhibited a significant affinity for binding to the receptor protein (5F19) than the standard drugs aspirin and ibuprofen. The improved pharmacokinetic features of certain derivatives with reduced acute oral toxicity were revealed by ADMET prediction. Overall, four heterocyclic amide analogs 3-6 were found to be more efficient in inhibiting COX-2 (5F19) than COX-1 (6Y3C), suggesting that they may be useful as COX-2-related inflammation drug candidates. [ABSTRACT FROM AUTHOR]

The role of androgens in vascular reactivity is controversial, particularly regarding their age-related actions. The objective of this study was to c onduct a temporal evaluation of the vascular reactivity of resistance arteries of young male rats, as well as to understand how male sex hormones can influence the vascula r function of these animals. Endothelium-mediated relaxation was characterized in third-order mesenteric arteries of 10-, 12-, 16-, and 18w (week-old) male rats. Concen tration--response curves to acetylcholine (ACh, 0.1 nmol/L--10 μmol/L) were constructed in arteries previously contracted with phenylephrine (PE, 3 μmol/L), before and after the use of nitric oxide synthase or cyclooxygenase inhibitors. PE concentration--response curves (1 nmol/L--100 μmol/L) were also built. The levels of vascular nitric oxide, su peroxide anion, and hydrogen peroxide were assessed and histomorphometry analysis was performed. The 18w group had impaired endothelium-dependent relaxation. All groups showed prostanoid-independent and nitric oxide-dependent vasodilatory response, although this dependence seems to be smaller in the 18w group. The 18w group had the lowest nitric oxide and hydrogen peroxide production, in addition to the highest superoxide anion levels. Besides functional impairment, 18w animals showed morphological differences in third-order mesenteric arteries compared with the other groups. Our data show that time-dependent exposure to male sex hormones appears to play an important role in the development of vascular changes that can lead to impaired v ascular reactivity in mesenteric arteries, which could be related to the onset of age -related cardiovascular changes in males. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7/N9 linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested β-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility. [ABSTRACT FROM AUTHOR]

Ibuprofen and aspirin are frequently used to relieve inflammation, pain, and fever. These are the two most significant non-steroidal and anti-inflammatory drugs (NSAIDs). They prevent the development of prostaglandin by blocking the function of cyclooxygenase (COX). The biological and physiochemical aspects of some hetero-cyclic aspirin derivatives have been investigated, and the compounds have been assessed by ibuprofen as well as quantum mechanical computations. Density functional theory (DFT) with the B3LYP/6-31G+ basis function has been used to elucidate the thermo-chemical, molecular orbital, and optimum geometrical aspects in the gas phase. Using molecular docking and non-bonding interactions, the binding affinities and behaviors of some heterocyclic aspirin analogs have been studied on human cyclooxygenase (COX-1 as well as COX-2) proteins (6Y3C and 5F19). The chemical stability of all structures is supported by geometry and thermo-chemical findings. In contrast to aspirin and ibuprofen, almost all tested analogs exhibited a substantial binding score to the receptor protein (5F19). The ADMET prediction revealed the enhanced pharmacokinetic properties of some derivatives with less acute oral toxicity. Overall, eight heterocyclic aspirin analogues 2-9 were shown to be more effective in inhibiting Cyclooxygenase-2 (5F19) than Cyclooxygenase-1 (6Y3C), indicating that they may be effective as COX-2-related inflammation therapeutic candidates. [ABSTRACT FROM AUTHOR]

Using the molecular docking approach the simulation of the complex formation of 17 uracil derivatives containing cyclic and acyclic sulfur- and oxygen substituents in the pyrimidine cycle with active centers of cyclooxygenase isoforms (COX) was performed. Of the set tested, two leading compounds were identified, namely, conjugates of 5-hydroxy-1,3,6-trimethyluracil with N-phthalyl-L-amino acids, which can be effective inhibitors of COX isoforms induced during inflammatory processes in the organism with an increased selectivity towards COX-2. The synthesized compounds were evaluated in vivo on the models of inflammation caused by carrageenan, lidocaine, egg white, and formalin. The conjugates of 5-hydroxy-1,3,6-trimethyluracil with N-phthalyl alanine and N-phthalyl methionine displayed pronounced anti-inflammatory activities with the efficacy comparable to that of Ortofen. The isoenzyme-specific inhibition of COX isoforms was assessed and the pronounced anti-inflammatory activity of the synthesized compounds was found. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX), which forms prostaglandins involved in pain and inflammation. COX inhibitors have analgesic and anti‐inflammatory effects, but also increase risks for gastrointestinal ulcers, bleeding, and renal and cardiovascular adverse events. Identification of two isoforms of COX, COX‐1 and COX‐2, led to the development of selective COX‐2 inhibitors, which were launched as having fewer gastrointestinal side effects since gastroprotective prostaglandins produced via COX‐1 are spared. The balance between COX‐1 mediated prothrombotic thromboxane and COX‐2 mediated antithrombotic prostacyclin is important for thrombotic risk. An increased risk of suffering myocardial infarction and death with COX‐2 inhibitor treatment is well established from clinical trials and observational research. Rofecoxib (Vioxx) was withdrawn from the market for this reason, but the equally COX‐2 selective etoricoxib has replaced it in Europe but not in the United States. The "traditional" NSAID diclofenac is as COX‐2 selective as celecoxib and increases cardiovascular risk dose dependently. COX inhibitor dosages should be lower in osteoarthritis than in rheumatoid arthritis. Randomized trials comparing COX‐2 inhibitors with NSAIDs have exaggerated their gastrointestinal benefits by using maximal NSAID doses regardless of indication, and/or hidden the cardiovascular risk by comparing with COX‐2 selective diclofenac instead of low‐dose ibuprofen or naproxen. Observational studies show increased cardiovascular risks within weeks of treatment with COX‐2 inhibitors and high doses of NSAIDs other than naproxen, which is the safest alternative. COX inhibitors are symptomatic drugs that should be used intermittently at the lowest effective dosage, especially among individuals with an increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) are a potential solution to the general problem of low solubility, polymorphism and low bioavailability of active pharmaceutical ingredients (APIs). In this work, we report on the synthesis of three pharmaceutically active ILs (API-ILs) based on ibuprofen, one of the most commonly available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), with imidazolium cations ([C2C1Im][Ibu] and [C2(OH)C1Im][Ibu]) and a cholinium cation ([N1112(OH)][Ibu]). An upgrade to the aqueous solubility (water and biological simulated fluids) for the ibuprofen-based ILs relative to the ibuprofen's neutral and salt form (sodium ibuprofen) was verified. The cytotoxic profiles of the synthesized API-ILs were characterized using two human cells lines, Caco-2 colon carcinoma cells and HepG-2 hepatocellular carcinoma cells, up to ibuprofen's maximum plasma concentration (Cmax) without impairing their cytotoxicity response. Additionally, the EC50 in the Caco-2 cell line revealed similar results for both parent APIs and API-ILs. The biocompatibility of the ibuprofen-based ILs was also evaluated through a hemolytic activity assay, and the results showed that all the ILs were hemocompatible at concentrations higher than the ibuprofen Cmax. Moreover, the anti-inflammatory properties of the API-ILs were assessed through the inhibition of bovine serum albumin (BSA) denaturation and inhibition of cyclooxygenases (COX-1 and COX-2). The results showed that [C2C1Im][Ibu], [C2(OH)C1Im][Ibu] and [N1112(OH)][Ibu] maintained their anti-inflammatory response to ibuprofen, with improved selectivity towards COX-2, allowing the development of safer NSAIDs and the recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Alzheimer's and Parkinson's. [ABSTRACT FROM AUTHOR]

Modulating the cyclooxygenase 2 (COX-2) pathway has improved responses to immune checkpoint inhibitors (ICIs) in certain solid tumors, such as melanoma. Little is known about COX-2 inhibition in response to ICIs in metastatic renal cell carcinoma (mRCC). In this retrospective cohort study, we examined the effect of COX-2 inhibitors on the long-term outcomes of mRCC patients undergoing ICI therapies. Among 211 patients with mRCC, 23 patients were excluded due to loss to follow-up. Among 188 included patients, 120 patients received either an NSAID or aspirin for at least three weeks during ICI therapies. Clear cell histology was present in 96% of cases. The median overall survival (OS) was similar regardless of the COX inhibitor (COXi) (i.e., NSAID or aspirin) use (27 months for COXi vs. 33 months for no-COXi groups; p = 0.73). The no-COXi group showed a trend toward longer median progression-free survival (8 months for COXi vs. 13 months for no-COXi groups; p = 0.13). When looking specifically at NSAID use in a multivariate analysis, NSAID use was associated with a higher risk of progression (HR = 1.52 [95% CI, 1.04–2.22]) and death (HR = 1.60 [95% CI, 1.02–2.52]). In summary, COXis did not improve disease control or survival among patients with mRCC who were undergoing ICI therapies. Instead, the concurrent use of NSAIDs was associated with worse outcomes. Larger studies are needed to validate our observation. [ABSTRACT FROM AUTHOR]

While the effects of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, have been studied extensively in the central nervous system, there is limited knowledge about its effects on the female reproductive system. The aim of this study was to assess the effect of THC on the expression and secretion of the angiogenic factor vascular endothelial growth factor (VEGF) in the ovary, and to determine if these effects were mediated by prostaglandins. Spontaneously immortalized rat granulosa cells (SIGCs) were exposed to THC for 24 h. Gene expression, proliferation and TNFα-induced apoptosis were evaluated in the cells and concentrations of VEGF and prostaglandin E2 (PGE 2), a known regulator of VEGF production, were determined in the media. To evaluate the role of the prostanoid pathway, cells were pre-treated with cyclooxygenase (COX) inhibitors prior to THC exposure. THC-exposed SIGCs had a significant increase in VEGF and PGE 2 secretion, along with an increase in proliferation and cell survival when challenged with an apoptosis-inducing factor. Pre-treatment with COX inhibitors reversed the THC-induced increase in both PGE 2 and VEGF secretion. Alterations in granulosa cell function, such as the ones observed after THC exposure, may impact essential ovarian processes including folliculogenesis and ovulation, which could in turn affect female reproductive health and fertility. With the ongoing increase in cannabis use and potency, further study on the impact of cannabis and its constituents on female reproductive health is required. • Cannabis components disturb ovarian cell function in vitro. • THC increases vascular endothelial growth factor (VEGF) output in granulosa cells • THC increases rat granulosa cell proliferation and decreases induced apoptosis. • THC increases prostaglandin E2 secretion in rat granulosa cells. • THC-induced increase in VEGF can be blocked with a prostaglandin synthase inhibitor [ABSTRACT FROM AUTHOR]

Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58–1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65–1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48–1.20; for DMFS, HR 0.80, 95% CI 0.49–1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45–6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58–1.53). NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab. • NSAIDs were not associated with recurrence-free survival. • NSAIDs were not associated with distant metastasis-free survival. • NSAIDs were not associated with the incidence of immune-related adverse events. [ABSTRACT FROM AUTHOR]

The identification and removal of all gross and microscopic tumor to render the patient disease free represents a huge challenge in ovarian cancer treatment. The presence of residual disease is an independent negative prognostic factor. Herein, we describe the synthesis and the "in vitro" evaluation of compounds as cyclooxygenase (COX)-1 inhibitors, the COX-1 isoform being an ovarian cancer biomarker, each bearing fluorochromes with different fluorescence features. Two of these compounds N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2-[7-(1,3-dihydro-1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)-1H-benz[e]indolium chloride, 23 (MSA14) were found to be potent and selective inhibitors of cyclooxygenase (COX)-1 "in vitro", and thus were further investigated "in vivo". The IC50 values were 0.032 and 0.087 µM for RR11 and 23 (MSA 14), respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while 23 (MSA14) did not inhibit COX-2 even at a 50 µM concentration. Together, this represented selectivity index = 75 and 874, respectively. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1. Fluorescent probes RR11 and 23 (MSA14), were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in human ovarian cancer (OVCAR-3 and SKOV-3) xenograft models. Surprisingly, a tumor-specific signal was observed for both tested fluorescent probes, even though this signal is not linked to the presence of COX-1. [ABSTRACT FROM AUTHOR]

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use. Methods: A 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. The primary outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at any time following COVID-19 diagnosis. Results: Logistic regression showed that NSAID use was not associated with increased COVID-19 severity (OR: 0.57 95% CI: 0.53–0.61). Analysis of secondary outcomes using logistic regression showed that NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: 0.47–0.56), invasive ventilation (OR: 0.59 95% CI: 0.55–0.64), AKI (OR: 0.67 95% CI: 0.63–0.72), or ECMO (OR: 0.51 95% CI: 0.36–0.7). In contrast, the odds ratios indicate reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between 1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder associations could explain away the observed associations. Conclusions: Study interpretation is limited by the observational design. Recording of NSAID use may have been incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A conservative interpretation in light of the quantitative bias analysis is that there is no evidence that NSAID use is associated with risk of increased severity or the other measured outcomes. Our results confirm and extend analogous findings in previous observational studies using a large cohort of patients drawn from 38 centers in a nationally representative multicenter database. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) is capable of catalysing the oxidative deamination of amines and neurotransmitters. MAO plays a pivotal role in maintaining neurotransmitters linked to neurological disorders viz. Alzheimer's disease (AD), Parkinson's disease (PD) etc. Therefore, inhibition of MAO can be implicated to the cure of such diseases. Synthetic MAO inhibitors are known to inhibit MAO activity. However, there are safety issues with synthetic MAO inhibitors and many of their effects are non-selective and irreversible. Contrasting synthetic drugs, plant-derived natural products have been popularized globally owing to their extensive acceptability and applicability, therapeutic potency and minimum side effects which potentiated the possibility of developing reversible, promising MAO inhibitors based on natural products. The present review comprehensively elucidates plant -derived natural reversible MAO inhibitors using the literature from the popular databases such as Google Scholar, Scopus, PubMed and Web of Science. This literature review reports approximately 51 plants that have been evaluated for MAO inhibitory activity. In addition, 93 plant-derived natural compounds were retrieved as MAO inhibitors. Majority of these investigations predominantly utilized an in vitro approach to evaluate the MAO inhibitors in relation to the developing treatments of related neurological diseases. However, in vivo studies and clinical trials are still lacking in evaluating the botanical-based MAO inhibitors. The aim of this review is to retrieve the recent literature to explore the in vitro and in vivo studies of plant-based natural products as MAO inhibitors, their structure-activity relationship and relevant molecular docking analyses and their roles in the emerging therapy against disorders like AD, and PD. Further, the review also discusses the shortcomings in the existing research in order to generate more coordinated and focused research in future. [Display omitted] • Plant natural products acts as promising MAO-inhibitors. • They are capable of inhibiting both MAO-A and MAO-B. • MAO-inhibition is implicated to the treatment of many neurological diseases. • A number of in vitro and in vivo studies described MAO-inhibition by botanicals [ABSTRACT FROM AUTHOR]

Cyclooxygenase inhibitors are widely used in prescription. They are the choice of drugs worldwide. The drug naproxen, which is a propionic acid nonselective cyclooxygenase inhibitor, is still preferred in arthritis, osteoarthritis and gout. The drawback associated with this drug is that it causes nausea, vomiting or gastrointestinal upsets. The cause of gastrointestinal upset may be due to perforation of gastric mucosa or ulceration. To overcome this problem, this is associated with the free carboxylic group present on naproxen. Here the parent drug is modified using glycolic acid precursors with phytophenols. The phytophenols are known for their antioxidant properties and they also reduce ulceration. The glycolic acid spacer provides a single bond rotation that promotes excellent binding with the receptor. The different derivatives of naproxen were designed and screened by computational technique based on virtual screening against human cyclooxygenase-2 enzyme through Auto Dock. The identified derivatives were curtained through Lipinski’s rule of pharmacokinetics. The effective and innocuous molecule was identified. The identified derivative was synthesized, purified, characterized and pharmacological studies were done. The result obtained clearly indicating that there is a depiction in molecular docking and pharmacological studies. [ABSTRACT FROM AUTHOR]

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs. [ABSTRACT FROM AUTHOR]

Symptomatic patent ductus arteriosus (sPDA) is common among preterm infants, and can lead to several complications. This is particularly true for extremely preterm infants, as closure of the ductus arteriosus using cyclooxygenase inhibitors is often difficult. A recent study using a preterm sheep model showed that intimal thickening—required for anatomical closure of the ductus arteriosus—is less developed in twins than in singletons. Therefore, this study primarily aimed to prove that the ductus arteriosus of extremely preterm twins is more resistant to cyclooxygenase inhibitors than those of extremely preterm singletons. Its secondary aim was to assess whether the resistance against cyclooxygenase inhibitors differed according to chorionicity. In this retrospective case–control study, medical records of 162 extremely preterm infants (gestational age < 28 weeks) were reviewed, and the treatment course of sPDA was subsequently compared between singletons (n = 131) and twins (n = 31). The median indomethacin doses for sPDA and the necessity for surgical ligation were significantly higher in twins than in singletons (5 vs 2 [p < 0.001] and 42% vs 21% [p = 0.018], respectively). No significant differences in sPDA treatment, including the number of indomethacin doses and the necessity for surgical ligation, were observed between monochorionic diamniotic and dichorionic diamniotic twins. This study confirms that the ductus arteriosus of extremely preterm twins is more resistant to cyclooxygenase inhibitors than those of singletons. However, there was no significant difference in sPDA treatment by chorionicity. [ABSTRACT FROM AUTHOR]

Piperine is a natural alkaloid that possesses a variety of therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and anticarcinogenic activities. The present study aims to assess the medicinal benefits of piperine as an anti-diarrheal agent in a chick model by utilizing in vivo and in silico techniques. For this, castor oil was administered orally to 2-day-old chicks to cause diarrhea. Bismuth subsalicylate (10 mg/kg), loperamide (3 mg/kg), and nifedipine (2.5 mg/kg) were used as positive controls, while the vehicle was utilized as a negative control. Two different doses (25 and 50 mg/kg b.w.) of the test sample (piperine) were administered orally, and the highest dose was tested with standards to investigate the synergistic activity of the test sample. In our findings, piperine prolonged the latent period while reducing the number of diarrheal feces in the experimental chicks during the monitoring period (4 h). At higher doses, piperine appears to reduce diarrheal secretion while increasing latency in chicks. Throughout the combined pharmacotherapy, piperine outperformed bismuth subsalicylate and nifedipine in terms of anti-diarrheal effects with loperamide. In molecular docking, piperine exhibited higher binding affinities towards different inflammatory enzymes such as cyclooxygenase 1 (−7.9 kcal/mol), cyclooxygenase 2 (−8.4 kcal/mol), nitric oxide synthases (−8.9 kcal/mol), and L-type calcium channel (−8.8 kcal/mol), indicating better interaction of PP with these proteins. In conclusion, piperine showed a potent anti-diarrheal effect in castor oil-induced diarrheal chicks by suppressing the inflammation and calcium ion influx induced by castor oil. [ABSTRACT FROM AUTHOR]

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 E 4 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. [Display omitted] • A total of 19 urinary eicosanoids, 9,10- and 12,13-DiHOME were retained by a single SPE extraction. • The SPE protocol was simplified to be conducted in 96-well format requiring only 300 µL urine. • The method can screen for the detection of cortisol/cortisone, 7 exogenous steroids and 3 COX-inhibitors. • All 19 urinary eicosanoids were stable over 3.5 years at − 80 °C. • Average intra-plate CVs were 8.5–15.1% and average inter-plate CVs (n = 35) were 22.1–34.9% for eicosanoids and DiHOMEs. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases (CAs, EC 4.2.1.1) are enzymes involved in a multitude of diseases, and their inhibitors are in clinical use as drugs for the management of glaucoma, epilepsy, obesity, and tumours. In the last decade, multitargeting approaches have been proposed by hybridisation of CA inhibitors (CAIs) of sulphonamide, coumarin, and sulphocoumarin types with NO donors, CO donors, prostaglandin analogs, β-adrenergic blockers, non-steroidal anti-inflammatory drugs, and a variety of anticancer agents (cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors). Many of the obtained hybrids showed enhanced efficacy compared to the parent drugs, making multitargeting an effective and innovative approach for various pharmacological applications. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a large group of common over-the-counter and prescription medications. As a group, NSAIDs are a common cause of drug hypersensitivity. However, the challenge is that the spectrum of hypersensitivity reactions to NSAIDs is varied, including classic IgE- and non-IgE-mediated reactions to individual NSAIDs, intolerance to all cyclooxygenase-1 inhibitors (COX-1 inhibitors) and delayed T-cell reactions to single or multiple NSAIDs. Allergy work-up and management differ based on understanding the phenotype and mechanism. In this case series we describe three different reactions to an individual NSAID - diclofenac. This highlights the clinical presentation, work-up and distinct management necessitated by each case. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Arachidonic acid (AA) stimulates NO production in antral mucous cells without any increase in [Ca2+]i. Given that the intracellular AA concentration is too low to measure, the relationship between AA accumulation and NO production remains uncertain. Is AA accumulation a key step for NO production?What is the main finding and its importance?We demonstrated that AA accumulation is a key step for NO production. The amount of AA released could be measured using fluorescence‐HPLC. The intracellular AA concentration was maintained at < 1 μM. Nitric oxide is produced by AA accumulation in antral mucous cells, not as a direct effect of [Ca2+]i. In the present study, we demonstrate that NO production is stimulated by an accumulation of arachidonic acid (AA) mediated via peroxisome proliferation‐activated receptor α (PPARα) and that the NO produced enhances Ca2+‐regulated exocytosis in ACh‐stimulated antral mucous cells. The amount of AA released from the antral mucosa, measured by fluorescence high‐performance liquid chromatography (F‐HPLC), was increased by addition of ionomycin (10 μM) or ACh, suggesting that AA accumulation is stimulated by an increase in [Ca2+]i. The AA production was inhibited by an inhibitor of cytosolic phospholipase A2 (cPLA2‐inhα). GW6471 (a PPARα inhibitor) and cPLA2‐inhα inhibited NO synthesis stimulated by ACh. Moreover, indomethacin, an inhibitor of cyclooxygenase, stimulated AA accumulation and NO production. However, acetylsalicylic acid did not stimulate AA production and NO synthesis. An analogue of AA (AACOCF3) alone stimulated NO synthesis, which was inhibited by GW6471. In antral mucous cells, indomethacin enhanced Ca2+‐regulated exocytosis by increasing NO via PPARα, and the enhancement was abolished by GW6471 and cPLA2‐inhα. Thus, AA produced via PLA2 activation is the key step for NO synthesis in ACh‐stimulated antral mucous cells and plays important roles in maintaining antral mucous secretion, especially in Ca2+‐regulated exocytosis. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory processes in the brain play an important role in the etiopathogenesis of Obsessive-Compulsive Disorder (OCD). Cyclooxygenase inhibitors, such as celecoxib reduce the production of proinflammatory cytokines. This double-blind study aimed to investigate the effects of adding celecoxib to Selective Serotonin Reuptake Inhibitors (SSRIs)on treating OCD. Methods: Sixty patients who met the diagnosis criteria for OCD based on the Diagnostic and Statistical Manual of Mental Disorders -Fourth Edition-Text Revision (DSM-IV-TR) were recruited in the present study. Two psychiatrists independently confirmed the diagnosis by performing structured interviews. The study participants included 23 patients who received SSRIs and celecoxib (400 mg twice daily) and 22 patients in the control group that received SSRIs and placebo. Moreover, at baseline, in weeks 4, 8, and 12, the explored patients were assessed by a psychiatrist using the Yale-Brown Obsessive-Compulsive Scale (Y-BCOS). Results: A significant difference was observed in the change of scores on the Y-BOCS in week 12, compared with the onset of the study between the study groups (t= -8.976, df=38, P=0.001). There was a significant difference between the study groups in obsession (F= 49.19, df= 1, P=0.001), compulsion (F= 13.78, df= 1, P= 0.001), and OCD (F= 57.25, df= 1, P=0.001), i.e., higher in the celecoxib group. Conclusion: This study showed that adjuvant treatment with celecoxib can further improve the symptoms of OCD in individuals receiving SSRIs. [ABSTRACT FROM AUTHOR]

Bovine Respiratory Syncytial virus (BRSV) is one of the major infectious agents in the etiology of the bovine respiratory disease complex. BRSV causes a respiratory syndrome in calves, which is associated with severe bronchiolitis. In this study we describe the effect of treatment with antiviral fusion protein inhibitor (FPI) and ibuprofen, on gene expression in lung tissue of calves infected with BRSV. Calves infected with BRSV are an excellent model of human RSV in infants: we hypothesized that FPI in combination with ibuprofen would provide the best therapeutic intervention for both species. The following experimental treatment groups of BRSV infected calves were used: 1) ibuprofen day 3–10, 2) ibuprofen day 5–10, 3) placebo, 4) FPI day 5–10, 5) FPI and ibuprofen day 5–10, 6) FPI and ibuprofen day 3–10. All calves were infected with BRSV on day 0. Daily clinical evaluation with monitoring of virus shedding by qRT-PCR was conducted. On day10 lung tissue with lesions (LL) and non-lesional (LN) was collected at necropsy, total RNA extracted, and RNA sequencing performed. Differential gene expression analysis was conducted with Gene ontology (GO) and KEGG pathway enrichment analysis. The most significant differential gene expression in BRSV infected lung tissues was observed in the comparison of LL with LN; oxidative stress and cell damage was especially noticeable. Innate and adaptive immune functions were reduced in LL. As expected, combined treatment with FPI and Ibuprofen, when started early, made the most difference in gene expression patterns in comparison with placebo, especially in pathways related to the innate and adaptive immune response in both LL and LN. Ibuprofen, when used alone, negatively affected the antiviral response and caused higher virus loads as shown by increased viral shedding. In contrast, when used with FPI Ibuprofen enhanced the specific antiviral effect of FPI, due to its ability to reduce the damaging effect of prostanoids and oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: Nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide (NO) signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of an NO donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen, and ibuprofen. Administration of indomethacin (5 mg·kg-1), ibuprofen (30 mg·kg-1), or naproxen (30 mg·kg-1) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. By contrast, only indomethacin was able to inhibit NO-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate NO-related signaling as a potential therapeutic approach to these disorders. [ABSTRACT FROM AUTHOR]

Dual cyclooxygenase 2/15-lipoxygenase inhibitors constitute a valuable alternative to classical non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 (cyclooxygenase-2) inhibitors for the treatment of inflammatory diseases, as well as preventing the cancer. Indeed, these latter present diverse side effects, which are reduced or absent in dual-acting agents. In this review, COX-2 and 15-LOX (15-lipoxygenase) pathways are first described in order to highlight the therapeutic interest of designing such compounds. Various structural families of dual inhibitors are illustrated. This study discloses various structural families of dual 15-LOX/COX-2 inhibitors, thus pave the way to design potentially-active anticancer agents with balanced dual inhibition of these enzymes. [Display omitted] • Cancer is a complex process, produces a number of inflammatory mediators. • Dual-acting COX-2/5-LOX inhibitors may treat cancer by suppressing COX-2 and 5-LOX enzymes. • 15-LOX inhibitors lack some of the side effects of 5-LOX inhibitors. • Implications of novel synthetic analogs as dual COX-2/15-LOX inhibitors are addressed in the present review paper. [ABSTRACT FROM AUTHOR]

The article titled "Electrospun Nanofibrous Composite Membranes for Long-Term Release of Celecoxib for Achilles Tendon Reconstruction Following Injury" discusses the development of a new implantable combination of nanofibers for Achilles tendon reconstruction. The nanofibers, called celecoxib-collagen-bupivacainepoly(lactic-co-glycolic acid) (CCBP), show improved therapeutic application and higher load-to-failure values compared to healthy tendons and nanofibers with doxycycline. The authors suggest that CCBP is a promising scaffold for repairing ruptured Achilles tendons and is superior to existing materials. [Extracted from the article]

Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with eye drops. A major challenge in the topical treatment of glaucoma patients is the many side effects and the resulting reduced adherence. Side effects may of course be due to the molecular properties of the active pharmaceutical ingredients (APIs). There are currently six different APIs available: prostaglandin analogues, β-adrenergic inhibitors, α-adrenergic agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors and muscarinic 3 agonists. But the additives used in eye drops are also known to cause damage to the ocular surface and to some extent also to the deeper tissues. Said additives are considered inactive molecular components and are added to secure for instance viscosity and pH value, and to prevent contamination. There has been an increasing focus on the harmful effects of preservatives, with the most commonly used preservative benzalkonium chloride (BAK) being particularly controversial. BAK has long been recognized as a toxin that increases the risk of ocular discomfort. This can affect the adherence and ultimately result in lack of disease control. Other issues include the addition of certain buffers, such as phosphates, and varying pH values. This review will address the different molecular components of the IOP-lowering eye drops and what to be aware of when prescribing topical glaucoma treatment. • Active and inactive molecules in IOP-lowering eye drops can cause adverse reactions. • Preservatives in IOP-lowering eye drops can cause significant side effects. • All components in IOP-lowering eye drops may impact the pathophysiology of glaucoma. • Adverse reactions in IOP-lowering eye drops may reduce adherence. • Attention should be paid to all the components of eye drops when treating glaucoma. [ABSTRACT FROM AUTHOR]

In the present study, the optimized geometrical parameters and vibrational frequencies of the Genkwanin (5- hydroxy-2-(4-hydroxyphenyl)-7-methoxychromen-4-one) were obtained by both hatree fock(HF) and density functional theory(DFT) methods. The experimental FT-IR, FT-Raman spectrum of the compound has been recorded in the region 4000-600 cm-1 and 50-4000 cm-1 respectively. The calculated structural parameters and vibrational frequencies were analyzed and compared with obtained experimental results. The frontier molecular orbital (FMO), molecular electrostatic potential (MEP) and UV-vis studies of the compound has been computed to elucidate the electronic properties. Moreover, molecular docking studies were also carried out to investigate the inhibitory effect of the compound against cyclooxygenase (COX) enzymes. Results of molecular docking study reveals that the chosen compound effectively inhibits the active sites of the human cyclooxygenase(COX-1 and COX-2) enzyme. The binding energy of the compound were studied and compared to standard drugs Ibuprofen, Nimesulide and Mefenamic acid. The investigated compound showed good binding affinity compared to standard drugs. Therefore, this study is an attempt to identify a safe and effective new drug from flavonoids for the treatment of inflammatory disease. [ABSTRACT FROM AUTHOR]

Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP2 receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINNinduced airway relaxation required TRPA1, prostaglandins, and PGE2 receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation. [ABSTRACT FROM AUTHOR]

Introduction: This meta-analysis aims to determine whether non-steroidal anti-inflammatory drug (NSAID) use is significantly associated with adverse bone healing outcomes within clinical settings, including trauma and elective spine settings. It will also explore bone healing outcomes with the type, route, dosage and duration of NSAID exposure and aims to demonstrate the effects of various other confounding factors on bone healing outcomes. Methods: Electronic databases including MedLine, Embase and Cochrane were searched from January 1975 to December 2017. A distinct analysis of observational long bone and spine studies in adult populations was performed, assessing the effects of NSAID exposure on bone healing. Studies from paediatric population and randomised trials also underwent separate assessment in the synthesis. Meta-analysis was conducted in compliance with QUORUM and PRISMA guidelines. Results: Quantitative assessment of observational studies suggested a significant risk of bone healing complications with NSAID exposure across each clinical group: long bone (p = 0.0004) and spine (p = 0.02). Analysis of paediatric studies revealed a non-significant association of poor outcomes with NSAID use (p = 0.36), while assessment of randomised trials demonstrated a statistically significant risk of complications following NSAID administration (p = 0.04). Meta-regression further suggested smoking to be a substantial confounder associated with adverse bone healing outcomes (p < 0.00001). Conclusion: Inclusion of only fair and moderate-quality retrospective cohort and case–control studies in the current synthesis limits the clinical application of its findings and therefore warrants the need for further research. Thus, attempts to conduct high-quality prospective cohort and randomised trials to study the effects of NSAID use on bone healing would be very helpful and will provide a basis for more extensive research in future. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the clinical blood gas indices and histopathological consequences after intrathecal injection of tolfenamic acid and lidocaine Hcl and moreover, to elucidate the spinal safety of tolfenamic acid as a cyclooxygenase inhibitor in donkeys. Ten clinically healthy donkeys were divided into two groups, 5 animals each. The first group received lidocaine Hcl 2% and the second one received tolfenamic acid 4% intrathecally. The physical parameters and ataxia, analgesia, and motor blockade scores were recorded. Blood gases and acid base balance indices and histopathological examination were done. Blood pH level was significantly decreased (P < 0.05) and the blood pCO2 level was significantly increased (P < 0.05) 15 min after intrathecal injection of tolfenamic acid. Additionally, there was a significant difference in the motor block scores between the two groups at 2 and 4 h post-injection. Histopathological findings of the spinal cord of tolfenamic acid–injected group revealed neurodegeneration and necrosis which were manifested clinically by paraplegia. In conclusion, the present study uncovered the analgesic and motor effects of commercially prepared tolfenamic acid following intrathecal injection in donkeys. Nevertheless, it is unsafe because of its neurotoxic effect on the spinal cord which was manifested clinically by paraplegia of donkeys. On the other hand, intrathecal administration of lidocaine Hcl was safe and causes nonserious cardiopulmonary changes. [ABSTRACT FROM AUTHOR]

The relevant information about the impacts caused by presence of emerging pollutants in mixtures on the ecological environment, especially on the more vulnerable compartments such as activated sludge (AS) is relatively limited. This study investigated the effect of ibuprofen (IBU) and triclosan (TCS), alone and in combination to the performance and enzymatic activity of AS bacterial community. The assays were carried out in a pilot AS reactor operating for two-weeks under continuous dosage of pollutants. The microbial activity was tracked by measuring oxygen uptake rate, esterase activity, oxidative stress and antioxidant enzyme activities. It was found that IBU and TCS had no acute toxic effects on reactor biomass concentration. TCS led to significant decrease of COD removal efficiency, which dropped from 90% to 35%. Continuous exposure to IBU, TCS and their mixtures increased the activities of glutathione s-transferase (GST) and esterase as a response to oxidative damage. A high increase in GST activity was associated with non-reversible toxic damage while peaks of esterase activity combined with moderate GST increase were attributed to an adaptive response. [ABSTRACT FROM AUTHOR]

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most prevalent causes of drug hypersensitivity reactions (DHRs), yet the underlying processes are far from clear. Despite the established role of histamine in allergic reactions, its precise implication in DHRs is elusive. Objectives: This study aimed to explore the connection of basal blood histamine levels to the reported NSAID hypersensitivity. Methods: Sixteen patients reporting hypersensitivity reactions to a single or multiple NSAIDs and/or paracetamol and 18 healthy volunteers serving as the normal control group enrolled in the study. The medical history was recorded and histamine was quantified spectrophotofluorometrically in whole peripheral blood and plasma. Results: Compared to the normal group, plasma but not whole blood histamine levels were significantly higher in patients (p < 0.001), mainly in the subgroup reporting hypersensitivity to a single agent (p < 0.001). Plasma histamine levels were significantly correlated with the culprit drug selectivity for cyclooxygenase (COX) isozymes (p < 0.001), with higher levels being obtained in patients reporting reactions to COX-1 than to COX-2 selective inhibitors (p < 0.05). Conclusions: The findings provide first evidence connecting basal blood histamine levels to the reported NSAID-triggered DHRs. Prospective studies are expected to decipher the contribution of histamine-associated parameters to the mechanisms underlying DHRs. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the relationship between the use of COX inhibitors and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB) using a nationwide population‐based data. A nested case‐control study was conducted using the National Health Insurance Service–National Sample Cohort (NHIS‐NSC) from 2002 to 2013 in Korea. We compared the use of COX inhibitors between HCC cases and matched controls by categorizing 5 groups according to the cumulative defined daily dose (cDDD, <28, 28‐90, 91‐180, 181‐360, and >360) adjusting the use of antiviral agents. A total of 4980 patients with CHB were analysed as 996 HCC cases and 3984 matched controls. The number of COX inhibitor users (≥28 cDDD) was 358 patients (36%) and 1814 patients (45%) in the HCC group and control group, respectively. The use of COX inhibitors was significantly associated with a decreased risk of HCC development compared with nonusers (adjusted odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52‐0.73, P <.001). There was a dose‐dependent inverse relationship between the use of COX inhibitors and the risk of HCC. The adjusted ORs were 0.75 (95% CI: 0.63‐0.90), 0.41 (95% CI: 0.31‐0.56), 0.38 (95% CI: 0.25‐0.57) and 0.49 (95% CI: 0.31‐0.79) for the 28‐90, 91‐180, 181‐360 and >360 cDDDs, respectively (P <.01). In conclusion, the use of COX inhibitors was associated with a reduced risk of HCC in CHB. COX inhibitor may have a chemopreventive role in HCC development in patients with chronic liver disease. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the diuretic efficacy of myricetin‐3‐O‐α‐rhamnoside (myricitrin), a common naturally occurring plant‐derived flavonoid, obtained from Marlierea eugeniopsoides (D.Legrand & Kausel) D.Legrand leaves in rats. Methods: For that, female Wistar rats were treated by oral route with the different treatments and kept in metaboloic cages for 8‐h or 24‐h experiment. The volume and urinary parameters were measured at the end of the period and compared between groups. Key findings: When orally given to rats and compared to the vehicle‐treated group, myricitrin (0.3 and 1 mg/kg) was able to stimulate rat diuresis, natriuresis and kaliuresis. The combination myricitrin plus hydrochlorothiazide, but not plus furosemide or amiloride, potentiated the urinary volume when compared to the effects of drugs alone. Besides, the 8‐h renal effects of myricitrin were prevented in the presence of a cyclooxygenase inhibitor and a muscarinic receptor antagonist. However, all groups treated with myricitrin showed a significant reduction in Cl− excretion. In addition, a reduction in the urinary excretion of Cl− and HCO3- was detected on 24‐h analysis, a result that showed to be associated with an increase of these anions in the blood samples from the myricitrin‐treated group. Despite these alterations, no changes in urinary or blood pH were detected. Conclusions: Taking together, although the results of this study point to the diuretic potential of myricitrin, the reduction in urinary Cl− and HCO3- excretion should be considered in future approaches, as well as for therapeutic applicability. [ABSTRACT FROM AUTHOR]

Introduction: Maintenance tocolysis, mostly defined as the continuation of tocolytic treatment beyond 48 h, remains a matter of debate. There is no sufficient evidence from randomized controlled trials, that maintenance tocolysis is able to prolong pregnancy significantly and to reduce severe neonatal morbidity and mortality. Hence, it is not recommended in current guidelines. On the contrary, maintenance tocolysis is commonly used in clinical practice and subject of current clinical-scientific investigations. Tocolytics for maintenance treatment: None of the conventional tocolytics (beta-sympathomimetics, calcium-channel blockers, magnesium, cyclooxygenase inhibitors, and oxytocin receptor antagonists) have proven to be appropriate for maintenance treatment. Progesterone and 17-α-hydroxyprogesterone caproate have shown promising results in low-quality randomized trials, but not in high-quality studies. Discussion: Basically, the value of studies regarding maintenance tocolysis is limited by a considerable heterogeneity, its mostly low quality, significant differences in methodology as well as the inadequate statistical power due to the small number of women studied. So far, maintenance tocolysis is a case-by-case decision outweighing the benefits and harms of tocolytic treatment. [ABSTRACT FROM AUTHOR]

Diclofenac sodium (DS), a potent inhibitor of cyclooxygenase, reduces the release of arachidonic acid and formation of prostaglandins. Being a nonsteroid drug that shows antiinflammatory action, the possible side effects of fetal DS administration gain importance in public and medical applications. Herein, the effects of DS administration (1 mg/kg) during gestational days 5–20 were investigated on the performance of Wistar rat pups in a variety of behavioral tasks. Four-week-old pups were subjected to sensory motor tests, a plus maze, an open field, the Morris water maze, and a radial arm maze. Fetal DS disrupted some sensory motor performances, such as visual placing and climbing in both females and males. In the open field, DS females had a higher level of anxiety and male DS pups habituated to the environment slowly compared to controls. The DS pups showed slower rates of learning, whereas no substantial between-group differences were found in the performance of spatial memory compared to both controls. Furthermore, working memory was negatively affected by fetal DS. In conclusion, it was indicated that DS administration during pregnancy had slight behavioral impacts with a delay in learning and a defect in the short-term memory in juvenile rats. [ABSTRACT FROM AUTHOR]

Background and aims: Though cyclooxygenase inhibitors are employed in rheumatoid arthritis treatment, modulators of leukotrienes are underexplored. We investigated the therapeutic potential of montelukast, a known cysteinyl leukotriene receptor-1 (CysLT1) inhibitor in an experimental rat model of arthritis. Methods: Arthritis was induced in rats, and montelukast (5 mg/kg body wt.) was administered prophylactically (PAM) and therapeutically (TAM) through oral route. Results and discussion: Blood and joint tissue markers of oxidative stress (lipid peroxidation, protein carbonyls, and nitric oxides) were significantly (p < 0.05) reduced in montelukast administered rats. Paw inflammation, RA markers (RF and CRP), eicosanoids (PGE2, LTB4, and LTC4), cytokines (IL-1β and MCP-1), activity of hydrolytic enzymes (collagenase, elastase, and hyaluronidase), expression of matrix metalloproteinases (MMP), and EP-4 receptor were significantly (p < 0.05) reduced in montelukast administered rats. This study established that leukotriene inhibition through montelukast lowered the severity of arthritis and thus a potential strategy for reducing the severity of arthritis. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is a highly toxic chemical warfare agent, which produces blisters after skin contact. Treatment of SM-induced adverse health effects, such as cutaneous blistering, ulceration, and inflammation remains a challenging task. Antidotes or specific therapeutic measures are lacking. Some drugs (e.g. cyclooxygenase (COX) inhibitors) exhibited beneficial effects after SM poisoning in vivo. However, in vitro studies that evaluate and compare the potency of COX inhibitors are missing. In the presented study, non-specific (acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, and piroxicam), COX-2-specific (celecoxib and parecoxib) inhibitors and COX-independent drugs (paracetamol and tofacitinib) were compared regarding anti-inflammatory and cytoprotective effects after SM exposure in post-exposure treatment settings. Normal human epidermal keratinocytes (NHEK) were used as a surrogate model. Prostaglandin E 2 (PGE 2) formation, a direct indicator for COX activity, was determined by ELISA. Changes in pro-inflammatory cytokine levels after SM exposures were assessed by quantitative determination of 27 inflammatory cytokines using a multiplex method. Cytotoxicity was determined using an XTT viability assay. The results demonstrated that SM highly increased PGE 2 production and release of pro-inflammatory cytokines, predominantly IL-6, IL-8 and TNF-α. In general, all COX inhibitors and paracetamol were able to reduce the PGE 2 formation, while tofacitinib, an inhibitor of Janus kinase, had no influence on PGE 2 levels. In addition, IL-6, IL-8, and TNF-α formation were also inhibited, but sometimes independently of PGE 2. The COX-2 specific celecoxib was identified as the most potent drug to reduce IL-6, IL-8 and TNF-α formation after SM exposures in vitro. However, cell viability was not improved significantly by any of the investigated drugs in our experiments. [ABSTRACT FROM AUTHOR]