-
Cells Mar 2021Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative... (Review)
Review
Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer's disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Fenamates; Humans; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Neuroprotective Agents
PubMed: 33809987
DOI: 10.3390/cells10030702 -
Data in Brief Apr 2021Here we describe the dataset of the first report of pharmacogenomics profiling in an outpatient spine setting with the primary aims to catalog: 1) the genes, alleles,...
Here we describe the dataset of the first report of pharmacogenomics profiling in an outpatient spine setting with the primary aims to catalog: 1) the genes, alleles, and associated rs Numbers (accession numbers for specific single-nucleotide polymorphisms) analysed and 2) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications. The present description applies to analgesic medication-metabolizing enzymes and may be especially valuable to investigators who are exploring strategies to optimize pharmacologic pain management (e.g., by tailoring analgesic regimens to the genetically identified sensitivities of the patient). Buccal swabs were used to acquire tissue samples of 30 adult patients who presented to an outpatient spine clinic with the chief concern of axial neck and/or back pain. Array-based assays were then used to detect the alleles of genes involved in the metabolism of pain medications, including all common (wild type) and most rare variant alleles with known clinical significance. Both CYP450 isozymes - including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 - and the phase II enzyme UDP-glucuronosyltransferase-2B7 (UGT2B7) were examined. Genotypes/phenotypes were then used to evaluate each patient's relative ability to metabolize 37 commonly used analgesic medications. These medications included both non-opioid analgesics (i.e., aspirin, diclofenac, nabumetone, indomethacin, meloxicam, piroxicam, tenoxicam, lornoxicam, celecoxib, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, naproxen, and mefenamic acid) and opioid analgesics (i.e., morphine, codeine, dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, alfentanil, fentanyl, sufentanil, meperidine, ketobemidone, dextropropoxyphene, levacetylmethadol, loperamide, methadone, buprenorphine, dextromethorphan, tramadol, tapentadol, and tilidine). The genes, alleles, and associated rs Numbers that were analysed are provided. Also provided are: 1) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications and 2) the mechanisms of metabolism of the analgesic medications by primary and ancillary pathways. In supplemental spreadsheets, the raw and analysed pharmacogenomics data for all 30 patients evaluated in the primary research article are additionally provided. Collectively, the presented data offer significant reuse potential in future investigations of pharmacogenomics for pain management.
PubMed: 33644270
DOI: 10.1016/j.dib.2021.106832 -
ACS Pharmacology & Translational Science Feb 2021Both cerium oxide (CeOx) nanoparticles and mefenamic acid (MFA) are known anti-inflammatory agents with hepatoprotective properties and are therefore prescribed for one...
Both cerium oxide (CeOx) nanoparticles and mefenamic acid (MFA) are known anti-inflammatory agents with hepatoprotective properties and are therefore prescribed for one of the major diseases in the world, nonalcoholic fatty liver disease (NAFLD). To study the potential cytotoxicity and anti-inflammatory effects as well as drug retention of a potential therapeutic CeOx/MFA supramolecular complex, a well-standardized hepatic (HepG2) spheroid model was used. Results showed that the highest cytotoxicity for the CeOx/MFA supramolecular complex was found at 50 μg/mL, while effective doses of 0.1 and 1 μg/mL yielded a significant decrease of TNF-α and IL-8 secretion. Time-resolved analysis of HepG2 spheroids revealed a spatiotemporal distribution of the supramolecular complex and limited clearance from the internal microtissue over a period of 8 days in cultivation. In summary, our results point at rapid uptake, distribution, and biostability of the supramolecular complex within the HepG2 liver spheroid model as well as a significant anti-inflammatory response at noncytotoxic levels.
PubMed: 33615164
DOI: 10.1021/acsptsci.0c00170 -
Journal of Enzyme Inhibition and... Dec 2021The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with β-cyclodextrin (β-CD). First, the...
The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with β-cyclodextrin (β-CD). First, the phase solubility diagram of MA in β-CD was drawn from 0 to 21 × 10 M of β-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:β-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:β-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 β-CD complexes was illustrated through a mathematical treatment. Finally, two experiments confirmed the interest to use a (2:1) MA:β-CD complex.
Topics: Animals; Cattle; Erythrocytes; Humans; Mefenamic Acid; Models, Molecular; Molecular Structure; Protein Denaturation; Serum Albumin, Bovine; Solubility; beta-Cyclodextrins
PubMed: 33557644
DOI: 10.1080/14756366.2020.1869225 -
CPT: Pharmacometrics & Systems... Feb 2021This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized... (Clinical Trial)
Clinical Trial
This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.
Topics: Administration, Oral; Adolescent; Antibiotics, Antitubercular; Area Under Curve; Benzhydryl Compounds; Child; Child, Preschool; Computer Simulation; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; Glucosides; Glucuronosyltransferase; Healthy Volunteers; Hepatic Insufficiency; Humans; Infant; Infant, Newborn; Male; Mefenamic Acid; Models, Biological; Predictive Value of Tests; Renal Insufficiency; Rifampin; Sodium-Glucose Transporter 2 Inhibitors; UDP-Glucuronosyltransferase 1A9
PubMed: 33439535
DOI: 10.1002/psp4.12577 -
Asian Pacific Journal of Cancer... Dec 2020To investigate the effectiveness of pre-procedural oral mefenamic acid compared with placebo in women undergoing Loop Electrosurgical Excision Procedure (LEEP) with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the effectiveness of pre-procedural oral mefenamic acid compared with placebo in women undergoing Loop Electrosurgical Excision Procedure (LEEP) with intracervical lidocaine injection.
STUDY DESIGNS
A prospective double-blinded randomized control trial. Materials, Setting, Methods: Women undergoing LEEP for any indications were asked to participate in the study. The participants were randomly allocated into two groups. In group 1 (oral mefenamic acid), the participants were offered oral mefenamic acid (500 mg) for 30 minutes before procedures. In group 2 (placebo), the patients were given oral placebo (identical tablet) for 30 minutes before operation. All participants received immediate 10 mL of 2% lidocaine with 1:100,000 of epinephrine intracervical injection before undergoing the LEEP. All participants were excised in one piece of LEEP. No top-hat excision in this study. The patients graded their pain on a 10-cm visual analog scale (VAS) at different points during the procedure, including speculum insertion, at starting excision, and 30 minutes post excision. Primary outcomes revealed the difference of VAS during all steps of LEEP by generalized estimating equations procedure.
RESULTS
Sixty participants (30 in mefenamic group and 30 in placebo group) participated in this study. The study did not find differences of VAS during all steps of LEEP and analgesic drug requirement at 30 minutes after LEEP procedure. All patients reported no immediate complications and no intervention-related adverse events were observed.
CONCLUSION
Using pre-procedural oral mefenamic acid before LEEP procedure was not associated with pain reduction during all steps of excision.
.Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cancer Pain; Double-Blind Method; Electrosurgery; Female; Follow-Up Studies; Humans; Mefenamic Acid; Middle Aged; Prognosis; Prospective Studies; Uterine Cervical Neoplasms
PubMed: 33369462
DOI: 10.31557/APJCP.2020.21.12.3633 -
CPT: Pharmacometrics & Systems... Feb 2021The sodium-glucose cotransporter 2 inhibitor ertugliflozin is metabolized by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes UGT1A9 and UGT2B4/2B7. This... (Clinical Trial)
Clinical Trial
Physiologically-Based Pharmacokinetic Modeling of the Drug-Drug Interaction of the UGT Substrate Ertugliflozin Following Co-Administration with the UGT Inhibitor Mefenamic Acid.
The sodium-glucose cotransporter 2 inhibitor ertugliflozin is metabolized by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes UGT1A9 and UGT2B4/2B7. This analysis evaluated the drug-drug interaction (DDI) following co-administration of ertugliflozin with the UGT inhibitor mefenamic acid (MFA) using physiologically-based pharmacokinetic (PBPK) modeling. The ertugliflozin modeling assumptions and parameters were verified using clinical data from single-dose and multiple-dose studies of ertugliflozin in healthy volunteers, and the PBPK fraction metabolized assignments were consistent with human absorption, distribution, metabolism, and excretion results. The model for MFA was developed using clinical data, and in vivo UGT inhibitory constant values were estimated using the results from a clinical DDI study with MFA and dapagliflozin, a UGT1A9 and UGT2B4/2B7 substrate in the same chemical class as ertugliflozin. Using the verified compound files, PBPK modeling predicted an ertugliflozin ratio of area under the plasma concentration-time curves (AUC ) of 1.51 when co-administered with MFA. ClinicalTrials.gov identifier: NCT00989079.
Topics: Adult; Area Under Curve; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Drug Interactions; Female; Glucuronosyltransferase; Healthy Volunteers; Humans; Male; Mefenamic Acid; Middle Aged; Models, Biological; Sodium-Glucose Transporter 2 Inhibitors; UDP-Glucuronosyltransferase 1A9; Uridine
PubMed: 33314761
DOI: 10.1002/psp4.12581 -
Electrophoresis Feb 2021The (tentative) identification of unknown drug-related phase II metabolites in plants upon drug uptake remains a challenging task despite improved analytical instrument...
A fast-screening approach for the tentative identification of drug-related metabolites from three non-steroidal anti-inflammatory drugs in hydroponically grown edible plants by HPLC-drift-tube-ion-mobility quadrupole time-of-flight mass spectrometry.
The (tentative) identification of unknown drug-related phase II metabolites in plants upon drug uptake remains a challenging task despite improved analytical instrument performance. To broaden the knowledge of possible drug metabolization, a fast-screening approach for the tentative identification of drug-related phase II metabolites is presented in this work. Therefore, an in silico database for the three non-steroidal anti-inflammatory drugs (ketoprofen, mefenamic acid, and naproxen) and a sub-group of their theoretical phase II metabolites (based on combinations with glucose, glucuronic acid, and malonic acid) was created. Next, the theoretical exact masses (protonated species and ammonia adducts) were calculated and used as precursor ions in an autoMS/MS measurement method. The applicability of this workflow was tested on the example of eleven edible plants, which were hydroponically grown in solutions containing the respective drug at a concentration level of 20 mg/L. For the three drugs investigated this led to the tentative identification of 41 metabolites (some of them so far not described in this context), such as combinations of hydroxylated mefenamic acid with up to four glucose units or hydroxylated mefenamic acid with two glucose and three malonic acid units.
Topics: Agricultural Irrigation; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Hydroponics; Mass Spectrometry; Plants, Edible; Water Pollutants, Chemical
PubMed: 33274757
DOI: 10.1002/elps.202000292 -
AACE Clinical Case Reports 2020Subacute thyroiditis (SAT) is an inflammatory disorder of the thyroid gland that causes destructive thyrotoxicosis and is attributed to a viral or post-viral response....
OBJECTIVE
Subacute thyroiditis (SAT) is an inflammatory disorder of the thyroid gland that causes destructive thyrotoxicosis and is attributed to a viral or post-viral response. SARS-CoV-2 is a novel coronavirus that caused a global pandemic in 2020. We present a case that suggests that there may be a relationship between SAT and corona-virus disease 2019 (COVID-19).
METHODS
We describe the clinical findings, thyroid function tests, and neck ultrasound of a patient presenting with anterior neck pain.
RESULTS
A 47-year-old, Filipino female presented with anterior neck pain associated with neck tenderness and goiter. She did not have fever or respiratory symptoms but had right lower lobe pneumonia on chest radiograph. Thyroid function tests were consistent with subclinical hyperthyroidism with thyroid-stimulating hormone of 0.05 μIU/mL (reference range is 0.47 to 4.68 μIU/mL), free thyroxine of 1.68 pg/mL (reference range is 0.78 to 2.19 pg/mL), and total triiodothyronine of 1.4 ng/mL (reference range is 0.97 to 1.69 ng/mL). Anti-thyroid peroxidase, anti-thyroglobulin, and thyroid-stimulating hormone receptor antibodies were negative. Neck ultrasound showed heterogenous thyroid tissues with normal vascularity. Reverse transcription-polymerase chain reaction for SARS-CoV-2 using nasopharyngeal and oropharyngeal swabs were positive. The patient was diagnosed as having SAT and was treated with mefenamic acid, which was later switched to celecoxib. Ceftriaxone and hydroxychloroquine were started for COVID-19 pneumonia. Complete resolution of symptoms and primary hypothyroidism occurred after 2 months.
CONCLUSION
SAT may be a presenting symptom or a sequela of COVID-19. Histopathology studies and definitive documentation of the virus in thyroid tissues may be required to confirm the relationship between SAT and COVID-19.
PubMed: 33244504
DOI: 10.4158/ACCR-2020-0524 -
Frontiers in Chemistry 2020Cereals are staple foods for human consumption in both developed and developing countries. In order to improve agricultural outputs, resources like reclaimed water for...
Cereals are staple foods for human consumption in both developed and developing countries. In order to improve agricultural outputs, resources like reclaimed water for irrigation and biosolids and manure as fertilizers are frequently used, although they may increase the input of contaminants that can potentially be absorbed by crops and enter the food chain. Emerging contaminants (human and veterinary pharmaceuticals, personal care products, surfactants, plasticizers, and industrial additives, among others) are continuously introduced in the environment from a variety sources and these contaminants may enter the food chain through plant uptake. In this study, an analytical method, based on ultrasound-assisted extraction and dispersive solid-phase cleanup, was developed for the determination of emerging contaminants from different classes in four highly consumed cereal grains (wheat, oat, barley, and rice). These analytes were selected considering the results of our previous studies carried out in soil and vegetables and those frequently detected in real samples were chosen. The target compounds selected were bisphenol A (BPA), bisphenol F (BPF), methyl paraben, propyl paraben, linear chain nonylphenol in position 4 (4-n-NP), mixture of ring and chain isomers of NP and six pharmaceutical compounds (allopurinol, mefenamic acid, carbamazepine, paracetamol, diclofenac and ibuprofen). Recoveries ranging from 68 to 119% with relative standard deviations (RSD) <18% were obtained for all the compounds except for allopurinol, with recoveries that ranged from 30 to 66% with RSD ≤ 12% and the limits of detection achieved ranged from 0.03 to 4.9 ng/g. The method was applied to the analysis of 16 cereal samples, ten were purchased in local supermarkets and the rest were collected directly from agricultural fields, five of which were fertilized with organic amendments. Bisphenol A (BPA) was detected in all samples at levels that ranged from 1.6 to 1,742 ng/g. Bisphenol F, a substitute for BPA, was also found in six samples (up to 22 ng/g). Linear 4-n-NP was found in a reduced number of samples but the mixture of NP isomers was found in all the samples, being the mean concentrations in wheat, barley, oat and rice 49, 90, 142, and 184 ng/g, respectively.
PubMed: 33195058
DOI: 10.3389/fchem.2020.571668