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Background: Varied responses to acute migraine medications have been observed, with over one-third (34.5%) of patients reporting insufficient headache relief. Sumatriptan-naproxen sodium, a single, fixed-dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care., Methods: A narrative review of clinical trials investigating sumatriptan-naproxen sodium for both adults and adolescents was performed in March 2024., Results: Across a total of 14 clinical trials in nine publications, sumatriptan-naproxen sodium offered greater efficacy for 2-h pain freedom (14/14) and sustained pain-free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well-tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan-naproxen sodium in participants with allodynia, probable migraine, menstrual-related migraine and those with poor responses to acute, non-specific, migraine medication., Conclusions: Multi-mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan-naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen-sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The average rate of patient dissatisfaction following total knee arthroplasty (TKA) is 10%. Multi-modal analgesia is the present standard of pain management after TKA. Studies show that with multi-modal analgesia, approximately 60% of patients experience severe knee pain following surgery, while around 30% experience moderate pain. To date, there is no literature available on targeted pain management using bone cement., Objectives: To investigate the feasibility of incorporating anti-inflammatory medications and identify the analgesic with the best release pharmacokinetics from bone cement for application in pain management., Methods: In an in-vitro study, 100 mg of five drugs (aceclofenac, diclofenac, naproxen, paracetamol and methyl prednisolone) were incorporated into bone cement (Palacos). Cement cubes holding each drug were made and allowed to harden for 30 min. Each drug-containing cube was placed in a beaker with saline for 72 h. Fractions of 10 ml were collected at 0, 6, 24, 48 and 72 h and analysed using high-pressure liquid chromatography to measure the percentage release of the drug from bone cement., Results: Naproxen showed superior elution from bone cement, with 10.9% at 24 h and 9.08% at 72 h. Paracetamol showed 4.9% at 24 h and 3.78% at 72 h, aceclofenac 0.2% at 24 h and 0.4% at 72 h, diclofenac 3.03% at 24 h and 1.99% at 72 h, and methylprednisolone 0.26% at 24 h and 0.32% at 72 h., Conclusions: Polymethylmethacrylate bone cement can elute analgesics in vitro. Among the five drugs studied, naproxen had the best release kinematics from polymethylmethacrylate bone cement. Analgesic eluting bone cement is a novel approach for targeted postoperative pain management in TKA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults., Methods: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554., Results: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I 2 between the studies was low., Conclusions: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).

In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) isopropyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log P O/W ) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The In vitro permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q 24h ) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (J ss ) 32.5 µg NAP cm -2 h -1 , and Q 24h  = 246.4 µg NAP cm -2 , it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles - Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the J ss and Q 24h of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other - as the sodium salt., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (μ 3  - OH, and - OH 2 ) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done., (Copyright © 2024. Published by Elsevier B.V.)

As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (C max,ss ) and area under plasma concentration-time curve over dosing interval at steady state (AUC τ,ss ) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in C max , 19% in AUC τ,ss ) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for C max,ss and AUC τ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hydrogen sulfide (H 2 S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H 2 S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H 2 S levels has a potential therapeutic value. Consequently, synthetic H 2 S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H 2 S donors; furthermore, herein we discuss their preparation, the H 2 S-releasing mechanisms, and their -biological applications.

Aim of this study was to evaluate and compare the efficacy of anti-arthritic drugs (naproxen, prednisolone, and hydroxychloroquine) alone and in combination. The in vitro anti-arthritic activity was evaluated by stabilization of human erythrocytes (HRBCs) membrane assays. In vivo activity was carried out using Complete Freund's Adjuvant (CFA) induced arthritic model in Wistar rat. Individual and combination drugs were administered for 21 days in rats 8 days post inoculation with CFA (0.15 ml injected in right hind paw). Body weight and paw edema were measured at different intervals. Combination treatments exhibited more HRBC stabilization than individual treatments. All individual and combination treatments reduced the level of C-reactive protein (CRP), liver function enzymes, malondialdehyde, white blood cells and platelets, with the most pronounced activity exhibited by the combination of three drugs. The level of oxidative stress biomarkers (reduced glutathione, catalase, and superoxide dismutase), red blood cells, and hemoglobin were notably increased in all treatment groups in contrasts to diseased control rats. Histopathological evaluation of the paw showed that all the treatments had reduced (p < 0.05-0.001) the arthritic indices in contrasts to diseased control rats. The serum concentrations of TNF-α and PGE2 were provoked in diseased control rats but had been notably (p < 0.0001) restored by treatments with individual and combination drugs. It was also found that combination treatments, more precisely triple drug was remarkably effective in treating arthritis. It can be concluded that naproxen, prednisolone, and hydroxychloroquine effectively ameliorated the CFA-induced arthritis and were more effective in combination as compared to individual drug therapy probably due to reduction in oxidative stress and inflammatory markers. Moreover, two lower doses (half NPH/2 and one-third NPH/3) of triple combination therapy naproxen, prednisolone, and hydroxychloroquine (NPH) showed no significant difference in anti-arthritic effect as compared to the highest dose level of NPH., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A drug delivery system based on mesoporous particles MCM-41 was post-synthetically modified by photo-sensitive ligand, methyl-(2E)-3-(4-(triethoxysilyl)-propoxyphenyl)-2-propenoate (CA) and the pores of MCM-41 particles were loaded with Naproxen sodium salt (NAP). The CA was used as a photoactive molecule that can undergo a reversible photo-dimerization by [2π + 2π] cycloaddition when irradiated with UV light of specific wavelengths. Thus, it has a function of gate-keeper that is responsible for opening/closing the pores and minimizing premature release of NAP. The physicochemical properties of the prepared system were studied by infrared spectroscopy (IR), nitrogen adsorption measurements, thermogravimetric analysis (TGA), scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDX). The mechanism of the opening/closing pores was confirmed by UV measurements. In vitro and in vivo drug release experiments and the concentration of released NAP was determined by UV spectroscopy and high-performance liquid chromatography (HPLC). In vivo drug release in the blood circulatory system of rats has demonstrated the effective photo-cleavage reaction of CA molecules after UV-light stimulation. The localization and morphological changes of the particles were studied in the blood and liver of rats at different time intervals. The particles in the blood have been shown to retain their original rod-like shape, and the particles in the liver have been hydrolysed, which has resulted in spherical shape with a reduced size., (© 2021. The Author(s).)

Background and Objective: Bioequivalence tests are fundamental step in assessing the equivalence in bioavailability between a test and reference product. In practice, two separate linear mixed models (LMMs) with random subject effects, which have an area under the concentration-time curve (AUC) and the peak concentration (C max ) as the responses, have become the gold standard for evaluating bioequivalence. Recently, Lee et al developed a multivariate hierarchical generalized linear model (HGLM) for several responses that modeled correlations among multivariate responses via correlated random effects. The objective of this study was to apply this multivariate analysis to the bioequivalence test in practice and to compare the performance of multivariate HGLM and separate LMMs., Methods: Three pharmacokinetic datasets, fixed-dose combination (naproxen and esomeprazole), tramadol and fimasartan data were analyzed. We compared the 90% confidence interval (CI) for the geometric mean ratio (GMR) of a test product to a reference product using the multivariate HGLM and two conventional separate LMMs., Results: We found that the 90% CIs for the GMRs of both AUC and C max from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for C max of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for C max in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for C max and (1.163, 1.332) vs (1.009, 1.341) for AUC in fimasartan data, consistent with the random subject effects from two separate LMMs being highly correlated in the three datasets (correlation coefficient r = 0.883; r = 0.966; r = 0.832)., Conclusion: This multivariate HGLM had good performance in the bioequivalence test with multiple endpoints. This method would provide a more reasonable option to reduce the 90% CI by adding correlation parameters and thus an advantage especially in evaluating the bioequivalence of highly variable drugs with broad 90% CIs., Competing Interests: The authors have no conflicts of interest to disclose., (© 2021 An and Shin.)

Layered rare-earth hydroxides have begun to gather increasing attention as potential theranostic platforms owing to their extensive intercalation chemistry combined with magnetic and fluorescent properties. In this work, the potential of layered terbium hydroxide (LTbH) as a platform for simultaneous drug delivery and fluorescence imaging was evaluated. LTbH-Cl ([Tb2(OH)5]Cl·yH2O) was loaded with three nonsteroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) via ion-exchange. Drug release studies in phosphate buffered saline (pH = 7.4) revealed all three formulations release their drug cargo rapidly over the course of approximately 5 hours. In addition, solid state fluorescence studies indicated that fluorescence intensity is strongly dependent on the identity of the guest anion. It was postulated that this feature may be used to track the extent of drug release from the formulation, which was subsequently successfully demonstrated for the ibuprofen loaded LTbH. Overall, LTbH exhibits good biocompatibility, high drug loading, and a strong, guest-dependent fluorescence signal, all of which are desirable qualities for theranostic applications.

In this study, the aerogel technology was used to prepare pulmonary drug carriers consisting of alginate and alginate-hyaluronic acid by an emulsion gelation technique and supercritical CO 2 drying. During the preparation process, the emulsification rate and inner phase viscosity were varied to control the diameter of aerogel microspheres. Results showed that the aerogel microspheres were highly porous (porosity > 98%) with low densities in the range between 0.0087 and 0.0634 g/cm 3 as well as high surface areas between 354 and 759 m 2 /g. The obtained microspheres showed aerodynamic diameter below 5 µm making them suitable for pulmonary drug delivery. An in vitro drug release study with the model drug sodium naproxen was conducted and a non-Fickian drug release mechanism was observed, with no significant difference between the release profiles of alginate and alginate-hyaluronic acid microspheres. During the emulsion gelation step, the feasibility of using the capillary number to estimate the largest stable droplet size in the emulsions was also studied and it was found that using this number, the droplet size in the emulsions may well be predicted.

Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu ( M1L ) , a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as ( S ) - warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of ( S )-naproxen O -demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of ( S ) - naproxen, ( S ) -O -desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of ( S ) -O -desmethylnaproxen to unchanged ( S ) - naproxen in urine was 18.0 ± 8.0 ( n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 ± 6.6 ( n = 11) for the Leu1 variant carrier group ( P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated ( S ) - naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 by The Author(s).)

Objective: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS., Design: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs)., Results: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control., Conclusions: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity., Trial Registration Number: gov Identifier: NCT02052908., Competing Interests: Competing interests: JS has a consulting role with Janssen Research and Development, and Cancer Prevention Pharmaceuticals. IW has an advisory role with Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health and MSD, has received speaker fees from Medscape, MSD, Genentech/Roche, Pfizer and received research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. SL and EV are co-principal investigators in an NIH/NCI U01 award with co-investigators employed by Nouscom, s.r.l. EV has a consulting and advisory role with Janssen Research and Development and Recursion Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Though pharmaceutical polymers were widely used in inhibiting drug recrystallization via strong intermolecular hydrogen and ionic bonds, the improved drug stability was achieved at the cost of the drug release rate or amount in the drug-in-adhesive transdermal patch. To overcame the difficulty, this study aimed to increase drug loading utilizing a novel drug-ionic liquid (drug-IL) strategy and illustrate the underlying molecular mechanism. Here, naproxen (NPX) and triamylamine (TAA) were chosen as the model drug and corresponding counterion, respectively. In addiiton, carboxylic pressure-sensitive adhesive (PSA) was chosen as the model polymer. The drug-IL (NPX-TAA) was synthesized and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and proton nuclear magnetic resonance. The miscibility between NPX-TAA and PSA was assessed using microscopy study, X-ray diffraction, fluorescence spectroscopy, and solubility parameter calculation. In addition, molecular mechanisms of crystallization inhibition were revealed by FT-IR, Raman spectroscopy, DSC, X-ray photoelectron spectroscopy (XPS), and molecular docking. Finally, the release pattern of the high load patch of NPX-TAA was evaluated using in vitro drug release and verified by a skin permeation experiment. The results showed that drug loading in PSA was increased by 5.0 times, which was caused by the synergistic effect of strong ionic hydrogen bonding (the decreased intensity and blue shift of the O-H peak of COOH in PSA) formed between NPX-TAA and PSA-COO - and normal hydrogen bonding (red shift of the C═O peak in PSA) formed between NPX-TAA and the carbonyl group of PSA. In addition, -NH + of TAA was confirmed as the molecular basis of ionic hydrogen bonding through new peak appearance (binding energy: 400.0 eV) in XPS spectra. Moreover, high drug release percent (80.8 ± 1.8%) was achieved even at high drug loading compared with the control group (72.4 ± 2.2%). Thus, this study introduced an effective drug-IL method to enhance drug loading capacity and illustrated the brand-new action mechanism, which provided a powerful instrument for the development of a high drug loading-high release patch.

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.

In this work, the tabletability and dissolution of spray-dried forms of naproxen and its sodium salt were compared with those of unprocessed drugs. Solutions of naproxen or naproxen sodium alone or with HPMC (5% w/w of drug content) were spray dried. Scanning electron micrographs showed that naproxen sodium spray-dried particles were spherical, whereas those of naproxen were non-spherical but isodiametric. Powder x-ray diffraction and thermal analysis indicated that co-spray drying with HPMC resulted in reduced crystallinity of naproxen and higher naproxen sodium dihydrate content. FTIR and Raman analysis showed shifting, merging or elimination of bands in the spectra of the co-spray dried products signifying solid-state alterations. When mixed with suitable processing aids (7% w/w), all co-spray dried powders produced satisfactory tablets in the pressure range 73-295 MPa. Conversely, physical mixtures of naproxen compressed with the same aids failed tableting, whereas naproxen sodium produced weak tablets. Dissolution tests showed significant improvement for co-spray dried drugs tablets. Therefore, since the large therapeutic doses of naproxen and sodium naproxen limit the use of tableting aids, the improved compaction and dissolution performance of the spray-dried forms may be a formulation alternative.

Background: There is no identified pharmacological therapy for COVID-19 patients, where potential therapeutic strategies are underway to determine effective therapy under such unprecedented pandemic. Therefore, combination therapies may have the potential of alleviating the patient's outcome. This study aimed at comparing the efficacy of two different combination regimens in improving outcomes of patients infected by novel coronavirus (COVID-19)., Methods: This is a single centered, retrospective, observational study of 60 laboratory-confirmed COVID-19 positive inpatients (≥18 years old) at two wards of the Baqiyatallah Hospital, Tehran, Iran. Patient's data including clinical and laboratory parameters were recorded. According to the drug regimen, the patients were divided into two groups; group I who received regimen I consisting azithromycin, prednisolone, naproxen, and lopinavir/ritonavir and group II who received regimen II including meropenem, levofloxacin, vancomycin, hydroxychloroquine, and oseltamivir., Results: The oxygen saturation (SpO2) and temperature were positively changed in patients receiving regimen I compared to regimen II (P = 0.013 and P = 0.012, respectively). The serum level of C-reactive protein (CRP) changed positively in group I (P < 0.001). Although there was a significant difference in platelets between both groups (75.44 vs 51.62, P < 0.001), their change did not clinically differ between two groups. The findings indicated a significant difference of the average length of stay in hospitals (ALOS) between two groups, where the patients under regimen I showed a shorter ALOS (6.97 vs 9.93, P = 0.001)., Conclusion: This study revealed the beneficial effect of the short-term use of low-dose prednisolone in combination with azithromycin, naproxen and lopinavir/ritonavir (regimen I), in decreasing ALOS compared to regimen II. Since there is still lack of evidence for safety of this regimen, further investigation in our ongoing follow-up to deal with COVID-19 pneumonia is underway. Graphical abstract.

Amorphous solid dispersion (ASD) is a formulation strategy extensively used to enhance the bioavailability of poorly water soluble drugs. Despite this, they are limited by various factors such as limited drug loading, poor stability, drug-excipient miscibility and the choice of process platforms. In this work, we have developed a strategy for the manufacture of high drug loaded ASD (HDASD) using hot-melt extrusion (HME) based platform. Three drug-polymer combinations, indomethacin-Eudragit®E, naproxen-Eudragit®E and ibuprofen-Eudragit®E, were used as the model systems. The design spaces were predicted through Flory-Huggins based theory, and the selected HDASDs at pre-defined conditions were manufactured using HME and quench-cooled melt methods. These HDASD systems were also extensively characterised via small angle/wide angle x-ray scattering, differential scanning calorimetry, Infrared and Raman spectroscopy and atomic force microscopy. It was verified that HDASDs were successfully produced via HME platform at the pre-defined conditions, with maximum drug loadings of 0.65, 0.70 and 0.60 w/w for drug indomethacin, ibuprofen and naproxen respectively. Enhanced physical stability was further confirmed by high humidity (95%RH) storage stability studies. Through this work, we have demonstrated that by the implementation of predictive thermodynamic modelling, HDASD formulation design can be integrated into the HME process design to ensure the desired quality of the final dosage form., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Naproxen is a widely used non-steroidal anti-inflammatory drug for the control of postoperative inflammatory signs and symptoms in dentistry. Its association with esomeprazole has been widely studied and has yielded good results for the control of acute pain, even with the delayed absorption of naproxen owing to the presence of esomeprazole. To further understand the absorption, distribution, and metabolism of this drug alone and in combination with esomeprazole, we will analyze the pharmacokinetic parameters of naproxen and its major metabolite, 6-O-desmethylnaproxen, in saliva samples. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naproxen and 6-O-desmethylnaproxen in saliva will be developed and validated. Sequential saliva samples from six patients will be analyzed before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72, and 96 h after the ingestion of one naproxen tablet (500 mg) and esomeprazole-associated naproxen tablets (500 + 20 mg), at two different times. After liquid-liquid extraction with ethyl acetate and HCl, the samples will be analyzed using an 8040 Triple Quadrupole Mass Spectrometer (Shimadzu, Kyoto, Japan). Separation of naproxen and its major metabolic products will be performed using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column (Shimadzu, Kyoto, Japan) at 40°C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time will be 5 min. The detection and quantification of naproxen and its metabolite will be validated, which elucidate the pharmacokinetics of this drug, thereby contributing to its proper prescription for the medical and dental interventions that cause acute pain., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study was to design naproxen sodium (NS)-containing, biomimetic, porous poly(lactide- co -glycolide) (PLGA) scaffolds for regeneration of damaged corneal epithelium. Methods: NS-incorporated PLGA scaffolds were prepared using the emulsion freeze-drying method and then coated with collagen or poly-l-lysine. Porosity measurements of the scaffolds were performed by the gas adsorption/desorption method and the scaffolds demonstrated highly porous, open-cellular pore structures with pore sizes from 150 to 200 μm. Results: The drug loading efficiency of scaffolds was found to be higher than 84%, and about 90%-98% of NS was released at the end of 7 days with a fast drug release rate at the initial period of time and then in a slow and sustained manner. The corneal epithelial cells were isolated from New Zealand white rabbits. The obtained cells were seeded onto scaffolds and continued to increase during the time period of the study, indicating that the scaffolds might promote corneal epithelial cell proliferation without causing toxic effects for at least 10 days. Conclusions: The NS-loaded PLGA scaffolds exhibited a combination of controlled drug release and biomimetic properties that might be attractive for use in treatment of corneal damage both for controlled release and biomedical applications.

Background: Integrins are interesting targets in oncology. RGD sequence has high affinity for α V β 3 integrin receptors. Diagnostic/therapeutic agents can be selectively delivered into cancer cells overexpressing α V β 3 integrin by using RGD as a carrier. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown anticancer properties in in vitro and in vivo studies. The anti-cancer properties of NSAIDs occur though COX-2 inhibition. Regarding the anti-cancer properties of NSAIDs and overexpression of COX-2 enzyme in cancer cells, targeted delivery of NSAIDs into cancer cells to maximize their efficiency and minimize their side effects may gain increased clinical interest., Objectives: In this study, RGD was conjugated to ketoprofen/Naproxen to selectively transfer these non-selective COX inhibitors into cancer cells., Methods: Keto/Nap-RGD-N4 peptides were synthesized based on solid phase fmoc peptide synthesis. Radiolabeling with [ 99m Tc] via N4 (GGAG) ligand was done for biological evaluation. Affinity and specificity of Keto/Nap-RGD-N4 to integrin was determined using A2780, OVCAR-3, SKOV-3 and HT-1080 cell lines. Percentage of Intenalization was measured in A2780 cells. Biodistriburion was studied in normal and tumor model mice., Results: Radiolabeled compounds showed high affinity to cells expressing α V β 3 integrin in comparison to cells not expressing α V β 3 . The affinity to A2780 was significantly higher than OVCAR-3 cells. The %internalization into A2780 cells was quite low. Compounds showed more than 50% inhibition on A2780 and OVCAR-3 cells, less than 10% on MCF-7 and HT-1080 cells and no cytotoxicity on fibroblast cells after 48 h incubation. Although uptake of radiolabeled compounds in tumor was high at 1 h post-injection, the tumor/blood ratio was less than 1.5 which made SPECT imaging impossible., Conclusion: Provided that NSAID drugs are conjugated to RGD, there will be a selective delivery to target tissues as well as synergetic anti-tumor effects which reduce systemic doses and toxicity. Graphical abstract.

Background: In drug therapy for patients with arthritis, a naproxen/esomeprazole combination drug may be a tolerable choice because it can minimize gastrointestinal and cardiovascular adverse effects. The aim of this study was to investigate the changes in quality of life (QOL), medication adherence, and satisfaction after switch from the existing drug to the combination drug. In addition, we analyzed the correlation between the above-mentioned variables and the stratified demographic and medical data of the patients., Methods: A prospective, noninterventional, observational study was conducted in 30 hospitals between May 2014 and July 2016. In total, 2,308 patients with osteoarthritis, 99 patients with rheumatoid arthritis, and 76 patients with ankylosing spondylitis were enrolled. Demographic information (age, sex, body mass index [BMI], alcohol consumption, and smoking) and medical information (type of arthritis, duration of disease, and comorbidities) were collected via a self-administered questionnaire. Patients were observed for more than three months after switching to the combination drug. Data on the QOL (EuroQoL 5-Dimension questionnaire [EQ-5D questionnaire]), medication adherence (Morisky Medication Adherence Scale [MMAS]), and satisfaction were collected at the first and last visits., Results: A total of 2,483 patients enrolled at 30 hospitals completed the questionnaire. After the switch to the combination drug, the mean EQ-5D score improved from 0.72 ± 0.17 to 0.79 ± 0.14 ( p < 0.001), and significant improvement was associated with female sex ( p = 0.016), shorter disease duration ( p < 0.001), and absence of comorbidities ( p < 0.001). The mean MMAS score was 6.38 ± 1.77, indicating medium adherence. Satisfaction was significantly higher in female patients ( p < 0.001), in patients with a shorter disease duration ( p < 0.001), osteoarthritis ( p = 0.003), and no comorbidities ( p < 0.001). Serious drug-related adverse effects did not occur., Conclusions: The overall QOL was improved with medium adherence after the switch to the combination drug. On the basis of the analysis of stratified data, sex, age, drinking, smoking, disease duration, comorbidities, and BMI might be associated with QOL, satisfaction, and adherence., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 by The Korean Orthopaedic Association.)

Daily dosing of either NSAIDs or EGFR inhibitors has been shown to prevent bladder cancer development in a N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced rat model. However, these inhibitors cause gastrointestinal ulceration and acneiform rash, respectively, limiting their continuous use in a clinical prevention setting. We studied chemopreventive efficacy of pulsatile dosing of EGFR inhibitor erlotinib (42 mg/kg BW, once/week) combined with intermittent or continuous low doses of the NSAID naproxen (30 mg/kg BW/day, 3 weeks on/off or 128 ppm daily in diet) in the OH-BBN induced rat bladder cancer model. The interventions were started either at 1 or 4 weeks (early intervention) or 3 months (delayed intervention) after the last OH-BBN treatment, by which time the rats had developed microscopic bladder lesions. All combination regimens tested as early versus late intervention led to the reduction of the average bladder tumor weights (54%-82%; P < 0.01 to P < 0.0001), a decrease in tumor multiplicity (65%-85%; P < 0.01 to P < 0.0001), and a decrease in the number of rats with large palpable tumors (>200 mg; 83%-90%; P < 0.01 to P < 0.0001). Levels of signal transduction markers, Ki-67, cyclin D1, IL1β, pSTAT3, and pERK, were significantly ( P < 0.05 to P < 0.001) reduced in the treated tumors, demonstrating their potential utility as predictive markers for efficacy. These findings demonstrate that significant chemopreventive efficacy could be achieved with alternative intervention regimens designed to reduce the toxicity of agents, and that starting erlotinib and/or naproxen treatments at the time microscopic tumors were present still conferred the efficacy., (©2019 American Association for Cancer Research.)

Liqui-pellet is a new dosage form stemming from pelletisation technology and concept from liquisolid technology. In spite of liqui-pellet overcoming a major hurdle in liquisolid technology through achieving excellent flow property with high liquid load factor, the formulation requires to be optimised in order to improve drug release rate. Liqui-pellets of naproxen containing Tween 80, Primojel, Avicel and Aerosil were extruded and spheronised. Flowability test confirmed that all liqui-pellet formulations have excellent-good flow property (Carr's index between 3.9-11.17%), including liqui-pellets with a high liquid load factor of 1.52, where 38% of the total mass is co-solvent. This shows a relatively high liquid load factor can be achieved in liqui-pellet without compromising the flowability, which is one of the key novelty of this work. It was found that the improved drug release rate was due to the remarkably improved disintegration of the supposedly non-disintegrating microcrystalline-based pellet; the optimised liqui-pellet seems to explode into fragments in the dissolution medium. At pH 1.2, the optimised formulation had ~ 10% more drug release than non-optimised formulation after 2 h, and at pH 7.4, the drug release of the optimised pellet was nearing 100% at ~ 15 min, whereas the none-optimised pellet only achieved ~ 79% drug release after 2 h. DSC and XRPD indicated an increase in the dissolution rate could be due to molecularly dispersion of naproxen in the pellets. Overall results showed that liqui-pellet exhibited an enhanced drug release and the capacity for high liquid load factor whilst maintaining excellent flowability, rendering it a potentially commercially feasible drug delivery system.

Objectives: To compare the effectiveness and safety of naproxen and low-dose colchicine for treating gout flares in primary care., Methods: This was a multicentre open-label randomised trial. Adults with a gout flare recruited from 100 general practices were randomised equally to naproxen 750 mg immediately then 250 mg every 8 hours for 7 days or low-dose colchicine 500 mcg three times per day for 4 days. The primary outcome was change in worst pain intensity in the last 24 hours (0-10 Numeric Rating Scale) from baseline measured daily over the first 7 days: mean change from baseline was compared between groups over days 1-7 by intention to treat., Results: Between 29 January 2014 and 31 December 2015, we recruited 399 participants (naproxen n=200, colchicine n=199), of whom 349 (87.5%) completed primary outcome data at day 7. There was no significant between-group difference in average pain-change scores over days 1-7 (colchicine vs naproxen: mean difference -0.18; 95% CI -0.53 to 0.17; p=0.32). During days 1-7, diarrhoea (45.9% vs 20.0%; OR 3.31; 2.01 to 5.44) and headache (20.5% vs 10.7%; 1.92; 1.03 to 3.55) were more common in the colchicine group than the naproxen group but constipation was less common (4.8% vs 19.3%; 0.24; 0.11 to 0.54)., Conclusion: We found no difference in pain intensity over 7 days between people with a gout flare randomised to either naproxen or low-dose colchicine. Naproxen caused fewer side effects supporting naproxen as first-line treatment for gout flares in primary care in the absence of contraindications., Trial Registration Number: ISRCTN (69836939), clinicaltrials.gov (NCT01994226), EudraCT (2013-001354-95)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The present work aimed to develop an ethosomal gel of naproxen sodium for the amelioration of rheumatoid arthritis., Objective: In the present work, we have explored the potential of ethosomes to deliver naproxen into deeper skin strata. Further, the anti-inflammatory efficacy of naproxen ethosomal formulation was assessed using the carrageenan-induced rat paw edema model., Methods: Naproxen sodium nanoethosomes were prepared using different proportions of lipoid S100 (50mg-200mg), ethanol (20-50%) and water, and were further characterized on the basis of vesicle morphology, entrapment efficiency, zeta potential, in-vitro drug release and ex-vivo permeation studies., Results: The optimized ethosomal formulation was found to have 129 ± 0.01 nm particle size, 0.295 Polydispersity Index (PDI), -3.29 mV zeta potential, 88% entrapment efficiency and 96.573% drug release in 24 hours. TEM and SEM analysis of the optimized formulation showed slightly smooth spherical structures. The Confocal laser scanning microscopy showed that ethosomes could easily infiltrate into deeper dermal layers (upto 104.9μm) whereas the hydroalcoholic solution of the drug could penetrate up to 74.9μm. Further, the optimized ethosomal formulation was incorporated into 1% carbopol 934 gel base and optimized wherein the transdermal flux was found to be approximately 10 times more than the hydroethanolic solution. Also, the in-vivo pharmacodynamic study of the optimized ethosomal gel exhibited a higher percentage inhibition of swelling paw edema than marketed diclofenac gel., Conclusion: The ethosomal gel was successfully developed and has shown the potential to be a good option for the replacement of conventional therapies of rheumatoid arthritis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Due to numerous therapeutic applications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs worldwide. However, long-term use of these drugs can lead to damage to the gastrointestinal mucosa. The enteric nervous system (ENS), which is part of the autonomic nervous system, controls most aspects of gastrointestinal activity. Enteric neurons are characterized by considerable chemical plasticity and the appearance of a pathological factor results in a change in the synthesis of neurotransmitters. The purpose of this study was to determine the effects of naproxen on expression of biologically active substances by intramural neurons supplying the porcine duodenum. The study was performed on eight immature pigs of the Pietrain x Duroc race (approximately 20kg of body weight). The animals were divided into two groups - a control (C group) and an experimental group (N group). Group C (n=4) consisted of animals which received empty gelatine capsules. Group N (n=4) was composed of pigs who received naproxen orally for 28 days, approximately one hour before feeding. After this time, animals from both groups were euthanized. Frozen sections (14μm thickness) were then prepared from the collected duodenum and subjected to double immunofluorescence staining. Antibodies against the neuronal marker PGP 9.5 and against vasoactive intestinal polypeptide (VIP), substance P (SP), neuronal nitric oxide synthase (nNOS), galanin (GAL), pituitary adenylate cyclase-activating polypeptide (PACAP) and cocaine- and amphetamine- regulated transcript peptide (CART) were used as primary antibodies. The polyclonal donkey anti-rabbit, anti-mouse and anti-guinea pig IgG antibodies - Alexa Fluor 488 and 546 - were also used for staining. Analysis of the results obtained with a fluorescence microscope showed a significant increase in the number of nNOS-, VIP-, GAL-, PACAP- and CART-immunoreactive ganglionated neurons and a decrease in the number of SP-positive neurons in the myenteric and submucosal plexuses of the porcine duodenum. The obtained results indicate the participation of enteric neurotransmitters in the neuronal duodenal response to naproxen-induced inflammation., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Competing Interests: Competing interests: None declared.

Objectives: Many women experience menstrual cramps, which adversely affects quality-of-life. Both naproxen and acetaminophen are indicated to relieve menstrual pain. This study assessed the analgesic efficacy of a single, maximum non-prescription dose of naproxen sodium compared with that of acetaminophen in the treatment of primary dysmenorrhea. Methods: Healthy females with primary dysmenorrhea were included in our double-blind, randomized, crossover study (trial registration no. NCT03448536). When pain was moderate (≥5 on 0-10 numerical rating scale), subjects took a single dose of naproxen sodium (440 mg) and crossed over to acetaminophen (1000 mg) in the next cycle, or vice versa. Total pain relief over 12 h (TOTPAR0-12) was the primary outcome, while secondary outcomes included summed pain intensity differences (SPID) and TOTPAR scores throughout 12 h, and subject overall evaluation of treatment. Results: The per protocol population ( n  = 189) used naproxen sodium ( n  = 170) and acetaminophen ( n  = 160). TOTPAR0-12 was significantly greater with naproxen sodium than acetaminophen (least-squares (LS) mean difference = 4.31; p  < .001), and pain intensity was significantly lower (SPID0-12 LS mean difference = 9.80; p  < .001). Some measures of pain intensity favoring naproxen sodium became significant at earlier time points (e.g. SPID4-6 LS mean difference = 1.49; p  = .02). After 6 h post-dose, naproxen sodium was significantly more effective than acetaminophen, maintained for 12 h (SPID6-12 LS mean difference = 8.27; TOTPAR6-12 LS mean difference = 3.75; both p  < .001). Significantly more subjects rated naproxen sodium as good-to-excellent (70.6%) vs acetaminophen (63.1%) ( p  = .002). Conclusions: A single, maximum non-prescription dose of naproxen sodium was more effective than acetaminophen over 12 h.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line medications in mild-to-moderate acute pain. However, comparative data regarding the duration of analgesia for commonly-used NSAIDs at non-prescription doses is lacking. This study evaluated the time to rescue medication following a single dose of naproxen sodium (NAPSO) vs ibuprofen (IBU) and placebo in subjects with moderate-to-severe post-surgical dental pain. Methods: This single-center, randomized, double-blind, parallel group, placebo-controlled study included healthy subjects with moderate-to-severe baseline pain (Categorical Pain Intensity Scale) who also rated their pain ≥ 5 on a 0-10 pain intensity Numerical Rating Scale following extraction of two impacted mandibular third molars. A single oral dose of NAPSO (440 mg), IBU (400 mg), or placebo was administered. The primary efficacy endpoint was the time to first rescue medication, while secondary endpoints included the sum of pain intensity difference (SPID) and total pain relief (TOTPAR) over 24 h. ClinicalTrials.gov trial registration number: NCT03404206 (EudraCT 2017-005049-67). Results: In the per protocol population ( n  = 385; mean age = 19 years), the time to rescue medication was significantly ( p  < .001) longer with NAPSO than IBU and placebo. After treatment, the greatest separation of NAPSO from IBU occurred at 9-14 h and from placebo at 1-6 h. Fewer NAPSO subjects required rescue medication (58/166, 34.9%) compared with IBU (137/165, 83.0%) and placebo (44/54, 81.5%). SPID 0-24 h and TOTPAR 0-24 h were both greater with NAPSO than IBU or placebo. Conclusions: The duration of pain relief after a single dose of NAPSO was significantly longer than after IBU, and significantly fewer NAPSO-treated subjects required rescue medication over a 24-h period.

Objective: To quantify the rate of adverse events reported with naproxen compared with placebo, ibuprofen and acetaminophen at non-prescription doses in multiple-dose, multi-day (7-10 days) duration clinical trials and further contribute towards current knowledge regarding the safety profile of naproxen. Methods: Safety data were retrospectively collected from eight randomized, controlled trials that included subjects exposed to a fixed dosing regimen of 220-750 mg naproxen per day over 7-10 days. All data on adverse events and their duration, severity and possible relationship to the study drug were taken from the clinical study reports. The data were used in a post-hoc pooled analysis of participants exposed to naproxen 220-750 mg/day ( N  = 1494) and grouped according to age (<65 and ≥65 years), daily dose, race and gender. Results: The safety profile of naproxen closely resembled that of placebo, with similar rates of adverse events across treatment groups as the active comparators. There was no dose effect of naproxen, and there were no differences in older versus younger participants. Most events were mild to moderate. The most frequently reported adverse events in all groups were related to the gastrointestinal system (most commonly dyspepsia with naproxen), with no differences between groups. Conclusions: Our pooled analysis did not find an increased risk of adverse events with short-term use of non-prescription doses of naproxen compared with placebo, or compared to other common analgesics.

Objective: To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine., Methods: We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence., Results: There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia., Recommendations: Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counseling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse., (© 2019 American Academy of Neurology.)

Migraine is a debilitating condition; however, the pharmacological effects on central nervous system networks after successful therapy are poorly understood. Defining this neurocircuitry is critical to our understanding of the disorder and for the development of antimigraine drugs. Using an established inflammatory soup model of migraine-like pathophysiology (N = 12) compared with sham synthetic interstitial fluid migraine induction (N = 12), our aim was to evaluate changes in network-level functional connectivity after sumatriptan-naproxen infusion in awake, conscious rodents (Sprague-Dawley rats). Sumatriptan-naproxen infusion functional magnetic resonance imaging data were analyzed using an independent component analysis approach. Whole-brain analysis yielded significant between-group (inflammatory soup vs synthetic interstitial fluid) alterations in functional connectivity across the cerebellar, default mode, basal ganglia, autonomic, and salience networks. These results demonstrate the large-scale antimigraine effects of sumatriptan-naproxen co-administration after dural sensitization.

Inflammatory conditions of the temporomandibular joint (TMJ) and peripheral tissues affect many people around the world and are commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs). However, in order to get desirable results, treatments with NSAIDs may take weeks, causing undesirable side effects and requiring repeated administration. In this sense, this work describes the development of an optimized nanostructured lipid carrier (NLC) formulation for intra-articular administration of naproxen (NPX). An experimental design (2 3 ) selected the best formulation in terms of its physicochemical and structural properties, elucidated by different methods (DLS, NTA, TEM, DSC, and ATR-FTIR). The chosen formulation (NLC-NPX) was tested on acute inflammatory TMJ nociception, in a rat model. The optimized excipients composition provided higher NPX encapsulation efficiency (99.8%) and the nanoparticles were found stable during 1 year of storage at 25 °C. In vivo results demonstrated that the sustained delivery of NPX directly in the TMJ significantly reduced leukocytes migration and levels of pro-inflammatory cytokines (IL-1β and TNF-α), for more than a week. These results point out the NLC-NPX formulation as a promising candidate for the safe treatment of inflammatory pain conditions of TMJ or other joints.

The blood brain barrier is a major obstacle to the entry of the majority of CNS-active agents. In the present research, the potential of magnetic polymeric micelles (MPMs) for brain-targeting of naproxen was evaluated. The MPMs were made of methoxy poly(ethyleneglycol)-poly (caprolactone) copolymer and super paramagnetic iron oxide nanoparticles (SPIONs). To investigate the impact of particle size on the in vivo biofate of nanoparticles, MPMs with two different sizes were prepared. The prepared magnetic polymeric micelles had diameters of 137 ± 3.5 nm (MPM137) and 242 ± 6.2 nm (MPM242) and their surface charges were about -6.5 and - 4.5 mV, respectively. Pharmacokinetic and biodistribution of nanoparticles were characterized in rats using an external magnet of 0.4 Tesla field strength located on the skull of anesthetized animals. Significant differences in volumes of central as well as peripheral compartments were observed between both MPM formulations and free naproxen solution. After 8 h of administration, the brain concentration of naproxen was shown to be higher in the case of MPM137 in comparison with MPM242 and free drug. The findings revealed that the polymeric magnetic micelles with diameters smaller than 150 nm could be initially considered as a promising carrier to improve therapeutic agent accumulation in the brain for the treatment of CNS diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To determine the most effective analgesia for pain relief during the outpatient endometrial biopsy (OEB) or outpatient hysteroscopy with endometrial aspiration (EA)., Design: Systematic review and network meta-analysis of randomized controlled trials., Setting: Not applicable., Patient(s): Pre- or postmenopausal women undergoing OEB or outpatient hysteroscopy with EA for evaluation of uterine pathology., Intervention(s): We conducted an electronic search of the following bibliographic databases: Medline via PubMed, SCOPUS, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL)., Main Outcome Measure(s): The intensity of pain during, immediately after, and 10-30 minutes after procedure assessed by the 10-cm visual analog scale., Result(s): Lidocaine spray was the most effective medication for reducing pain during OEB (P-score = 0.83) and immediately after OEB (P-score = 0.96). On the other hand, naproxen sodium was the most effective medication for reducing pain during outpatient hysteroscopy with EA (P-score = 1.00), followed by misoprostol plus lidocaine (P-score = 0.87)., Conclusion(s): Lidocaine spray, either alone or with topical application of lidocaine, is the most effective medication for reducing the pain during and after the OEB. Naproxen sodium is the most effective analgesic option during outpatient hysteroscopy with EA., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The effect of naproxen on the treatment of neoplastic fever is still unclear. A systematic review and meta-analysis were performed to investigate the effect of naproxen in the treatment of cancer fever or suspicion. Besides, the latest and most convincing evidence was provided for the earlier use of naproxen in treating cancer patients with fever of unknown origin., Methods: A literature review was conducted to identify all published studies on the naproxen for the treatment of neoplastic fever. Electronic databases (eg, PUBMED, EMBASE and the Cochrane Library) were searched until October 2018. Data were extracted, and the risk of bias was assessed by 2 authors independently. Standard meta-analyses on the rate of successful treatment were conducted using a random-effects model, and relative risks were calculated with 95% confidence intervals (CIs)., Results: A total of 15 studies, recruiting 582 participants, were included, which were 1 randomized controlled trial (RCT), 1 non-RCT, 3 cross-sectional studies, and 10 case-series studies. The result of our meta-analysis revealed that the success rate on the treatment of neoplastic fever using naproxen was 94.1% (95% CI: 87.6%-97.3%). The success rate of the suspected neoplastic fever was 79.8%; for fever of unknown origin, it also reached 67.7%. In this meta-analysis, the success rate was 98.1% (95% CI: 95.0%-99.3%) in the dosage of 250 mg twice a day. Besides, a small dose of 125 mg naproxen, 375 mg twice a day and 250 mg 3 times a day were also useful. The result of the subgroup analysis revealed that the difference was not statistically significant in the treatment success rate for solid tumors and hematologic malignant., Conclusions: The result of our meta-analysis suggested that naproxen exhibited a highly successful rate for the treatment of neoplastic fever. Besides, naproxen was also satisfactory in improving symptoms of suspected neoplastic fever and fever of unknown origin. The earlier use of naproxen might be able to mitigate cancer patient's suffering and enhanced their quality of life. These findings, however, rely primarily on observational data and should be interpreted rigorously. Further well-conducted trials are required to assess naproxen for the treatment of neoplastic fever.

The embedding of nanoparticles in orodispersible films (ODFs) is an innovative strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (API). As the films are supposed to disintegrate within seconds when placed in the mouth, the disintegration time of the ODFs as well as the dissolution behavior of the API are of great interest. This study introduces a new possibility for a model-based description of these film properties to enable a prediction for the process layout for the manufacturing of the nanoparticle-loaded ODFs. Furthermore, this fundamental understanding can provide information on process robustness as a tool applied in future Quality by Design (QbD) approaches. The disintegration times of the nanoparticle-containing ODFs were measured with the SFaB method (slide frame and ball) and could be mathematically described considering the impact of the particle load and the dry film thickness on the disintegration behavior. Furthermore, it is considered if the films are disintegrated at the calculated time with a probability of 50% or any other probability. Besides the disintegration time, a clear influence of film parameters like the particle load, size of the embedded particles, film thickness and sample sizes was shown which affect the dissolution rate of the API from the ODF. The second model developed in the study identified a clear correlation between the total surface area of API particles in the film and the dissolution rate of the API, to predict the time period needed to release the API embedded in the ODFs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to assess the efficacy of naproxen in preventing heterotopic ossification (HO) after hip surgery (total hip arthroplasty [THA] and hip arthroscopy)., Methods: Using databases (PubMed, EMBASE, and Web of Science), we conducted an electronic, systematic search of randomized controlled trials (RCTs) comparing naproxen versus placebo on HO after hip surgery. The risk ratio (RR) of the dichotomous data, weighted mean difference (WMD) of continuous data, and 95% confidence intervals (CIs) were calculated to assess the effects of naproxen in patients with hip surgery., Results: A total of 4 studies including 269 patients were analyzed. Risk of bias was relatively high in allocation concealment and blinding. Compared with control group, administration naproxen was associated with a significantly reduction of the occurrence of HO at final follow-up after hip surgery (P < .05). What's more, naproxen was associated with a reduction of the Brooker I and II HO (P < .05). However, there was no significant difference between the Brooker III HO between naproxen and control groups (P > .05). Furthermore, there was no significant difference between the complications (P > .05) between naproxen and control groups., Conclusion: Naproxen has a beneficial role in reducing the total occurrence of HO, Brooker I and II HO after hip surgery. However, conclusions are limited due to the lack of high-quality studies. More high quality studies may help in a more reliable therapy for HO.

Hyaluronic acid (HA) is widely investigated due to its high potential for wound dressing applications. The fabrication of biomimetic HA-based scaffolds by electrospinning is thus extensively studied. However, HA is often dissolved in toxic organic solvents to allow the efficient production of electrospun nanofibers. Indeed, although HA is soluble in water, its ionic nature leading to long-range electrostatic interactions and the presence of counter ions induce a dramatic increase of the viscosity of aqueous HA solutions without insuring enough chain entanglements necessary for a stable and efficient electrospinning. In this study, biocompatible insoluble HA-based nanofibers were fabricated by electrospinning in pure water. To this end, poly(vinyl alcohol) (PVA) was added as a carrier polymer and it was found that the addition of hydroxypropyl-βcyclodextrin (HPβCD) stabilized the process of electrospinning and led to the efficient formation of uniform nanofibrous scaffolds. An in situ crosslinking process of the scaffolds is also proposed, insuring a whole fabrication process without any toxicity. Furthermore, the beneficial presence of HPβCD in the HA-based scaffolds paves the way for wound dressing applications with controlled drug encapsulation-release properties. As a proof of concept, naproxen (NAP), a non-steroidal anti-inflammatory drug was chosen as a model drug. NAP was impregnated into the scaffolds either in aqueous solution or under supercritical CO 2 . The resulting functional scaffolds showed a regular drug release profile along several days without losing the fibrous structure. This study proposes a simple approach to form stable HA-based nanofibrous scaffolds embedding HPβCD using water as the only solvent, enabling the development of safe functional wound dressings., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In spite of the large research efforts in the past two decades, it is still difficult, if possible at all, to predict what manufacturing technology will lead to the best amorphous solid dispersions (ASDs) in terms of drug to polymer ratio ("drug loading") and physical stability. In general, ASDs can be prepared by solvent based methods, heat based methods and mechanochemical activation. In the current study, one manufacturing technique per category was selected: spray drying, hot melt extrusion and cryo-milling, respectively. These processes were compared for their capability to formulate high drug loaded ASDs. High drug loadings may allow decreasing the pill burden and/or reducing dosage size, which both increase the therapeutic compliance. A fast crystallizer, naproxen, in combination with PVP K25, PVP-VA64, HPMC and HPMC-AS was used as a model system. Clear differences in the physical structure of the ASDs were observed. Our data indicate that not only the drug loading is dependent on the manufacturing process, but also the carrier that is able to incorporate the highest drug loading. This suggests that a carrier should be selected not only as function of the API, but also as function of the manufacturing process. Overall, hot melt extrusion showed to be most suited to reach high drug loadings for these naproxen-polymer combinations. This was in agreement with our finding that heat is an important energy input for mixing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This is a case study of the use of rapidly-dissolving naproxen crystalline nanoparticles to prepare compressed tablets. The dissolution rates of different formulations were determined: the crystalline pure-drug nanodispersion, a pure-drug microsuspension, a granule prepared by spray drying the nanodispersion with mannitol, and a tablet prepared by compressing the granule with a bulking agent and a disintegrant. The goal was to determine the influence of each of the process steps on the rapid dissolution of the nanodispersion. A procedure was developed to allow sampling during the first 120 s of dissolution. Dissolution of the nanodispersion was completed after 60 s under both sink and non-sink conditions. Spray drying with mannitol delayed dissolution slightly under both sink and non-sink conditions. Under sink conditions a microsuspension (volume median size 11 µm) showed similar rapid dissolution to the nanodispersion. We propose this to be a result of rapid shrinkage of the microparticles on dissolution under sink conditions. This nullifies any effects of specific surface on dissolution rate. Under non-sink conditions the microparticles retain their lower specific surface for a longer time during dissolution and dissolve therefore more slowly. When compressed into tablets, the dissolution rates of nanoparticles or microparticles were determined primarily by the tablet disintegration time; the influence of sink or non-sink conditions was only observable after disintegration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Liquid-assisted grinding (LAG) and dry ball milling (DBM) have recently been used to obtain different physical forms of drug-amino acid salts with promising dissolution and physical stability properties. In this work, crystalline and co-amorphous naproxen-arginine mixtures were prepared using LAG and DBM, respectively, and compared with regard to their in vitro and in vivo performance. X-ray powder diffraction and Fourier-transformed infrared spectroscopy showed that LAG led to the formation of a crystalline salt, while DBM led to a co-amorphous salt. These results agreed with the differential scanning calorimetry profiles: a melting point of 230 °C was determined for the crystalline salt, while the co-amorphous formulation showed a single glass transition temperature at approx. 92 °C. Both solid state forms of the salt showed increased intrinsic dissolution rates (14.8 and 74.1-fold, respectively) and also higher solubility (25.3 and 29.8-fold, respectively) compared to the pure crystalline drug in vitro. Subsequently, the co-amorphous salt revealed an improved bioavailability in a pharmacokinetic study, showing a 1.5-fold increase in AUC 0-t and a 2.15-fold increase in c max compared to the pure crystalline drug. In contrast, even though showing a better in vitro performance, the crystalline salt interestingly did not show an increase in bioavailability in comparison to pure crystalline naproxen., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This work describes S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential mucoadhesive platform. Preactivated thiomers (GC-NAC-MNA, GC-GSH-MNA) were synthesized by bond formation between GC-NAC or GC-GSH and 2-mercaptonicotinic acid (MNA) used as ligand. The presence of protected thiol moieties on this new class of thiolated GC made them not subject to oxidation. The structural modifications of the resulting derivatives were confirmed by proton Nuclear Magnetic Resonance ( 1 H NMR) and Size Exclusion Chromatography (SEC). The conjugates displayed 91.2% and 90.1% of S-preactivation for GC-NAC-MNA and GC-GSH-MNA, respectively. The polymers were tested in ex-vivo and in vitro for their mucoadhesive properties and toxicity. The results showed that the preactivation of GC-NAC and GC-GSH increased their mucoadhesive abilities compared to their thiolated precursors by 1.4-, 4.4-fold in time of adhesion evaluated using rotating cylinder method, 1.6-, 1.5-fold in total work of adhesion (TWA) and 2.0-, 1.3-fold in maximum detachment force (MDA) determined using tensile studies, respectively. Moreover, water-uptake studies showed an improved in weight indicating water-uptake strongly dependent on derivations, before erosion occurred, whereas disintegration took place for the thiolated polymers within the first hour. The S-preactivated modification did not affect the cell viability of Caco2 cells exposed to the polymers. The release of the model drug sodium naproxen from tablets prepared with a lyophilized mixture of drug and polymer was studied via dissolution apparatus revealing that the preactivation on GC-GSH and GC-NAC involves a slowdown in the drug release rate. The results shown that the novel preactivated thiolated GC-derivatives can be considered promising excipients for the development of mucoadhesive drug delivery systems., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Current osteoarthritis therapies aim to alleviate pain and maintain joint function. Non-prescription oral non-steroidal anti-inflammatory drugs are frequently used alone for pain relief in osteoarthritis. This post-hoc pooled analysis evaluated the analgesic efficacy and safety of two non-prescription doses of naproxen sodium for short-term use in patients with osteoarthritis of the knee or hip. A separate sub-group analysis of older patients who were administered a lower dose of naproxen sodium was performed., Methods: In four multi-center, multi-dose, randomized, parallel, double-blind, placebo-controlled studies, oral naproxen sodium (age-based dosing regimen: <65 years, 660 mg/day; ≥65 years, 440 mg/day) or placebo was administered over 7 days. Data at baseline and after 7 days in 818 patients who received naproxen sodium or placebo (n = 409 in each group) was pooled and analyzed. Five-point rating scales were used to assess knee or hip joint pain, stiffness after rest, day and night pain, and patient and investigator assessment of treatment, while function was evaluated using a timed 50-foot walk test., Results: Compared with placebo, there were significant improvements in pain and physical function with naproxen sodium (p < .05), and treatment was rated "good" to "excellent" significantly more often (p < .001) by investigators and patients. Efficacy results were similar among younger and older patients. There were no significant differences in adverse events between groups, regardless of age., Conclusions: For the acute management of underlying pain in patients with moderate osteoarthritis of the hip or knee, non-prescription naproxen sodium is effective and well tolerated in patients of all ages.