Non-steroidal Anti-inflammatory Drugs Naproxen Research Articles

Are Environmental Levels of Nonsteroidal Anti-Inflammatory Drugs a Reason for Concern? Chronic Life-Cycle Effects of Naproxen in Zebrafish.

The nonsteroidal anti-inflammatory drug naproxen (NPX) is among the most consumed pharmaceuticals worldwide, being detected in surface waters within the ng to μg/L range. Considering the limited chronic ecotoxicity data available for NPX in aquatic ecosystems, the present study aimed at evaluating its impact in the model organism Danio rerio, following a full life-cycle exposure to environmentally relevant concentrations (0.1 to 5.0 μg/L). An integration of apical endpoints, i.e., survival, growth, and reproduction, with gonad histopathology and gene transcription (RNA-seq) was performed to provide additional insights into the mode of action (MoA) of NPX. NPX decreased zebrafish growth and reproduction and led to histopathological alterations in gonads at concentrations as low as 0.1 μg/L. At the molecular level, 0.7 μg/L of NPX led to a disruption in gonads transcription of genes involved in several biological processes associated with reproduction, mainly involving steroid hormone biosynthesis and epigenetic/epitranscriptomic machineries. Collectively, these results show that environmentally realistic concentrations of NPX affect zebrafish reproduction and associated signaling pathways, indicating that current hazard and risk assessment data for NPX underestimate the environmental risk of this pharmaceutical.

In Vitro Evaluation of Pharmacokinetic Properties of Selected Dual COX-2 and 5-LOX Inhibitors.

Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds 1, 2, 3, 11, and 12, respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC k values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA -logPe values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC logk values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds 1, 2, 3, 11, and 12 will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07-58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%).

Drug Binding to Partially Unfolded Serum Albumin: Insights into Nonsteroidal Anti-Inflammatory Drug Naproxen-BSA Interactions from Spectroscopic and MD Simulation Studies.

Understanding the binding details of a small-molecule drug to a protein in its partially unfolded state is important for drug delivery as it provides insight into the overall drug-binding ability of the protein, even when the majority of binding pockets in its unfolded state are impaired. The interaction of partially unfolded proteins with drugs remains poorly understood due to a lack of structural information on proteins in their partially unfolded states. Here, we studied the interaction between serum albumin (bovine serum albumin (BSA) as a model system), an abundant protein in blood serum that is an effective carrier for numerous known drugs, and a nonsteroidal anti-inflammatory drug (NSAID) naproxen (NPS) using various spectroscopic and computational methods. Molecular dynamics simulations starting from the drug-unbound state and performed at physiological and higher temperatures revealed novel hydrophobic sites on the BSA surface. We analyzed the BSA-NPS interaction in the presence and absence of the cationic organized assembly CTAB and two oligosaccharides (β-CD and 2-HP-β-CD) at different excitation wavelengths. The solvation dynamics of BSA under NPS-bound conditions became ∼4.6% faster. Oligosaccharides were found to increase the solubility of NPS by providing a hydrophobic environment for the formation of inclusion complexes through host-guest interactions. These findings provide a comprehensive overview and uncover the binding model and mechanism of interaction of NPS with BSA, revealing hydrophobic and electrostatic interactions and hydrogen bonds required for BSA to bind NPS at these noncanonical sites. The molecular-level understanding of the binding mechanism of commonly used NSAIDs like NPS with partially unfolded BSA will be useful in designing pharmaceutically important molecules with efficient loading and delivery properties.

Mesoporous silica-encapsulated nitrogen-doped fluorescent carbon dots modified polydopamine composites for monitoring non-steroidal anti-inflammatory drugs

A one-pot hydrothermal process incorporated nitrogen-doped fluorescent carbon dots (N-FCDs) into the pores of mesoporous silica (m-SiO2). Under weakly alkaline conditions, the m-SiO2/N-FCDs were further functionalized with dopamine to develop m-SiO2/N-FCDs modified polydopamine (m-SiO2/N-FCDs/PDA). The m-SiO2/N-FCDs/PDA exhibited emission at a wavelength of 520 nm (λexc. = 440 nm) and demonstrated excellent quenching efficiency in the presence of NSAIDs (aspirin, diclofenac, ketoprofen, naproxen, and ibuprofen) with a detection limit of 0.045 – 1.43 nM. Furthermore, the m-SiO2/N-FCDs/PDA was utilized to detect NSAIDs in tap and river water and pharmaceutical commercial tablets showing high recoveries of 90.96–100.41 % with RSD < 4.

Aqueous photolysis of naproxen exposed to UV and natural sunlight: Formation of excited triplet and photosensitizing product

Photochemical transformation is an important attenuation process for the non-steroidal anti-inflammatory drug naproxen (NPX) in both engineered and natural waters. Herein, we investigated the photolysis of NPX in aqueous solution exposed to both ultraviolet (UV, 254 nm) and natural sunlight irradiation. Results show that N2 purging significantly promoted NPX photolysis under UV irradiation, suggesting the formation of excited triplet state (3NPX*) as a critical transient. This inference was supported by benzophenone photosensitization and transient absorption spectra. Sunlight quantum yield of NPX was only one fourteenth of that under UV irradiation, suggesting the wavelength-dependence of NPX photochemistry. 3NPX* formed upon irradiation of NPX underwent photodecarboxylation leading to the formation of 2-(1-hydroxyethyl)-6-methoxynaphthalene (2HE6MN), 2-(1-hydroperoxyethyl)-6-methoxynaphthalene (2HPE6MN), and 2-acetyl-6-methoxynaphthalene (2A6MN). Notably, the conjugation and spin-orbit coupling effects of carbonyl make 2A6MN a potent triplet sensitizer, therefore promoting the photodegradation of the parent NPX. In hospital wastewater, the photolysis of NPX was influenced because the photoproduct 2A6MN and wastewater components could competitively absorb photons. Bioluminescence inhibition assay demonstrated that photoproducts of NPX exhibited higher toxicity than the parent compound. Results of this study provide new insights into the photochemical behaviors of NPX during UV treatment and in sunlit surface waters.

Abstract 7299: Preventing CRC progression in FAP rat model using a combinational targeting of TRAIL signaling and inflammation

Abstract Colorectal Cancer (CRC) is among the leading causes of mortality globally, with high incidence rates in developed countries including the US. While FAP patients are prone to develop CRC in their lifetime, recent rising trends among young adults is also a major concern. Hence, preventing CRC would aid in reducing cancer mortality, especially in high-risk FAP patients for which there are no FDA approved preventive agents. Here, we evaluated TRAIL-inducing, orally active small molecule ONC201, alone and in combination with the NSAID naproxen (NAP) for CRC prevention in the PIRC rat model representing FAP cohort. Male PIRC rats were bred inhouse and randomized by age into placebo and intervention groups (N=15). Starting at 6 weeks of age, experimental groups were administered either ONC201 alone by gavage [25mg/kg; 2X/week or 50mg/kg; 1X/week]; NAP in AIN-76A diet [200 ppm; continuously or 1 week ON/OFF]; or a combination of both agents, while placebo group received vehicle only. After 26 weeks of treatment, rats were euthanized and intestines were evaluated for tumor incidence and multiplicity. H&amp;E stained colonic tumor sections were histologically classified as hyperplastic polyps, adenomas (AD), and adenocarcinomas (ADCA). Gross tumor data indicated significant reduction in colonic polyps in both the NAP alone and NAP+ONC201 groups without any overt-toxicites. Histological analyses also demonstrated strong suppression of AD progression to ADCA as well as a significant decrease in the number of ADs and ADCAs (p&amp;lt;0.05) in the treatment groups compared to the placebo. ONC201 regimens modestly reduced AD (19%-27% less, p&amp;lt;0.05) but showed strong inhibition of ADCA (45%-59% less, p&amp;lt;0.0001). A significant reduction of AD and ADCA was seen in NAP continuous (54% &amp; 87% less respectively; p&amp;lt;0.0001) and intermittent (34% &amp; 68% less respectively; p&amp;lt;0.0001) dosing regimens. As anticipated, the NAP continuous treatment had better efficacy than the intermittent dosing regimen. Notably, the combination treatment showed &amp;gt;90% (p&amp;lt;0.0001) inhibition of ADCA and 40%-57% (p&amp;lt;0.0001) inhibition of ADs. Importantly, ONC201+ NAP treatment also resulted in an additional 45% - 70% reduction of ADCA (p&amp;lt;0.0001) when compared to the NAP alone treatment. Thus, our data showed that the combination groups with NAP intermittent dosing demonstrated ~90% inhibition of ADCA, suggesting the synergistic effect of the two agents in preventing CRC progression. Molecular analysis of the rat tumors and additional analyses in in-vitro tumoroid models suggested induction of TRAIL (TRAIL, DR5, FADD), increased apoptosis (Caspases), and a decrease in proliferation markers (PCNA, Cyclin D1) and pro-inflammatory cytokines (IL1b, IL13 etc.). Our data suggests NAP/ONC201 combo has no toxicities, warranting further investigation of CRC interception in high-risk FAP patients (Funding by NCI-PREVENT 75N91019D00020-75N91020F00004). Citation Format: Venkateshwar Madka, Gopal Pathuri, Karthikkumar Venkatachalam, Surya P. Singh, Anil Singh, Nicole Stratton, Stanley Lightfoot, Shizuko Sei, Mark S. Miller, Chinthalapally V. Rao. Preventing CRC progression in FAP rat model using a combinational targeting of TRAIL signaling and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7299.

Designing Powerful Biindole-Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements.

Among inherently chiral selectors of axial stereogenicity, usually resulting in very good enantiodiscrimination performances, the biindole-based family has the additional advantage of very easy functionalization of the two nitrogen atoms with a variety of substituents with desirable properties. Aiming to evaluate the possibility of exploiting such feature to enhance the enantiodiscrimination ability of the archetype structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2'-biindole atropisomeric core conjugated to bithiophene wings enabling fast and regular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl substituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the selector series was comparatively evaluated in proof-of-concept chiral voltammetry experiments with a "benchmark" chiral ferrocenyl probe as well as with chiral non-steroidal anti-inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl ≪ hydroxyethyl sequence of selector substituents, supporting our assumption on the beneficial role of an additional coordination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.

A new multifunctional electrocatalyst based on PbS nanostructures decorated with graphene/polyaniline-modified glassy carbon electrode for selective detection of non-steroidal anti-inflammatory drug naproxen

Naproxen (NAP), a well-known anti-inflammatory drug, has also been considered for its antiviral prospective and acceptable potential for in vitro activity against serious respiratory syndrome-related coronavirus (SARS-CoV) and anti-influenza activity. However, designing a selective, sensitive and efficient electrocatalyst for the determination of NAP is still a great challenge. In this research, a new electrocatalytic sensor was constructed for the electrochemical recognition of NAP by a glassy carbon electrode modified with PbS nanostructures incorporated graphene/polyaniline nanocomposite. The synthesized samples were characterized by physicochemical analyses like EDS, XRD, FTIR, FESEM, and PL. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV) were carried out to examine the electrocatalytic behavior of the modified electrodes. The EIS plot obviously demonstrated rapid electron transport at low frequencies for the PbS/graphene/PANI/GC electrode. It was observed that the PbS/graphene/PANI/GC electrode exhibited better-defined oxidation peaks, and greater peak currents for NAP detection compared to other electrodes. Under the optimum conditions, the proposed PbS/graphene/PANI nanoplatform provided a reliable linear range of 1 to 100 µM with a detection limit as low as 0.08 μM. Meanwhile, the PbS/graphene/PANI electrode possessed acceptable selectivity, good repeatability with an RSD of about 2.6 %, and a reduction of about 3 % after two weeks, and long-term stability of about 97 % of its original response for the recognition of NAP. Furthermore, the constructed electrode demonstrated NAP detection in real samples, such as human plasma and urine with good recoveries ranging from 98.8 % to 99.9 %, suggesting its promising prospects in clinical diagnostics.

Clinical and Demographic Profile of Patients with Juvenile Idiopathic Arthritis in a Tertiary Care Center in Mumbai, Western India

Abstract Background: Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic rheumatic disease affecting children younger than 16 years of age and lasting six weeks or longer. It causes both short-term and long-term disability. There are very few epidemiological studies from western India on JIA. The objectives of this study were to identify the clinical and demographic profile of JIA patients and compare to existing epidemiological data. Material and Methods: It was a retrospective observational study carried out at BJ Wadia Hospital for children in Mumbai, over a period of 30 months. The analysis of their clinical, demographic and treatment profile was done. Results: We had a total of 61 cases, 31 were male and 30 female. Maximum cases were of SoJIA and ERA (n=18 in each, 29.5%), followed by polyarticular JIA (n=16, 26.2%) and oligoarticular JIA (n=8, 13.1%). Knee (75.4%) was the commonest joint involved. Two patients had uveitis (one with chronic and other with acute anterior uveitis). The mean ESR was 72mm and CRP 45.87mg/dL. ANA was positive in 7 patients, whereas RF in 3 patients. There was a mean 6 months delay in their diagnosis, maximum being in polyarticular JIA with 11 months dealy. All patient were treated with NSAIDs (naproxen or indomathacin). cDmards were given for treatment - either methotrexate or sulfasalzine. Twelve were given biologicals DMARDs. Conclusion: SoJIA and ERA followed by polyarticular JIA were most common subtypes of JIA in our study. Uveitis and ANA positivity were rare findings in our subset of children.

SrNiO3 perovskite synthesis for enhanced photodegradation of the nonsteroidal anti-inflammatory drug Naproxen: A clean and sustainable process for water treatment

The need to find effective and environmentally friendly ways to prevent pharmaceuticals from contaminating water is due to the growing concern about water pollution caused by hazardous organic pollutants. Photocatalysis is crucial for the degradation of organic pollutants. For this reason, many uses of nanostructured perovskite in various energy and environmental fields have aroused interest. The innovative aspect of this study is the use of SrNiO3 synthesis via the one-pot citrate nitrate method in photocatalysis. The sample was calcined at 450 °C and 900 °C for 5 h. Crystalline phase purity, morphology, surface area, pore size, and optical properties were investigated through X-ray diffraction (XRD), scanning electron microscopy (SEM), Brunauer–Emmett–Teller (BET), Barrett-Joyner-Halenda (BJH), Fourier transform infrared spectroscopy (FTIR), and diffuse reflectance spectroscopy (DRS). The prepared sample of SrNiO3 was used as a photocatalyst for the photodegradation of naproxen, one of the most common pharmaceutical compounds detected in wastewater. The effects of catalyst dose, naproxen amount, and reaction kinetics were investigated. After 60 min of UV irradiation exposure, the photocatalytic removal efficiency was found to be optimal using 1 g/L of SrNiO3. In summary, perovskite SrNiO3 exhibited excellent physicochemical and mechanical stability after five cycles of reaction.

A novel sorbent based on electrospun for electrically-assisted solid phase microextraction of six non-steroid anti-inflammatory drugs, followed by quantitation with HPLC-UV in human plasma samples

BackgroundAlthough NSAIDs possess notable therapeutic and pharmaceutical qualities, it's essential to acknowledge that excessive doses can result in toxicity within the human body. Moreover, the importance lies in identifying and measuring their trace amounts. Due to their existence within intricate matrices, the creation of novel electrospun nanofibers as sorbents for electrically-assisted solidphase microextraction (EA-SPME) becomes vital. This innovation caters to the requirement for the effective pre-treatment of NSAID samples, providing a strategic approach to managing the complexities associated with trace quantities found in various matrices. ResultsFirst, polyvinylalcohol/casein/tannic acid/polyaniline/titanium dioxide nanoparticles (PVA/CAS/TA/PANI/TiO2 NPs) electrospun nanofibers were prepared for EA-SPME on pewter rode and then, trace amounts of six NSAIDs (Acetaminophen, Caffeine, Naproxen, Celecoxib, Ibuprofen and mefenamic acid) were adsorbed chemically on these nanofibers. In the next step, the desorption of six NSAIDs was electrochemically done from prepared electrospun nanofibers on a pewter rod which was as working electrode at three electrodes system. Finally, these drugs were quantified from different human plasma samples with HPLC-UV. The synthesis of electrospun nanofibers was confirmed through a series of analytical techniques including field emission-scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy with elemental mapping analysis (EDX-Mapping), X-ray diffraction (XRD), and Fourier transform-infrared (FT-IR). The optimal percentage of additive compounds to PVA/CAS for electrospinning, as well as the factors influencing adsorption and desorption processes, were determined through both of Design Expert software and MATLAB programming language. SignificanceUnder optimum conditions, the wide linear range was 27–8000 ng mL−1 with R2≥ 0.9897, low detection limits were ranged from 8 to 27.3 ng mL−1 based on S/N = 3 and significant enrichment factors were acquired. The intra-day and inter-day RSDs% were obtained within the 4.51% - 5.68% and 4.28%–5.45%, respectively. Finally, The effectiveness of the EA-SPME-HPLC-UV method was assessed for determining NSAIDs in plasma samples, demonstrating good recoveries ranging from 90.2% to 105.2%.

SYNTHESIS, CHARACTERIZATION, ANTIBACTERIAL TEST AND MOLECULAR DOCKING OF SOME AMIDE DERIVATIVES

The amide group is an organic group synthesized by reaction between an amine and carboxylic acid and is known to have many biological activities like antibacterial, antifungal, anti-inflammatory, antitumor and many other activities.the traditional and easy method to synthesize amides by first convert carboxylic acid to acyl chloride and then the acyl chloride react with amine to give the amide .the goal is to synthesize new amide derivatives by one pot reaction between two drugs one is amine ( bromohexine which act as mucolytic) And the other drug is carboxylic acid like NSAIDs ( diclofenac, naproxen, indomethacin and mefenamic acid) using thionyl chloride and triethylamine as catalytic agents and stirring for 1 hr. The result products will be characterized by physical examination, melting point and IR spectroscopy. As mentioned the amide derivatives have many biological activities so the antibacterial activity will be tested on some bacterial species 2 g+ve( staph.aureus and streptococcus) and 2 g-ve ( E.coli and Klebsiella). Finally the docking study will be done on the synthesized derivatives on the proposed targets to see the inhibition score for each derivatives and compare it with the reference inhibitor and with antibacterial test.

Cardiovascular risks of continuing vs. initiating NSAIDs after first-time myocardial infarction or heart failure: a nationwide cohort study.

It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use. Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996-2018 (n=273 682). NSAID users (n=97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings<60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23-1.27) was driven by initiators (HR=1.39, 1.36-1.41) and not continuing users (HR=1.03, 1.00-1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR=1.11, 95% CI: 1.05-1.18). Among initiators, the HR was 1.63 (CI: 1.57-1.69) for diclofenac, 1.31 (CI: 1.27-1.35) for ibuprofen, and 1.19 (CI: 1.08-1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses. NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users.

Impact of hemoglobin A1c level on the association between non-steroidal anti-inflammatory drug use and cardiovascular events in patients with type 2 diabetes: A population-based cohort study.

Non-steroidal anti-inflammatory drugs (NSAIDs) should be used cautiously in patients with type 2 diabetes. We examined whether the cardiovascular risks associated with NSAID use depended on HbA1c level in patients with type 2 diabetes. We conducted a population-based cohort study of all adult Danes with a first-time HbA1c measurement ≥48 mmol/mol during 2012-2020 (n = 103 308). We used information on sex, age, comorbidity burden, and drug use to calculate time-varying inverse probability of treatment weights. After applying these weights in a pooled logistic regression, we estimated hazard ratios (HRs) of the association between use of NSAIDs (ibuprofen, naproxen, or diclofenac) and cardiovascular events (a composite of myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, and all-cause death). We stratified all analyses by HbA1c level (<53 or ≥53 mmol/mol). For ibuprofen use, the HR of a cardiovascular event was 1.53 (95% confidence interval [CI]: 1.34-1.75) in patients with HbA1c <53 and 1.24 (95% CI: 1.00-1.53) in patients with HbA1c ≥53 mmol/mol. For naproxen use, the HR was 1.14 (95% CI: 0.59-2.21) in patients with HbA1c <53 and 1.30 (95% CI: 0.49-3.49) in patients with HbA1c ≥53 mmol/mol. For diclofenac use, the HR was 2.40 (95% CI: 1.62-3.56) in patients with HbA1c <53 and 2.89 (95% CI: 1.65-5.04) in patients with HbA1c ≥53 mmol/mol. In patients with type 2 diabetes, glycemic dysregulation did not affect the cardiovascular risk associated with NSAID use.

PH-Sensitive Gold Nanorods for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Delivery and DNA-Binding Studies.

A facile experimental protocol for the synthesis of poly(ethylene glycol)-modified (PEGylated) gold nanorods (AuNRs@PEG) is presented as well as an effective drug loading procedure using the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP). The interaction of AuNRs@PEG and drug-loaded AuNRs (AuNRs@PEG@NAP) with calf-thymus DNA was studied at a diverse temperature revealing different interaction modes; AuNRs@PEG may interact via groove-binding and AuNRs@PEG@NAP may intercalate to DNA-bases. The cleavage activity of the gold nanoparticles for supercoiled circular pBR322 plasmid DNA was studied by gel electrophoresis while their affinity for human and bovine serum albumins was also evaluated. Drug-release studies revealed a pH-sensitive behavior with a release up to a maximum of 24% and 33% NAP within the first 180 min at pH = 4.2 and 6.8, respectively. The cytotoxicity of AuNRs@PEG and AuNRs@PEG@NAP was evaluated against MCF-7 and MDA-MB-231 breast cancer cell lines. The development of AuNRs as an efficient non-steroidal anti-inflammatory drugs (NSAIDs) delivery system for chemotherapy is still in its infancy. The present work can shed light and inspire other research groups to work in this direction.

Abstract LB114: Colon cancer preventive efficacy of ONC201 and naproxen alone or in combination in FAP relevant PIRC rat model

Abstract Colorectal Cancer (CRC) is the third most common cancer and leading cause of mortality in the US. While the rate of CRC incidence has steadily dropped in the last decades, recent rising trends among young adults are a major concern. Hence, preventing CRC in the general population would aid in reducing cancer mortality, especially in high-risk FAP patients for which there are no FDA approved preventive agents. Here, we evaluated TRAIL-inducing agent ONC201, alone and in combination with NSAID naproxen (NAP) for CRC prevention in PIRC rat model of FAP. PIRC rats (20 female rats/group) are bred and randomized by age into control and intervention groups. Starting at 6 weeks of age, PIRC rats were treated with ONC201 by gavage [25mg/kg; 2X/week (LD) or 50mg/kg; 1X/week (HD)]; NAP 200 ppm in AIN-76A diet [continuously or 1 week ON/OFF]; or the combination of ONC201 and NAP. Control group rats received vehicle only. Colonic polyps’ (CP) development (occurrence, number, and size) was monitored by periodic colonoscopies and upon termination at 32 weeks of age. Colonoscopy data indicated significantly fewer CPs in the HD ONC201, NAP alone dosing regimens, and combination groups. At termination, colonic tumors were harvested and subjected to histopathological evaluation. Colonic tumors were histologically classified as hyperplastic polyps, adenomas, and adenocarcinomas (ADCA). In vehicle treated rats, histological assessment showed multiplicity of 2.4±0.4 (Mean±SEM) hyperplastic polyps; 9.14±0.92 adenomas, and 2.4±0.27 ADCA. A significant decrease in the number of hyperplastic polyps (p&amp;lt;0.05) was observed in rats treated with combination of ONC201 and NAP continuous dosing regimens. LD and HD ONC201 regimens resulted in modest (11.3%, p=0.45) and significant (48.8%, p&amp;lt;0.0001) inhibition of colonic adenoma multiplicity, respectively. As anticipated, NAP dosing regimens showed 78-85% inhibition (p&amp;lt;0.0001) of adenoma multiplicity. Combination treatment showed &amp;gt;90% inhibition of adenomas. Importantly, LD ONC201 inhibited colonic ADAC multiplicity by 78.8% (p&amp;lt;0.0001) and remaining treatment groups showed no colonic ADACs. This histological data clearly showed that ONC201 (25 mg 2X/week or 50 mg 1x/week) significantly suppresses colonic tumor progression to colon adenoma and adenocarcinomas. NAP, either continuously or intermittent dosing, resulted in 85% and 78% inhibition of adenoma multiplicities, respectively, suggesting that intermittent dosing may be similarly effective for CRC prevention. Biomarker analysis suggested increased apoptosis (TRAIL, Caspase-3) and decrease in proliferation markers (PCNA, Cyclin D1). Our data warrants investigating ONC201 with NAP combination for CRC prevention in high risk FAP patients. (Supported by NCI-PREVENT 75N91019D00020-75N91020F00004) Citation Format: Venkateshwar Madka, Gopal Pathuri, Karthikkumar Venkatachalam, Srikanth Chiliveru, Yuting Zhang, Nandini Kumar, Nicole Stratton, Stanley Lightfoot, Mark S. Miller, Shizuko Sei, Chinthalapally V. Rao. Colon cancer preventive efficacy of ONC201 and naproxen alone or in combination in FAP relevant PIRC rat model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB114.

Distribution and photodegradation of typical nonsteroidal anti-inflammatory drugs in an ice-water system: Simulation of surface waters with an ice cover

In surface waters at middle and high latitudes during winter, the coexistence of ice and water is a natural phenomenon. Nonsteroidal anti-inflammatory drugs (NSAIDs) as emerging contaminants have been found frequently in aquatic environments, including waters that are seasonally covered in ice. However, little is available for the environmental behaviors and fate of NSAIDs in ice, particularly in the system where ice and water coexist. In this study, the distribution and photodegradation of model NSAIDs naproxen (NPX), diclofenac (DCF), and acetaminophen (APAP) in an ice-water system were investigated. The findings demonstrated a 66.7%, 60.5%, and 66.7% increase in the ice-water distribution coefficient Kiw of NPX, DCF, and APAP with initial concentrations of 10 ng L−1 relative to 500 ng L−1. The Kiw values were in decreased order of DCF, NPX, and APAP. The photodegradation rate constants of NPX, DCF, and APAP in ice increased by 27.0%, 35.6%, and 56.6% relative to those in water. With the increase in freezing time, the contribution ratios of distribution to the mass loss of NPX, DCF, and APAP increased by 19.9%, 21.1%, and 16.1%, respectively. The ratios of photodegradation to the mass loss of NPX, DCF, and APAP decreased by 5.0%, 5.7%, and 0.9%, respectively. An ice cover as the predominant factor could affect the distribution and photodegradation of drugs in the surface water. This study can close a knowledge gap regarding the transport and transformation of NSAIDs in the ice-water system and provide fresh insights into the behaviors and fate of emerging contaminants in seasonally ice-covered waters.

Interactions between DMPC Model Membranes, the Drug Naproxen, and the Saponin β-Aescin.

In this study, the interplay among the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) as a model membrane, the nonsteroidal anti-inflammatory drug naproxen, and the saponin β-aescin are investigated. The naproxen amount was fixed to 10 mol%, and the saponin amount varies from 0.0 to 1.0 mol%. Both substances are common ingredients in pharmaceutics; therefore, it is important to obtain deeper knowledge of their impact on lipid membranes. The size and properties of the DMPC model membrane upon naproxen and aescin addition were characterized with differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SAXS, WAXS), and photon correlation spectroscopy (PCS) in a temperature-dependent study. The interaction of all substances was dependent on the lipid phase state, which itself depends on the lipid's main phase transition temperature Tm. The incorporation of naproxen and aescin distorted the lipid membrane structure and lowers Tm. Below Tm, the DMPC-naproxen-aescin mixtures showed a vesicle structure, and the insertion of naproxen and aescin influenced neither the lipid chain-chain correlation distance nor the membrane thickness. Above Tm, the insertion of both molecules instead induced the formation of correlated bilayers and a decrease in the chain-chain correlation distance. The presented data clearly confirm the interaction of naproxen and aescin with DMPC model membranes. Moreover, the incorporation of both additives into the model membranes is evidenced.

Features of the clinical picture and severity of pain syndrome in girls with genital endometriosis on the background of conservative therapy of the disease in adolescence

Introduction. Endometriosis is characterised by a chronic course and significantly affects the quality of life of young patients. Aim. To study the features of the clinical picture and pain syndrome in adolescent girls with genital endometriosis against the background of 1 year of therapy.Materials and methods. A prospective longitudinal study included 32 girls (14–17 years old) with a confirmed diagnosis of genital endometriosis. The clinical picture and severity of pain syndrome were assessed against the background of conservative therapy with NSAID (naproxen) to relieve dysmenorrhea and gestagen (dienogest) for 1 year.Results. The main complaint of girls with endometriosis was pain, which appeared on the day before menstruation or in the middle of the cycle since menarche (64%) or increased in 1–1.5 years after menarche (23%) to very intense pain (8.3 ± 1.6 V scale) of a tensive (44%) or clutching (25%) nature. One third of adolescents reported daily pain (24%), the majority (75%) complained of restricted daily activity and performance, gastrointestinal symptoms (44%) and dysuria (22%). After 1 year of treatment with gestagens and NSAIDs patients had a significant decrease in pain on the days of menstruation (p &lt;0,001), as well as outside menstruation (p &lt;0,001), frequency of restriction of daily activities (p &lt;0,001), weakness, lowered working capacity on menstrual days (p &lt; 0.001), gastrointestinal symptoms (p &lt; 0.001) and urinary disorders (p &lt; 0.001) and the need for mandatory pain medication (p &lt; 0.001).Conclusion. A significant reduction in pain syndrome and clinical manifestations of dysmenorrhea against the background of an improved quality of life was observed in the adolescent patients during 1 year of conservative endometriosis therapy. No intensification or increase in the frequency of headache attacks or significant changes in BMI were observed in the study group, which is indicative of good tolerance and contributes to treatment adherence in young female patients.

Fluorescent sensing of non-steroidal anti-inflammatory drugs naproxen and ketoprofen by dansylated squaramide-based receptors.

Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH3CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.