Action Of Non-steroidal Anti-inflammatory Drugs Research Articles

Differential chemoproteomic analysis of RRS-1 candidate molecule and molecules of several nonsteroidal anti-inflammatory drugs

Background. To plan effective and safe pharmacotherapy for inflammation and pain, it is important to evaluate the mechanisms and spectrum of action of nonsteroidal anti-inflammatory drugs (NSAIDs), including their effects on human proteome.Objective: to identify and evaluate the most significant specific differences of candidate molecule RRS-1 (N-{(Z)-2-(1-methyl-1H-indol-3-yl)1-[(propylamino)carbonyl]vinyl}benzamide) from other NSAIDs through differential chemoreactome analysis.Material and methods. Chemoproteomic modeling of pharmacological effects of RRS-1 molecule and a number of well-known NSAIDs (diclofenac, nimesulide, ketorolac) on human proteome was carried out on the basis of numerical prediction algorithms over the space of heterogeneous feature descriptions, developed in the topological approach to recognition by Yu.I. Zhuravlev and K.V. Rudakov scientific school.Results. Significant differences in the effects of the studied molecules were found for 1232 proteins of human proteome. The features of assessing interactions of the studied molecules with 47 target proteins, which most distinguished the effects of RRS-1 molecule from all others were identified. RRS-1 could activate adenosine and dopamine receptors, cannabinoid receptor 2 and GABAA receptor to a greater extent than other molecules. Activation of these receptors corresponded to anti-inflammatory, anti-nociceptive and neuroprotective effects. RRS-1 could preferably inhibit a number of pro-inflammatory proteins, receptor bradykinin 1, metabotropic glutamate receptor 5, matrix metalloproteinases 8, 9, 12, and blood coagulation factor X. Additionally, RRS-1 molecule showed preferable inhibition of a number of kinases targeted in antitumor and anti-inflammatory therapy. RRS-1, less than other studied molecules, interacted with the receptors of vitamin D3, thyroid hormone, acetylcholine, cannabinoids and opioids, orexin, and various metabolic enzymes, which is important in assessment of the safety of using drugs based on this molecule. RRS-1 characteristically exhibited a moderate profile of antivitamin action: the total score of vitamin and mineral loss (7.4±3.7) was significantly less in comparison to diclofenac (11.7±4.5) and was actually on the same level as nimesulide (6.9±3.7) and ketorolac (6.7±3.6).Conclusion. Chemoreactomic and chemoproteomic profiling of RRS-1 candidate molecule provided pre-experimental assessments of its efficacy and safety through modeling interactions with the human proteome.

In vitro Cyclooxygenase inhibitory activity and GC-MS profiling of bioactive compounds in Bauhinia racemosa Lam.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a common treatment for chronic pain and inflammation. While NSAIDs have been shown to reduce inflammation and pain associated with them, they have an array of side effects. Researchers investigated the COX inhibitory action of NSAIDs. They revealed that there are two distinct COX enzymes: COX-1 and COX2. Developing COX inhibitors has remained critical for producing innovative and safe anti-inflammatory drugs. Bauhinia racemosa Lam belonging to the family Fabaceae has a wide range of medicinal properties. The plant is used to treat various diseases in traditional medicine, but there is less knowledge based on clinical efficacy as an anti-inflammatory agent. In the present study Bauhinia racemosa Lam hydroalcoholic extract were screened for COX inhibition and GC-MS analysis was done to screen phytochemicals. The results obtained were found to inhibit 89% of COX activity significantly as compared to standard drug (Diclofenac sodium). GC-MS analysis revealed a total of ten potent bioactive compounds. The samples were identified by comparing retention time and peak area to literature and interpreting mass spectra. Results observed from the study suggest that the hydroalcoholic extract of Bauhinia racemosa Lam possess anti-inflammatory activity and can be utilized as an alternate source for NSAIDs. Keywords: COX, Bauhinia racemosa Lam, Anti-inflammatory, NSAIDs.

Chemoproteomic analysis of the promising candidate molecule of the indole derivative with lab code SV-1010 and other non-steroidal anti-inflammatory drugs

Introduction: For effective and safe pharmacotherapy of pain, it is important to evaluate the mechanisms and spectrum of action of non-steroidal anti-inflammatory drugs (NSAIDs), including their effect on the proteom, central effect, as well as pain relieving and anti-inflammatory effects. The aim of the study was to evaluate the complex of differences between the promising candidate-molecule of indole derivative SV-1010 and the well-known NSAIDs. Materials and Methods: Chemoproteomic moduling of pharmacological effects of SV-1010 and NSAID diclofenac, nimesulide and ketorolac on the rat proteom by means of topological analysis of chemographs. Results: The significant differences in the effects of the studied molecules were found for 820 proteins of the rat proteom. SV-1010, to a lesser degree than the other molecules, can inhibit dopamine D1- and D2-type receptors and, at the same time, stimulate the release of dopamine in the neostriatum (EC50 = 27 nM). SV-1010, to a greater extent than the other molecules, can inhibit the GABA conveyor (EC50 = 65 nM) and the NMDA receptors Grin1/Grin2b (IC50 175 nM). SV-1010 can activate Cannabinoid CB2 receptors, inhibit enzymes of leukotriene biosynthesis, CC receptors of pro-inflammatory chemokines and leukotrienes. Conclusion: The chemoreactomic and chemoproteomic profiling of SV-1010 indicated its potential central effect through dopaminergic and GABA-neurotransmission and additional anti-inflammatory mechanisms, which can help increase pain-relieving effects.

NSAID use in orthopedic surgery:A review of current evidence and clinical practice guidelines.

Nonsteroidal anti-inflammatory drugs (NSAIDs)are a valuable class of medications for orthopedic surgeons and often play a pivotal role in pain control. However, there are many common stipulations resulting in avoidance of its use in the treatment of musculoskeletal disease. This review summarizes the mechanism of action of NSAIDs as well as provides an overview of commonly used NSAIDs and the differences between them. It provides a concise summary on the osseous effects of NSAIDs with regard to bone healing and heterotopic ossification. Most of all, it serves as a guide or reference for orthopedic providers when counseling patients on the risks and benefits of NSAID use, as it addresses the common stipulations encountered: "It irritates my stomach," "I have a history of bariatric surgery," "I'm already on a blood thinner," "I've had a heart attack," and "I've got kidney problems" and synthesizes both current research and society recommendations regarding safe use and avoidance of NSAIDs.

PPARγ, NF-κB and the UPR pathway as new molecular targets in the anti-inflammatory actions of NSAIDs: Novel applications in cancers and central nervous system diseases?

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, or celecoxib have a well-established and unquestionable role in the human therapeutic arsenal, but still new perspectives are being discovered. This review presents new anti-inflammatory mechanisms of NSAIDs action, other than the classical one, i.e., the inhibition of cyclooxygenase (COX) isoforms leading to the prostanoids synthesis blockage. Literature data show that this group of drugs can activate anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ), inhibit pro-inflammatory nuclear factor-κB (NF-κB) activation or modulate the components of the unfolded protein response (UPR) pathway. These alternative pathways induced by NSAIDs may not only enhance their basic anti-inflammatory mechanism of action but also promote other effects of the drugs such as anti-cancer. It was also proved that neuroinflammation, with the involvement of NF-κB, PPARγ and the components of the UPR pathway has an essential impact on the development of central nervous system (CNS) diseases. Thus, it seems possible that these new molecular targets may expand the use of NSAIDs, e.g., in the treatment of cancers and/or CNS disorders.

The Effect of Ketorolac on Bone Healing Rate Following Osteotomy in Pediatric Patients with Deformity or Limb-length Discrepancy

Abstract Background: The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) and the results of testing in some animal fracture models have created concerns with bone healing when these drugs are used for perioperative orthopedic analgesia. Given that distraction osteogenesis patients require new bone to be formed, they would potentially be sensitive to the effects of NSAIDs such as Ketorolac. We sought to determine the relationship between the perioperative use of Ketorolac and the duration of healing in pediatric patients undergoing distraction osteogenesis for either limb lengthening or deformity correction surgery. Materials and Methods: A single-center retrospective chart review of 94 pediatric patients aged 17 years or younger who had undergone surgery for limb lengthening, deformity correction, or a combination of limb lengthening and deformity correction was carried out. We collected and analyzed patient demographics, details of surgery and pathology, perioperative pain management, duration of healing, and incidence of complications in this cohort of patients. Results: Patients were divided into three groups: a deformity correction group (n = 46), a limb lengthening group (n = 30), and a combined deformity correction and limb lengthening group (n = 18). The mean magnitude of deformity was 21°. Patients in the lengthening group had a mean lengthening of 4.1 cm. Patients in the combined group had a mean magnitude of deformity of 14.7° and a mean lengthening of 3.8 cm. Patients in all three groups received an average of 4 doses of ketorolac in the perioperative period. We found no correlation between the total amount of ketorolac used and the duration of healing among patients who had deformity correction, limb lengthening, or a combination of deformity correction and limb lengthening surgery (P = 0.82, 0.20, and 0.18, respectively). The correlation results also showed no sex variations in either group. Conclusions: Ketorolac can safely be used as an analgesic in pediatric patients undergoing distraction osteogenesis for limb lengthening, deformity correction, or a combination of both procedures.

Efficacy of ibuprofen and indomethacin as prophylaxis of heterotopic ossification: a comparative study

The prophylactic action of non-steroidal anti-inflammatory drugs (NSAIDs) in heterotopic ossification (HO) was first described following analgesic therapy with indomethacin. Following that evidence, several compounds have been successfully used for prophylaxes of HO. Ibuprofen has been also proposed for the prevention of HO following THA. The present study compared the administration of ibuprofen for three weeks versus indomethacin as prophylaxis for HO following primary THA. In all THA procedures, pre- and post-operative protocols were conducted in a highly standardized fashion. The type of HO prophylaxis (indomethacin 100 mg/daily or ibuprofen 100 mg/daily) was chosen according to a chronological criterion: from 2017 to 2019 indomethacin was used, whereas from 2019 to 2022 ibuprofen was administered. In case of allergy or intolerance to NSAIDs, no prophylaxis was performed, and patients were included as a control group. All patients who underwent an anteroposterior radiography of the pelvis at a minimum of 12 months following THA were considered for inclusion. On admission, the age and sex of the patients were recorded. Moreover, the causes of osteoarthritis and the date of surgery were recorded. The grade of HO was assigned by a blinded assessor who was not involved in the clinical management of the patients. The modified Brooker Staging System was used to rate the efficacy of the interventions. Data from 1248 patients were collected. 62% (767 of 1248 patients) were women. The mean age was 67.0 ± 2.9 years. The mean follow-up was 21.1 ± 10.8 months. In the ibuprofen group, 73% of patients evidenced Brooker 0, 17% Brooker I, and 10% Brooker II. In the indomethacin group, 77% of patients evidenced Brooker 0, 16% Brooker I, 6% Brooker II. No patient in the ibuprofen and indomethacin group developed Brooker III or IV. In the control group, 64% of patients evidenced Brooker 0, 21% Brooker I, 3% Brooker II, and 12% Brooker III. No patient in the control group developed Brooker IV HO. Concluding, three weeks of administration of ibuprofen demonstrated similar efficacy to indomethacin in preventing HO following primary THA. The prophylaxis with ibuprofen or indomethacin was more effective in preventing HO compared to a control group who did not receive any pharmacological prophylaxis.

Lipid mediators in the regulation of innate and adaptive immunity.

Lipid mediators in the regulation of innate and adaptive immunity.

The Safety of Celecoxib as an Acute Treatment for Migraine: A Narrative Review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line choice for the acute treatment of migraine attacks for decades; however, the safety of a particular NSAID is related to its treatment dose, duration, and mechanism of action. Although adverse event (AE) risks differ substantially among individual migraine treatments, increased or prolonged exposure to any NSAID elevates risks and severity of AEs. For this narrative review, we conducted a literature search of PubMed until July 2022, focusing on the history, mechanism of action, and treatment guidelines informing the safety and efficacy of celecoxib oral solution for the acute treatment of migraine attacks. Here we discuss the mechanisms of action of nonselective NSAIDs vs. cyclooxygenase-2 (COX-2) inhibitors, and how these mechanisms underlie the AEs associated with these treatments. We review the clinical trials that influenced the regulatory history of NSAIDs, specifically COX-2 inhibitors, the role of traditional and new formulations of NSAIDs including celecoxib oral solution, and special considerations in the acute treatment of migraine attacks. Low-dose formulations of NSAIDs, such as celecoxib oral solution, provide acute migraine analgesia with similar or fewer associated cardiovascular and gastrointestinal events than previous formulations.

Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.

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

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

Experimental study of the antiulcer effect of cryopreserved placenta extract on a model of acetylsalicylic acid-induced ulcerogenesis

Abstract Introduction. The gastrotoxicity of nonsteroidal anti-inflammatory drugs is a leading side effect that significantly limits their clinical use, among other types of their toxicity (nephrotoxicity, hepatotoxicity, cardiotoxicity, etc.). Cryopreserved placenta extract has drawn our attention as a potential modifier of the ulcerogenic action of nonsteroidal anti-inflammatory drugs. Aim. To characterize the cytoprotective properties of cryopreserved placenta extract by the condition of the mucous membrane of the proximal (esophagus and stomach) and distal (small and large intestine) parts of the gastrointestinal (GI) tract on the model of ASA-induced ulcerogenesis. Material and methods. The study was performed using 28 male rats weighing 200-220 g. Subchronic ASA-induced ulcerogenesis of the digestive tract was reproduced by intragastrically administration to rats of ASA in a dose of 150 mg/kg. The effect of the studied drugs on the condition of the mucous membrane of the digestive tract was assessed macroscopically by the following criteria: edema, redness and hemorrhage on the surface of the mucous membrane. The ulcer index for each group of animals was calculated. Results and discussion. Five doses of ASA 150 mg/kg cause damage to the esophagus, stomach, small and large intestines in all of the rats. The use of the proton pump inhibitor esomeprazole has pronounced gastrocytoprotective properties, but does not affect the ulcerogenic effect in the small intestine, and in the colon, it enhances it. This is indicated by ulcerative lesions of the colon in 57.1% of all rats administered ASA and esomeprazole, as well as in the folding of the gastric mucosa. In contrast, mild hyperemia of the gastric mucosa was seen in 28.6% of all rats and moderate hemorrhage in 57.1% of all rats due to the combined use of ASA and cryoextract placenta. Conclusions. The use of cryopreserved placenta extract is statistically significantly (p <0.05) inferior to the antiulcer activity of esomeprazole in the stomach. Thus, the ulcer index on the background of the use of ASA and cryopreserved placenta extract was 0.97, and on the background of the use of ASA and esomeprazole – 0.39. In the distal parts of the GI tract cryoextract placenta showed cytoprotective properties against the background of induced ASA ulcerogenesis, in contrast to esomeprazole.

Циклооксигеназа: фізіологічні ефекти, дія інгібіторів та перспективи подальшого застосування парацетамолу

В аналітичному огляді надані сучасні погляди на особливості функціонування ферменту циклооксигенази (ЦОГ), функції простаноїдів та механізми дії нестероїдних протизапальних заходів, мішенню яких і є ЦОГ. Докладно розглянуто особливості фармакологічних ефектів парацетамолу — препарату, широке застосування якого з метою усунення больового синдрому та лихоманки триває. Висвітлено основні переваги та недоліки парацетамолу. Розглянуто питання гепатотоксичності та потрібних заходів для її профілактики, а також сучасна схема лікування пацієнтів із гострими токсичними гепатитами, що викликані передозуванням парацетамолу.

Гастропротективна дія кріоконсервованого екстракту плаценти за профілактичного режиму застосування

Introduction. Timely treatment and prevention of peptic ulcer of the stomach and duodenum is not only medical but also social. As a potential gastroprotective agent, our attention was drawn to the cryopreserved extract of human placenta, because the literature convincingly demonstrated that this cryoextract eliminates the ulcerogenic action of nonsteroidal anti-inflammatory drugs, which has a mechanism similar to peptic ulcer disease. The aim of the study was to characterize the gastroprotective activity of cryopreserved placenta extract under the prophylactic regimen of use in the model of ethanol-prednisolone gastric lesions in rats. Materials and methods. The study was performed on 28 male rats weighing 200–220 g. Gastric lesions in rats were simulated by intragastric single administration of prednisolone (20 mg/kg) dissolved in 80.0% ethanol (0.6 ml/100 g body weight). Cryoextracts of the placenta were administered intravenously in a prophylactic mode – 1 time per day for 5 days before the introduction of ethanol-prednisolone mixture. In 24 h. after administration of the mixture, rats were removed from the experiment and the size of the stomach (bloating) and the presence of adhesions with adjacent organs were evaluated macroscopically by the following criteria: erosions and hemographies, hyperemia, edema and mucosal fold disorders. For each group, the percentage of experimental animals was calculated according to these characteristics and the average value of their severity. The values of the ulcer index were calculated for each group. Research results and their discussion. The introduction of ethanol-prednisolone mixture causes erosive ulcerative lesions of the gastric mucosa in 100% of rats The introduction of cryoextract placenta significantly reduced the damaging effect of ulcerogenic mixture on the mucous membrane, advice on the performance of control rats. The severity of antiulcer activity of the studied cryoextract in the prophylactic mode of use is statistically significantly (p<0.05) exceeds the similar effect of esomeprazole. Conclusions. Prophylactic five-day administration of cryopreserved placenta extract is accompanied by a statistically significant (p<0.05) marked gastroprotective effect in a model of ethanol-prednisolone gastric lesions in rats.

Нестероидные противовоспалительные препараты: повреждающее действие на слизистую оболочку желудка и способы защиты от их ульцерогенного влияния

Non-steroidal anti-inflammatory drugs (NSAIDs) are used for various diseases to relieve pain and reduce inflammation. However, the use of NSAIDs can lead to adverse side effects on the kidneys, heart, gastrointestinal tract (GIT) and the central nervous system, which complicates the use of NSAIDs in medicine. The review analyses literature on the anti-inflammatory action of NSAIDs and their adverse side effects. A special focus is given to the side effects of NSAIDs on the gastrointestinal tract. Taking NSAIDs can lead to pathological changes in the GIT: dyspeptic symptoms, gastropathy, gastrointestinal mucosal damage, including erosion and ulcers, which can be accompanied by serious complications such as gastrointestinal bleeding and perforations. The main mechanisms of the damaging effect of NSAIDs on the gastric mucosa include a slowdown in the blood flow rate in the stomach microvessels, which leads to an increase in their permeability, as well as an increase in gastric motility, a decrease in the secretion of mucus and bicarbonates in the stomach, a change in lipid peroxidation with the formation of free radicals that destroy the structure of cell membranes. Nonselective NSAIDs, including the well-known and popular indomethacin and aspirin, have a pronounced deleterious effect on the GIT. The selective NSAIDs are safer regarding the gastrointestinal side effects compared with nonselective ones, however, they can lead to serious cardiac problems. To mitigate the ulcerogenic effect of NSAIDs, antacids and proton pump inhibitors are used. They reduce the secretion of hydrochloric acid in the stomach. Another solution are drugs associated with membrane phospholipids. These drugs contain nitric oxide and hydrogen sulfide. Taking NSAIDs increases the level of glucocorticoid hormones in the blood, which compensate for the absence of prostaglandins and have a gastroprotective effect. Physical exercise stimulates the body’s natural defenses and protects the gastric mucosa from the negative effects of NSAIDs. In this regard, it is crucial for physiology to conduct more studies focusing on the mechanisms of NSAID-induced deleterious influence on the GIT, gastroprotective mechanisms and the development of evidence-based approaches to reduce the adverse effects of NSAIDs.

CHARACTERISTICS OF THE MECHANISMS OF CYTOPROTECTIVE ACTIVITY OF CRYOPRESERVED PLACENTA EXTRACT ACCORDING TO MORPHOLOGICAL AND BIOCHEMICAL STUDIES OF THE GASTRIC MUCOSA IN THE EXPERIMENT

Relevance. Non-steroidal anti-inflammatory drugs (NSAIDs) are used as antipyretics and analgesics. In this case, NSAIDs have a side effect - ulcerogenic. Therefore, it is important to find means to correct the ulcerogenic action of NSAIDs. Potential antiulcerogenic action may be in cryopreserved human placenta extract "Cryocell-placental cryoextract".
 Objective: to investigate the effect of cryopreserved placenta (CEP) extract on the morphological state of the stomach and the processes of protein synthesis in the gastric mucosa with the introduction of NSAIDs diclofenac sodium in rats with experimental rheumatoid arthritis.
 Materials and methods. The study was performed on 28 nonlinear male rats weighing 200-220 g. The animals were divided into 4 groups: I (n = 7) – intact rats; II (n = 7) – rats with adjuvant arthritis (AA), this is a treatment without treatment; III (n = 7) – rats with AA, treated with diclofenac sodium (DN), 8.0 mg / kg, intragastrically (i/g); IV (n = 7) – rats with AA, treated with DN, 8.0 mg / kg, i/g and CEP, 0.16 ml / kg body weight, intramuscularly (i/m).
 AA was simulated by subplantar injection of complete Freund's adjuvant into the hind right limb at a rate of 0.1 ml per rat. The day of adjuvant administration was considered as the "0" day of the experiment. AA treatment was performed from 14 to 28 days. DN was applied daily, and CEP – with an interval of 3 days: for 14, 17, 20, 23 and 26 days. On day 28, the animals were removed from the experiment by cervical dislocation under inhalation anesthesia.
 To assess morphological changes, gastric fragments were fixed in 10.0% neutral formalin solution. Histological sections 5–7 μm thick were stained with hematoxylin and eosin, as well as Schiff's reagent (fuchsin sulfuric acid) with iodic acid. The concentration of total protein (TP) was determined spectrophotometrically by light absorption at a wavelength of 546 nm. The content of RNA and DNA in the homogenates of the gastric mucosa was determined spectrophotometrically by reaction with perchloric acid.
 Results. In rats with AA, the mucous membrane (MM) had a preserved structure in all animals. There were no signs of hyper- or hyposecretion of mucins when stained with a chic reaction with alcyan blue. There were foci of desquamation of the superficial epithelium and single lymphocytes. The introduction of DN in rats with AA led to signs of erosive changes in MM. Deep erosions and single ulcerative defects were found in 28.6% of rats, reaching the depth of the lesion to the muscle plate. There is a small amount of mucopolysaccharides with a predominance of acidic glycoproteins. Reduced content of neutral glycoproteins. Single desquamated epitheliocytes were detected. Focal lympho-plasmacytic infiltration with exudate with eosinophilic leukocytes was noted in the submucosal layer of MM. Against the background of the combined use of DN and CEP in rats with AA in any animal, no significant violations of the histoarchitectonics of the MM, except for isolated foci of desquamation of the superficial epithelium.
 In gastric MM homogenates in rats with AA there was a decrease (p <0.01) in the level of TP by 14.1% and a decrease (p <0.05) in the content of RNA and DNA by 27.5% and 14.3%, respectively, relative to indicators of intact animals.
 Against the background of DN monotherapy, there was an even greater decrease (p <0.001) in the level of TP: by 26.2% (40.3 ± 1.43 μg / mg) relative to intact animals (54.6 ± 1.39 μg / mg). And the content of RNA and DNA was 0.59 ± 0.57 μg / ml and 2.21 ± 0.27 μg / ml, respectively.
 Against the background of the combined use of DN and CEP, comparable to the level of intact animals indicators of TP and DNA were noted. Thus, the level of TP was 53.0 ± 2.09 μg / mg, which was only 2.9% lower than intact animals (54.6 ± 1.39 μg / mg), and the DNA content by 5.1% (p = 0.3) was lower than intact animals (3.1 ± 0.12 μg / ml) and was respectively 2.94 ± 0.08 RNA level (1.72 ± 0.12 μg / ml) on 17.6% exceeded (p = 0.1) intact animals (1.46 ± 0.08 μg / ml).
 Conclusions. The combined use of placental cryoextract and diclofenac sodium eliminates the negative effect of the latter on protein metabolism in the gastric mucosa of rats with adjuvant arthritis. Thus, the level of total protein was 53.0 ± 2.09 μg / mg, which is only 2.9% lower than intact animals. Restoration of diclofenac sodium-induced mucin secretion by the integumentary epithelium of the gastric mucosa is one of the mechanisms of cytoprotective activity of cryopreserved placenta extract in experimental ulcerogenesis.

Effect of genetic polymorphisms and haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery

Abstract Background Most cardiac surgeries are associated with post-sternotomy pain syndrome. Pain causes elevation of blood pressure, heart rate and may be associated with hemodynamic instability, respiratory infections, and other postoperative complications. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics in cardiac surgery. The majority of NSAIDs are metabolized by cytochrome P-450. The mechanism of action of NSAIDs is associated with blocking of prostaglandin-endoperoxide synthase (PTGS). Individual variabilities and gene polymorphisms may affect ketoprofen exposure, efficacy and safety. Purpose Evaluation of the influence of CYP2C9 - CYP2D6 and PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. Methods The study included 90 patients. Pain intensity assessment was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury was determined by Kidney Disease Improving Global Outcomes criteria. Genotyping of polymorphisms CYP2C9*3 (1075A>C) rs1057910, CYP2D6*4 (1846G>A) rs3892097, PTGS-2 (G>C) rs20417, PTGS-1 (C>T) rs12353214 was performed. Results The study revealed the following haplotypes: (1) CYP2C9*3 rs1057910 (AA) – CYP2D6*4 rs3892097 (GG), (2) CYP2C9*3 rs1057910 (AC) – CYP2D6*4 rs3892097 (GA), (3) PTGS-2 rs20417 (GG) – PTGS-1 rs12353214 (CT), (4) PTGS-2 rs20417 (CC) – PTGS-1 rs12353214 (CC). Pain intensity by the NRS score was significantly higher in patients with AA-GG haplotype compared to AC-GA haplotype for CYP2C9*3 - CYP2D6*4: 7,13±2,14 and 5±1,52 (p=0,009); 7,06±1,99 and 4,86±1,57 (p=0,007); 4,96±1,83 and 3,29±1,79 (p=0,04); 4,57±1,66 and 2,86±1,57 (p=0,02), on days 1, 2, 3 and 5 in the postoperative period, respectively. There were no significant differences in pain intensity by the NRS in patients with PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes. Also there were no significant differences in GSRS score and acute kidney injury frequency in patients with AA-GG and AC-GA haplotypes for CYP2C9*3 – CYP2D6*4 and GG-CT and CC-CC haplotypes for PTGS-2 rs20417 – PTGS-1 rs12353214. Conclusion CYP2C9*3 - CYP2D6*4 haplotypes affect efficacy of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. Further studies are needed to develop genotype-guided postoperative pain management. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was financially supported by RF President's grant for scientific schools, project No. NSh 2698.2020.7 Pain intensity by NRSDyspepsia symptoms by GSRS

Design, Synthesis and Biological Evaluation of New N-Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX-2 Inhibitors.

The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX-1 enzyme. Therefore, the use of COX-2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX-2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX-2 inhibitors remain necessary. It is important to develop new COX-2 inhibitors in the field of medicinal chemistry. Accordingly, novel N-acyl hydrazone derivatives were synthesized as new COX-2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX-2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a-3j) was characterized by spectroscopic methods. Evaluation of in vitro COX-1/COX-2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX-2 enzyme inhibition. Compound 3j showed important COX-2 inhibition with a value of IC50 =0.143 uM. Interaction modes between the COX-2 enzyme and compound 3j were investigated by docking studies.

Limitations of drug concentrations used in cell culture studies for understanding clinical responses of NSAIDs.

In this review, the in vitro cellular effects of six nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate, ibuprofen, naproxen, indomethacin, celecoxib and diclofenac, are examined. Inhibition of prostanoid synthesis in vitro generally occurs within the therapeutic range of plasma concentrations that are observed in vivo, consistent with the major action of NSAIDs being inhibition of prostanoid production. An additional probable cellular action of NSAIDs has been discovered recently, viz. decreased oxidation of the endocannabinoids, 2-arachidonoyl glycerol and arachidonyl ethanolamide. Many effects of NSAIDs, other than decreased oxidation of arachidonic acid and endocannabinoids, have been put forward but almost all of these additional processes are observed at supratherapeutic concentrations when the concentration of albumin, the major protein that binds NSAIDs, is taken into account. However, one exception is salicylate, a very potent inhibitor of the neutrophilic enzyme, myeloperoxidase, the inhibition of which leads to reduced production of the inflammatory mediator, hypochlorous acid, and inhibition of the inflammation associated with rheumatoid arthritis.

Simulation of the Level of Prostaglandins in Open Systems under the Action of Nonsteroidal Anti-Inflammatory Drugs

Simulation of the Level of Prostaglandins in Open Systems under the Action of Nonsteroidal Anti-Inflammatory Drugs