Effects of Strong Inhibition of Cytochrome P450 3A and UDP glucuronosyltransferase 1A9 and Strong Induction of Cytochrome P450 3A on the Pharmacokinetics, Safety, and Tolerability of Soticlestat: Two Drug-Drug Interaction Studies in Healthy Volunteers.

Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1-11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1-7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1-13 and soticlestat 300 mg on day 11 (rifampin study). Twenty-eight healthy adults participated in the itraconazole/mefenamic acid study (14 per part) and 15 participated in the rifampin study (mean age, 38.1-40.7 years; male, 79-93%). For maximum observed concentration, the geometric mean ratios (GMRs) of soticlestat + itraconazole, mefenamic acid, or rifampin to soticlestat alone were 116.6%, 107.3%, and 13.2%, respectively, for soticlestat; 10.7%, 118.0%, and 266.1%, respectively, for M-I, and 104.6%, 88.2%, and 66.6%, respectively, for M3. For area under the curve from time 0 to infinity, the corresponding GMRs were 124.0%, 100.6%, and 16.4% for soticlestat; 13.3%, 117.0%, and 180.8% for M-I; and 120.3%, 92.6%, and 58.4% for M3. Soticlestat can be administered with strong CYP3A and UGT1A9 inhibitors, but not strong CYP3A inducers (except for antiseizure medications, which will be further evaluated in ongoing phase 3 studies). In both studies, all treatment-emergent adverse events were mild or moderate. SIGNIFICANCE STATEMENT: These drug-drug interaction studies improve our understanding of the potential changes that may arise in soticlestat exposure in patients being treated with CYP3A inhibitors, UGT1A9 inhibitors, or CYP3A inducers. The results build on findings from previously published soticlestat studies and provide important information to help guide clinical practice. Soticlestat has shown positive phase 2 results and is currently in phase 3 development for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Silver(I) Complexes with Mefenamic Acid and Nitrogen Heterocyclic Ligands: Synthesis, Characterization, and Biological Evaluation.

Four Ag(I) complexes with mefenamato and nitrogen heterocyclic ligands, [Ag(2-apy)(mef)]2 (1), [Ag(3-apy)(mef)] (2), [Ag2(tmpyz)(mef)2] (3), and {[Ag(4,4'-bipy)(mef)]2(CH3CN)1.5(H2O)2}n (4), (mef = mefenamato, 2-apy = 2-aminopyridine, 3-apy = 3-aminopyridine, tmpyz = 2,3,5,6-tetramethylpyrazine, 4,4'-bipy = 4,4'-bipyridine), were synthesized and characterized. The interactions of these complexes with BSA were investigated by fluorescence spectroscopy, which indicated that these complexes quench the fluorescence of BSA by a static mechanism. The fluorescence data also indicated that the complexes showed good affinity for BSA, and one binding site on BSA was suitable for the complexes. The in vitro cytotoxicity of the four complexes against human cancer cell lines (MCF-7, HepG-2, A549, and MDA-MB-468) and one normal cell line (HTR-8) was evaluated by the MTT assay. Complex 1 displayed high cytotoxic activity against A549 cells. Further studies revealed that complex 1 could enhance the intracellular levels of ROS (reactive oxygen species) in A549 cells, cause cell cycle arrest in the G0/G1 phase, and induce apoptosis in A549 cells in a dose-dependent manner.

Development of an eco-friendly fluorescent probe for mefenamic acid sensing in pharmaceuticals and biofluids.

Mefenamic acid, renowned for its analgesic properties, stands as a reliable choice for alleviating mild to moderate pain. However, its versatility extends beyond pain relief, with ongoing research unveiling its promising therapeutic potential across diverse domains. A straightforward, environmentally friendly, and sensitive spectrofluorometric technique has been developed for the precise quantification of the analgesic medication, mefenamic acid. This method relies on the immediate reduction of fluorescence emitted by a probe upon interaction with varying concentrations of the drug. The fluorescent probe utilized, N-phenyl-1-naphthylamine (NPNA), was synthesized in a single step, and the fluorescence intensities were measured at 480 nm using synchronous fluorescence spectroscopy with a wavelength difference of 200 nm. Temperature variations and lifetime studies indicated that the quenching process was static. The calibration curve exhibited linearity within the concentration range of 0.50-9.00 µg/mL, with a detection limit of 60.00 ng/mL. Various experimental parameters affecting the quenching process were meticulously examined and optimized. The proposed technique was successfully applied to determine mefenamic acid in pharmaceutical formulations, plasma, and urine, yielding excellent recoveries ranging from 98% to 100.5%. The greenness of the developed method was evaluated using three metrics: the Analytical Eco-scale, AGREE, and the Green Analytical Procedure Index.

Mefenamic Acid Loaded and TPGS Stabilized Mucoadhesive Nanoemulsion for the Treatment of Alzheimer's Disease: Development, Optimization, and Brain-Targeted Delivery via Olfactory Pathway.

Alzheimer's disease (AD) is a very common disorder that affects the elderly. There are relatively few medications that can be used orally or as a suspension to treat AD. A mucoadhesive (o/w) nano emulsion of mefenamic acid was made by adding Carbopol 940P to the optimised drug nanoemulsion using distilled water as the aqueous phase (6%); Solutol HS: tween 20 (3.6%) as the surfactant and co-surfactant; and clove oil: TPGS (0.4%) as the oil phase and mefenamic acid as the drug (2.8 mg/ml). The mucoadhesive nanoemulsion (S40.5%w/v) had a particle size of 91.20 nm, polydispersity index of 0.270, and surface charge of - 12.4 mV. Significantly higher (p < 0.001) drug release (89.37%) was observed for mucoadhesive drug formulation in comparison to mucoadhesive drug suspension (25.64%) at 8 h. The ex vivo nasal permeation of 83.03% in simulated nasal fluid and 85.71% in artificial cerebrospinal fluid was observed. The percent inhibition and inhibitory concentration (IC50) of mucoadhesive drug nanoemulsion were found to be 91.57 ± 2.69 and 6.76 respectively. Higher cell viability on glioblastoma cells (85-80%) was researched for mucoadhesive nanoemulsion as compared to drug suspension (80-70%). Significantly higher (p < 0.001) drug absorption and Cmax (491.94 ± 24.13 ng/ml) of mucoadhesive drug nanoemulsion were observed than mucoadhesive drug suspension (107.46 ± 11.46 ng/ml) at 8 h. The stability studies confirmed that the formulation was stable at 40°C ± 2°C and 75 ± 5% RH. The authors concluded that the mucoadhesive mefenamic acid-loaded nanoemulsion may be an effective technique for treating Alzheimer's disease by intranasal route.

Drug-drug interaction of ciprofol injectable emulsion with mefenamic acid capsules in healthy subjects.

AIMS: To investigate the drug-drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. METHODS: Twenty healthy subjects were enrolled in this single-centre, open-label, two-period DDI study. Ciprofol (0.4 mg kg-1 ) was administered as a single dose on days 1 and 5. A 500-mg oral loading dose of mefenamic acid was given on day 4 followed by a 250-mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). RESULTS: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ), area under the plasma concentration-time curve calculated from 0 to the last measurement point (AUC0-last ) and AUC to infinity (AUC0-inf ) were 91.6% (86.5-96.9%), 103.3% (100.3-106.4%) and 107.0% (101.2-113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. CONCLUSIONS: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid.

Cross-reactivity between nonsteroidal anti-inflammatory drugs in fixed drug eruption: Two unusual cases and a literature review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.

The effect of vitamin D on the severity of dysmenorrhea and menstrual blood loss: a randomized clinical trial.

BACKGROUND: Primary dysmenorrhea is considered as one of the women's main problems during reproductive age. The present study aimed to investigate the effect of vitamin D on the severity of dysmenorrhea and menstrual blood loss. METHODS: This double-blind, randomized, placebo-controlled trial, was performed on 84 single female college students between 18 and 25 years old who living in dormitories. Students with primary dysmenorrhea and vitamin D deficiency were divided into experimental (n = 42) and control (n = 42) groups. Five days before the putative beginning of their next menstrual cycle, the experimental group received 300,000 IU vitamin D (50,000 IU, two tablets every 8 h), and the control group received a placebo (oral paraffin). The effects of the supplement on the severity of dysmenorrhea and menstrual blood loss were evaluated one cycle before and during two successive cycles. Using the visual analog scale (VAS), verbal multidimensional scoring system (VMS), and pictorial blood assessment chart (PBLAC) questionnaires. Fisher's exact, Chi-square, independent sample t-test and repeated measurements were used. RESULTS: In total, 78 of the 84 students completed the study (39 students per group). The intervention resulted in a significant reduction in the mean scores of both the VAS and VMS in the experimental group, in the first and second menstrual cycles (p < 0.001, p < 0.001, respectively), but not in the means score of PBLAC. Mefenamic acid consumption at the first and second menstruation period, in the experimental group was lower than the control group (p = 0.009, p < 0.001, respectively). CONCLUSIONS: The results indicate that vitamin D supplementation could decrease the severity of primary dysmenorrhea and the need to consume pain-relief medications. Contrariwise vitamin D supplementation had no significant effect on menstrual blood loss. TRIAL REGISTRATION: This trial was registered in the Iranian Registry of Clinical Trials with code IRCT201305212324N on 18/1/2014. URL of registry: https://en.irct.ir/trial/1964 .

Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

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.

Exploring the Conformational Equilibrium of Mefenamic Acid Released from Silica Aerogels via NMR Analysis.

This study examines the influence of mefenamic acid on the physical and chemical properties of silica aerogels, as well as its effect on the sorption characteristics of the composite material. Solid state magic angle spinning nuclear magnetic resonance (MAS NMR) and high-pressure 13C NMR kinetic studies were conducted to identify the presence of mefenamic acid and measure the kinetic rates of CO2 sorption. Additionally, a high-pressure T1-T2 relaxation-relaxation correlation spectroscopy (RRCOSY) study was conducted to estimate the relative amount of mefenamic acid in the aerogel's pores, and a high-pressure nuclear Overhauser effect spectoscopy (NOESY) study was conducted to investigate the conformational preference of mefenamic acid released from the aerogel. The results indicate that mefenamic acid is affected by the chemical environment of the aerogel, altering the ratio of mefenamic acid conformers from 75% to 25% in its absence to 22% to 78% in the presence of aerogel.

Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis.

The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for the reduction of inflammatory parameters and mitochondrial damage in animals submitted to polymicrobial sepsis. To test our hypothesis, adult male Wistar rats were submitted to the cecal ligation and perforation (CLP) model for sepsis induction and after receiving an injection of MFA (doses of 10, 30, and 50 mg/kg) or sterile saline (1 mL/kg). At 24 h after sepsis induction, the frontal cortex and hippocampus were dissected to analyze the levels of TNF-α, IL-1ß, and IL-18; oxidative damage (thiobarbituric acid reactive substances (TBARS), carbonyl, and DCF-DA (oxidative parameters); protein expression (mitochondrial transcription factor A (TFAM), NLRP-3, 8-oxoG; Bax, Bcl-2 and (ionized calcium-binding adaptor molecule 1 (IBA-1)); and the activity of mitochondrial respiratory chain complexes. It was observed that the septic group in both structures studied showed an increase in proinflammatory cytokines mediated by increased activity in NLRP-3, with more significant oxidative damage and higher production of reactive oxygen species (ROS) by mitochondria. Damage to mtDNA it was also observed with an increase in 8-oxoG levels and lower levels of TFAM and NGF-1. In addition, this group had an increase in pro-apoptotic proteins and IBA-1 positive cells. However, MFA at doses of 30 and 50 mg/kg decreased inflammasome activity, reduced levels of cytokines and oxidative damage, increased bioenergetic efficacy and reduced production of ROS and 8-oxoG, and increased levels of TFAM, NGF-1, Bcl-2, reducing microglial activation. As a result, it is suggested that MFA induces protection in the central nervous system early after the onset of sepsis.

Sericin-Based Bio-Inspired Nano-Engineering of Heterometallic AgAu Nanocubes for Attomolar Mefenamic Acid Sensing in the Mobile Phone-Based Surface Plasmon-Coupled Interface.

Engineering photo-plasmonic platforms with heterometallic nanohybrids are of paramount significance for realizing augmented sensitivity in fluorescence-based analytical detection. Although myriad nanomaterials with versatile functionalities have been explored in this regard in the surface plasmon-coupled emission (SPCE) interface, light harvesting using nano-antennas synthesized via sustainable bio-inspired routes still remains a high priority in current research. Our study provides a rational design for in situ fabrication of nanoparticles of silver, gold, and their plasmonic hybrids using biocompatible, non-hazardous sericin protein (obtained Bombyx mori) as the reducing and capping agent. The one-pot, user-eco-friendly technology demonstrated here utilizes UV irradiation to promote the photo-induced electron transfer mechanism, thereby yielding nanomaterials of tunable optoelectronic functionalities. The resulting homometallic and heterometallic nanohybrids with robust localized surface plasmon resonances (LSPR) showed strong light-confining attributes when interfaced with the propagating surface plasmon polaritons (SPPs) of the SPCE platform, thereby yielding tunable, highly directional, polarized, and amplified fluorescence emission. The experimentally obtained emission profiles displayed an excellent correlation with the theoretically obtained dispersion diagrams validating the spectro-plasmonic results. The abundant hotspots from AgAu nanocubes presented in excess of 1300-fold dequenched fluorescence enhancement and were utilized for cost-effective and real-time mobile phone-based sensing of biologically relevant mefenamic acid at an attomolar limit of detection. We believe that this superior biosensing performance accomplished using the frugal bioinspired nano-engineering at hybrid interfaces would open new doors for developing nanofabrication protocols with the quintessential awareness of the principles of green nanotechnology, consequently eliminating hazardous chemicals and solvents in the development of point-of-care diagnostic tools.

Prediction of Mefenamic Acid Crystal Shape by Random Forest Classification.

OBJECTIVE: Particle shape can have a significant impact on the bulk properties of materials. This study describes the development and application of machine-learning models to predict the crystal shape of mefenamic acid recrystallized from organic solvents. METHODS: Crystals were grown in 30 different solvents to establish a dataset comprising solvent molecular descriptors, process conditions and crystal shape. Random forest classification models were trained on this data and assessed for prediction accuracy. RESULTS: The highest prediction accuracy of crystal shape was 93.5% assessed by fourfold cross-validation. When solvents were sequentially excluded from the training data, 32 out of 84 models predicted the shape of mefenamic acid crystals for the excluded solvent with 100% accuracy and a further 21 models had prediction accuracies from 50-100%. Reducing the feature set to only solvent physical property descriptors and supersaturations resulted in higher overall prediction accuracies than the models trained using all available or another selected subset of molecular descriptors. For the 8 solvents on which the models performed poorly (< 50% accuracy), further characterisation of crystals grown in these solvents resulted in the discovery of a new mefenamic acid solvate whereas all other crystals were the previously known form I. CONCLUSIONS: Random forest classification models using solvent physical property descriptors can reliably predict crystal morphologies for mefenamic acid crystals grown in 20 out of the 28 solvents included in this work. Poor prediction accuracies for the remaining 8 solvents indicate that further factors will be required in the feature set to provide a more generalized predictive morphology model.

Effect of Channel Assembly (KCNQ1 or KCNQ1 + KCNE1) on the Response of Zebrafish IKs Current to IKs Inhibitors and Activators.

ABSTRACT: In cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization, IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1 + KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1 ± 5.8 and 13.4 ± 2.8 µM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs channels with IC50 = 0.1 ± 0.1 µM and 1.5 ± 0.8 µM for KCNQ1 and KCNQ1 + KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited the current generated by KCNQ1 and KCNQ1 + KCNE1 channels with similar potency (IC50 1.1 ± 0.4 and 1.0 ± 0.4 µM, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50 = 9.5 ± 4.8 µM) and completely blocked KCNQ1 + KCNE1 channels (IC50 = 3.3 ± 1.8 µM). Although zebrafish IKs channels respond to IKs inhibitors in the same way as mammalian IKs channels, their response to activators is atypical, probably because of the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.

Interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine-device use.

BACKGROUND: Heavy menstrual bleeding and pain are common reasons women discontinue intrauterine device (IUD) use. Copper IUD (Cu IUD) users tend to experience increased menstrual bleeding, whereas levonorgestrel IUD (LNG IUD) users tend to have irregular menstruation. Medical therapies used to reduce heavy menstrual bleeding or pain associated with Cu and LNG IUD use include non-steroidal anti-inflammatory drugs (NSAIDs), anti-fibrinolytics and paracetamol. We analysed treatment and prevention interventions separately because the expected outcomes for treatment and prevention interventions differ. We did not combine different drug classes in the analysis as they have different mechanisms of action. This is an update of a review originally on NSAIDs. The review scope has been widened to include all interventions for treatment or prevention of heavy menstrual bleeding or pain associated with IUD use. OBJECTIVES: To evaluate all randomized controlled trials (RCTs) that have assessed strategies for treatment and prevention of heavy menstrual bleeding or pain associated with IUD use, for example, pharmacotherapy and alternative therapies. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL to January 2021. SELECTION CRITERIA: We included RCTs in any language that tested strategies for treatment or prevention of heavy menstrual bleeding or pain associated with IUD (Cu IUD, LNG IUD or other IUD) use. The comparison could be no intervention, placebo or another active intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, and extracted data. Primary outcomes were volume of menstrual blood loss, duration of menstruation and painful menstruation. We used a random-effects model in all meta-analyses. Review authors assessed the certainty of evidence using GRADE. MAIN RESULTS: This review includes 21 trials involving 3689 participants from middle- and high-income countries. Women were 18 to 45 years old and either already using an IUD or had just had one placed for contraception. The included trials examined NSAIDs and other interventions. Eleven were treatment trials, of these seven were on users of the Cu IUD, one on LNG IUD and three on an unknown type. Ten were prevention trials, six focused on Cu IUD users, and four on LNG IUD users. Sixteen trials had high risk of detection bias due to subjective assessment of pain and bleeding. Treatment of heavy menstrual bleeding Cu IUD Vitamin B1 resulted in fewer pads used per day (mean difference (MD) -7.00, 95% confidence interval (CI) -8.50 to -5.50) and fewer bleeding days (MD -2.00, 95% CI -2.38 to -1.62; 1 trial; 110 women; low-certainty evidence) compared to placebo. The evidence is very uncertain about the effect of naproxen on the volume of menstruation compared to placebo (odds ratio (OR) 0.09, 95% CI 0.00 to 1.78; 1 trial, 40 women; very low-certainty evidence). Treatment with mefenamic acid resulted in less volume of blood loss compared to tranexamic acid (MD -64.26, 95% CI -105.65 to -22.87; 1 trial, 94 women; low-certainty evidence). However, there was no difference in duration of bleeding with treatment of mefenamic acid or tranexamic acid (MD 0.08 days, 95% CI -0.27 to 0.42, 2 trials, 152 women; low-certainty evidence). LNG IUD The use of ulipristal acetate in LNG IUD may not reduce the number of bleeding days in 90 days in comparison to placebo (MD -9.30 days, 95% CI -26.76 to 8.16; 1 trial, 24 women; low-certainty evidence). Unknown IUD type Mefenamic acid may not reduce volume of bleeding compared to Vitex agnus measured by pictorial blood assessment chart (MD -2.40, 95% CI -13.77 to 8.97; 1 trial; 84 women; low-certainty evidence). Treatment of pain Cu IUD Treatment with tranexamic acid and sodium diclofenac may result in little or no difference in the occurrence of pain (OR 1.00, 95% CI 0.06 to 17.25; 1 trial, 38 women; very low-certainty evidence). Unknown IUD type Naproxen may reduce pain (MD 4.10, 95% CI 0.91 to 7.29; 1 trial, 33 women; low-certainty evidence). Prevention of heavy menstrual bleeding Cu IUD We found very low-certainty evidence that tolfenamic acid may prevent heavy bleeding compared to placebo (OR 0.54, 95% CI 0.34 to 0.85; 1 trial, 310 women). There was no difference between ibuprofen and placebo in blood volume reduction (MD -14.11, 95% CI -36.04 to 7.82) and duration of bleeding (MD -0.2 days, 95% CI -1.40 to 1.0; 1 trial, 28 women, low-certainty evidence). Aspirin may not prevent heavy bleeding in comparison to paracetamol (MD -0.30, 95% CI -26.16 to 25.56; 1 trial, 20 women; very low-certainty evidence). LNG IUD Ulipristal acetate may increase the percentage of bleeding days compared to placebo (MD 9.50, 95% CI 1.48 to 17.52; 1 trial, 118 women; low-certainty evidence). There were insufficient data for analysis in a single trial comparing mifepristone and vitamin B. There were insufficient data for analysis in the single trial comparing tranexamic acid and mefenamic acid and in another trial comparing naproxen with estradiol. Prevention of pain Cu IUD There was low-certainty evidence that tolfenamic acid may not be effective to prevent painful menstruation compared to placebo (OR 0.71, 95% CI 0.44 to 1.14; 1 trial, 310 women). Ibuprofen may not reduce menstrual cramps compared to placebo (OR 1.00, 95% CI 0.11 to 8.95; 1 trial, 20 women, low-certainty evidence). AUTHORS' CONCLUSIONS: Findings from this review should be interpreted with caution due to low- and very low-certainty evidence. Included trials were limited; the majority of the evidence was derived from single trials with few participants. Further research requires larger trials and improved trial reporting. The use of vitamin B1 and mefenamic acid to treat heavy menstruation and tolfenamic acid to prevent heavy menstruation associated with Cu IUD should be investigated. More trials are needed to generate evidence for the treatment and prevention of heavy and painful menstruation associated with LNG IUD.

A composite adsorbent of graphene quantum dots, mesoporous carbon, and molecularly imprinted polymer to extract nonsteroidal anti-inflammatory drugs in milk.

A composite magnetic adsorbent was developed by embedding graphene quantum dots (GQDs), silica-modified magnetite (Fe3O4-SiO2), and mesoporous carbon (MPC) into a molecularly imprinted polymer (GQDs/Fe3O4-SiO2/MPC/MIP). The adsorbent was applied to extract nonsteroidal anti-inflammatory drugs (NSAIDs) in milk. The MIP was formed via a sol-gel copolymerization using flurbiprofen, diflunisal, and mefenamic acid as template molecules, 3-aminopropyltriethoxysilane as a monomer, and tetraethyl orthosilicate as a cross-linker. GQDs and MPC enhanced affinity binding between NSAIDs and the adsorbent through π-π stacking, hydrogen bonding, and hydrophobic interaction. The Fe3O4-SiO2 nanoparticles embedded in the composite adsorbent enabled its rapid isolation from the sample solution. The extracted NSAIDs were quantified by high-performance liquid chromatography and exhibited good linearity from 1.0 to 100.0 µg L-1 for flurbiprofen and 0.5 to 100.0 µg L-1 for diflunisal and mefenamic acid, respectively. The limits of detection ranged from 0.5 to 1.0 µg L-1. Recoveries of NSAIDs from spiked milk samples ranged from 81.4 to 93.7%, with RSDs below 7%. The reproducibility of the fabricated adsorbent was good and in the optimal conditions, the developed adsorbent could be used for up to six extraction-desorption cycles.

Inflammasome, Inflammation, Infection and Mefenamic Acid.

Nucleotide-binding oligomerization domain like receptors (NLRs) -intracellular proteins, are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases. Mefenamic acid which belongs to fenamate group inhibits the NLRP3 inflammasome by inhibiting efflux of chloride ions and influx of calcium ions through blocking VRAC and TRPM2 respectively. Thus, Mefenamic acid provides a potentially practical pharmacological approach for treating NLRP3- driven diseases.

Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition.

BACKGROUND/AIM: Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse. METHODS: Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples. RESULTS: Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles. CONCLUSION: Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.

Characterization of human sulfotransferases catalyzing the formation of p-cresol sulfate and identification of mefenamic acid as a potent metabolism inhibitor and potential therapeutic agent for detoxification.

p-Cresol sulfate, the primary metabolite of p-cresol, is a uremic toxin that has been associated with toxicities and mortalities. The study objectives were to i) characterize the contributions of human sulfotransferases (SULT) catalyzing p-cresol sulfate formation using multiple recombinant SULT enzymes (including the polymorphic variant SULT1A1*2), pooled human liver cytosols, and pooled human kidney cytosols; and ii) determine the potencies and mechanisms of therapeutic inhibitors capable of attenuating the production of p-cresol sulfate. Human recombinant SULT1A1 was the primary enzyme responsible for the formation of p-cresol sulfate (Km = 0.19 ±â€¯0.02 µM [with atypical kinetic behavior at lower substrate concentrations; see text discussion], Vmax = 789.5 ±â€¯101.7 nmol/mg/min, Ksi = 2458.0 ±â€¯332.8 µM, mean ±â€¯standard deviation, n = 3), while SULT1A3, SULT1B1, SULT1E1, and SULT2A1 contributed negligible or minor roles at toxic p-cresol concentrations. Moreover, human recombinant SULT1A1*2 exhibited reduced enzyme activities (Km = 81.5 ±â€¯31.4 µM, Vmax = 230.6 ±â€¯17.7 nmol/mg/min, Ksi = 986.0 ±â€¯434.4 µM) compared to the wild type. The sulfonation of p-cresol was characterized by Michaelis-Menten kinetics in liver cytosols (Km = 14.8 ±â€¯3.4 µM, Vmax = 1.5 ±â€¯0.2 nmol/mg/min) and substrate inhibition in kidney cytosols (Km = 0.29 ±â€¯0.02 µM, Vmax = 0.19 ±â€¯0.05 nmol/mg/min, Ksi = 911.7 ±â€¯278.4 µM). Of the 14 investigated therapeutic inhibitors, mefenamic acid (Ki = 2.4 ±â€¯0.1 nM [liver], Ki = 1.2 ±â€¯0.3 nM [kidney]) was the most potent in reducing the formation of p-cresol sulfate, exhibiting noncompetitive inhibition in human liver cytosols and recombinant SULT1A1, and mixed inhibition in human kidney cytosols. Our novel findings indicated that SULT1A1 contributed an important role in p-cresol sulfonation (hence it can be considered a probe reaction) in liver and kidneys, and mefenamic acid may be utilized as a potential therapeutic agent to attenuate the generation of p-cresol sulfate as an approach to detoxification.

Solidified floating organic drop microextraction (SFODME) for the simultaneous analysis of three non-steroidal anti-inflammatory drugs in aqueous samples by HPLC.

In this work, a liquid-liquid microextraction methodology using solidified floating organic drop (SFODME) was combined with liquid chromatography and UV/Vis detection to determine non-steroidal anti-inflammatory drugs (NSAIDs) naproxen (NPX), diclofenac (DCF), and mefenamic acid (MFN) in tap water, surface water, and seawater samples. Parameters that can influence the efficiency of the process were evaluated, such as the type and volume of the extractor and dispersive solvents, effect of pH, agitation type, and ionic strength. The optimized method showed low detection limits (0.09 to 0.25 µg L-1), satisfactory recovery rates (90 to 116%), and enrichment factors in the range between 149 and 199. SFODME showed simplicity, low cost, speed, and high concentration capacity of the analytes under study. Its use in real samples did not demonstrate a matrix effect that would compromise the effectiveness of the method, being possible to apply it successfully in water samples with different characteristics.

Solubility enhancement of mefenamic acid by inclusion complex with ß-cyclodextrin: in silico modelling, formulation, characterisation, and in vitro studies.

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with ß-cyclodextrin (ß-CD). First, the phase solubility diagram of MA in ß-CD was drawn from 0 to 21 × 10-3 M of ß-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:ß-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:ß-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the ß-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:ß-CD complex.