H2S Donors and Their Use in Medicinal Chemistry.

Hydrogen sulfide (H2S) 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 H2S 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 H2S levels has a potential therapeutic value. Consequently, synthetic H2S-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 H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.

In vivo study of light-driven naproxen release from gated mesoporous silica drug delivery system.

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.

Multivariate Assessment for Bioequivalence Based on the Correlation of Random Effect.

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 (Cmax) 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 Cmax from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for Cmax of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for Cmax in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for Cmax 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.

Comparison of individual and combination treatments with naproxen, prednisolone and hydroxychloroquine to treat Complete Freund's Adjuvant induced arthritis.

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.

Layered terbium hydroxides for simultaneous drug delivery and imaging.

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.

Liqui-Tablet: the Innovative Oral Dosage Form Using the Newly Developed Liqui-Mass Technology.

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.

Pulmonary drug delivery with aerogels: engineering of alginate and alginate-hyaluronic acid microspheres.

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 CO2 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/cm3 as well as high surface areas between 354 and 759 m2/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.

In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup'ik Alaska Native Population.

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.

Enhanced Drug Loading in the Drug-in-Adhesive Transdermal Patch Utilizing a Drug-Ionic Liquid Strategy: Insight into the Role of Ionic Hydrogen Bonding.

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.

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

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.

Spray drying of naproxen and naproxen sodium for improved tableting and dissolution - physicochemical characterization and compression performance.

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.

Simultaneous separation of naproxen and 6-O-desmethylnaproxen metabolite in saliva samples by liquid chromatography-tandem mass spectrometry: Pharmacokinetic study of naproxen alone and associated with esomeprazole.

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.

Exploration of Nanoethosomal Transgel of Naproxen Sodium for the Treatment of Arthritis.

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.

The clinical value of two combination regimens in the Management of Patients Suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.

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.

The design and development of high drug loading amorphous solid dispersion for hot-melt extrusion platform.

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.

Factors Affecting Quality of Life and Satisfaction in Patients with Arthritis after Change to a Fixed-Dose Naproxen/Esomeprazole Combination Drug.

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.

Development of an Anti-Inflammatory Drug-Incorporated Biomimetic Scaffold for Corneal Tissue Engineering.

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.

Optimising the release rate of naproxen liqui-pellet: a new technology for emerging novel oral dosage form.

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.

Long-term treatment with naproxen changes the chemical coding of the porcine intramural duodenum neurons.

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.