Non-selective Cyclooxygenase Inhibitor Research Articles

Design and Development of Nanoparticle-loaded In-situ Gel for Enhanced and Sustained Ophthalmic Delivery

Background: Flurbiprofen, a non-selective COX inhibitor utilized for managing mild to moderate pain and inflammation, operates through reversible inhibition of both COX-1 and COX-2 pathways. However, as a BCS class II drug, it exhibits limited aqueous solubility, leading to suboptimal ocular bioavailability and a brief corneal contact. Objective: The goal of this study was to amplify the aqueous solubility of Flurbiprofen by formu-lating it into a nanosuspension, which was subsequently incorporated into an in-situ gelling sys-tem so as to extend the ocular residence time and to achieve sustained drug release. Methods: Nanosuspensions were crafted through the anti-solvent precipitation ultra-sonication method. The assessment included parameters, such as particle size, surface morphology, XRD, and FT-IR. The optimized nanosuspension was then incorporated into a pH-sensitive in-situ gel. Results: The developed formulation was stable and showed enhanced contact time, minimizing the frequency of administration. Morphological analysis unveiled spherical drug nanoparticles in the nanosuspension without any signs of aggregation, supported by high-resolution transmission electron microscopy. The ex vivo permeation studies showed a drug release of 83.48%, indicating good permeation and histopathology, and isotonicity indicated no ocular irritation and tissue damage. Conclusion: The design and development of Flurbiprofen nanosuspension were found to be liq-uid at the formulated pH and formed gel due to changes in bonds between polymers. In-situ ocu-lar gels minimize the risk of systemic absorption of the drug, as they are designed to stay local-ized on the ocular surface and within the eye. An optimum point can be reached in the shortest time with minimum efforts to achieve desirable rheological and in-vitro release properties for in-situ gelling systems.

Identification of Indole Derivatives as Selective Cyclooxygenase-2 Inhibitors by Virtual Screening and Molecular Dynamic Simulation

Selective COX-2 inhibitors present a promising strategy in pain management due to their reduced adverse effects compared to non-selective COX inhibitors targeting COX-1. This study focuses on the design and virtual exploration of 8 indole derivatives using molecular docking, ADMET, and molecular dynamics (MD) simulations. Molecular docking highlighted the significance of hydrophobic and hydrophilic amino acid residues for ligand stability, with compounds 4 and 5 exhibiting notably strong in silico affinities to COX-2 (docking scores of -11.349 kcal/mol and -10.872 kcal/mol, respectively). Molecular dynamics simulations confirmed the stability of the COX-2-compound 4 complex over 50 ns, revealing consistent ligand-protein interactions through Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and ligand binding analysis. ADMET analysis of the active compounds showed favorable drug-like profiles and desirable pharmacokinetic properties. This comprehensive computational approach sheds light on the structural dynamics and pharmacological characteristics of these indole derivatives, underscoring their potential as selective COX-2 inhibitors for pain management and paving the way for further experimental validation and clinical exploration.

Hyperalgesic Effect Evoked by il-16 and its Participation in Inflammatory Hypernociception in Mice

The systemic administration of interleukin-16 (IL-16, 3–30 ng/kg) induced thermal hyperalgesia in mice, that was prevented by the acute injection of an anti-CD4 antibody (1 µg/kg), the depletion of circulating white blood cells by cyclophosphamide or the specific reduction of circulating CD4+ cells provoked by a high dose of an anti-CD4 antibody (30 µg/mouse, 24 h before). IL-16-induced hyperalgesia was locally inhibited after intraplantar (i.pl.) administration of the non-selective cyclooxygenase (COX) inhibitor diclofenac, the COX-1 inhibitor SC-560, the COX-2 inhibitor celecoxib, the TRPV1 antagonist capsazepine or the TRPA1 antagonist HC030031, thus demonstrating that prostaglandins and TRP channels are involved in this effect. The i.pl. administration of low doses of IL-16 (0.1–1 ng) evoked local hyperalgesia suggesting the possibility that IL-16 could participate in hypernociception associated to local tissue injury. Accordingly, IL-16 concentration measured by ELISA was increased in paws acutely inflamed with carrageenan or chronically inflamed with complete Freund´s adjuvant (CFA). This augmentation was reduced after white cell depletion with cyclophosphamide or neutrophil depletion with an anti-Ly6G antibody. Immunofluorescence and flow cytometry experiments showed that the increased concentration of IL-16 levels found in acutely inflamed paws is mainly related to the infiltration of IL-16+ neutrophils, although a reduced number of IL-16+ lymphocytes was also detected in paws inflamed with CFA. Supporting the functional role of IL-16 in inflammatory hypernociception, the administration of an anti-IL-16 antibody dose-dependently reduced carrageenan- and CFA-induced thermal hyperalgesia and mechanical allodynia. The interest of IL-16 as a target to counteract inflammatory pain is suggested.Graphical

Repeated seizure-induced brainstem neuroinflammation contributes to post-ictal ventilatory control dysfunction.

Patients with epilepsy face heightened risk of post-ictal cardiorespiratory suppression and sudden unexpected death in epilepsy (SUDEP). Studies have shown that neuroinflammation, mediated by the activation of microglia and astrocytes, may be a cause or consequence of seizure disorders. Kcnj16 (Kir5.1) knockout rats (SS kcnj16-/- ) are susceptible to repeated audiogenic seizures and recapitulate features of human SUDEP, including post-ictal ventilatory suppression, which worsens with repeated seizures and seizure-induced mortality. In this study, we tested the hypothesis that repeated seizures cause neuroinflammation within key brainstem regions that contribute to the control of breathing. Audiogenic seizures were elicited once/day for up to 10days in groups of adult male SS kcnj16-/- rats, from which frozen brainstem biopsies of the pre-Bötzinger complex/nucleus ambiguus (preBötC/NA), Bötzinger complex (BötC), and raphe magnus (RMg) regions were subjected to a cytokine array. Several cytokines/chemokines, including IL-1α and IL-1ß, were increased selectively in preBötC/NA after 3 or 5days of seizures with fewer changes in other regions tested. In additional groups of male SS kcnj16-/- rats that underwent repeated seizures, we quantified microglial (IBA-1+) cell counts and morphology, specifically within the preBötC/NA region, and showed increased microglial cell counts, area, and volume consistent with microglial activation. To further test the role of inflammation in physiological responses to seizures and seizure-related mortality, additional groups of SS kcnj16-/- rats were treated with anakinra (IL-1R antagonist), ketoprofen (non-selective COX inhibitor), or saline for 3days before and up to 10days of seizures (1/day), and breathing was measured before, during, and after each seizure. Remarkably, IL-1R antagonism mitigated changes in post-ictal ventilatory suppression on days 7-10 but failed to prevent seizure-related mortality, whereas ketoprofen treatment exacerbated post-ictal ventilatory suppression compared to other treatment groups but prevented seizure-related mortality. These data demonstrate neuroinflammation and microglial activation within the key brainstem region of respiratory control following repeated seizures, which may functionally but differentially contribute to the pathophysiological consequences of repeated seizures.

Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

(003) LOCALIZED PROVOKED VULVODYNIA: THE ROLE OF CYCLOOXYGENASE ENZYMES IN PROMOTING INFLAMMATION AND PAIN SIGNALING

Abstract Introduction Localized provoked vulvodynia (LPV) is a chronic condition in which patients experience disabling pain in the vulvar vestibule. This condition’s mechanisms are poorly understood, and the lack of adequate treatment reflects the misunderstanding of the disease’s origins. Many LPV patients attempt to treat their pain with NSAIDS, but their use has been clinically shown to be ineffective against LPV associated vulvar pain. Recent evidence, utilizing fibroblasts isolated from vestibular and vulvar tissue of LPV patients, supports a link between inflammation and symptomology of LPV. These fibroblasts have shown to be sensitive to pro-inflammatory stimuli and overproduce inflammatory mediators such as Interleukin-6 (IL-6) and Prostaglandin E2 (PGE2). Increased production of IL-6 and PGE2 correlates with decreased pain thresholds, endorsing these levels as a surrogate measure for pain. Lipidomic data collected via mass spectroscopy also demonstrates LPV fibroblast strains have dysregulated arachidonic acid metabolism, resulting in an imbalance in pro-resolving lipids. Utilizing this fibroblast model, different cyclooxygenase (COX) inhibitors were used to better illuminate the mechanism behind fibroblast inflammation in LPV. Objective Using a fibroblast cell model, we set out to better understand pathophysiology of LPV and use that information to guide development of effective and pragmatic medical treatments. Methods Fibroblast strains were generated from vulvar and vestibular tissue samples of LPV patients and non-LPV age and race-matched controls. These cells were then treated with Interleukin 1 beta (IL-1β), selective cyclooxygenase-1 inhibitor (SC560), celecoxib (selective COX-2 inhibitor), and ibuprofen (nonselective COX inhibitor) to investigate differences in cellular response when blocking different enzymes in the inflammatory pathway. IL-1β is known to induce IL-6 and PGE2 which acted as a positive control. Results were then quantified via ELISA assay. Results Vestibular and vulvar tissues showed an increase in IL-6 and PGE2 production following treatment with IL-1B. When concurrently treated with IL-1B (to stimulate inflammation) and SC560 (to inhibit COX-1 signaling) ELISA analysis showed a significant decrease in PGE2. A significant PGE2 decrease was shown with concurrent IL-1B/Ibuprofen treatment as well as with IL-1B/Celecoxib treatments. In all three cases, IL-6 signaling was generally not decreased, while PGE2 was decreased, but not to baseline levels. Ibuprofen treatment in fact showed a trend towards increased IL-6 production. Conclusions Fibroblast response to inflammation in the case of LPV is complex. COX inhibitors do not fully inhibit the pain signaling that contributes to the symptomology of LPV patients (IL-6 production remains elevated). NSAIDs leave patients with dysregulated inflammation cascades, which does not remediate pain. Future areas of study for pharmaceutical targets include investigating lipid regulation, other pain signaling mechanisms, such as transient receptor potential cation channel subfamily V member 4 (TRPV4), and combination topical NSAID use to create more appropriate and robust treatment for patients with LPV. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: SPM Therapeutics.

Structural Characterization, Spectroscopic Profile, Molecular Docking, ADMET Properties, Molecular Dynamics Simulation Studies, and Molecular Mechanics Generalized Born Surface Area Analysis of 5-(Adamantan-1-yl)-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione as a Potential COX Inhibitor.

Employing a synergistic combination of theoretical density functional theory (DFT) and experimental techniques, we conducted a comprehensive analysis elucidating the structural and pharmacological attributes of 5-(adamantan-1-yl)-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5A4BT) as a potent COX inhibitor. The X-ray crystallographic data of 5A4BT showed the pivotal role played by weak interactions, notably π-π and C-H-π interactions, alongside hydrogen bonding, in orchestrating the intricate supramolecular architectures within the crystalline lattice. A quantitative analysis of the arrangement of the crystal structure, as well as both inter- and intramolecular interactions, was conducted using Hirshfeld surfaces and 2D fingerprint plots. Additionally, a comprehensive examination of the IR spectra was undertaken, employing both experimental methods and theoretical DFT techniques, to elucidate the vibrational characteristics of the compound. The strength of intermolecular N-H···S hydrogen bonding and charge transfer within the system was assessed through natural bonding orbital analysis. Moreover, Bader's atoms in molecules theory was employed to estimate the strength of intermolecular hydrogen bonds, revealing strong interactions within the 5A4BT dimer. The title compound exhibited binding affinities of -6.4 and -6.5 kcal/mol for COX1 (PDB 3KK6) and COX2 (1CX2) target proteins, respectively. For the first time, predictions regarding ADMET properties, drug-likeness, and toxicity, including favorable bioavailability, along with 100 ns molecular dynamics simulations, binding free energy, and energy decomposition per residue in the binding cavity of the protein from molecular mechanics generalized born surface area approach, collectively indicate the potential of 5A4BT as a nonselective COX inhibitor.

Early Celecoxib Use in Spontaneous Intracerebral Hemorrhage is Associated with Reduced Mortality.

Hemorrhagic strokes constitute 10-15% of all strokes and have the worst mortality and morbidity of all subtypes. Mortality and morbidity of spontaneous intracerebral hemorrhage (sICH) are often secondary to the effects of inflammation, brain edema, and swelling. Studies have shown that celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, reduces perihematomal edema formation and inflammation. This study aimed to examine the impact of celecoxib on sICH outcomes. TriNetX, a multi-institutional research database, was retrospectively queried to identify patients with sICH. Outcomes in patients who received celecoxib within 5days (cohort 1) were analyzed and compared to those in patients who did not receive celecoxib (cohort 2). The primary end point was mortality within 1year of sICH. Secondary end points included ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures. Further analysis was performed to assess these outcomes for patients treated with ibuprofen, a nonselective COX inhibitor. After propensity score matching, 833 patients were identified in each cohort based on celecoxib use. Mortality at 1year was significantly reduced in patients with sICH receiving celecoxib compared to those who did not (13.33% vs. 17.77%; p = 0.0124). Risks of ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures were not significantly increased in patients who received celecoxib within 5days of sICH compared to those who did not receive celecoxib. There was no significant difference in mortality between patients based on ibuprofen administration. There exists a growing interest in using COX-2 as a potential target strategy for neuroprotection in patients with sICH, with some evidence of a mortality benefit in small cohort studies. This study shows that early celecoxib use is associated with decreased mortality in patients with sICH.

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.

Acute heat trauma model in rats, gender-dependent thermoresistance, and screening of potential thermoprotectors

Heat trauma (HT) is an urgent medical and social problem. Heat damage is a widespread effect of the environment on humans, driven by global warming, military conflicts, technological disasters, work in hot environments, and engagement in extreme sports and tourism. The aim of the study: to propose a model of acute HT in rats that does not cause the death of animals, to determine the dependence of thermoresistance on gender, and to compare the effectiveness of the thermoprotective effects of a range of non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, and glucosamine hydrochloride in this model. Materials and Methods: The experiment was conducted on adult white rats of both genders. Acute HT was modelled by using a specially developed method involving heat exposure to animals at +55 °C for 30 minutes, followed by a recovery period of 60 minutes. Rectal temperature was measured every 15 minutes. The degree of hyperthermia in males and females was determined. The presence and intensity of the thermoprotective effect of glucosamine hydrochloride (G h/ch), diclofenac sodium, acetylsalicylic acid (ASA), nimesulide, etoricoxib, celecoxib, and paracetamol were evaluated through intragastric administration 60 minutes before heat exposure. The results were analyzed using the STATISTICA 12.0 program. Results: It was established that heat exposure at +55 °C for 30 minutes effectively replicates acute HT in rats without causing animal fatalities, adhering to bioethical requirements. Body temperature increases by 10-13 %, characterized as a heat stroke. Occasionally, thermoresistant animals are encountered, where the temperature increase during the first 15 minutes of exposure is less than 1 °C. These animals should not be used for further modelling of heat trauma. Male rats are more sensitive to the effect of high environmental temperatures than females, exhibiting greater hyperthermia (temperature increase of 5.03±0.39°C compared to 3.72±0.22 °C in females, p<0.01). The thermoprotective effect of glucosamine hydrochloride depends on gender, being more pronounced in males. Among the 6 tested COX inhibitors, the most significant thermoprotective effect was observed in the highly selective COX-2 inhibitor celecoxib and the weakly selective central inhibitor paracetamol, warranting in-depth research into their impact on organ and system states following heat trauma, as well as the mechanisms of their thermoprotective action. The thermoprotective effect is not associated with selectivity towards COX (cyclooxygenase): it is not observed in the highly selective COX-2 inhibitor etoricoxib and moderately selective COX-2 inhibitor nimesulide, as well as in non-selective COX inhibitors such as diclofenac sodium and aspirin, which also slows down the recovery of body temperature after heat exposure. Conclusions: A convenient and simple model of acute HT in rats is proposed, demonstrating higher thermosensitivity and a more pronounced thermoprotective effect of glucosamine hydrochloride in males. A significant thermoprotective effect was identified in celecoxib and paracetamol, surpassing other investigated NSAIDs. The mechanism and specific features of this effect require further clarification

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

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

Polmacoxib: A Review of the Newer Non-steroidal Anti-inflammatory Drug in Osteoarthritis.

Osteoarthritis represents a huge socioeconomic burden and has a significant impact on daily life and productivity. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of osteoarthritis to curbinflammation, pain, and stiffness and improve physical function. However, due to the various side effects, most healthcare professionals avoid using NSAIDs for a long period. Nonselective cyclooxygenase (COX) inhibitors and cyclooxygenase-1 (COX-1) inhibitors are associated with increased gastrointestinal adverse effects due to the inhibition of prostaglandins, which are responsible for protecting the gastric mucosa. Cyclooxygenase-2 (COX-2) inhibitors are associated with an increased incidence of adverse cardiovascular effects due to their COX-2 inhibitory activity in the circulatory system. Therefore, there is a need for a newer NSAID that has a better safety profile to be used in osteoarthritis. Polmacoxib is a new, orally active, first-in-class NSAID that is a dual inhibitor of COX-2 and carbonic anhydrase (CA). The dual mode of action exhibited by polmacoxib is expected to minimize adverse cardiovascular effects while achieving maximum effectiveness in inflamed osteoarthritic joints. This article aims toreview the pharmacological properties, clinical efficacy, and safety data of polmacoxib in osteoarthritis.

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study

BackgroundAging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. MethodsA case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1–7 days and 181–187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. ResultsThe study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70–4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47–5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15–26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82–66.64). ConclusionsNSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

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

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

The Roles of Potassium Channels and Nitric oxide in the Modulation of Apelin induced-relaxation in Isolated Diabetic Rat Aorta

Diabetes is associated with endothelial dysfunction, which impairs blood vesselscapacity to maintain vascular tone. Apelin is an adipocyte-produced relaxing factor that has endothelium-dependent and nitric oxide (NO)-mediated vasorelaxant effects. The current study investigated how streptozotocin (STZ)-induced type one diabetes modulates the mechanisms involved in aortic vascular response to apelin, focusing on the role of potassium channels and endothelial derived relaxing factors (EDRF). In this study, precontracted rat thoracic aortic segments were pre-incubated with the NO inhibitor, cyclooxygenase (COX) inhibitor and potassium channels blockers including: non-selective calcium-activated potassium channel, big conductance calcium-activated potassium channels (BKca), intermediate conductance calcium activated potassium channels (IKca), delayed inward rectifier potassium channels (Kir), adenosine triphosphates-sensitive potassium channels (KATP) and voltage sensitive potassium channels (Kv) blockers, then cumulative concentrations of apelin were applied to each group in both non-diabetic and diabetic conditions. The statistical analysis between diabetic and non-diabetic groups revealed that endothelial impairment induced by diabetes in rat thoracic aorta remarkably attenuated the vascular responses to apelin. An important new finding in this study was that almost all potassium channels blockers noticeably P<0.001 increased apelin efficacy with relatively no changes in the peptide potency. However, in diabetic aortic segments, the non-selective Kca, BKca blockers, NO inhibitor and COX inhibitor reversed vascular responses to apelin, but Kir, KATP and Kv blockers significantly reduced vascular responses to apelin in comparison to control rats. It is worth noting that diabetes did not only alter the peptide potency in these experimental groups but also significantly increased the maximum responses when Kca and BKca blockers preincubated. In conclusion, our findings shed light on the mechanisms behind diabetes-induced aortic artery hypo-reactivity to apelin which involve the inhibition of endothelial NO synthase activities and decreased contribution of Kca, BKca, IKca, Kv, Kir and KATP channels.

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways

AimsPutative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model.Main methodsIn anesthetized male Sprague–Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 μg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day.Key findingsNPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin.SignificanceIn conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

The effect of nonsteroidal anti-inflammatory drug use on soft tissue and bone healing in the knee: a systematic review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to mitigate pain and inflammation associated with musculoskeletal conditions; however, there is conflicting data on the adverse effects of these drugs on tissue and bone healing. The objective of this study was to investigate the effect of NSAIDs on the healing of knee, soft tissue, and bone. A systematic literature search was conducted across PubMed/MEDLINE, Excerpta Medical Database (Embase)/Ovid, and the Cochrane Central Register of Controlled Trials databases. Clinical, animal, and in vitro studies on the effect of NSAIDs on knee healing were included. Risk of bias assessment was performed using the Cochrane bias assessment tool and Methodological Index for Non-Randomized Studies scoring system for included clinical studies, and the Systematic Review Center for Laboratory Animal Experimentation assessment tool for all included animal studies. General study population characteristics, interventions used, NSAIDs utilized, outcome measures, and study results were analyzed using descriptive statistics. Fifteen articles met the inclusion criteria. Of the 15 studies, there were three clinical, ten animal, and two in vitro studies. In clinical studies, nonselective cyclooxygenase (COX) inhibitors and selective COX-2 inhibitors did not cause a significant increase in failure of anterior cruciate ligament (ACL) reconstructions or meniscal repairs with NSAID administration pre-, peri-, or post-operatively in comparison to placebo or no NSAID administration. Among animal studies assessing COX-2 inhibitor effects on soft tissue, healing was impaired (2/4), delayed but unaffected (1/4), or unaffected (1/4). In animal studies assessing COX-1 inhibitors, ligament healing was either increased (1/4), unaffected (2/4), or impaired (1/4). Meanwhile, administration of non-selective COX inhibitors in animals did not affect soft tissue (3/3) and cartilage (1/1) healing. Two in vitro studies identified a negative outcome on patellar tendon and ACL cell proliferation or viability after non-selective COX inhibition and variable results after selective COX-2 inhibition. Animal studies on postoperative NSAID use after knee surgery suggest that administration of selective and nonselective COX-2 inhibitors may impair healing of soft tissue, bone and tendon-to-bone; however, further clinical studies are needed to better characterize dose and duration dependent risks of NSAIDs.

Chemical Characterization and Pharmacological Evaluation of Phytophenols-Etodolac Mutual Prodrugs

Etodolac is choice of drug for pain and inflammation but has major side effects of gastric ulcers that are due to free carboxylic group. Etodolac belongs to the chemical class of non-selective COX-inhibitor but preferentially COX-2 inhibitor. Here the ester linked mutual prodrugs of etodolac with phytophenols like vanillin, carvacrol, umbelliferone, guaiacol, sesamol and syringaldehyde were synthesized. All the prodrugs were characterized by IR-spectroscopy, 1H-NMR, 13C-NMR and mass spectrometry. Among the synthesized prodrugs, the Eto-van, Eto-umbe, Eto-sesa and Eto-syr showed improved analgesic and anti-inflammatory activity compared to etodolac. All the synthesized prodrugs showed less ulcerogenic side effects compared to etodolac.

Cyclooxygenase inhibition does not blunt thermal hyperemia in skeletal muscle of humans.

Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. The cyclooxygenase pathway is active in skeletal muscle, is heat sensitive, and contributes to cutaneous thermal hyperemia in young healthy humans. Therefore, the purpose of this study was to test the hypothesis that cyclooxygenase inhibition would attenuate blood flow in the vastus lateralis muscle during localized heating. Twelve participants (6 women) were studied on two separate occasions: 1) time control (i.e., no ibuprofen); and 2) ingestion of 800 mg ibuprofen, a nonselective cyclooxygenase inhibitor. Experiments were randomized, counter-balanced, and separated by at least 10 days. Pulsed short-wave diathermy was used to induce unilateral deep heating of the vastus lateralis for 90 min, whereas the contralateral leg served as a thermoneutral control. Microdialysis was utilized to bypass the cutaneous circulation and directly measure local blood flow in the vastus lateralis muscle of each leg via the ethanol washout technique. Heat exposure increased muscle temperature and local blood flow (both P < 0.01 vs. baseline). However, the thermal hyperemic response did not differ between control and ibuprofen conditions (P ≥ 0.2). Muscle temperature slightly decreased for the thermoneutral leg (P < 0.01 vs. baseline), yet local blood flow remained relatively unchanged across time for control and ibuprofen conditions (both P ≥ 0.7). Taken together, our data suggest that inhibition of cyclooxygenase-derived vasodilator prostanoids does not blunt thermal hyperemia in skeletal muscle of young healthy humans.NEW & NOTEWORTHY Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. Using a pharmacological approach combined with microdialysis, we found that thermal hyperemia in the vastus lateralis muscle was well maintained despite the successful inhibition of cyclooxygenase. Our results suggest that cyclooxygenase-derived vasodilator prostanoids do not contribute to thermal hyperemia in skeletal muscle of young healthy humans.

Preparation of Piroxicam nanosuspensions by high pressure homogenization and evaluation of improved bioavailability

Objective Inflammation is a natural response of the organism, involving events responsible for releasing chemical mediators and requiring treatments of symptoms such as pain, redness, heat, swelling, and loss of tissue function. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug with the effect of nonselective COX inhibitor activity; however, it shows poor bioavailability caused by the poor and slow water solubility. In this study, we developed PRX nanosuspensions with 200–500 nm in diameter to increase the bioavailability of PRX by improving its solubility. Methods PRX nanosuspensions were fabricated by High pressure homogenization method with PVA, SDS and Tween 80. The nanosuspensions were characterized by XRD, FTIR, DSC, and in vitro release. In vivo pharmacokinetic properties and anti-inflammatory effects were also investigated in rabbits. Results PRX nanosuspensions significantly increased the solubility (14.89 ± 0.03 mg/L for pure PRX and 16.75 ± 0.05 mg/L for PRX nanosuspensions) and dissolution rate as compared to the pure PRX (p < 0.05). Orally administered PRX nanosuspension (AUC 0-t is 49.26 ± 4.29 μg/mL × h) significantly improved the bioavailability of PRX (AUC 0-t is 28.40 ± 12.11 μg/mL × h). The anti-inflammatory effect of PRX nanosuspension was also investigated in rabbits and it was observed that PRX nanosuspension treatment significantly improved the inhibition of COX-2 and NFκB expression as compared to the PRX treatment (p < 0.05). Conclusions The results in this study indicate that PRX nanosuspension is a promising nanomedicine for enhancing the anti-inflammatory activity of PRX and has a high potential for the treatment of inflammation.