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Free Radical Biology & Medicine Jun 2024Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of...
Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of ferroptosis could be of potential use in treating diseases: such as drug induced liver injury (DILI). Ferroptosis can be antagonized by the xCT/GSH/GPX4, FSP1/CoQ, DHODH/CoQ, GCH1/BH, and NRF2 pathways. Identifying novel anti-ferroptosis pathways will further promote our understanding of the biological nature of ferroptosis and help discover new drugs targeting ferroptosis related human diseases. In this study, we identified the clinically used drug mifepristone (RU486) as a novel ferroptosis inhibitor. Mechanistically, RU486 inhibits ferroptosis by inducing GSH synthesis pathway, which supplies GSH for glutathione-S-transferase (GST) mediated 4-HNE detoxification. Furthermore, RU486 induced RLIP76 and MRP1 export 4-HNE conjugate contributes to its anti-ferroptosis activity. Interestingly, RU486 induced GSH/GSTs/RLIP76&MRP1 anti-ferroptosis pathway acts independent of classic anti-ferroptosis systems: including xCT/GSH/GPX4, FSP1, DHODH, GCH1, SCD1 and FTH1. Moreover, NRF2 was identified to be important for RU486's anti-ferroptosis activity by inducing downstream gene expression. Importantly, in mouse model, RU486 showed strong protection effect on acetaminophen (APAP)-induced acute liver injury, evidenced by decreased ALT, AST level and histological recovery after APAP treatment. Interestingly, RU486 also decreased oxidative markers, including 4-HNE and MDA, and induced NRF2 activation as well as GSTs, MRP1 expression. Together, these data suggest NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway as an important independent anti-ferroptosis pathway act both in vitro and in vivo.
PubMed: 38906233
DOI: 10.1016/j.freeradbiomed.2024.06.014 -
The American Journal of Emergency... Jun 2024Low back pain is a common reason for presentation to the Emergency Department (ED). However, there are limited large-scale, recent data on the epidemiology, disposition,...
INTRODUCTION
Low back pain is a common reason for presentation to the Emergency Department (ED). However, there are limited large-scale, recent data on the epidemiology, disposition, and medication administration for this condition. The objective of this was to assess the incidence, admission rates, medication administrations, and discharge prescriptions among ED visits for low back pain in the United States.
METHODS
This was a cross-sectional study of ED presentations for low back pain from 1/1/2016 to 12/31/2023 using the Epic Cosmos database. All ED visits for adults with low back pain identified by ICD-10 codes were included. Outcomes included admission rates, distribution of opioid, benzodiazepine, (non-benzodiazepine) muscle relaxant, acetaminophen, NSAID, and corticosteroid medications administered in the ED, and distribution of opioid, benzodiazepine, muscle relaxant, and corticosteroid medications given upon discharge. Subgroup analyses were performed by specific medication.
RESULTS
Of 207,154,419 ED encounters, 12,241,240 (5.9%) were due to back pain with 1,957,299 of these (16.0%) admitted. The admission rate increased over time from 12.8% to 17.1%. The most common medication given in the ED was opioids (40.7%), followed by acetaminophen (37.8%), NSAIDs (22.6%), muscle relaxants (18.4%) benzodiazepines (12.8%), and corticosteroids (5.5%). The most common medications prescribed upon discharge were muscle relaxants (32.1%), followed by opioids (23.2%), corticosteroids (12.2%), and benzodiazepines (3.0%).
CONCLUSION
Low back pain represents a common reason for presentation to the ED, and admissions have been increasing over time. Opioids remain the most common ED medication, whereas muscle relaxants have arisen as the most common discharge prescription. These findings can help inform health policy decisions, resource allocation, and evidence-based interventions for medication administration.
PubMed: 38905718
DOI: 10.1016/j.ajem.2024.06.020 -
American Family Physician Jun 2024
Topics: Humans; Pregnancy; Female; Acetaminophen; Acne Vulgaris; Diabetes, Gestational; Infant, Newborn; Electronic Nicotine Delivery Systems; Syphilis, Congenital; Drug Overdose; Adult
PubMed: 38905545
DOI: No ID Found -
Scientific Reports Jun 2024Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated...
Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject's age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood-brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.
Topics: Animals; Acetaminophen; Cognitive Dysfunction; Mice; Astrocytes; Microglia; Male; Brain; Mice, Inbred C57BL; Blood-Brain Barrier; Aging; Disease Models, Animal; Spatial Memory
PubMed: 38902507
DOI: 10.1038/s41598-024-65185-z -
International Journal of Pharmaceutics Jun 2024The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of...
The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of APIs. Three APIs, very-cohesive micronized acetaminophen (mAPAP, 7 μm), cohesive acetaminophen (cAPAP, 23 μm), and easy-flowing ibuprofen (IBU, 53 μm), were selected. High DL (60 wt%) binary blends were prepared with different fine-milled MCC-based excipients (ranging 20- 37 μm) with or without A200 silica coating during milling. The blend flowability (flow function coefficient -FFC) and bulk density (BD) of the blends for all three APIs were significantly improved by 1 wt% A200 dry coated MCCs; reaching FFC of 4.28 from 2.14, 7.82 from 2.96, and > 10 from 5.57, for mAPAP, cAPAP, and IBU blends, respectively, compared to the uncoated MCC blends. No negative impact was observed on the tablet tensile strength (TS) by using dry coated MCCs despite lower surface energy of silica. Instead, the desired tablet TS levels were reached or exceeded, even above that for the blends with uncoated milled MCCs. The novelty here is that milled and silica coated fine MCCs could promote DC tableting for cAPAP and IBU blends at 60 wt% DL through adequate flowability and tensile strength, without having to dry coat the APIs. The effect of the silica amount was investigated, indicating lesser had a positive impact on TS, whereas the higher amount had a positive impact on flowability. Thus, the finer excipient size and silica amounts may be adjusted to potentially attain blend DC processability for high DL blends of fine APIs.
PubMed: 38901539
DOI: 10.1016/j.ijpharm.2024.124359 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2024Choline chloride (ChCl) based binary and ternary deep eutectic solvents (DES) were evaluated for methylene green electropolymerization with oxalic acid (OA) and ethylene...
Choline chloride (ChCl) based binary and ternary deep eutectic solvents (DES) were evaluated for methylene green electropolymerization with oxalic acid (OA) and ethylene glycol (EG) as hydrogen bond donors. Binary DES ChCl:OA in molar ratios 1:1 and 2:1 and ChCl:EG 1:2 and ternary DES (tDES) in different molar ratios and percentages of water were evaluated. The highest polymer growth was in ChCl:OA:EG-tDES with added water, that had a lower viscosity and higher ionic conductivity when associated with HCl as dopant. This enhanced the formation of more cation radicals and, consequently, more polymer formation. The PMG/MWCNT/GCE-tDES sensor was successfully applied to the simultaneous determination of 5-aminosalicylic acid (5-ASA) and acetaminophen (APAP) by differential pulse voltammetry in the concentration range 2 µM - 200 µM, with detection limits of 0.37 µM and 0.49 µM for 5-ASA and APAP, respectively. The sensor demonstrated good repeatability, reproducibility and stability, and was successfully applied in pharmaceutical formulations.
PubMed: 38900538
DOI: 10.1002/chem.202401752 -
Cureus May 2024With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been...
With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.
PubMed: 38899269
DOI: 10.7759/cureus.60649 -
Mikrochimica Acta Jun 2024The introduced work represents an implementation of the automatic benchtop electrochemical station (BES) as an effective tool for the possibilities of high-throughput...
The introduced work represents an implementation of the automatic benchtop electrochemical station (BES) as an effective tool for the possibilities of high-throughput preparation of modified sensor/biosensors, speeding up the development of the analytical method, and automation of the analytical procedure for the determination of paracetamol (PAR) and dopamine (DOP) as target analytes. Within the preparation of gold nanoparticles modified screen-printed carbon electrode (AuNPs-SPCE) by electrodeposition, the deposition potential E, the deposition time t, and the concentration of HAuCl were optimized and their influence was monitored on 1 mM [Ru(NH)] redox probe and 50 μM DOP. The morphology of the AuNPs-SPCE prepared at various modification conditions was observed by SEM. The analytical performance of the AuNPs-SPCE prepared at different modification conditions was evaluated by a construction of the calibration curves of DOP and PAR. SPCE and AuNPs-SPCE at modification condition providing the best sensitivity to PAR and DOP, were successfully used to determine PAR and DOP in tap water by "spike-recovery" approach. The BES yields better reproducibility of the preparation of AuNPs-SPCE (RSD = 3.0%) in comparison with the case when AuNPs-SPCE was prepared manually by highly skilled laboratory operator (RSD = 7.0%).
Topics: Acetaminophen; Dopamine; Gold; Metal Nanoparticles; Electrochemical Techniques; Electrodes; Biosensing Techniques; Limit of Detection; Carbon
PubMed: 38898321
DOI: 10.1007/s00604-024-06454-6 -
Mikrochimica Acta Jun 2024Amlodipine (AM) is a long active calcium channel blocker used to relax blood vessels by preventing calcium ion transport into the vascular walls and its supporting...
Binder-free and efficient voltammetric sensor based on Zn-CaCuO nanoparticles for simultaneous determination of amlodipine, acetaminophen, and ascorbic acid in hypertension patients.
Amlodipine (AM) is a long active calcium channel blocker used to relax blood vessels by preventing calcium ion transport into the vascular walls and its supporting molecules acetaminophen (AP) and ascorbic acid (AA) are recommended for hypertension control and prevention. Considering their therapeutic importance and potential side effects due to over dosage, we have fabricated a sensor for individual and simultaneous determination of AA, AP, and AM in pharmaceuticals and human urine using novel Zn-doped CaCuO nanoparticles modified glassy carbon electrode (GCE). Optimally doped CaCuO (2.5 wt% Zn at Cu site) enhanced the detection of target molecules over much wider concentration ranges of 50 to 3130 µM for AA, 0.25 to 417 µM for AP, and 0.8 to 354 µM for AM with the corresponding lowest detection limits of 14 µM, 0.05 µM, and 0.07 µM, respectively. Furthermore, the Zn-CaCuO/GCE exhibited excellent selectivity and high sensitivity even in the presence of several potential interfering agents. The usefulness of the developed electrode was tested using an amlodipine besylate tablet and urine samples of seven hypertension patients under medication. The results confirmed the presence of a significant amount of AP and AM in six patients' urine samples indicating that the personalized medication is essential and the quantum of medication need to be fixed by knowing the excess medicines excreted through urine. Thus, the Zn-CaCuO/GCE with a high recovery percentage and good sensitivity shall be useful in the pharmaceutical and biomedical sectors.
Topics: Amlodipine; Humans; Ascorbic Acid; Copper; Acetaminophen; Zinc; Hypertension; Electrodes; Electrochemical Techniques; Limit of Detection; Metal Nanoparticles; Nanoparticles; Carbon
PubMed: 38898141
DOI: 10.1007/s00604-024-06473-3 -
RSC Advances Jun 2024A supramolecular complex μ--tetra(4-pyridyl) porphyrinate nickel(ii)tetrakis[bis(bipyridine)(chloro)ruthenium(ii)] ([NiTPyP{Ru(bipy)Cl}]) was intercalated into the...
Glassy carbon electrode modified with a film of tetraruthenated nickel(ii) porphyrin located in natural smectite clay's interlayer for the simultaneous sensing of dopamine, acetaminophen and tryptophan.
A supramolecular complex μ--tetra(4-pyridyl) porphyrinate nickel(ii)tetrakis[bis(bipyridine)(chloro)ruthenium(ii)] ([NiTPyP{Ru(bipy)Cl}]) was intercalated into the interlayer space of natural smectite clay (shortened as Ba) collected in a Cameroonian deposit at Bagba hill. Physicochemical characterization of the resulting material using ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) confirmed the intercalation of the porphyrin within the interlayer space of the clay. The intercalated clay was then used to form a stable thin film onto a glassy carbon electrode (GCE) by drop casting a suspension of the hybrid material. The GCE modified with the intercalated organoclay endowed the electrode with a larger electrochemically active surface area, good stability, high selectivity, and sensitivity toward dopamine (DA), acetaminophen (AC) and tryptophan (Trp). In addition, it was observed that the modified electrodes exhibited good and pH-dependent electrocatalytic properties toward these analytes. The simultaneous determination of DA, AC and Trp at [NiTPyP{Ru(bipy)Cl}]-Ba/GCE was thus possible without the interference of one analyte on the others, and the resulting calibration curve exhibits two segments for the three analytes. For DA, AC and Trp, the detection limits were found to be 0.8 μM, 0.3 μM and 0.3 μM, respectively. The [NiTPyP{Ru(bipy)Cl}]-Ba/GCE modified electrodes were successfully applied for the determination of AC in Paracetamol, a commercial product, and Trp in real pharmaceutical formulation samples.
PubMed: 38895529
DOI: 10.1039/d4ra03253e