Non-selective Cyclooxygenase Inhibitor Research Articles

Diuretic, Natriuretic, And Ca2+-Sparing Effect Of The Alkaloid Boldine In Rats

Abstract Background Previous studies indicate the renal vasodilating effects of boldine, an alkaloid found in Peumus boldus. However, its potential to induce diuresis still needs to be studied. Methods Wistar rats were used and the urine volume was noted for 8 h and further studied. Results The acute treatment at 0.1 and 0.3 mg/kg of boldine showed a diuretic, natriuretic, and Ca2+-sparing effect in rats without changing the urinary elimination of K+and Cl-. When boldine was given in combination with hydrochlorothiazide, there was an increase in urinary volume compared to the vehicle group. However, this was not different from the treatments in its isolated form. Urine Ca2+values ​​remained low but were not enhanced by this association. The excretion of Na+and Cl- was significantly increased compared to the group that received only vehicle or boldine. On the other hand, although the association of amiloride plus boldine did not result in a diuretic effect, the increase in Na+and the reduction in K+excretion were significantly potentiated. Furthermore, in the presence of the non-selective muscarinic receptor antagonist atropine, boldine showed reduced capacity to increase urinary volume, maintaining the natriuretic and Ca2+-sparing effect, besides a very evident K+-sparing action. Similar results were obtained in the presence of the non-selective cyclooxygenase inhibitor indomethacin. Furthermore, boldine showed an ex vivo antiurolithiasis activity, reducing calcium oxalate’s precipitation and crystallization. Conclusions This study reveals the diuretic, natriuretic, Ca2+-sparing, and antiurolithiatic effects of boldine, an action possibly related to muscarinic receptor activation and prostanoid generation.

Effects of phenylbutazone, firocoxib, and dipyrone on the diuretic response to furosemide in horses.

Treatment with phenylbutazone (nonselective COX inhibitor) decreases the diuretic and natriuretic effects of furosemide by nearly 30% but the effects of COX-2 specific inhibitors (firocoxib) and atypical NSAIDs (dipyrone) are unknown. Furosemide-induced diuresis after pretreatment with firocoxib or dipyrone is diminished to a lesser extent than after pretreatment with phenylbutazone. Eight healthy mares. Each mare received 4 treatments in a prospective experimental crossover study using a replicated 4 × 4 Latin Square design: furosemide alone (FU), furosemide and phenylbutazone (PB), furosemide and firocoxib (FX), and furosemide and dipyrone (DP). After 24 hours of NSAID treatment at recommended dosages, ureteral catheters were placed for continual urine collection. After a 30-minute baseline collection period, furosemide (1.0 mg/kg, IV) was administered, and urine and blood samples were collected for 4 hours. Data were assessed by repeated measures ANOVA. Four-hour urine volume was (mean ± SD) ~25% less (P < .001) after pretreatment with all NSAIDs (PB 19.1 ± 2.1 mL/kg, FX 17.7 ± 3.5 mL/kg, DP 19.1 ± 3.9 mL/kg), as compared to FU (23.4 ± 5.1 mL/kg) (P < .001), but there were no differences between PB, FX, or DP. Interindividual variability in furosemide diuresis after pretreatment with different NSAIDs was observed. Though COX-2 selective NSAIDs and dipyrone might have less severe or fever gastrointestinal adverse effects in horses, our data suggest minimal differences in effects on furosemide-induced diuresis, and possibly, risk of nephrotoxicosis.

Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China

The Gutong Patch (GTP) is common in clinical practice for bone diseases. This study compared the efficacy and safety of GTP and nonsteroidal anti-inflammatory drugs (NSAIDs) for KOA patients from 35 medical centers assigned to GTP, selective COX-2 inhibitor (SCI), GTP + SCI, non-selective COX-2 inhibitor (NSCI), and GTP + NSCI groups. The visual analog scale (VAS) pain score, EuroQol-VAS, EuroQol 5D-3 L, time to articular pain relief / disappearance, and joint motion recovery were the efficacy assessments. Safety assessments included contact dermatitis, gastrointestinal disorders, etc. The p-value < 0.05 was considered statistically significant. After statistical analysis, the SCI and GTP + SCI groups showed better improvement of VAS than the GTP group; the time to articular pain relief in the NSCI group was shorter than that in GTP and SCI group; the time to joint motion recovery in the GTP + NSCI group was longer than that in the SCI group. Additionally, the improvement of the quality of life in all groups was significant after treatments. While the incidence of gastrointestinal adverse events in the NSAIDs group was higher than that in the GTP and GTP + NSAIDs groups. GTP and NSAIDs are effective for KOA patients, and GTP is more suitable for KOA patients with cardiovascular and gastrointestinal comorbidities. This study was approved by the Ethics Committee at Peking Union Medical College Hospital (HS-1766) and registered in the Chinese Clinical Trial Registry (ChiCTR2100046391).

Roles of endothelial prostaglandin I2 in maintaining synchronous spontaneous Ca2+ transients in rectal capillary pericytes.

In hollow visceral organs, capillary pericytes appear to drive spontaneous Ca2+ transients in the upstream arterioles. Here, mechanisms underlying the intercellular synchrony of pericyte Ca2+ transients were explored. Ca2+ dynamics in NG2 chondroitin sulphate proteoglycan (NG2)-expressing capillary pericytes were examined using rectal mucosa-submucosa preparations of NG2-GCaMP6mice. Spontaneous Ca2+ transients arising from endoplasmic reticulum Ca2+ release were synchronously developed amongst capillary pericytes in a gap junction blocker (3μM carbenoxolone)-sensitive manner and could spread into upstream vascular segments. Spontaneous Ca2+ transients were suppressed by the Ca2+ -activated Cl- channel (CaCC) blocker niflumic acid and their synchrony was diminished by a TMEM16A inhibitor (3μM Ani9) in accordance with TMEM16A immunoreactivity in pericytes. In capillaries where cyclooxygenase (COX)-2 immunoreactivity was expressed in endothelium but not pericytes, non-selective COX inhibitors (1μM indomethacin or 10μM diclofenac) or COX-2 inhibitor (10μM NS 398) disrupted the synchrony of spontaneous Ca2+ transients and raised the basal Ca2+ level. Subsequent prostaglandin I2 (PGI2 ; 100nM) or the KATP channel opener levcromakalim restored the synchrony with a reduction in the Ca2+ level. PGI2 receptor antagonist (1μM RO1138452) also disrupted the synchrony of spontaneous Ca2+ transients and increased the basal Ca2+ level. Subsequent levcromakalim restored the synchrony and reversed the Ca2+ rise. Thus, the synchrony of spontaneous Ca2+ transients in pericytes appears to be developed by the spread of spontaneous transient depolarisations arising from the opening of TMEM16A CaCCs. Endothelial PGI2 may play a role in maintaining the synchrony, presumably by stabilising the resting membrane potential in pericytes. KEY POINTS: Capillary pericytes in the rectal mucosa generate synchronous spontaneous Ca2+ transients that could spread into the upstream vascular segment. Spontaneous Ca2+ release from the endoplasmic reticulum (ER) triggers the opening of Ca2+ -activated Cl- channel TMEM16A and resultant depolarisations that spread amongst pericytes via gap junctions, establishing the synchrony of spontaneous Ca2+ transients in pericytes. Prostaglandin I2 (PGI2 ), which is constitutively produced by the endothelium depending on cyclooxygenase-2, appears to prevent premature ER Ca2+ releases in the pericytes allowing periodic, regenerative Ca2+ releases. Endothelial PGI2 may maintain the synchrony of pericyte activity by stabilising pericyte resting membrane potential by opening of KATP channels.

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

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

Effect of Concomitant Medications on Treatment Response and Survival in De Novo Metastatic Prostate Cancer: Secondary Analysis of the LATITUDE Study

It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs). We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance. Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001). This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS.

Preoperative flurbiprofen diminishes the rate of reoperation after free flap reconstruction: A retrospective study

This study aimed to evaluate the association between preoperative flurbiprofen, a non-selective COX inhibitor, and reoperation for flap crisis after free flap reconstruction.In this retrospective study, patients who underwent head and neck surgery with free flap reconstructions were collected. To identify risk factors for reoperation from demographic features and perioperative variables, univariate and multivariate logistic analyses were conducted. After propensity score matching (PSM), univariate and adjusted multivariate analyses were employed to explore the impact of preoperative flurbiprofen on reoperation after free flap reconstruction.This study comprised 437 patients, 33 of whom underwent reoperations for flap crisis. After multivariate analysis, radiotherapy history (P = 0.005; odds ratio [OR] = 0.225; 95% CI, 0.080–0.636) and preoperative flurbiprofen (P = 0.038; OR = 5.059; 95% CI, 1.094–23.386) were identified as independent factors for reoperation. PSM was achieved, and preoperative flurbiprofen was found to diminish the reoperation rate (P = 0.046; OR = 4.765; 95% CI, 1.029–22.202) without increasing bleeding complications.Within the limitations of the study, flurbiprofen should be administered preoperatively to reduce the rate of reoperations for flap crisis whenever appropriate.

Elucidating the Anti-Inflammatory Properties of Garcinia kola and Vernonia amygdalina through in silico Molecular Biology Techniques

Introduction: Inflammation is implicated in many disorders, including communicable and noncommunicable diseases. Cyclooxygenase-2 (Cox-2) is a key enzyme involved in the production of prostaglandins implicated in inflammatory disorders. Garcinia kola and Vernonia amygdalina are medicinal plants being used for treating various ailments in many parts of the world and extensive in vitro and in vivo studies have been conducted on them. Five phytochemicals were selected from the two plants; aspirin and celecoxib were used as reference drugs. This study investigated the interactions of the seven ligands with the Cox-2 enzyme, using in silico molecular biology techniques. Materials and Methods: The 3-D structures of the seven ligands were retrieved from the PubChem database in their Structure Data Format (SDF). Cox-2 was retrieved in its Protein Data Bank (PDB) format. The ligands and the protein were converted to their pdbqt formats through the open babel software. The Cox-2 was docked with the ligands using the Auto-Dock Vina software. The binding energies and the root mean square deviation values were noted. Pharmacophore modeling was visualized by using the Biovia Discovery Studio Visualizer. One of the ligands (luteolin) was further subjected to molecular dynamics simulation using the desmond maestro software. Results: While celecoxib had the best binding property with Cox-2 (-10.8 kcal/mol, 3 H bonds), the five ligands from the two plants had better binding properties than aspirin (which had -6.5kcal/mol, 1 H bond). Kolaviron, from G. kola (-9.1 kcal/mol, 3 H bonds) and luteolin, from V. amygdalina (-8.5kcal/mol, 2 H bonds) demonstrated the best binding properties among the five phytochemicals. Additional interactions of H bonds and hydrophobic bonds were noticed post molecular dynamics simulation of luteolin with Cox-2, indicating dynamic forces’ fluctuations. MD simulations showed that Ser530 and Tyr385 were the best amino acid side chains that interacted with luteolin for the stabilization of the protein-ligand complex. Conclusion: The energy values and protein-ligand interactions indicate affinity and stability of the complex. Luteolin can be taken as a promising drug target and subjected to ADMET (absorption, distribution, metabolism, excretion, toxicity) properties analysis and clinical trials. This is especially important in view of the various side effects associated with both nonselective and selective Cox-2 inhibitors, including aspirin and celecoxib.

Principles of effective use of non-steroidal anti-inflammatory drugs

The article provides an overview of references on the rational use of nonsteroidal anti-inflammatory drugs (NSAIDs) in modern medicine. Nonsteroidal anti-inflammatory drugs are a group of drugs with different chemical structures (mostly acid derivatives) that have anti-inflammatory, analgesic, antipyretic, antiplatelet (acetylsalicylic acid, acetylsalicylate, ketoprofen, diclofenac sodium, niflumic acid, indomethacin) effects. NSAIDs are divided according to the selectivity of action relative to cyclooxygenase (COX) isoforms: non-selective COX inhibitors, selective COX-1 inhibitors, approximately equal inhibition of COX-1 and COX-2, selective COX-2 inhibitors. They are characterized by general pharmacological properties: high degree of absorption in the gastrointestinal tract; a high degree of binding to albumins; approximately the same volume of distribution; the ability to accumulate in the focus of inflammation. Indications for NSAIDs use are: acute arthritis and chronic arthritis; acute and chronic pain syndrome of various nature (lower back pain syndrome, joint and soft tissue injuries, migraine, dysmenorrhea, preoperative and postoperative pain, renal colic, fever in various rheumatic and non-rheumatic diseases). Аdditional indications for prescribing NSAIDs are: pleurisy, pericarditis, erythema nodosum, polycystic lung disease, sciatica. The most frequent and dangerous side effects include gastrointestinal, kidney complications. Special attention is paid to the cardiovascular safety of NSAIDs and, above all, COX-2 inhibitors because of risk of cardiovascular events. The most effective drug with the best tolerability should be selected for a specific patient. Before starting NSAID therapy, the patient's age, comorbidities, previous medical or surgical history, concomitant use of medications (including antiplatelet agents, anticoagulants, corticosteroids, ACE inhibitors, and selective serotonin reuptake inhibitors), H. pylori infection, and blood pressure monitoring should be considered. Keywords: inflammation, pain, side effects, gastropathy, selectivity.

Comparative structural study of selective and non-selective NSAIDs against the enzyme cyclooxygenase-2 through real-time molecular dynamics linked to post-dynamics MM-GBSA and e-pharmacophores mapping.

Inflammation-provoked disorders including cancer are arbitrated by cyclooxygenase-2 (COX-2). Celecoxib and niflumic acid are amongthe potent and selective inhibitors of this enzyme while aspirin (acetylsalicylic acid) and sodium salicylate are its non-selective and lesser potent inhibitors. Despite these proven studies, the comparative structural study of these selective and non-selective molecules at atomistic scale in complex state with COX-2 that may answer this differential inhibitory behavior has not been accomplished spotlighting the imperative need of additional research in this area. Thus, this study was framed to provide a strong explanation for the enigma of higher inhibitory activity of celecoxib-niflumic acid duo in comparison to aspirin and sodium salicylate towards COX-2. A contemporary approach including advanced molecular docking against COX2, molecular dynamics of receptor-ligand complexes, simulation-trajectory-backed MMGBSA for different time points, radius of gyration (Rg) calculations, and e-pharmacophores approach was employed to attain a rational conclusion. Our findings demonstrated the higher binding affinity of celecoxib and niflumic acid over aspirin and sodium salicylate against COX-2. Although both selective and non-selective COX-2 inhibitors manifested nearly the same stability in the active site of this enzyme but the e-pharmocophoric features found in the case of selective inhibitors scored over non-selective ones. Thus, our findings excluded the differential stability to be the cause of stronger potency of selective inhibitors but attributed their potency to greater number of complementary features present in these inhibitors against the active site of inflammation engendering COX-2.

Effect of multiple-dose regimens of cyclooxygenase inhibitors and their combinations with mexidol on behavior in mature rats

Effects of multiple-dose regimens (oral, daily, once a day for 15 days) of cyclooxygenase (COX) inhibitors etoricoxib (1 and 10 mg/kg), diclofenac sodium (1 and 5 mg/kg) and their combinations with 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol 25 mg/kg) on rat behavior were studied in the open field test, rotarod test and elevated plus maze test. Exploratory (in open field test) and locomotor (in rotarod test) behavior of rats was significantly weakened only by the non-selective COX inhibitor diclofenac sodium at 5 mg/kg, which is due to the peripheral side effect of the drug. The selective COX-2 inhibitor etoricoxib increased the time in the central area of the elevated plus maze at 1 and 10 mg/kg and reduced the latent period of locomotion in the open field test at 10 mg/kg. A combination of diclofenac sodium (1 mg/kg) with mexidol neither reduced exploratory behavior nor caused motor deficit in contrast to diclofenac sodium at 5 mg/kg. However, a combination of etoricoxib (1 mg/kg) with mexidol inhibited locomotor activity in the rotarod test. Nevertheless, it produced no significant effects on the exploratory behavior or anxiety of animals in the open field test and elevated plus maze test.

TXA2 mediates LPA1-stimulated uterine contraction in late pregnant mouse

Lysophosphatidic acid (LPA) is known to increase uterine contraction in the estrus cycle and early pregnancy, however, the effect of LPA in late pregnant uterus and its mechanisms are not clear. In the present study, we show the LPA receptor subtypes expressed and the mechanism of LPA-induced contractions in late pregnant mouse uterus. We determined the relative mRNA expression of LPA receptor genes by quantitative PCR and elicited log concentration-response curves to oleoyl-L-α-LPA by performing tension experiments in the presence and absence of nonselective and selective receptor antagonists and inhibitors of the TXA2 pathway. LPA1 was the most highly expressed receptor subtype in the late pregnant mouse uterus and LPA1/2/3 agonist (Oleoyl-L-α LPA) elicited increased contractions in this tissue that had lesser efficacy compared to oxytocin. LPA1/3 antagonist, Ki-16425, and a potent LPA1 antagonist (AM-095) significantly inhibited the LPA-induced contractions. Further, the nonselective COX inhibitor, indomethacin, and potent thromboxane A2 synthase inhibitor, furegrelate significantly impaired LPA-induced contractions. Moreover, selective thromboxane receptor (TP) antagonist, SQ-29548, and Rho kinase inhibitor, Y-27632 almost eliminated LPA-induced uterine contractions. LPA1 stimulation elicits contractions in the late pregnant mouse uterus using the contractile prostanoid, TXA2 and may be targeted to induce labor in uterine dysfunctions/ dystocia.

Proton pump inhibitors increase the risk of nonsteroidal anti-inflammatory drug-related small bowel injury: A Systematic Review with Meta-analysis.

Conflicting results exist on the association between proton-pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug (NSAID)-related small bowel damage. Aims: To determine whether PPIs increased the risk of NSAID-related small bowel damage by meta-analysis. Methods: A systematic electronic search in PubMed, Embase, and Web of Science was conducted from the time the database was created until 31 March 2022 for studies reporting associations between PPI use and outcomes, including the endoscopy-verified prevalence of small bowel injury, mean number of small bowel injuries per patient, change in hemoglobin level, and risk of small bowel bleeding in subjects taking NSAIDs. Meta-analytical calculations for odds ratio (OR) and mean difference (MD) were performed with the random-effects model and interpreted with 95% confidence intervals (CIs). Results: Fourteen studies comprising 1996 subjects were included. Pooled analysis demonstrated that concomitant use of PPIs significantly increased the prevalence and number of endoscopy-verified small bowel injuries (prevalence: OR=3.00; 95% CI: 1.74-5.16; number: MD=2.30; 95% CI: 0.61-3.99) and decreased hemoglobin levels (MD=-0.50 g/dL; 95% CI: -0.88 to -0.12) in NSAID users but did not change the risk of small bowel bleeding (OR=1.24; 95% CI: 0.80-1.92). Subgroup analysis demonstrated that PPIs significantly increased the prevalence of small bowel injury in subjects taking nonselective NSAIDs (OR=7.05; 95% CI: 4.70-10.59, 4 studies, I2=0) and COX-2 inhibitors (OR=4.00; 95% CI: 1.18-13.60, 1 study, no calculated I2) when compared to COX-2 inhibitors alone.Conclusion: PPIs increased the risk of NSAID-related small bowel damage, and the clinical significance of higher prevalence of small bowel injuries should be studied in future.

Molecular docking of 5-o-benzoylpinostrobin derivatives from Boesenbergia pandurata roxb. as anti-inflammatory.

The use of NSAIDs, also known as non-steroidal anti-inflammatory drugs, has numerous adverse effects and consequences. For this reason, it is necessary to develop rational drugs as safer anti-inflammatory drugs with fewer side effects. Temu Kunci rhizome contains Pinostrobin (5-hydroxy-7-methoxyflavanone), which is believed to have anti-inflammatory properties. This study aims to determine the strongest antiinflammatory activity at the cyclooxygenase-2 (COX-2) receptor through the 5-O-Benzoylpinostrobin derivative design. Methods: AutoDockTools on the COX-2 receptor (PDB code: 5IKR) were used in molecular docking in this study. The metrics employed were binding afinity (ΔG), inhibition constant (Ki), which serve as indicators of affinities, and amino acid residue similarity, which serves as a measure of the similarity of interactions. Predictive scores were confirmed by Molecular Docking Simulation. The top five 5-O-Benzoylpinostrobin derivatives show a high affinity for the COX-2 receptor compared to Pinostrobin as a marker compound of Boesenbergia pandurata Roxb and furthermore give the lowest inhibition constant (Ki) and the highest negative binding free energy (ΔG), 35.40, 45.21, 54.75, 64.43, 76.97 nM and -10.16, -10.02, -9.91, -9.81, -9.7 kcal/mol. Interestingly, the five 5-O-Benzoylpinostrobin derivatives also have higher affinity than the native ligand Mefenamic acid, which is known to be a non-selective COX-2 inhibitor. The highest predicted affinity was shown by 4-Nitro-5-O-benzoylpinostrobin for the COX-2 receptor (PDP ID: 5IKR), with a higher predicted affinity for Mefenamic acid. The five selected 5-O-Benzoylpinostrobin derivatives were potent modifications of pinostrobin as an antiinflammatory because they showed a higher affinity than Pinostrobin and Mefenamic acid. This study demonstrated that it is highly feasible to produce and test the novel 5-OBenzoylpinostrobin derivative in vivo, specifically 4-Nitro-5-Obenzoylpinostrobin.

Synthesis and Anti-Inflammatory Activity of the Natural Cyclooxygenase-2 Inhibitor Axinelline A and Its Analogues.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used medications to treat conditions such as arthritis, pain, and fever. They reduce inflammation by inhibiting cyclooxygenase (COX) enzymes that catalyze the committed step in prostaglandin (PG) biosynthesis. Despite their significant therapeutic benefits, many NSAIDS have undesirable adverse effects. The aim of this study was to discover novel COX inhibitors from natural sources. Here, we describe the synthesis and anti-inflammatory activity of the COX-2 inhibitor axinelline A (A1), which was isolated from Streptomyces axinellae SCSIO02208, and its analogues. Compared to the synthetic analogues, the natural product A1 has stronger COX inhibitory activity. Although A1 is more active against COX-2 than COX-1, its selectivity index is low; therefore, it may be classified as a nonselective COX inhibitor. Its overall activity is comparable to the clinically used drug diclofenac. In silico studies showed that A1 binds to COX-2 in a similar manner to diclofenac. Inhibition of COX enzymes by A1 in LPS-stimulated murine RAW264.7 macrophages resulted in suppression of the NF-κB signaling pathway, leading to reduced expression of pro-inflammatory factors such as iNOS, COX-2, TNF-α, IL-6, and IL-1β and reduced production of PGE2, NO, and ROS. The potent in vitro anti-inflammatory activity of A1, together with its lack of cytotoxicity, makes it an attractive candidate for a new anti-inflammatory lead.

DENTAL USE OF KETOROLAC TROMETHAMINE: STATUS AND FUTURE PERSPECTIVES

The history of evidence-based use of non-steroidal anti-inflammatory drugs (NSAIDs) goes back at least two hundred and fifty years. Over the past period, the path has been passed from the use of willow bark decoctions to the synthesis and introduction of selective cyclooxygenase inhibitors into clinical practice. To date, the research direction has shifted from the search for new substances to the search for new routes of administration. The wide range of existing drug substances, however, has only in a few dosage forms. Thus, ketorolac tromethamine is known only as a solution for parenteral and intranasal administration, as well as oral tablets. This drug belongs to NSAIDs, particularly non-selective cyclooxygenase inhibitors, and shows a pronounced analgesic activity. Due to this property, ketorolac can serve as an alternative to opioid analgesics or can reduce the dosage of the latter when used in combination. However, a number of systemic side effects (ulcerogenic properties, negative effect on the blood), unfortunately, impose their limitations. A possible solution to this situation may be the creation of local delivery systems, in particular, in situ implants. This review highlights the problem of developing local systems for the delivery of ketorolac tromethamine for the relief of acute pain. Special attention is paid to in situ implants based on bioadhesive polymers.

Piezo1 activation induces relaxation of the pudendal artery and corpus cavernosum.

Piezo1 channel is a sensor for shear-stress in the vasculature. Piezo1 activation induces vasodilation, and its deficiency contributes to vascular disorders, such as hypertension. In this study, we aimed to determine whether Piezo1 channel has a functional role in the dilation of pudendal arteries and corpus cavernosum (CC). For this, male Wistar rats were used, and the relaxation of the pudendal artery and CC was obtained using the Piezo1 activator, Yoda1, in the presence and absence of Dooku (Yoda1 antagonist), GsMTx4 (non-selective mechanosensory channel inhibitor) and L-NAME (nitric oxide synthase inhibitor). In the CC, Yoda1 was also tested in the presence of indomethacin (non-selective COX inhibitor) and tetraethylammonium (TEA, non-selective potassium channel inhibitor). The expression of Piezo1 was confirmed by Western blotting. Our data show that Piezo1 activation leads to the relaxation of the pudendal artery and CC as the chemical activator of Piezo1, Yoda1, relaxed the pudendal artery (47%) and CC (41%). This response was impaired by L-NAME and abolished by Dooku and GsMTx4 in the pudendal artery only. Indomethacin and TEA did not affect the relaxation induced by Yoda1 in the CC. Limited tools to explore this channel prevent further investigation of its underlying mechanisms of action. In conclusion, our data demonstrate that Piezo1 is expressed and induced the relaxation of the pudendal artery and CC. Further studies are necessary to determine its role in penile erection and if erectile dysfunction is associated with Piezo1 deficiency.

Oral Administration of Meloxicam and Flunixin Meglumine Have Similar Analgesic Effects After Lipopolysaccharide-Induced Inflammatory Response in Thoroughbred Horses.

Flunixin meglumine (FM), a nonselective cyclooxygenase (COX) inhibitor, is most frequently selected for the treatment of equine systemic inflammatory response syndrome (SIRS)/endotoxemia. However, FM has considerable adverse effects on gastrointestinal function. The aims of this study were to compare the effect of meloxicam (MX), a COX-2 selective inhibitor commonly used in equine clinical practice, with FM, and to investigate the potential for clinical application in horses with SIRS/endotoxemia. Fifteen horses were divided into three groups of five and orally administered MX (0.6 mg/kg), FM (1.1 mg/kg), or saline as placebo at 30 minutes after LPS challenge. Clinical parameters, including behavioral pain scores, were recorded and blood for clinical pathological data was collected at various times from 60 minutes before to 420 minutes after LPS infusion. The pain score were significantly lower in both the MX and FM groups than in the placebo group, with no significant difference between them. Body temperature was significantly lower in the MX and FM groups than in the placebo group. Heart rates and respiratory rates, hoof wall surface temperature, and leukocyte counts changed similarly between the MX and FM groups. TNF-α and cortisol were lower in the FM group than in the MX group. The results suggest that MX suppresses the inflammatory response after LPS infusion and has an analgesic effect similar to that of FM. Given the adverse effects of nonselective COX inhibitors, clinical application of MX may be beneficial in horses with SIRS/endotoxemia.

EFFECTIVENESS OF NSAIDS FOR PAIN MANAGEMENT IN PERIODONTAL SURGERY

Introduction: The perception of pain is subjective and many factors may affect its power and duration in various oral surgical procedures. An effective treatment suggests a certain volume of knowledge and skills of dental practitioners. A combination of non-pharmacological and pharmacological agents is often used to relieve the pain. There is evidence that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in treating acute pain. Hypotheses suggest that NSAIDs have analgesic and anti-inflammatory effects by reducing the synthesis of arachidonic acid’s metabolites - prostaglandins (PGE2, PGI2), thromboxane (TxA2, TxB2) which are responsible for the occurrence of both - inflammation and pain. With the hyperalgesia initiated by PGE2 and bradykinin, we can explain the presence of postoperative pain because it reduces the pain threshold and increases susceptibility to available threshold inducements. Aim: To evaluate the effectiveness of postoperative NSAID administration in order to prevent the production of inflammatory components induced by the surgical treatment. Material and methods: The study included 15 patients who received surgical therapy. The selective COX-2 inhibitor of the new class Aulin® and the non-selective COX-2 inhibitor Ibuprofen® were taken from the patients as systemic administration postoperatively for a period of 3 days. The VRS-4 scale was used to assess the pain. Results: The assessment of the mean values for the degree of pain did not show statistically significant differences in the inhibition of pain for the two drugs in the three postsurgical days. Conclusion: In the absence of a significant difference between the two drugs - Aulin® and Ibuprofen®, we may confirm that according to our study they are both sufficiently effective in controlling postoperative pain in surgical periodontal procedures.

Prescription patterns of diclofenac in patients with cardiovascular diseases or at high risk for cardiovascular diseases at primary health care level in Montenegro: Retrospective, national, drug utilization study

Background/Aim. Diclofenac, a non-selective inhibitor of cyclooxygenase with analgesic, anti-inflammatory, and antipyretic effects, is one of the most prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to analyze the prescription patterns of diclofenac systemic formulations at primary health care (PHC) level in Montenegro, in patients with cardiovascular (CV) diseases (CVD) and patients with risk factors for CVD, from 2016 to 2020. Methods. A retrospective national drug utilization study was conducted and it included patients with CVD, to whom prescribing diclofenac was contraindicated, and patients with risk factors for CVD, to whom diclofenac could be prescribed but with increased precaution. PHC information system has been used as a source of medical data for these patients. Results. Within the observed period, prescribing diclofenac systemic formulations, dominantly oral formulations in 75 mg dose, increased by 36.9% [from 4.6 of defined daily doses (DDD) /1,000 inhabitants/day in 2016 to 6.3 DDD/1,000 inhabitants/day in 2020]. A rising trend in prescribing diclofenac was also recorded in patients with CVD or those with risk factors for CVD, to whom diclofenac prescribing is contraindicated. Out of the overall number of patients who were prescribed diclofenac in 2016, 2017, 2018, 2019, and 2020, 16%, 18%, 24%, 15%, and 20% of them, respectively, already had a CVD or some risk factor for CVD. Most CV patients (39.7%), for whom the use of diclofenac was contraindicated, had ischemic heart disease and were prescribed 40.7% of the total amount of diclofenac prescribed for this group of patients (expressed in DDD/1,000 inhabitants/day for the given medicine). The majority (77.4%) of CV patients to whom the drug could be prescribed, but with increased precautions, had hypertension, and they were prescribed 77.2% of the total amount of diclofenac prescribed for this group of patients (expressed in DDD/1,000 inhabitants/day for the given medicine). Conclusion. Despite the undertaken regulatory measures aimed at a safer prescription of diclofenac to patients with CVD or at high risk of developing CVD, this medicine is still widely prescribed at the level of PHC in Montenegro, even in cases that represent a contraindication for its use.