Effect of Substitution Degree and Homogeneity on Cyclodextrin-Ligand Complex Stability: Comparison of Fenbufen and Fenoprofen Using CD and NMR Spectroscopy.

The stability of host-guest complexes of two NSAID drugs with similar physicochemical properties, fenbufen and fenoprofen, was investigated by comparing induced circular dichroism and 1H nuclear magnetic resonance methods using eight cyclodextrins of different degrees of substitution and isomeric purity as guest compounds. These cyclodextrins include native ß-cyclodextrin (BCyD), 2,6-dimethyl-ß-cyclodextrin 50 (DIMEB50), 80 (DIMEB80) and 95% (DIMEB95) isomerically pure versions, low-methylated CRYSMEB, randomly methylated ß-cyclodextrin (RAMEB) and 4.5 and 6.3 average substitution grade hydroxypropyl-ß-cyclodextrin (HPBCyD). The stability constants obtained by the two methods show good agreement in most cases. For fenbufen complexes, there is a clear trend that the stability constant increases with the degree of substitution while isomer purity has a smaller effect on the magnitude of stability constants. A significant difference was found in the case of DIMEB50 when compared to DIMEB80/DIMEB95, while the latter two are similar. In the fenbufen-fenoprofen comparison, fenbufen, with its linear axis, gives a more stable complex, while fenoprofen shows lower constants and poorly defined trends.

Carborane Analogues of Fenoprofen Exhibit Improved Antitumor Activity.

Fenoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) against rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Like other NSAIDs, fenoprofen inhibits the synthesis of prostaglandins by blocking both cyclooxygenase (COX) isoforms, COX-1 the "house-keeping" enzyme and COX-2 the induced isoform from pathological stimuli. Unselective inhibition of both COX isoforms results in many side effects, but off-target effects have also been reported. The steric modifications of the drugs could afford the desired COX-2 selectivity. Furthermore, NSAIDs have shown promising cytotoxic properties. The structural modification of fenoprofen using bulky dicarba-closo-dodecaborane(12) (carborane) clusters and the biological evaluation of the carborane analogues for COX inhibition and antitumor potential showed that the carborane analogues exhibit stronger antitumor potential compared to their respective aryl-based compounds.

Advantages of Induced Circular Dichroism Spectroscopy for Qualitative and Quantitative Analysis of Solution-Phase Cyclodextrin Host-Guest Complexes.

The presence of a chiral or chirally perturbed chromophore in the molecule under investigation is a fundamental requirement for the appearance of a circular dichroism (CD) spectrum. For native and for most of the substituted cyclodextrins, this condition is not applicable, because although chiral, cyclodextrins lack a chromophore group and therefore have no characteristic CD spectra over 220 nm. The reason this method can be used is that if the guest molecule has a chromophore group and this is in the right proximity to the cyclodextrin, it becomes chirally perturbed. As a result, the complex will now provide a CD signal, and this phenomenon is called induced circular dichroism (ICD). The appearance of the ICD spectrum is clear evidence of the formation of the complex, and the spectral sign and intensity is a good predictor of the structure of the complex. By varying the concentration of cyclodextrin, the ICD signal changes, resulting in a saturation curve, and from these data, the stability constant can be calculated for a 1:1 complex. This article compares ICD and NMR spectroscopic and molecular modeling results of cyclodextrin complexes of four model compounds: nimesulide, fenbufen, fenoprofen, and bifonazole. The results obtained by the different methods show good agreement, and the structures estimated from the ICD spectra are supported by NMR data and molecular modeling.

Designing coordination polymers as multi-drug-self-delivery systems for tuberculosis and cancer therapy: in vitro viability and in vivo toxicity assessment.

A proof of concept for designing multi-drug-delivery systems suitable for self-drug-delivery is disclosed. Simple coordination chemistry was employed to anchor two kinds of drugs namely isoniazid (IZ - anti-tuberculosis), various non-steroidal-anti-inflammatory-drugs (NSAIDs) namely ibuprofen-IBU, fenoprofen-FEN, naproxen-NAP, diclofenac-DIC and mefenamic acid-MEF and Zn(NO3)2 to synthesize a series of 1D coordination polymers namely IZIBU, IZFEN, IZNAP, IZDIC and IZMEF which were structurally characterized by single crystal X-ray diffraction (SXRD). The coordination polymers wherein both types of drugs were anchored to Zn(II) metal centers could easily be ground to nano-sized particles suitable for biological studies by hand grinding in a mortar and pestle. Zone inhibition studies revealed that all the coordination polymers possessed antibacterial properties against Gram positive, Gram negative and mycobacteria namely Mycobacterium tuberculosis (M.tb). Detailed studies carried out on IZDIC employing flow cytometry and confocal microscopy under various staining conditions established that such antibacterial activity was due to the generation of reactive oxygen species (ROS) such as nitric oxide (NO) and also inhibition of mycolic acid leading to incomplete cell wall formation. It was also established that IZDIC could indeed inhibit the growth of M.tb within a mouse macrophage host cell namely RAW 264.7 thereby simulating the treatment of Tuberculosis (TB) under in vitro conditions. Scratch assay and cell cycle analysis on a human lung cancer cell line (A549) revealed its anti-cancer property, thereby indicating its potential as a multi-drug-delivery system. In vivo toxicity assessment (serum parameters, histopathology, and haemolysis) carried out on BALB/c mice showed that IZDIC was safe up to a concentration of 100 mg kg-1. Finally, a reasonably high yield in bulk synthesis, stability under high temperature and humid conditions, tabletability and, slow and sustained release of the drug component of IZDIC suggested its suitability in real-life applications as multi-drug-delivery systems.

Unusual human serum albumin fibrillation inhibition by ketoprofen and fenoprofen: Mechanistic insights.

Development of efficient therapeutic strategies to combat protein misfolding and fibrillation is of great clinical significance. In the current study, efforts have been made to obtain qualitative and quantitative insights into interactions of anti-inflammatory drugs; ketoprofen and fenoprofen with the transport protein HSA and their inhibitory action on fibrillation by employing a combination of calorimetric, spectroscopic, microscopic, and molecular docking methods. Interestingly, both ketoprofen and fenoprofen are able to completely inhibit fibrillation of HSA when added at a concentration of 0.5 mM for fenoprofen or 1 mM ketoprofen. Further, no amorphous aggregates are formed. Isothermal titration calorimetric studies highlight the predominant role of polar interactions of these drugs with protein in prevention of fibrillation. The role of conformational flexibility of benzoyl and phenoxy groups of drugs has been correlated with inhibition efficiency. Such studies highlight the role of functionality required for an inhibitor in addressing neurodegenerative diseases.

Copper(II) complexes with non-steroidal anti-inflammatory drugs: Structural characterization, in vitro and in silico biological profile.

Six novel copper(II) complexes with the non-steroidal anti-inflammatory drugs ibuprofen, loxoprofen, fenoprofen and clonixin as ligands were synthesized and characterized by diverse techniques including single-crystal X-ray crystallography. The in vitro scavenging activity of the complexes against 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) free radicals and the ability to reduce H2O2 were studied in the context of the antioxidant activity studies. The complexes may interact with calf-thymus DNA via intercalation as revealed by the techniques employed. The affinity of the complexes for bovine and human serum albumins was evaluated by fluorescence emission spectroscopy and the corresponding binding constants were determined. Molecular docking simulations on the crystal structure of calf-thymus DNA, human and bovine serum albumins were also employed in order to study in silico the ability of the studied compounds to bind to these target biomacromolecules, in terms of impairment of DNA and transportation through serum albumins, to explain the observed in vitro activity and to establish a possible mechanism of action.

Overloading behavior of fenoprofen and naproxen as two model compounds on a non-porous silicon pillar array column.

In this study, the adsorption behavior of naproxen and fenoprofen as two model compounds on a non-porous pillar array column (NPAC) was investigated under reverse phase liquid chromatography conditions. Band profiles of both analytes were recorded in overloaded concentrations using 30% methanol/water (v/v) as the mobile phase. Breakthrough experiments under the same chromatographic condition were carried out to measure the adsorption isotherms. Single-component adsorption isotherm data were acquired by frontal analysis for each analyte. The isotherms were found to be concave upward and downward for naproxen and fenoprofen, respectively. To find the best agreement between the experimental data points and the adsorption isotherm models, the obtained isotherms were modeled using several isotherm models. The Langmuir-Freundlich and anti-Langmuir models provided the best fitting for fenoprofen and naproxen, respectively. The solute and stationary phase properties determine the appropriate model. Adsorbate-adsorbate interaction is important in the case of naproxen, while the adsorbate- adsorbent (stationary phase) plays the main role in retention of fenoprofen on the NPAC. The validity of the selected isotherm models were checked by comparing calculated and experimental band profiles and plate heights. An excellent agreement was observed for the whole concentration range of both analytes, which confirmed the accuracy of the selected models.

Quantification of fenoprofen in human plasma using UHPLC-tandem mass spectrometry for pharmacokinetic study in healthy subjects.

A rapid, simple and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed to quantify fenoprofen, a nonsteroidal anti-inflammatory drug in human plasma for a pharmacokinetic study in healthy subjects. Owing to high levels of protein binding, protein precipitation followed by solid-phase extraction was employed for the extraction of fenoprofen and fenoprofen-d3 (used as internal standard) from 200 µL human plasma. Separation was performed on a BEH C18 (50 × 2.1 mm, 1.7 µm) column using methanol-0.2% acetic acid in water (75:25, v/v) under isocratic elution. Electrospray ionization was operated in the negative mode for sample ionization. Ion transitions used for quantification in the selected reaction monitoring mode were m/z 241/197 and m/z 244/200 for fenoprofen and fenoprofen-d3, respectively. Under the optimized conditions, fenoprofen showed excellent linearity in the concentration range 0.02-20 µg/mL (r2 ≥ 0.9996), adequate sensitivity, favorable accuracy (96.4-103.7%) and precision (percentage coefficient of variation ≤4.3) with negligible matrix effect. The validated method was successfully applied to a pharmacokinetic study of fenoprofen in healthy subjects. The significant features of the method include higher sensitivity, small plasma volume for processing and a short analysis time.

Fenoprofen-An Old Drug Rediscovered as a Biased Allosteric Enhancer for Melanocortin Receptors.

It is time-consuming and costly to bring new drugs to market, making it necessary and urgent to exploit existing drugs for new uses. Recently, fenoprofen was demonstrated as an allosteric modulator at melanocortin receptors (MCRs), although the exact mode of action has not been clarified. MCRs regulate multiple functions, including pigmentation, adrenal steroidogenesis, inflammation, energy homeostasis, and exocrine gland secretion. In this study, we showed that fenoprofen failed to displace the orthosteric agonist Nle4-d-Phe7-α-melanocyte stimulating hormone from binding to MC3-5R while possessing positive allosteric modulator activities at these receptors. In addition, fenoprofen induced biased signaling at MC3-5R, as it selectively activated ERK1/2 cascade but not the canonical cAMP signaling. Notably, fenoprofen stimulated biased signaling at MC3-5R, but not at MC1R, hence acting selectively among this highly conserved family of receptors. Moreover, PAM activity and biased signaling induced by fenoprofen were observed not only at wild-type but also at naturally occurring mutant MC3Rs, suggesting that this biased allosteric enhancer action might constitute as novel therapeutic opportunity for obese patients harboring these mutations. Our study might guide novel therapeutic applications for repurposing current drugs or designing new drugs combining allosteric and biased properties.

Synthesis of a molecularly imprinted polymer and its application in selective extraction of fenoprofen from wastewater.

The presence of various classes of pharmaceutical drugs in different environmental compartments has been reported worldwide. In South Africa, the detection of pharmaceuticals especially the non-steroidal anti-inflammatory drugs is recent, and more studies are being done in order to fully understand their fate in the aquatic environment. With considerations for the need of better sample preparation techniques, this study synthesized a molecularly imprinted polymer for the selective extraction of a non-steroidal anti-inflammatory drug, fenoprofen in aqueous environmental samples. Batch adsorption studies showed that adsorption of fenoprofen onto the cavities of the polymer followed a Langmuir isotherm as well as a pseudo second order model implying formation of a monolayer on the surface through chemisorption. The polymer had a maximum adsorption capacity of 38.8 mg g-1 and a Langmuir surface area of 1607 m2 g-1. The imprinted polymer was then used as the selective sorbent for solid phase extraction in the analysis of fenoprofen from wastewater followed by chromatographic determination. The analytical method gave a detection limit of 0.64 ng mL-1 and recovery of 99.6%. The concentration of fenoprofen detected in influent and effluent samples from two wastewater treatment plants ranged from 24 to 58 ng mL-1. The ability of the treatment plants to remove fenoprofen during wastewater processing based on the difference in concentrations in influent and effluent samples was found to be 41%. This work has shown that there is a possibility of release of fenoprofen from wastewater treatment plants into surface water sources.

Dried blood spots and parallel artificial liquid membrane extraction-A simple combination of microsampling and microextraction.

In this paper, parallel artificial liquid membrane extraction (PALME) was used for the first time to clean-up dried blood spots (DBS) prior to ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Fundamental studies exploring amongst others desorption from the DBS in alkaline or acidic aqueous conditions, total extraction time and absolute recoveries were executed. Desorption and PALME were performed using a set of two 96-well plates, one of them housing the sample and the other comprising the supported liquid membrane (SLM) and the acceptor solution. In one procedure, amitriptyline and quetiapine (basic model analytes) were desorbed from the DBS using 250 µL of 10 mM sodium hydroxide solution (aqueous), and subsequently extracted through the SLM consisting of 4 µL of 1% trioctylamine in dodecyl acetate, and further into an acceptor solution consisting of 50 µL of 20 mM formic acid. In a second procedure, ketoprofen, fenoprofen, flurbiprofen, and ibuprofen (acidic model analytes) were desorbed from the DBS into 20 mM formic acid, extracted through an SLM with dihexyl ether, and further into an acceptor solution of 25 mM ammonia. Within 60 min of PALME, both basic and acidic model analytes were effectively desorbed from the DBS and extracted into the acceptor solution, which was injected directly into the analytical instrument. Recoveries between 63 and 85% for the six model analytes were obtained. PALME provided excellent clean-up from the DBS samples, and acceptor solutions were free from phospholipids. Linearity was obtained with r2 > 0.99 for five of the six analytes. Accuracy, precision and UHPLC-MS/MS matrix effects were in accordance with the European Medicines Agency (EMA) guideline. Based on these experiments, PALME shows great potential for future processing of DBS in a short and simple way, and with the presented setup, up to 96 DBS can be processed within a total extraction time of 60 min.

Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation.

The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25-68%), water (2-3%), and the mixture of surfactant and cosurfactant (1:1) (24-67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1: 1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p < 0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.

Spectrophotometric determination of fenoprofen calcium drug in pure and pharmaceutical preparations. Spectroscopic characterization of the charge transfer solid complexes.

Simple, accurate and robust spectrophotometric method was developed for determination of fenoprofen calcium drug (FPC). The proposed method was based on the charge transfer (CT) reaction of FPC drug (as n-electron donor) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,4,6-trinitrophenol (picric acid, PA) or 1,2,5,8-tetrahydroxyanthraquinone (Quinalizarin, QZ) (as π-acceptors) to give highly colored charge transfer complexes. Different variables affecting the reaction such as reagent concentration, temperature and time have been carefully optimized to achieve the highest sensitivity. Beer's law was obeyed over the concentration ranges of 2-60, 0.6-90 and 4-30µgmL-1 using DDQ, PA and QZ CT reagents, respectively, with correlation coefficients of 0.9986, 0.9989 and 0.997 and detection limits of 1.78, 0.48 and 2.6µgmL-1 for the CT reagents in the same order. Elucidation of the chemical structure of the solid CT complexes formed via reaction between the drug under study and π-acceptors was done using elemental, thermal analyses, IR, 1H NMR and mass spectrometry. X-ray diffraction was used to estimate the crystallinity of the CT complexes. Their biological activities were screened against different bacterial and fungal organisms. The method was applied successfully with satisfactory results for the determination of FPC drug in fenoprofen capsules. The method was validated with respect to linearity, limit of detection and quantification, inter- and intra-days precision and accuracy. The proposed method gave comparable results with the official method.

Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain. OBJECTIVES: To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables. MAIN RESULTS: We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/159; fenoprofen 0/79; ketoprofen 0/30; ibuprofen 4/45; indomethacin 0/30; meloxicam 11/147; naproxen 10/285; and rofecoxib 0/209 (very low-quality evidence).There were few or no data for our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning as defined by validated scales; and quality of life as defined by validated scales (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for our primary and secondary outcomes as very low because there were limited data from studies and no opportunity for a meta-analysis. AUTHORS' CONCLUSIONS: We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.

Topical Delivery of Fenoprofen Calcium via Elastic Nano-vesicular Spanlastics: Optimization Using Experimental Design and In Vivo Evaluation.

The aim of this study was to investigate the potential of surfactant-based nanovesicular system (spanlastics) for topical delivery of fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. FPCa-loaded spanlastics were prepared by thin film hydration (TFH) technique according to a full factorial design to investigate the influence of formulation variables on the drug entrapment efficiency (%EE), particle size (PS), deformability index (DI), and the % drug released after 24 h through the cellulose membrane (Q24h) using Design-Expert® software. The optimized formula (composed of Span 60 and Tween 60 as an edge activator at weight ratio of 8: 2 in presence of Transcutol P as a cosolvent in the hydration media) exhibited the highest %EE (49.91 ± 2.60%), PS of 536.1 ± 17.14 nm, DI of 5.07 ± 0.06 g, and Q24h of 61.11 ± 2.70%; it was also characterized for morphology and physical stability. In vitro release study of FPCa-loaded spanlastic gel and conventional FPCa gel through a synthetic membrane and hairless rat skin were evaluated. The skin permeation study revealed that spanlastic gel exhibited both consistent and prolonged action. Finally, the % inhibition of carrageenan-induced rat paw edema of spanlastic gel was three times higher than the conventional FPCa gel after 24 h. In conclusion, spanlastic-based gel could be a great approach for improving topical delivery of fenoprofen calcium, providing both prolonged and enhanced anti-inflammatory activity in the treatment of arthritis.

Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A2 from Vipera russelli.

Secretory phospholipase A2 (sPLA2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC50 value of 11.52 µM. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the α-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r-/- mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.

Albumin Supplement Affects the Metabolism and Metabolism-Related Drug-Drug Interaction of Fenoprofen Enantiomers.

The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 µM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 µM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction.

A supramolecular topical gel derived from a non-steroidal anti-inflammatory drug, fenoprofen, is capable of treating skin inflammation in mice.

A new series of bioconjugates derived from a non-steroidal anti-inflammatory drug (NSAID), namely fenoprofen, has been synthesised by amidation with various biogenic molecules such as ß-alanine, aminocaproic acid and tyramine with the aim of converting the NSAID into a supramolecular gelator for plausible biomedical applications. One such bioconjugate (2) showed gelation ability with methylsalicylate (MS) and 1% menthol in methyl salicylate (MMS) solvents. These gels were characterized by table top rheology, high resolution-transmission electron microscopy (HR-TEM) and dynamic rheology. Gelator 2 was found to be biostable both in proteolytic enzymes and in blood serum of BALB/c mouse under physiological conditions. It was also found to be biocompatible, as revealed by the methyl thiazolyldiphenyl tetrazolium bromide (MTT) assay in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cells. The anti-inflammatory response (prostaglandin E2 assay, denoted PGE2 assay) of 2 was comparable to that of the parent drug fenoprofen calcium salt. Finally, a topical gel formulation of 2 displayed in vivo self-delivery application in treating imiquimod (IMQ) induced skin inflammation in BALB/c mice.

Enhanced analgesic properties and reduced ulcerogenic effect of a mononuclear copper(II) complex with fenoprofen in comparison to the parent drug: promising insights in the treatment of chronic inflammatory diseases.

Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm(2) while the one caused by [Cu(fen)2(im)2] was 22 mm(2). The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed.