Mefenamic acid exhibits antitumor activity against osteosarcoma by impeding cell growth and prompting apoptosis in human osteosarcoma cells and xenograft mice model.

The study investigates the anticancer activity of mefenamic acid against osteosarcoma, shedding light on its underlying mechanisms and therapeutic potential. Mefenamic acid exhibited robust inhibitory effects on the proliferation of MG-63, HOS, and H2OS osteosarcoma cells in a dose-dependent manner. Moreover, mefenamic acid induced cellular toxicity in MG63 cells, as evidenced by LDH leakage, reflecting its cytotoxic impact. Furthermore, mefenamic acid effectively suppressed the migration and invasion of MG-63 cells. Mechanistically, mefenamic acid induced apoptosis in MG-63 cells through mitochondrial depolarization, activation of caspase-dependent pathways, and modulation of the Bcl-2/Bax axis. Additionally, mefenamic acid promoted autophagy and inhibited the PI3K/Akt/mTOR pathway, further contributing to its antitumor effects. The molecular docking studies provide compelling evidence that mefenamic acid interacts specifically and strongly with key proteins in the PI3K/AKT/mTOR pathway, suggesting a novel mechanism by which mefenamic acid could exert anti-osteosarcoma effects. In vivo studies using a xenograft mouse model demonstrated significant inhibition of MG-63 tumor growth without adverse effects, supporting the translational potential of mefenamic acid as a safe and effective therapeutic agent against osteosarcoma. Immunohistochemistry staining corroborated the in vivo findings, highlighting mefenamic acid's ability to suppress tumor proliferation and inhibit the PI3K/AKT/mTOR pathway within the tumor microenvironment. Collectively, these results underscore the promising therapeutic implications of mefenamic acid in combating osteosarcoma, warranting further investigation for clinical translation and development.

κ-Carrageenan/sericin polymer matrix modified with different crosslinking agents and thermal crosslinking: Improved release profile of mefenamic acid.

The crosslinking of the polymer matrix with compatible macromolecules results in a three-dimensional network structure that offers an enhancement in the controlled release properties of the material. In this sense, this work aimed to improve the release profile of mefenamic acid (MAC) through crosslinking strategies. κ-Carrageenan/sericin crosslinked blend was obtained by covalent and thermal crosslinking and the different formulations were characterized. The gastroresistant potential and release profile were evaluated in the dissolution assay. The effect and characterization of the particles were investigated. Multiple units presented high entrapment efficiency (94.11-104.25), high drug loading (36.50-47.50 %) and adequate particle size (1.34-1.57 mm) with rough surface and visually spherical shape. The Weibull model showed that drug release occurred by relaxation, erosion and Fickian diffusion. Material stability and absence of MAC -polymer interactions were demonstrated by FTIR and thermogravimetric analysis. DSC showed a stable character of MAC in the drug-loaded beads. Moreover, the application studies of κ-Car/Ser/carboxymethylcellulose in the in vitro intestine mode showed that the crosslinked blend increased cell viability (>85 %), while free MAC exhibited a cytotoxic effect. Finally, the crosslinked k-Car/Ser blend MAC -loaded showed promising properties of a sustained release form of anti-inflammatory drug.

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.

Applied physiologically-based pharmacokinetic modeling to assess uridine diphosphate-glucuronosyltransferase-mediated drug-drug interactions for Vericiguat.

Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate-glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug-drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically-based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration-time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7-fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non-wild-type variants for both isoforms. This study is a first cornerstone to qualify the PK-Sim platform for use of UGT-mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.

Neocuproine-Based Sensitive Flow Injection Method for Mefenamic Acid Determination in Aqueous Solutions and Pharmaceutical Formulations

Introducción: Se presenta un enfoque novedoso y preciso para la estimación del ácido mefenámico (MEF) en for-mulaciones farmacéuticas y soluciones acuosas, utilizando espectrofotometría de inyección de flujo. Del mismo modo, este método demuestra un alto nivel de sensibilidad y precisiónMétodo: Se basa en la reducción del complejo Cu (II)-2,9DMP a complejo Cu (I)-2,9DMP coloreado, mediante dos pasos de reacción. Sin embargo, en el primer paso se produce la reacción entre la neocuproína y el Cu (ΙΙ) para for-mar un complejo incoloro de Cu (II) -2,9DMP, y en el segundo paso el ácido mefenámico redujo el complejo incoloro formado a Cu (I) - 2,9DMP con color amarillo anaranjado, se desarrolló y validó el método de inyección de flujo.Resultados: La medición de la densidad óptica de las sustancias amarillo-naranja se realizó a una longitud de onda de 454 nm. Los gráficos de calibración muestran linealidad dentro de los rangos de concentración especificados de 1,00-80,00 μg / ml. El límite de detección (LOD) se determina en 0,360 μg/ml, mientras que el límite de cuantifi-cación (LOQ) se encuentra en 1.093 μg/ml.Conclusiones: la metodología propuesta exhibió atributos notables como rapidez, sensibilidad y confiabilidad, lo que la hace adecuada para la cuantificación precisa de (MEF) en formulaciones farmacéuticas y soluciones acuosas en diversas formulaciones disponibles comercialmente. (AU)

Introduction: A novel and precise approach is presented for the mefenamic acid (MEF) estimation in pharmaceuti-cal formulations and aqueous solutions, utilizing flow injection spectrophotometry. Similarly, this method demon-strates a high level of sensitivity and accuracy.Method: The suggested method is based on the reducing of Cu(II)-2,9DMP complex to coloured Cu(I)- 2,9DMP com-plex ,by two step of reaction. However, in the first step the reaction is occur between neocuproine and Cu(ΙΙ) to form colorless complex of Cu(II)-2,9DMP, then in second step mefenamic acid reduced the formed colorless complex to Cu(I)- 2,9DMP with yellow orange colour, Flow Injection Method were developed and validated.Results: The measurement of the optical density of the yellow-orange substances was conducted at a wavelength of 454 nm. The calibration graphs exhibit linearity within the specified concentration ranges of 1.00-80.00 μg/mL. The detection limit (LOD) is determined to be 0.360 μg/ mL, while the limit of quantification (LOQ) is found to be 1.093 μg/ mL.Conclusions: the proposed methodology exhibited notable attributes such as rapidity, sensitivity, and reliability, rendering it suitable for the accurate quantification of (MEF) in pharmaceutical formulations and aqueous solutions in various commercially available formulations. (AU)

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.

Niosomal formulation of mefenamic acid for enhanced cancer targeting; preparation, characterization and biodistribution study using radiolabeling technique.

BACKGROUND: This work aimed to prepare niosomal formulations of an anticancer agent [mefenamic acid (MEF)] to enhance its cancer targeting. 131I was utilized as a radiolabeling isotope to study the radio-kinetics of MEF niosomes. METHODS: niosomal formulations were prepared by the ether injection method and assessed for entrapment efficiency (EE%), zeta potential (ZP), polydispersity index (PDI) and particle size (PS). MEF was labeled with 131I by direct electrophilic substitution reaction through optimization of radiolabeling-related parameters. In the radio-kinetic study, the optimal 131I-MEF niosomal formula was administered intravenously (I.V.) to solid tumor-bearing mice and compared to I.V. 131I-MEF solution as a control. RESULTS: the average PS and ZP values of the optimal formulation were 247.23 ± 2.32 nm and - 28.3 ± 1.21, respectively. The highest 131I-MEF labeling yield was 98.7 ± 0.8%. The biodistribution study revealed that the highest tumor uptake of 131I-MEF niosomal formula and 131I-MEF solution at 60 min post-injection were 2.73 and 1.94% ID/g, respectively. CONCLUSION: MEF-loaded niosomes could be a hopeful candidate in cancer treatment due to their potent tumor uptake. Such high targeting was attributed to passive targeting of the nanosized niosomes and confirmed by radiokinetic evaluation.

Layered double hydroxide nanocarriers: potential delivery systems for mefenamic acid.

Tweetable abstract Layered double hydroxide nanocarriers are capable of intercalating hydrophobic NSAIDs, such as mefenamic acid, which improves their pharmacokinetics and bioavailability.

Biomass-Derived Core-Shell Carbon Dots with Embedded Tripodal Receptors for the Selective Recognition of Mefenamic Acid in Pharmaceutical Formulations and Urine.

A tripodal amine (TPA) with -OH, N, and S donors is synthesized to functionalize a core-shell carbon dot composite (FCDs@SiO2-TPA) for sensing application. The TPA is characterized by spectroscopic and spectrometric techniques, and the composite is characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy-dispersive X-ray spectra (EDS) techniques. The composite has the ability to recognize mefenamic acid (MFA) selectively even in the presence of other drugs like ibuprofen sodium, acetylsalicylic acid, naproxen sodium, diclofenac sodium, and ketoprofen. It can also be used for the quantification of MFA by recording the emission quenching response of the sample at λexc. = 350 nm and λems. = 460 nm (linear range = 1-8 µM and LOD = 197 nM). The density functional theory calculations and 1H NMR titration suggest quenching of the emission signal due to photoinduced electron transfer via hydrogen bonding between the probe and MFA. The composite FCDs@SiO2-TPA has been demonstrated as a reliable and cost-effective sensing probe for the detection of MFA in pharmaceutical formulations, water samples, and cow urine samples.

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.

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.

New fluorescent probe for sensing of mefenamic acid in aqueous medium: An integrated experimental and theoretical analysis.

Abnormal levels of mefenamic acid (MFA) in living organisms can result in hepatic necrosis, liver, and gastrointestinal diseases. Therefore, development of accurate and effective method for detection of MFA is of great significance for the protection of public health. Herein, we designed a stilbene based sensor ECO for the sensitive and selective detection of mefenamic acid by employing fluorescence spectroscopy for the first time. The developed sensor ECO displayed fluorescence turn-off response towards MFA based on PET (photoinduced electron transfer) and hydrogen bonding. The sensing mechanism of MFA was investigated through 1H NMR titration experiment and density functional theory (DFT) calculations. The presence of non-covalent interaction was confirmed through spectroscopic analysis and was further supported by non-covalent interaction (NCI) analysis and Bader's quantum theory of atoms in molecules (QTAIM) analysis. Additionally, the sensor ECO coated test strips were fabricated for on-site detection of mefenamic acid. Furthermore, the practical applicability of sensor ECO to detect MFA was also explored in human blood and artificial urine samples.

Genipin and glutaraldehyde based laccase two-layers immobilization with improved properties: New biocatalysts with high potential for enzymatic removal of trace organic contaminants.

This research proposes the preparation of a two-layer laccase biocatalyst using genipin or/and glutaraldehyde as cross-linking agents. The multilayer biocatalysts were prepared using different combinations of genipin and glutaraldehyde in the individual preparation of the first and second laccase layers. First, chitosan was treated with genipin or glutaraldehyde, followed by the immobilization of the first laccase layer to form a single-layer biocatalyst. Then, the immobilized laccases were coated once again with genipin or glutaraldehyde, and a new laccase layer was immobilized onto the system, resulting in the final two-layer biocatalyst. Compared to the single-layer biocatalysts, catalytic activity increased 1.7- and 3.4-fold when glutaraldehyde coating was used to prepare the second laccase layer. However, adding a second layer did not always produce more active biocatalysts, since the two-layer biocatalysts prepared with genipin (GenLacGenLac and GluLacGenLac) presented a decrease in activity of 65% and 28%, respectively. However, these two-layer biocatalysts prepared with genipin maintained 100% of their initial activity after 5 cycles of ABTS oxidation. Nevertheless, the two-layer, genipin-coated biocatalyst resulted in a higher removal of trace organic contaminants, since it removed 100% of mefenamic acid and 66% of acetaminophen, compared with the glutaraldehyde-coated biocatalyst, which removed 20% of mefenamic acid, and 18% of acetaminophen.

Use of non-steroidal anti-inflammatory drugs in renal transplant patients: A retrospective study.

BACKGROUND: Renal transplants are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for analgesic purposes. OBJECTIVE: Considering the dearth of data, we carried out the present study to evaluate the use of various NSAIDs and the incidence of acute kidney injury (AKI) in transplant patients. METHODS: A retrospective study amongst renal transplant patients prescribed at least one dose of NSAID was carried between January and December 2020 at the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. The patients' demographic details, serum creatinine values, and drug-related details were obtained. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used for defining AKI. RESULTS: Eighty-seven patients were included. Forty-three patients were prescribed diclofenac, 60 received ibuprofen, six received indomethacin, 10 were administered mefenamic acid, and 11 received naproxen. Due to multiple courses of NSAID prescription, a total of 70 prescriptions were identified for diclofenac, 80 for ibuprofen, six for indomethacin, 11 for mefenamic acid, and 16 for naproxen. No significant differences were observed in the absolute (p = 0.08) and percent changes in serum creatinine (p = 0.1) between the NSAIDs. Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. Age (OR: 1.1, 95% CI: 1.007, 1.2; p = 0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p = 0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p = 0.005) administration were observed with significant risk of NSAID-induced AKI. CONCLUSION: We observed possible NSAID-induced AKI to an extent of around 15.2% in our renal transplant patients. No significant differences were observed in the incidence of AKI between various NSAIDs and none of them had either graft failure or death.

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.

Multi-spectroscopic assay methods for concurrent determination of recent anti-gout combination, a comparative study.

Recently, Chemometric calibration methods in spectrophotometric analysis are achieving significant attention in the quality control of resolving drug mixtures and pharmaceutical formulations containing two or more drugs with overlapping spectra. The simple univariate methods have been used over the last few decades and has proven to be highly efficient and easy to apply. In this study, a comparative study was performed between some univariate and multivariate methods to determine if chemometric methods can substitute univariate methods in pharmaceutical analysis. In this study, three chemometric techniques were compared to seven univariate techniques to resolve a mixture of mefenamic acid and febuxostat in their raw materials, dosage forms and spiked human plasma. Mefenamic acid and febuxostat were used together for treatment of gout. The applied chemometric methods are partial least squares (PLS), artificial neural network (ANN) and genetic algorithm partial least squares (GA-PLS), while the used univariate methods include first derivative, second derivative, ratio spectra, derivative ratio spectra, ratio subtraction, Q-Absorbance ratio and mean centering spectrophotometric methods. The ten proposed methods were found to be green, sensitive, and rapid. They are simple and did not require any pre-separation steps. The results of both univariate and multivariate approaches were statistically compared with the reported spectrophotometric methods using student's t test and ratio variance F-test. They were also compared with each other, using one-way analysis of variance (ANOVA). These methods were assessed and validated according to ICH guidelines. The studied drugs were analyzed in their pharmaceutical dosage forms and spiked human plasma with good recoveries using the developed methods, which qualify them for routine quality control of the studied drugs.

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 .

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.

Anticancer Activity of 3,5-Bis(dodecyloxy)Benzoate-PAMAM Conjugates with Indomethacin or Mefenamic Acid.

BACKGROUND: The synthesis of conjugates with nonsteroidal anti-inflammatory drugs could improve their activity with less toxicity and these compounds could be used for the treatment of cancer. OBJECTIVE: The aim of the present investigation was the synthesis of 3,5-bis(dodecyloxy)benzoate - PAMAM conjugates with indomethacin and mefenamic acid to examine their anticancer activity. METHODS: The anticancer activity was studied of the conjugates against six human cancer cells U- 251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and the COS-7 (as a control) cell lines. The conjugates with indomethacin and mefenamic acid were characterized by 1H, 13C NMR one- and twodimension spectroscopy. RESULTS: All the conjugates synthetized with indomethacin or mefenamic acid showed anticancer activity against all the human cancer cell lines. The first generation of indomethacin conjugates showed better activity against the PC-3 (human prostatic adenocarcinoma) cell line than the second generation. But the second generation with indomethacin showed better activity against PC-3 than the first generation. The second-generation conjugate with mefenamic acid had strong selectivity to PC-3 cells with an IC50 value of 10.23 ± 1.2 µM in vitro. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new indomethacin or mefenamic acid conjugates. The overall results showed that the conjugate of the second generation with mefenamic acid could be a potential nanocarrier for human prostatic adenocarcinoma cancer treatment, our research will be continued.

Enhanced photocatalytic activity of hydrozincite-TiO2 nanocomposite by copper for removal of pharmaceutical pollutant mefenamic acid in aqueous solution.

Nanocomposites based on hydrozincite-TiO2 and copper-doped HZ-xCu-TiO2 (x = 0.1; 0.25; 0.35) were synthesized in a single step using the urea method. The samples were characterized by XRD, FTIR, SEM/TEM, and DRS. The study of adsorption capacity and photocatalytic efficiency of these nanocomposites have been tested on a pharmaceutical pollutant, mefenamic acid (MFA). Kinetic study of removal of MFA indicates that this pollutant was adsorbed on the surface of the synthesized phases, according to Langmuir's model. Such adsorption proved to be well adapted in a kinetic pseudo-second-order model with capacity of 13.08 mg/g for HZ-0.25Cu-TiO2. Subsequently, the kinetics of photocatalytic degradation under UV-visible irradiation was studied according to several parameters, which allowed us to optimize our experimental conditions. The nanocomposite HZ-0.25Cu-TiO2 showed significant removal efficiency of MFA. Elimination rate reached 100% after 20 min under UV-vis irradiation, and 77% after 7 h under visible light irradiation. Repeatability tests have shown that this nanocomposite is extremely stable after six photocatalytic cycles. By-products of MFA were detected by LC/MS. These photoproducts was produced by three types of reactions of hydroxylation: cyclization and cleavage of the aromatic ring. MFA underwent complete mineralization after 22 h of irradiation in the presence of the HZ-0.25Cu-TiO2.