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Toxics Aug 2023Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent...
Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent antioxidant properties and a neuroprotective effect against oxidative stress. However, its impact on the liver is unclear. This study aimed to elucidate the antioxidative effects of MFA and their underlying mechanisms. We observed that MFA treatment upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Treatment with various anthranilic acid derivative-class NSAIDs, including MFA, increased the expression of sequestosome 1 (SQSTM1) in HepG2 cells. MFA disrupted the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, activating the Nrf2 signaling pathway. SQTM1 knockdown experiments revealed that the effect of MFA on the Nrf2 pathway was masked in the absence of SQSTM1. To assess the cytoprotective effect of MFA, we employed tert-Butyl hydroperoxide (tBHP) as a ROS inducer. Notably, MFA exhibited a protective effect against tBHP-induced cytotoxicity in HepG2 cells. This cytoprotective effect was abolished when SQSTM1 was knocked down, suggesting the involvement of SQSTM1 in mediating the protective effect of MFA against tBHP-induced toxicity. In conclusion, this study demonstrated that MFA exhibits cytoprotective effects by upregulating SQSTM1 and activating the Nrf2 pathway. These findings improve our understanding of the pharmacological actions of MFA and highlight its potential as a therapeutic agent for oxidative stress-related conditions.
PubMed: 37755745
DOI: 10.3390/toxics11090735 -
Allergologie Select 2023Not available.
Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for...
Not available.
PubMed: 37705676
DOI: 10.5414/ALX02422E -
Pakistan Journal of Medical Sciences 2023To evaluate the clinical efficacy of dydrogesterone combined with non-steroidal anti-inflammatory drugs(NSAIDs) in the treatment of patients with mild endometriosis.
OBJECTIVE
To evaluate the clinical efficacy of dydrogesterone combined with non-steroidal anti-inflammatory drugs(NSAIDs) in the treatment of patients with mild endometriosis.
METHODS
This was a clinical comparative study. Eighty patients with mild endometriosis were recruited at Affiliated Hospital of Hebei University, randomly divided experimental group (n=40) and control group (n=40) from March 2022 to March 2023. Both groups started treatment with dydrogesterone on the 5th day of menstruation. Patients in the control group were treated with dydrogesterone monotherapy, while those in the experimental group were treated with mefenamic acid the basis of the therapy of the control group. The clinical efficacy, differences in the levels of humoral immune indexes, the levels of inflammatory factor and the incidence of adverse drug reactions of the two groups was compared and analyzed.
RESULTS
The efficacy of the experimental group was significantly higher than the control group, with a statistically significant difference(P=0.02). The levels of C3 and C4 in the experimental group after treatment were significantly lower than those in the control group, with a statistically significant difference(P=0.00). After treatment, TNF-a, CRP, IL-6 and other indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences(P=0.00). The incidence of adverse reactions after treatment had no statistically significant difference(P=0.45).
CONCLUSION
Dydrogesterone combined with non-steroidal anti-inflammatory drugs is a safe and effective treatment for patients with endometriosis. It can improve various obvious curative effects, such as marked relief of pain symptoms, reduction of complement and inflammatory factor levels without a significant increase in adverse reactions.
PubMed: 37680832
DOI: 10.12669/pjms.39.5.7138 -
Current Drug Research Reviews Aug 2023Dysmenorrhea is the most common periodic pain, which affects more than 50% of women with regular menstruation. Fenugreek is one of the medicinal plants with analgesic...
INTRODUCTION
Dysmenorrhea is the most common periodic pain, which affects more than 50% of women with regular menstruation. Fenugreek is one of the medicinal plants with analgesic properties. This study aimed to determine the effect of fenugreek application in the severity of dysmenorrhea and its side effects in women with dysmenorrhea. PICO: population: women with dysmenorrhea; intervention: fenugreek; comparison: control groups; and outcome: reduction in the severity of dysmenorrhea and its side effects Methodology: English database (PubMed, Cochrane Library, Scopus, and Web of Science) and Persian database [SID (Scientific Information Database) and Magiran] were used for research until February 11, 2023, using the keywords "Dysmenorrhea [Mesh]," "Foenum [Mesh]," "fenugreek [Mesh]," and "Trigonella [Mesh]." The reference list of the selected articles was also checked. The quality assessment was conducted through the Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0. The RevMan 5.3 software was used to analyze and report the data of the entered studies. Meta-analysis results were reported with the standardized mean difference (95% confidence interval). A subgroup analysis was performed based on the type of control groups. The quality of evidence was assessed using the GRADE approach.
RESULTS
After removing duplicates and ineligible cases, four articles were included in the systematic review out of the 1526 records obtained. The results showed that the pain intensity caused by primary dysmenorrhea decreased with fenugreek compared to placebo (pooled result SMD: -2.21; 95% CI: -3.26 to -1.17; Z: 4.17; P <0.001). There was no significant difference between fenugreek with mefenamic acid (SMD: 0.05; 95% CI: -0.57 to 0.67; Z: 0.17; P = 0.86) and fenugreek with Chandrasura churna (SMD: 0.06; 95% CI: -0.56 to 0.68; Z: 0.19; P = 0.85). Bias, in terms of incomplete outcome data and selective reporting, was low risk in all studies, and the available evidence was low quality according to the GRADE approach.
CONCLUSION
The results showed that the effect of fenugreek on pain intensity in dysmenorrhea is highly uncertain. The true effect is likely to be substantially different from the estimate of effect. Regarding the importance of the health and quality of life of women of reproductive age and the low quality of evidence of the studies, clinical trials with stronger methodology are suggested in this field.
PubMed: 37594100
DOI: 10.2174/2589977515666230818092814 -
Journal of Integrative Neuroscience Jul 2023Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA)...
BACKGROUND
Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity.
METHODS
The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted.
RESULTS
Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities.
CONCLUSIONS
The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.
Topics: Mice; Animals; Flumazenil; Mefenamic Acid; Receptors, GABA-A; Catalepsy; Central Nervous System; Seizures; gamma-Aminobutyric Acid; Behavior, Animal
PubMed: 37519168
DOI: 10.31083/j.jin2204104 -
Chemico-biological Interactions Sep 2023Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this...
Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide.
Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this characteristic potently attenuate the catalytic function of CYP4A11, drug-drug interactions may occur. Acidic non-steroidal anti-inflammatory drugs (NSAIDs) possess a carboxylic acid in their structure. However, it remains unclear whether these drugs inhibit CYP4A11 activity. The present study examined the inhibitory effects of acidic NSAIDs on CYP4A11 activity using human liver microsomes (HLMs) and recombinant CYP4A11. Sulindac sulfide, ibuprofen, and flurbiprofen effectively decreased the luciferin-4A O-demethylase activity of HLMs and recombinant CYP4A11 (inhibition rates of 30-96% at an inhibitor concentration of 100 μM), while salicylic acid, aspirin, diclofenac, mefenamic acid, indomethacin, etodolac, ketoprofen, loxoprofen, S-naproxen, pranoprofen, zaltoprofen, and oxaprozin exhibited weaker inhibitory activity (inhibition rates up to 23%). Among the drugs tested, sulindac sulfide was the most potent inhibitor of CYP4A11 activity. A kinetic analysis of the inhibition of CYP4A11 by sulindac sulfide revealed mixed-type inhibition for HLMs (K = 3.38 μM) and recombinant CYP4A11 (K = 4.19 μM). Sulindac sulfide is a pharmacologically active metabolite of sulindac (sulfoxide form), which is also oxidized to sulindac sulfone. To elucidate the role of a sulfur atom of sulindac sulfide in the inhibition of CYP4A11, the inhibitory effects of sulindac sulfide and its oxidized forms on CYP4A11 activity were examined. The potency of inhibition against HLMs was greater in the order of sulindac sulfide, sulindac, and sulindac sulfone; IC values were 6.16, 52.7, and 71.6 μM, respectively. The present results indicate that sulindac sulfide is a potent inhibitor of CYP4A11. These results and the molecular modeling of CYP4A11 with sulindac sulfide and its oxidized forms suggest that a sulfur atom of sulindac sulfide as well as its carboxylic acid play important roles in the inhibition of CYP4A11.
Topics: Humans; Sulindac; Carboxylic Acids; Kinetics; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37499995
DOI: 10.1016/j.cbi.2023.110644 -
Journal of Public Health in Africa Mar 2023The 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...
BACKGROUND
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.
OBJECTIVE
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.
RESULTS
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.
CONCLUSION
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 , specifically 4-Nitro-5-Obenzoylpinostrobin.
PubMed: 37492536
DOI: 10.4081/jphia.2023.2532 -
International Medical Case Reports... 2023Pain management becomes important in the treatment of oral mucosal diseases since it can impair the quality of life. Photobiomodulation (PBM) as an alternative therapy,...
INTRODUCTION
Pain management becomes important in the treatment of oral mucosal diseases since it can impair the quality of life. Photobiomodulation (PBM) as an alternative therapy, has potency in reducing pain through several mechanisms targeting peripheral nerves in the target tissue.
PURPOSE
To discuss the effectiveness of PBM in the management of four cases of oral mucosal diseases.
CASE
Four patients, two females and two males, with an age ranging from 24 to 63 years came to the Oral Medicine Department complaining of painful lesions in their oral cavity. Three cases showed ulceration of the oral mucosa and had been diagnosed with recurrent aphthous stomatitis, recalcitrant chronic ulcer, and non-specific chronic sialadenitis. One patient who complained of intense pain and swelling on the right side of the face was diagnosed with post-herpetic neuralgia (PHN).
CASE MANAGEMENT
PBM was administered in all four cases (976 nm diode laser, three cases with spot size 0.01 cm, fluency 10 J/cm, and one case with spot size 0.5 cm; fluency 3 J/cm). Visual analog scale (VAS) control was performed before and after the PBM at each visit. The recorded VAS results show a reduction in pain that started at the post-laser time, with VAS before PBM ranging from 5 to 7 and after PBM ranging from 0 to 4. Three patients were given triamcinolone acetonide 0.1%, chlorhexidine gluconate 0.2% mouthwash, petroleum jelly, and multivitamins. One patient was given mefenamic acid and multivitamins.
CONCLUSION
PBM can be a useful adjunctive treatment to relieve the pain of oral mucosal diseases due to its ability to reduce pain intensity.
PubMed: 37465549
DOI: 10.2147/IMCRJ.S414313 -
Journal of Ethnopharmacology Jan 2024Although the root of Cannabis sativa L. has been mentioned in some regions, such as the Vale do São Francisco, for its potential traditional medicinal use as an...
ETHNOPHARMACOLOGICAL RELEVANCE
Although the root of Cannabis sativa L. has been mentioned in some regions, such as the Vale do São Francisco, for its potential traditional medicinal use as an anti-inflammatory, anti-asthmatic, and against gastrointestinal diseases, it has received little exploration and discussion.
AIM OF THE STUDY
This study aimed to perform a chemical analysis of an aqueous extract of Cannabis sativa roots (AqECsR) and evaluate its pharmacological effects against uterine disorders, in vivo and ex vivo, in rodents.
MATERIALS AND METHODS
The roots were provided by the Brazilian Federal Police, and the freeze-dried extract was used for the chemical analysis of the AqECsR by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The sample was subsequently used in three doses for pharmacological assays (12.5, 25, and 50 mg/kg), which included the spasmolytic activity test and the primary dysmenorrhea test. The primary dysmenorrhea test aimed to verify the effect of AqECsR on induced abdominal contortions in female mice in vivo and to perform a morphometric analysis of the organs. Association tests at subtherapeutic doses of AqECsR with antidysmenorrheic drugs were also performed.
RESULTS
The data obtained by HPLC-MS suggested the presence of four substances: cannabisativine, anhydrocannabisativine, feruloyltyramine, and p-coumaroyltyramine. In the pharmacological assays, the AqECsR showed no spasmolytic effect. However, in the antidysmenorrheal activity test, AqECsR demonstrated a significant in vivo effect of reducing oxytocin-induced abdominal contortions. Morphometric analysis of the uterus showed no significant organ enlargement effect, and the association of AqECsR with subtherapeutic doses of three drugs used in antidysmenorrheal therapy (mefenamic acid, scopolamine, and nifedipine) showed an effect in reducing abdominal contortions.
CONCLUSIONS
In conclusion, AqECsR contains four chemical compounds and exhibits an antidysmenorrheic effect both alone and in association with drugs, reducing abdominal contortions in female mice without generating organ enlargement in the animals. Further studies are needed to prove the mechanism of action by which AqECsR promotes its effect on primary dysmenorrhea and to explore its associations.
Topics: Humans; Female; Mice; Animals; Cannabis; Dysmenorrhea; Brazil; Gas Chromatography-Mass Spectrometry; Uterus; Plant Extracts
PubMed: 37423518
DOI: 10.1016/j.jep.2023.116891 -
Membranes Jun 2023The present work analyzes the H NOESY MAS NMR spectra of three fenamates (mefenamic, tolfenamic, and flufenamic acids) localized in the lipid-water interface of...
The present work analyzes the H NOESY MAS NMR spectra of three fenamates (mefenamic, tolfenamic, and flufenamic acids) localized in the lipid-water interface of phosphatidyloleoylphosphatidylcholine (POPC) membranes. The observed cross-peaks in the two-dimensional NMR spectra characterized intramolecular proximities between the hydrogen atoms of the fenamates as well as intermolecular interactions between the fenamates and POPC molecules. The peak amplitude normalization for an improved cross-relaxation (PANIC) approach, the isolated spin-pair approximation (ISPA) model, and the two-position exchange model were used to calculate the interproton distances indicative of specific conformations of the fenamates. The results showed that the proportions of the A+C and B+D conformer groups of mefenamic and tolfenamic acids in the presence of POPC were comparable within the experimental error and amounted to 47.8%/52.2% and 47.7%/52.3%, respectively. In contrast, these proportions for the flufenamic acid conformers differed and amounted to 56.6%/43.4%. This allowed us to conclude that when they bind to the POPC model lipid membrane, fenamate molecules change their conformational equilibria.
PubMed: 37367811
DOI: 10.3390/membranes13060607