Dipyrone Research Articles

Preparation of monoclonal antibodies recognizing pharmacologically active metabolites of metamizole based on rational hapten design and their application in the detection of animal-derived food

Metamizole (MET) is an antipyretic and analgesic drug, the illegal use of which can result in residues of MET metabolites in edible tissues of animals. In this study, a computational chemistry-assisted hapten screening strategy was used to screen for the optimal immunogenic hapten-A and the optimal coating antigen hapten-G-OVA. A monoclonal antibody capable of recognizing two pharmacologically active metabolites of MET, 4-methylamidinoantipyrine (MAA) and 4-aminoantipyrine (AA), was prepared from the hapten-A. The antibody showed excellent specificity for MAA and AA and almost no cross-reactivity with the pharmacologically inactive metabolites 4-formamidinoantipyrine (FAA) and 4-acetamidinoantipyrine (AAA). An ic-ELISA was developed for the simultaneous detection of MAA and AA in animal-derived food, the limits of detection for MAA ranged from 0.93 to 1.18 μg/kg, while those for AA ranged from 1.74 to 4.61 μg/kg. The recovery rate fell within the range of 82 %–110 %, with a coefficient of variation less than 16.39 %.

The embryotoxic and teratogenic effects of metamizole sodium.

Drug use during pregnancy is an important issue that must be investigated due to its adverse effects on maternal and foetal health. This study aimed to determine the embryotoxic and teratogenic effects of in-ovo administered metamizole (dipyrone), which can be used when needed during pregnancy and has potent analgesic, antipyretic, anti-inflammatory, and long bone (tibia and femur) effects. This study used 240 fertile eggs from Atak S breed chickens, divided into eight equal groups: control, vehicle control, and 15.62, 31.25, 62.5, 125, 250 and 500 mg/kg metamizole. The eggs were hatched on the 21st day of incubation, and the chicks' body weights and mortality rates were determined. The right and left femur and tibia bones were resected from the chicks. Anatomical reference points were determined after removing the soft tissues of the bones, and necessary morphometric measures were taken from these points with a 0.01 mm precision using digital callipers. The 100% lethal dose (LD100) was identified in the highest examined dose (500 mg/kg) in the Chicken Embryotoxicity Screening Test (CHEST)-I stage. The CHEST-II stage determined the 50% lethal dose (LD50). High-dose metamizole affected skeletal development, significantly decreasing tibia and femur lengths and corpus thicknesses and increasing mortality.

Toxicological effect of acetaminophen, metamizole, and nimesulide cocktail on early developmentof zebrafish.

Several countries' most incorrectly discarded medicines are acetaminophen (ACM), metamizole (MTZ), and nimesulide (NMS). These xenobiotics easily reach the aquatic environment; such contamination is very important for the health of humans and other species, yet little explored. To evaluate the cocktail effect of ACM, MTZ, and NMS during zebrafish's initial development. Zebrafish embryos 6-8h post-fertilization (hpf) were exposed to different concentrations of ACM, MTZ, and NMS, separately, to obtain the 50% lethal concentrations (LC50). Next, the embryos were exposed to distinct concentrations of the cocktail (LC50/2, LC50/5, LC50/10, and LC50/20) in a semi-static system. Samples were analyzed 0, 24, 48, and 96h after exposure, and the drugs' concentrations in E3 medium were assessed by high-performance liquid chromatography. For embryotoxicity evaluation, the mortality, hatching, and heart rates; total length; and pericardial and yolk sac areas were determined. In addition, body malformations, edemas, presence of pigmentation, and histopathological assessments were also recorded. The LC50 values obtained for MTZ, ACM, and NMS were 4.69 mgmL-1, 799.98 μgmL-1, and 0.92 μgmL-1, respectively. No difference was observed between the drugs' nominal and observed concentrations at each time point. The cocktail significantly induced mortality and decreased hatching in the LC50/10, LC50/5, and LC50/2 groups. Additionally, body malformations, pigmentation loss, and yolk sac and pericardial edemas were observed in the cocktail groups. The cocktail groups' larvae had decreased total length and slower heart rates compared to the controls (p < 0.05). The histopathological assessment showed that yolk sac edema promoted severe histological changes in the esophageal-intestine junction and intestine in larvae treated with cocktails. Moreover, PAS-positive structures decreased in the esophageal-intestine junction, intestine, and liver in larvae exposed to pharmaceutical cocktails. This study's findings suggest the cocktail of ACM, MTZ, and NMS may be hazardous to aquatic organisms in case of environmental contamination.

Unused, leftover and expired medicine and disposal practices among health sciences faculty students in Burdur, Turkey.

To evaluate the opinions of university-level Health Sciences students about unused, leftover and expired medicine, as well as their disposal practices, and to classify the medicines. The cross-sectional study was conducted from April 1 to May 31, 2023, at the Faculty of Health Sciences, Burdur Mehmet Akif Ersoy University, Turkey, and comprised those studying at the Nursing, Nutrition Dietetics and Physical Therapy and Rehabilitation departments. Data was collected using Google Forms. The Anatomical Therapeutic Chemical classification was used for classifying pharmaceutical active ingredients. Data was analysed using SPSS 24. Of the 373 participants, 272(73%) were females and 101(27%) were males. The overall mean age was 20.8±2.8 years. There were 348(93.3%) subejcts who reported having a total of 845 boxes of leftover and unused medicines in their homes (2.3±1.9 per capita), while 25(6.7%) participants had none. The medicines were stored in the kitchen 261(61.5%) as the storage area, and in the refrigerator 181(40.2%) as the storage unit. The expired medicine was disposed of in the garbage in 328(86.1%) cases. Self-medication was prevalent in 325(87.1%) cases. Anatomical Therapeutic Chemical classification analysis showed that paracetamol, acetylsalicylic acid, paracetamol+caffeine and metamizole sodium was the most common group of leftover and unused medicines 283(81.3%). High prevalence of unused and leftover medicine, disposal of medicine in household garbage, and selfmedication behaviour indicated a serious public health and environmental problem.

Criteria-based assessment of analgesic activity of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines derivatives based on dataexperimental studies

BACKGROUND: An urgent task in pharmacology is to identify highly effective drugs with analgesic and anti-inflammatory activity. Heterocyclic cyanothioacetamide compounds are of considerable interest. Most authors evaluate the results of studies with separate private indicators of analgesic activity, and their comprehensive criterion assessment is insufficiently defined.&#x0D; AIM: Development of a criterion assessment in the study of analgesic activity and the establishment of its generalized criteria for samples of chemical compounds of medicinal products.&#x0D; MATERIALS AND METHODS: The experiments were performed on 390 male rats weighing 250–280 g in the laboratory of the Department of Fundamental and Clinical Pharmacology of St. Luke Lugansk State Medical University. Intact, control and reference (comparison group) groups of ten animals in each group were formed for each pharmacological test. In the intact group, the rats were unharmed. The control group received 2 mL of 0.9% sodium chloride solution intragastrically before each pharmacological test to establish analgesic activity. The reference group was injected with sodium metamizole at a dose of 7 mg/kg intragastrally once 1.5 h before modelling an acute pain reaction. Ten experimental groups were also formed, in which rats were injected with appropriate samples of new original studied derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridine intragastrically at a dose of 5 mg/kg 1.5 h before modelling acute pain syndrome. Tests for orofacial trigeminal pain, thermal immersion and hot plate were simulated. The indicators of the analgesic effect were the frequency of scratching movements in the orofacial trigeminal pain test and a statistically significant increase in the latent reaction period after the administration of the studied substances in the thermal immersion tests of the tail and hot plate.&#x0D; RESULTS: The studied samples with ciphers AZ-023, AZ-331 and AZ-383 showed maximum analgesic activity. The proposed criterion of analgesic activity in the experimental groups receiving thienopyridine derivatives with the AZ-023 cipher, according to the results of three tests, was 50.1, exceeding the indicator in the comparison group by 42 times. The values of this criterion in the experimental groups that received new 1,4-dihydropyridine derivatives with laboratory ciphers AZ-331 and AZ-383 for preventive purposes were the maximum in this series of experiments (64.3 and 68.4), which is 53–57 times higher than that of sodium metamizole.&#x0D; CONCLUSION: The methodology for assessing analgesic activity can be improved based on a criteria-based approach with the aggregation of particular indicators into an abstract model that allows quantifying the degree of analgesic activity. An integral criterion for the analgesic activity of cyanothioacetamide derivatives based on experimental data is proposed. In the future, the proposed approach can be used in studies of various analgesic samples.

Study of the anti-exudative activity of new 3-cyano-1,4- dihydropyridines, cyanotioacetamide derivatives, on the model of acute formalin edema

The inflammatory process accompanies most of the pathologies and requires pharmacological correction. In spite of significant achievements of scientists in the field of medicine and pharmacology, existing steroid and nonsteroidal antiinflammatory drugs have a number of undesirable reactions. To date, one of the most urgent directions is the search for new effective and safe drugs with anti-inflammatory activity. The aim of the study was to investigate the anti-exudative properties of new 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives in the classical test of acute formalin edema. Material and methods. The study was conducted on 88 white rats weighing 210–250 g. The effectiveness of compounds was determined in a model of acute formalin edema, which was induced by subplantar injection of 0.1 ml of 2 % formalin solution into the right hind limb of the animals. The severity of exudation was evaluated oncometrically in comparison with reference drugs – ibuprofen, indomethacin, meloxicam and metamizole sodium. The studied substances were administered intragastrically at a dose of 5 mg/kg 1.5 hours before the induction of inflammation. Results. It was found that some compounds exhibit anti-exudative activity, more pronounced or similar to the activity of reference drugs. The laboratory sample with code mar-137 was the leading sample and outperformed the comparators; 24 hours after the modeling of edema, it exceeded ibuprofen (by 2.39 %), metamizole sodium (by 4.77 %) in anti-exudative efficacy and had an anti-inflammatory effect similar to the activity of indomethacin and meloxicam. Conclusions. Newly synthesized laboratory samples of 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives, were found to exhibit pronounced anti-exudative activity and are of interest for further research as a new class of anti-inflammatory drugs.

Physical compatibility of colistin with analgesics during simulated Y-site administration.

Special consideration is needed when intravenous drugs are administered simultaneously using a Y-site connector. This study aimed to investigate the physical compatibility of colistin with 6 analgesics at concentrations commonly used in clinical practice. A pharmaceutical preparation of colistin was dissolved according to the manufacturer's instructions and diluted to a concentration of 1.5 mg/mL or 0.67 mg/mL (of colistin base). Simulated administration via Y-site infusion set was performed by mixing 5 mL of colistin solution with an equal volume of a solution of one of 6 intravenous analgesics. Infusion solutions of ibuprofen, ketoprofen, metamizole sodium, morphine sulfate, paracetamol, and tramadol hydrochloride were studied. For each analgesic tested, concentrates for injection were diluted with 2 solvents, resulting in 11 different combinations with each concentration of the colistin solution. The mixtures were visually inspected, and their turbidity was measured directly after mixing and at 3 consecutive time points (30, 60, and 120 minutes). Additionally, the pH of the mixtures was measured after 120 minutes and compared with the pH of the analgesic and the colistin solutions. During visual inspection with the unaided eye, no precipitate formation or gas evolution was observed in any of the tested analgesics except for sodium metamizole, where the yellow color of the solutions was observed. For samples containing the mixture of ibuprofen and colistin, the turbidity measurements revealed the presence of turbidity in the studied mixtures. The greatest change in pH relative to the value immediately after preparation was noted for combinations of ketoprofen and morphine sulfate with the tested antibiotic. Colistin was found to be incompatible with ibuprofen and metamizole sodium formulations. It should also not be combined with morphine sulfate due to the significant differences in the pH value of the preparations. The colistin 0.67 mg/mL and 1.5 mg/mL infusion solutions were physically compatible with ketoprofen, tramadol hydrochloride, and paracetamol.

Synthesis and antinociceptive activity of 2,2’-(1,4-phenylene)bis[3-aryl-2-azaspiro[3.5]nonan-1-ones

Over the years, azetidin-2-ones, or β-lactams, have received a lot of attention from scientists as potential drug candidates due to their diverse biological activity. Spiro-β-lactams also exhibit biological activity; therefore, it is of interest to synthesize and study the properties of new compounds belonging to this class. The study aims to examine the antinociceptive activity of several synthesized bis(spirolactams), specifically 2,2’-(1,4-phenylene)bis[3-aryl-2azaspiro[3.5]nonan-1-ones]. These bis(spiroazetidine-2-ones) were obtained in the interaction of a twofold excess of the Reformatsky reagent, derived from methyl 1-bromocyclohexane carboxylate and zinc, with N,N-(1,4-phenyle- ne)bis(1-arylmethanimines) by means of boiling them in a 10:1 mixture of toluene and hexamethylphosphorictriamide for four hours. Bis(spiro-β-lactams) on the basis of diimines derived from p-phenylenediamine, 2-methoxybenzaldehyde, p-tolualdehyde, and 3-bromobenzoic aldehyde were synthesized for the first time. The composition and structure of the previously undescribed products were established using IR, [1]H, and 13C NMR spectroscopy and elemental analysis. The antinociceptive activity of the obtained compounds was studied on outbred white mice of both sexes via the hot plate test with an intraperitoneal injection. The effect was estimated two hours after administration. Several synthesized compounds were found to exhibit antinociceptive activity at or above the level of the comparator product – metamizole sodium. Nerve endings can be considered the target of the antinociceptive activity of examined substances since under the effect of these substances, no signs of central action are observed in the behavior of animals. Thus, the conducted studies showed the promise of further search for biologically active substances among the compounds of this series.

Discovery of GPX4 inhibitors through FP-based high-throughput screening

Ferroptosis is a form of non-apoptotic cell death, regulated by phospholipid hydroperoxide glutathione peroxidase 4 (GPX4), a selenoprotein with a selenocysteine residue (sec) in the active site. GPX4 is a promising target for cancer cells in therapy-resistant conditions via ferroptosis, which can reduce the level of lipid reactive oxygen species (ROS). So far, all existing GPX4 inhibitors covalently bind to GPX4 via a reactive alkyl chloride moiety or masked nitrile-oxide electrophiles with poor selectivity and pharmacokinetic properties and most were obtained by cell phenotype-based screening. Lacking of effective high-throughput screening methods for GPX4 protein limits the discovery of GPX4 inhibitors. Here, we report a fluorescence polarization (FP)-based high throughput screening (HTS) assay for GPX4-U46C-C10A-C66A in vitro, and found Metamizole sodium from our in-house compound library inhibits GPX4-U46C-C10A-C66A enzyme activity. Structure-activity relationships (SAR) demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46C-C10A-C66A. Our FP assay could be an effective tool for discovery of GPX4 inhibitors and Metamizole sodium was a potential inhibitor for GPX4 in vitro.

Gold particle-modified glassy carbon electrode: an advanced electrochemical sensor for dipyrone monitoring

This study presents the development and optimization of a gold particle-modified glassy carbon electrode (Au/GCE) as an advanced electrochemical sensor for monitoring dipyrone (DIP), a commonly used pharmaceutical compound. The objective of this study was to enhance the sensitivity and accuracy of DIP quantification through efficient experimental planning and the incorporation of gold particles onto the surface of the GCE. The electrodeposition of gold particles onto the GCE significantly improved the response of DIP in a 0.5 mol L−1 H2SO4 solution. By employing a design of experiments (DoE) approach, we optimized the differential pulse voltammetric (DPV) method, resulting in enhanced performance, including the achievement of a remarkably low limit of detection (0.15 µmol L−1). To assess the accuracy of the electroanalytical method, we conducted extensive recovery tests, which yielded recovery values ranging from 98.9% to 104% for DIP concentration in pharmaceutical formulations. These results emphasize the selectivity and robustness of the developed electroanalytical method, positioning it as a reliable tool for monitoring DIP. The comprehensive account of experimental procedures, optimization strategies, and analytical validation presented in this study establish the efficacy and potential applications of the developed sensor in pharmaceutical analysis. Overall, this research contributes valuable insights into the field of electrochemical sensing and offers promising prospects for its application in various pharmaceutical and clinical settings.

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.

Study of anti-inflammatory and antinociceptive properties of new derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines

Background. α-сyanothioacetamide derivatives are promising targets for the search for effective and safe antinociceptive agents with antipyretic and antiexudative activity. The aim. To conduct in vivo experimental study of anti-inflammatory and analgesic effects of new thienopyridines and 1,4-dihydropyridines derivatives. Materials and methods. The synthesized cyanothioacetamide derivatives were subjected to virtual bioscreening using Swiss Target Prediction online service. 140 laboratory rats were randomly distributed into intact and control (dextran edema) groups, reference groups (acetylsalicylic acid and nimesulide) and ten experimental groups for the investigated derivatives of thieno[2,3-b]pyridine and 1,4-dihydropyridine. The anti-inflammatory activity of the compounds at a dose of 5 mg/kg was evaluated by modeling acute dextran edema of rat paw. Determination of analgesic activity was carried out in the hotplate analgesic assay on 130 rats in comparison with sodium metamizole. Results. 1,4-dihydropyridines AZ331 and AZ420, as well as thienopyridine derivative AZ023 were determined to have strong anti-inflammatory activity (2.5 times more effective than nimesulide and 2.2 times more effective than acetylsalicylic acid). Compounds AZ023, AZ331 and AZ383 showed pronounced analgesic activity. The time of stay on the heated plate for rats of experimental groups that were fed with AZ331 and AZ383 for prophylactic purpose was respectively 9.56 and 9.93 times more than the same index in the reference group. The animals receiving AZ023 were characterized by an increase in the latent reaction time up to 241.2 seconds, which is 14.53 times higher than that in the rats received sodium metamizole. Conclusion. New thienopyridine and 1,4-dihydropyridine derivatives with high antiinflammatory and analgesic activity were synthesized and studied; they were recognized as promising targets for further preclinical studies.

Influence of N‐butylscopolammonium bromide and metamizol sodium on echocardiographic variables in healthy Warmblood horses

Influence of N‐butylscopolammonium bromide and metamizol sodium on echocardiographic variables in healthy Warmblood horses

Empirical determination of the degree of analgesic activity of some new 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines based on a complex criterion

Introduction: It is revelant to solve the problem of anesthesia based on the research of new highly effective and safe medicines. Among modern studies, the preparation of heterocyclic compounds starting from cyanothioacetamide with analgesic and anti-inflammatory activities is of considerable interest. Materials and Methods: болевой синдром Results: It is shown that all the studied 1,4-dihydropyridines and condensed thieno[2,3-b]pyridines and reveal analgesic activity of varying degrees of severity, based on the values of the criterion Anat. Discussion: It was found that the most pronounced analgesic activity was shown by three studied samples: compounds AZ-023, AZ-331 and AZ-383. The complex criterion of analgesic activity of Anat for animals receiving a sample AZ-023 was 50.1, exceeding the indicator in the comparison group by 42 times. The values of this criterion in animals that had received samples AZ-331 and AZ-383 were the highest, namely 64.3 and 68.4, which is 53 and 57 times higher than that of sodium metamizole, respectively. Conclusion: The obtained results and the advantage of the studied samples over the reference drug determine the expediency of further preclinical studies and a detailed study of their acute and chronic toxicity, as well as hepato-, nephro-, hemato- and gastrotoxicity. Graphical Abstract

Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4

Selenoprotein glutathione peroxidases (GPX), like ubiquitously expressed GPX1 and the ferroptosis modulator GPX4, enact antioxidant activities by reducing hydroperoxides using glutathione. Overexpression of these enzymes is common in cancer and can be associated with the development of resistance to chemotherapy. GPX1 and GPX4 inhibitors have thus shown promise as anti-cancer agents, and targeting other GPX isoforms may prove equally beneficial. Existing inhibitors are often promiscuous, or modulate GPXs only indirectly, so novel direct inhibitors identified through screening against GPX1 and GPX4 could be valuable. Here, we developed optimized glutathione reductase (GR)-coupled GPX assays for the biochemical high-throughput screen (HTS) of almost 12,000 compounds with proposed mechanisms of action. Initial hits were triaged using a GR counter-screen, assessed for isoform specificity against an additional GPX isoform, GPX2, and were assessed for general selenocysteine-targeting activity using a thioredoxin reductase (TXNRD1) assay. Importantly, 70% of the GPX1 inhibitors identified in the primary screen, including several cephalosporin antibiotics, were found to also inhibit TXNRD1, while auranofin, previously known as a TXNRD1 inhibitor, also inhibited GPX1 (but not GPX4). Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2. Some compounds inhibiting GPX4 but not GPX1 or GPX2, also inhibited TXNRD1 (26%). Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR). The detected overlaps in chemical space suggest that the counter screens introduced here should be imperative for identification of specific GPX inhibitors. With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds.

Development of a detection method for 10 non-steroidal anti-inflammatory drugs residues in four swine tissues by ultra-performance liquid chromatography with tandem mass spectrometry

The ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) detection method was developed for the residues of 10 NSAIDs (salicylic acid, acetylsalicylic acid, acetaminophen, diclofenac, tolfenamic acid, antipyrine, flunixin meglumine, aminophenazone, meloxicam, metamizole sodium) in swine muscle, liver, kidney, and fat. Swine tissue samples were extracted by phosphorylated acetonitrile with the addition of an appropriate amount of internal standard working solution, defatted with acetonitrile-saturated n-hexane, and purified by Hydrophile-Lipophile Balance (HLB) solid-phase extraction column, then separated by UPLC BEH shield RP18 column with 0.1% formic acid in water/0.1% formic acid in acetonitrile with gradient elution, which was detected in the multiple reaction monitoring (MRM) modes. The correlation coefficient of the standard curve equation is greater than 0.99, and the coefficient of variation within and between batches is less than 14.4%. We evaluated the analytical method using two green assessment tools. The method established in this study met the requirements of NSAID residue analysis and provides analytical tools for determining and confirming NSAIDs in swine tissue samples. This is the first report on the simultaneous determination of 10 NSAIDs in four swine tissues by the UPLC-MS/MS method and accurate quantification using deuterated internal standards.

Novel 1,4-Dihydropyridine Derivatives as Potential Agents with Analgesic Activity IN Orofacial Trigeminal Pain Test: Experimental Preclinical Randomized Trial

Background. In the majority of cases, contemporary pharmacological correction mainly focuses on the most effective analgesia. Therefore, the search for and research into new analgesic drugs are a priority in modern pharmacology.Objective — to establish the level of analgesic activity in eight novel heterocyclic compounds of 1,4-dihydropyridine derivatives synthesized in a classic test of orofacial trigeminal pain in animal experiments.Methods. An experimental preclinical randomized trial of the analgesic activity in 1,4-dihydropyridine derivatives was carried out. The experiment was conducted on 100 white male outbred rats in the laboratory of the Fundamental and Clinical Pharmacology Department, St. Luke Lugansk State Medical University, Lugansk People’s Republic. Novel 1,4-dihydropyridine derivatives were preliminarily investigated in a virtual biological screening by means of Swiss Target Prediction tool (Swiss Institute of Bioinformatics, Switzerland). The laboratory animals were divided into a control group (rats were exposed to acute pain syndrome by injecting 0.1 ml of 5% formalin solution into the vibrissae area without pharmacological correction), a comparison group (rats which received metamizole sodium (OOO Farmstandard) at a dose of 7 mg/kg 1.5 hour prior to acute pain syndrome modeling in the vibrissae area), and eight experimental groups (1.5 hours before formalin administration, novel 1,4-dihydropyridine derivatives under study at a dose of 5 mg/ kg were intragastrically injected). 10, 15 and 20 minutes after simulating acute pain, the number of scratching movements of the forelegs around orofacial region per minute was counted. Statistical processing of the results involved methods of mathematical statistics for quantitative variability and was carried out using Statistica 12.5 (IBM, USA).Results. Animals treated with 1,4-dihydropyridine derivatives d02-133 and d02-172 under the experimental conditions showed a significant (13–21 times) decrease in scratching movements frequency by the 10th minute of observation in comparison with the control group. By 15th minute, the analgesic activity of the cyanothioacetamide derivatives increased 14 and 11 times as compared to these indicators of the reference group. After 20 minutes, the analgesic activity of these compounds in terms of inhibiting nociceptive impulses, as compared to the control group, was also high, as the number of scratching movements in the vibrissae area in animals of these experimental groups was 8–9 times lower than in control group. The orofacial trigeminal pain test detected the most exhibited analgesic activity in novel cyanothioacetamide derivatives d02-139, d02-133, and d02-172, which appeared to be higher than that of metamizole sodium.Conclusion. It was found that novel original derivatives of 1,4-dihydropyridine showed a high degree of analgesic activity.

Mortality and Survival Factors in Patients with Moderate and Severe Pneumonia Due to COVID-19.

During the pandemic, some mortality-related factors were age, sex, comorbidities (obesity, diabetes mellitus, and hypertension), recovery time, hospitalizations, and biochemical markers. The present work aimed to identify the mortality and survival factors in adults with moderate and severe pneumonia due to COVID-19 during the first and second waves of the pandemic in Mexico at a third-level hospital (High-Specialty Regional Hospital of Ixtapaluca (HRAEI), Ixtapaluca, Estado de Mexico, Mexico). A database was generated using information from the electronic clinical records of patients hospitalized from December 2021 to August 2022. Survival analysis was performed associating age, sex, longer recovery times, and some drugs. The risk factors found were age in the patients between 40 and 60 years (OR = 1.70), male sex (OR = 1.53), the presence of comorbidities (OR = 1.66) and hypertension (OR = 2.19), work occupation (construction workers OR = 5.22, factory workers OR = 3.13, unemployed OR = 2.93), the prehospital use of metamizole sodium (OR = 2.17), cough (OR = 1.73), and in-hospital oxygen therapy (reservoir mask OR = 6.6). The survival factors found in this study were working in the healthcare field (OR = 0.26), the prehospital use of certain medications (paracetamol OR = 0.65, dexamethasone OR = 0.55, and azithromycin OR = 0.47), presenting ageusia (OR = 0.5) and hyporexia (OR = 0.34), and the time using in-hospital oxygen therapy (device 1 OR = 0.72). Prehospital treatment needs to be reevaluated as dexamethasone and azithromycin proved to be protective factors. Likewise, providing aggressive oxygen therapy during hospital admission decreased mortality risk.

UV-Vis Spektrofotometrisi ile Geleneksel Bitkisel Ürünlerde (Jamu) Tıbbi Kimyasalların Doğrulanması

Traditional medicine "Jamu" is becoming very popular used by the community as an alternative treatment that can minimize side effects. However, it is profitable for manufacturers who are not responsible for herbal products by adding medicinal chemicals (BKO) to traditional herbal products. The samples used in this study were samples of traditional herbal medicine coded A1, A2; B1, B2; C1, C2; D1, D2; E1, E2; and F1, F2, which were analyzed qualitatively and quantitatively using thin-layer chromatography (TLC) and UV-Vis spectrophotometry. Based on the results obtained from the analysis using the TLC method, the herbal samples with code A1 A2 had a staining profile, Rf value, and chromatographic peak that were almost the same as the comparison standard for sodium metamizole with levels of 51.99% (A1) and 53.06% (B). the herbal medicine samples with codes B1, B2, and C1, C2 had stain profiles, Rf values, and spectrophotometric chromatography peaks that were almost the same as the comparison standard for paracetamol with paracetamol levels contained in the “Jamu” samples of 81.31% (B1), 81.66% (B2), 89.59% (C1) and 81.62% (C2). The results obtained from this study can be concluded that the samples of traditional herbal products with codes A1 and A2 contain sodium metamizole with levels of &gt;50%. Samples of traditional herbal products B1, B2, C1, and C2 contain paracetamol with paracetamol levels contained &gt; 50%, while the traditional herbal medicine samples with codes D1, D2, E1, E2, F1, and F2 have been identified as containing no medicinal chemicals in the traditional herbal medicine samples.

Toxic reactions of non-steroidal anti-inflammatory drugs in the Russian Federation, analysis of the national database “Pharmacovigilance”

Non-steroidal anti-inflammatory drugs are widely used by patients and medical workers, both in the Russian Federation and abroad. Despite the well-established public opinion about the safety of this group of drugs, their use is associated with toxic reactions. This study analyzed the download of the national database “Pharmacovigilance” for 11 years (for the period 2010 to 2020) with the identification of the main representatives of this class of drugs that cause adverse reactions. To compare several independent samples of patients who received different groups of NSAIDs, Kruskel-Wallis ANOVA rank analysis of variations was used using Microsoft Excel 2013, STATISTICA 10.0 packages. Based on the results obtained, it can be concluded that the main proportion of adverse drug reactions (ADR) is associated with the female sex and the use of metamizole sodium. In addition, fatal AEs have been reported, most of which are associated with the use of paracetamol.