SBA-15表面S-naproxen分子印迹聚合物微球的合成与分子识别特性

以手性药物左旋萘普生(S-naproxen)为模板分子,四乙烯基吡啶(4-VPy)为功能单体,采用表面印迹法,以介孔材料SBA-15为载体合成了能选择性识别S-naproxen的分子印迹聚合物微球。扫描电镜及孔结构分析结果表明,所合成的分子印迹聚合物微球具有粒径均匀、孔径分布窄、比表面积大等特点;同时扫描电镜、X射线衍射和红外光谱分析结果表明载体表面形成了分子印迹聚合物层,Scatchard分析表明分子印迹聚合物在自组装过程中存在两类结合位点,聚合物高亲和力和低亲和力结合位点的最大表观结合容量分别为Qmax1=2.504μmol/g,Qmax2=16.680μmol/g;分子印迹聚合物的热力学研究表明,吸附过程可以自发进行。

Chiral separation by (S)-naproxen imprinted monolithic column with mixed functional monomers

Molecularly imprinted polymers （MIPs）, using （S）-naproxen as template and the combination of butyl methacrylate （BMA） and MAA （1：1 molar ratio） as functional monomers were synthesized by an in situ polymerization reaction. The rendered monolithic column was evaluated in HPLC mode. The result showed that the monolithic MIPs with the combination of two monomers produced better chiral resolution of rac-naproxen （Rs = 1.55） and column efficiencies of imprinted molecules （N = 2860 plates/m） than that with pure MAA.

Suppository naproxen reduces incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis: Randomized controlled trial

AIM: To determine the efficacy of rectally administered naproxen for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).METHODS: This double-blind randomized control trial conducted from January 2013 to April 2014 at the Gastrointestinal and Liver Diseases Research Center in Rasht, Iran. A total of 324 patients were selected from candidates for diagnostic or therapeutic ERCP by using the simple sampling method. Patients received a single dose of Naproxen (500 mg; n = 162) or a placebo (n = 162) per rectum immediately before ERCP. The overall incidence of PEP, incidence of mild to severe PEP, serum amylase levels and adverse effects were measured. The primary outcome measure was the development of pancreatitis onset of pain in the upper abdomen and elevation of the serum amylase level to > 3 × the upper normal limit (60-100 IU/L) within 24 h after ERCP. The severity of PEP was classified according to the duration of therapeutic intervention for PEP: mild, 2-3 d; moderate 4-10 d; and severe, > 10 d and/or necessitated surgical or intensive treatment, or contributed to death.RESULTS: PEP occurred in 12% (40/324) of participants, and was significantly more frequent in the placebo group compared to the naproxen group (P < 0.01). Of the participants, 25.9% (84/324) developed hyperamylasemia within 2 h of procedure completion, among whom only 35 cases belonged to the naproxen group (P < 0.01). The incidence of PEP was significantly higher in female sex, in patients receiving pancreatic duct injection, more than 3 times pancreatic duct cannulations, and ERCP duration more than 40 min (Ps < 0.01). There were no statistically significant differences between the groups regarding the procedures or factors that might increase the risk of PEP, sphincterotomy, precut requirement, biliary duct injection and number of pancreatic duct cannulations. In the subgroup of patients with pancreatic duct injection, the rate of pancreatitis in the naproxen group was significantly lower than that in the placebo (6 patients vs 23 patients, P < 0.01, RRR = 12%, AR = 0.3, 95%CI: 0.2-0.6). Naproxen reduced the PEP in patients with ≥ 3 pancreatic cannulations (P < 0.01, RRR = 25%, AR = 0.1, 95%CI: 0.1-0.4) and an ERCP duration > 40 min (P < 0.01, RRR = 20%, AR = 0.9, 95%CI: 0.4-1.2).CONCLUSION: Single dose of suppository naproxen administered immediately before ERCP reduces the incidence of PEP.

Increased susceptibility of ethanol-treated gastric mucosa to naproxen and its inhibition by DA-9601, an Artemisia asiatica extract

AIM： To examine the effect of DA-9601, a new gastroprotective agent, on the vulnerability of ethanoltreated rat＇s stomach to naproxen （NAP）. METHODS： Male Sprague-Dawley rats were pretreated with 1 mL of 50% ethanol twice a day for 5 d and then NAP （50 mg/kg） was administered. DA-9601 was admin- istered 1 h before NAP. Four hours after NAP, the rats were killed to examine gross injury index （mm2）, histologic change and to determine mucosal levels of malondialdehyde （MDA）, prostaglandin E2 （PGE2）, glutathione （GSH） and myeloperoxidase （MPO）. RESULTS： Pretreatment of ethanol significantly increased NAP-induced gastric lesions, as well as an increase in NDA and MPO. On the contrary, mucosal PGE2 and GSH contents were decreased dramatically by ethanol pretreatment, which were aggravated by NAR DA-9601 significantly reduced NAP-induced gastric injury grossly and microscopically, regardless of pretreatment with ethanol. DA-9601 preserved, or rather, increased mucosal PGE2 and GSH in NAP-treated rats （P〈0.05）, with reduction in mucosal MDA and MPO levels. CONCLUSION： These results suggest that repeated alcohol consumption renders gastric mucosa more susceptible to NSAIDs though, at least in part, reduction of endogenous cytoprotectants including PGE2 and GSH, and increase in MPO activation, and that DA-9601, a new gastroprotectant, can reduce the increased vulnerability of ethanol consumers to NSAIDs-induced gastric damage via the mechanism in which PGE2 and GSH are involved.

Flow injection chemiluminescence determination of loxoprofen and naproxen with the acidic permanganate-sulfite system

A novel flow injection chemiluminescence（CL）method for the determination of loxoprofen and naproxen was proposed based on the CL system of KMnO4 and Na2SO3 in acid media.The CL intensity of KMnO4-Na2SO3 was greatly enhanced in the presence of loxoprofen and naproxen.The mechanism of the CL reaction was studied by the kinetic process and UV-vis absorption and the conditions were optimized.Under optimized conditions,the CL intensity was linear with loxoprofen and naproxen concentration in the range of 7.0×10^-8-1.0×10^-5g/mL and 2.0×10^-7-4.0×10^-6g/mL with the detection limit of 2.0×10-8g/mL and 3.0×10-8g/mL（S/N=3）,respectively.The relative standard deviations were 2.39% and 1.37% for 5.0×10^-7g/mL naproxen and 5.0×10^-7g/mL loxoprofen（n=10）,respectively.The proposed method was satisfactorily applied to the determination of loxoprofen and naproxen in pharmaceutical preparations.

Naproxen-induced liver injury

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the- counter medication since 1994, but has rarely been reported to cause liver injury. METHODS: We treated a 30-year-old woman with jaundice and intractable pruritus that developed shortly after taking naproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. RESULTS: The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. CONCLUSIONS: Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.

Preparation and evaluation of monolithic molecularly imprinted stationary phase for S-naproxen

An S-naproxen（S-NAP）molecularly imprinted monolithic stationary phase（MIMSP）with specific recognition for S-NAP and naproxen（NAP）was prepared by in situ technique,utilizing 4-vinylpridine（4-VP）as a function monomer,ethylene glycol dimethacrylate（EDMA）as a cross-linking agent,and low-polar solvents（toluene and dodecanol）as porogenic solvents.The selectivity of the polymers for S-NAP and NAP was evaluated by high performance liquid chromatography（HPLC）.The binding characteristics were tested by Scatchard analysis.Racemic NAP could be specifically separated to some extent.At the same time,NAP could be separated from ibuprofen under optimized conditions.Scatchard analysis showed that two classes of binding sites existed in the S-NAP-imprinted polymers,with their dissociation constants estimated to be 1.045 and 5.496 μM,respectively.The results demonstrate that S-NAP and NAP can be recognized specifically on the obtained MIMSP.

Insights and relative effect of aspirin, naproxen and ibuprofen containing hydrogels: From design to performance as a functional dual capacity restorative material and build in free radical defense: <i>In-vitro</i>studies

Restorative materials in the new era aim to be “bio-active” and long-lasting. It has been suggested that the anti-inflammatory activity of some non-steroidal anti-inflammatory drugs (NSAIDs) may be partly due to their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as to inhibit the respiratory burst of neutrophils triggered by various activating agents. As a part of our continuous interest of developing functional dual action restorative materials capable of being “bio-active” and long-lasting, we design and evaluate novel chitosan hydrogels containing krill oil (antioxidant containing material), naproxen, ibuprofen (non steroidal anti-inflammatory medication), aspirin (pain relieve medication and free radical scavengers) and combinations thereof (chitosan-H-krill oil, chitosan-H-krill oil-aspirin and chitosan-H-naproxen, chitosan-H-naproxen-krill oil, chitosan-H-krill oil-ibuprofen and chitosan-H-ibuprofen) as functional additive prototypes for further development of “dual function restorative materials”;secondly, determine their effect on the dentin bond strength of a composite and thirdly, evaluate the capability of newly designed hydrogels to play an integral role of “build in” free radical defense mechanism by using BSA solubility as a “molecular prototype” of the site of free radical attack in vitro. Materials and Methods: The above mentioned hydrogels were prepared by dispersion of the corresponding component in glycerol and acetic acid with the addition of chitosan gelling agent. The surface morphology (SEM), release behaviors (physiological pH and also in acidic conditions), stability of the therapeutic agent-antioxidant-chitosan and the effect of the hydrogels on the shear bond strength of dentin were also evaluated. Results: The release of aspirin, ibuprofen and naproxen confers the added benefit of synergistic action of a functional therapeutic delivery when comparing the newly designed chitosan-based hydrogel restorative materials to the commercially available products alone. Neither the release of aspirin, ibuprofen or naproxen nor the antioxidant stability was affected by storage over a 6- month period. The hydrogel formulations have a uniform distribution of drug content, homogenous texture and yellow color (SEM study). All chitosan dentin treated hydrogels gave significantly (P < 0.05;non-parametric ANOVA test) higher shear bond values (P < 0.05) than dentin treated or not treated with phosphoric acid. The model protein (BSA) was adopted to evaluate the chitosan-based functional biomaterials as defense for undesired free radical formation under in vitro conditions. Conclusion: The added benefits of the chitosan treated hydrogels involved positive influence on the aspirin, ibuprofen and naproxen release, increased dentin bond strength as well as demonstrated in vitro “build in” free radical defense mechanism, therefore acting as a “proof of concept” for the functional multi-dimentional restorative materials with the build in free radical defense mechanism.

Evaluation of naproxen-induced oxidative stress, hepatotoxicity and in-vivo genotoxicity in male Wistar rats

Naproxen(NP), a nonsteroidal anti-inflammatory drug(NSAID), is used for the treatment of common pain, inflammation and tissue damage. Genotoxicity testing of NP is of prime importance as it represents the largest group of drugs to which humans are exposed. Not many genotoxic studies are reported on NP;therefore, the present study investigated the detailed genotoxic and oxidative stress properties of NP.Male Wistar rats were administered NP orally at the doses of 38.91 and 65.78 mg/kg body weight for 14 days. Reduced glutathione(GSH), superoxide dismutase(SOD), catalase(CAT) and lipid peroxidation(LPO) activities/levels were measured in the liver, kidney and brain tissues. The aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(ALP) activities, and total bilirubin(TBIL) levels were measured in the liver tissues. Micronucleus frequency(micronucleus test MNT)and DNA damage(comet assay) were performed in the bone marrow cells and leukocytes, respectively.The results showed that NP treatment decreased the GSH levels and increased the SOD, CAT, LPO, ALT,AST, ALP and TBIL activities/levels compared to the control(p o 0.05). Results of MNT showed an increased micronucleus induction and comet assay showed a significant increase in DNA damage in the NP treated animals(p o 0.05). Treatment of NP resulted in the biochemical imbalance and induced oxidative stress that deteriorated the integrity of the cells, which caused significant damage to the genetic material and affected liver function in male Wistar rats. Therefore, NP is a potential genotoxic agent that induces genotoxicity and oxidative stress.

Synthesis and Evaluation of Glyceride Prodrugs of Naproxen

The glyceride ester derivatives 6a and 6b were prepared by reacting 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate with (S)-naproxen as potential prodrugs. The synthesis was achieved successfully with the aid of N,N’-dicyclohexyl- carbodiimide. These prodrugs were evaluated for anti inflammatory, analgesic and gastroprotective activity. It was found that prodrugs 6a and 6b showed less irritation to gastric mucosa as indicated by ulcer index. The synthesized glyceride esters were found to possess good pharmacological profile as shown by results of anti inflammatory and analgesic activity. The aqueous studies were performed in order to ensure the release of prodrugs. Both prodrugs were found to stable at acidic pH while undergoes hydrolysis at pH 7.4. These findings suggest that the glyceride prodrugs 6a and 6b might be used as potential biolabile derivatives.

A Validated Stability-Indicating UHPLC Method for Determination of Naproxen and Its Related Compounds in Bulk Drug Samples

A simple, rapid, precise, accurate, rugged and robust stability-indicating ultra-fast high performance liquid chromatographic (UHPLC) method has been developed for the estimation of related compounds (imp-A, imp-B, imp-C, imp-D and imp-E) in Naproxen and also the assay of Naproxen from bulk drug samples. The stability indicating capability of the method was proven by subjecting the samples to stress conditions such as acid, base, oxidation, photolysis and thermal degradation. The efficient chromatographic separation was achieved using mobile phase solution A prepared as buffer solution 10 mM monobasic potassium phosphate pH 4.0 ± 0.05 adjusted with diluted ortho phosphoric acid solution and solution B acetonitrile with linear gradient elution on poroshell 120 EC-C18 shot column (50 mm × 4.6 mm, 2.7 μm) and UV detection at 235 nm at a flow rate 1.0 mL/min, column oven temperature was set to 25?C. The above are all known impurities and degradation impurities are well resolved with Naproxen peak and these are eluted within a 10 min runtime of HPLC. The photo diode array detector was used for peak homogeneity testing during stress study experiments and the overall mass balance was found to be 99.2% to 100.2% in all stress conditions. The linear calibration range was found to be 0.05 μg/mL to 0.75 μg/mL for related compounds and 50 μg/mL to 150 μg/mL for Naproxen and the accuracy of the method was found to be 91.5% to 98.5% recovery for the related substance method and 95.4% to 97.4% recovery for the assay method. The Naproxen and related compounds were found to be stable up to 48 hours and the method validation data show excellent results for precision, linearity, specificity, limit of detection, limit of quantitation and robustness. The present method can be successfully used for routine QC and stability studies and it will help to reduce the analysis cost, time and effluent load compared to conventional HPLC methods.

Enantioseparation of Racemic Naproxen Esters on Cellulose Tris (4-methylbenzoate) Chiral Stationary Phase

Several kinds of racemic naproxen ester were successfully separated on CTMB chiral stationary phase with hexane-ethanol (98:2, vol./vol.) as the mobile phase. The influence of mobile phase composition and structure of racemic naproxen ester on chiral separation was studied and the chiral recognition mechanism of CTMB was discussed.

Synthesis and Characterization of Magnetic SiO_2 Nanoparticles Loaded with Naproxen for Anti-inflammatory Therapy

The aim of this study is to synthesize of magnetic SiO2 nanoparticles(MSNPs)loaded with Naproxen(NAP-MSNPs)for targeting anti-flammatory therapy.The Fe3O4 nanoparticles were coated with a thin layer of silica by stber method and the drug was encapsulated in it simultaneously.The optimal conditions were investigated for the synthesis of MSNPs.The shape,size,and phase structure of NAP-MSNP were characterized by transmission electron micrographs(TEM)and X-ray diffraction(XRD).The drug encapsulation efficiency was confirmed by FT-IR and measured by UV spectrometry.The NAP-MSNPs show the response at the external magnetic field and the drug could be released readily from NAP-MSNPs.All of these facts suggest the NAP-MSNPs could be applied in a promising drug release-controlling system for targeting anti-inflammatory therapy.

Controlled Release of Naproxen Sodium from Supermacroporous Cryogels

Cryogels are gel matrices that have interconnected macropores and are formed in freezing-thawing systems. These interconnected macropores give elasticity to cryogels. Transdermal controlled-release systems can be used to deliver drugs with short biological half-life and can maintain plasma levels of very potent drugs within a narrow therapeutic range for prolonged periods. In this study, cryogels have been used in a different area--transdermal controlled-release system, to obtain controlled drug release medium. For this purpose, naproxen sodium has been selected as a model drug. Naproxen, a propionic acid derivative, is a NSAID （nonsteroidal anti-inflammatory drug）. For controlled releasing of naproxen sodium, cryogels that have naproxen sodium in macropores have been prepared in sheet form for local application. Acrylamide based cryogel bands have been synthesized by flee radical cryogelation process. These cryogel bands have different pore size and includes naproxen sodium in their pores. This cryogel material has been characterized by swelling tests and SEM. Then, releasing ofnaproxen sodium from cryogels has been investigated at two different pH values, 7.4 and 5.5. According to experimental data, it has seen that these cryogel matrices that including naproxen sodium in macropores could be used in controlled drug releasing systems as bandages or other transdermal controlled releasing agents at room temperature

Synthesis and characterizations of naproxen intercalated Mg-Al layered double hydroxides

Naproxen （Nap）, a non-steroidal anti-inflammatory drug （NSAIDs）, was intercalated into the gallery of Mg-A1 layered double hydroxides （LDHs） by ion exchange and co-precipitation with different location of magnesium ion and aluminum ion solutions, respectively. The product was characterized with powder X-ray diffraction （XRD）, Fourier Transform Infrared spectral （FT-IR） and Thermogravimetry （TG）. The results showed an expanded LDH structure, indicating that the drug was successfully intercalated into LDH with the monolayer perpendicular to （along the short axis orientation in proper angle） Nap anion. As compared to the pure form of Nap, the thermal stability of the intercalated Nap was significantly enhanced due to the host-guest interaction involving hydrogen bond and electrostatic attraction. We further investigated the drug release characteristics of the pillared LDH materials by a dissolution test in simulation gastrointestinal and intestinal fluids under different pH values. The results indicated that the release percentages decrease upon increasing pH from 4.60 to 7.43, likely due to the dependence of release mechanism on pH. We have carded out a kinetic simulation to the release data and found that the dissolution mechanism was mainly responsible for the release behavior of Nap-LDHs at pH 4.60, while the ion-exchange mechanism was responsible for that at pH 7.43. In addition, the initial release rates and equilibrium percent releases of the nanohybrids depended significantly on the synthesis methods, from which we have proposed a schematic model. The current study clearly showed that this drug-inorganic layered material has prospective applications in drug delivery system.

Chemical inhibition of Arabidopsis PIN-FORMED auxin transporters by the anti-inflammatory drug naproxen

The phytohormone auxin plays central roles in many growth and developmental processes in plants.Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture.Here we reveal that naproxen,a synthetic compound with anti-inflammatory activity in humans,acts as an auxin transport inhibitor targeting PIN-FORMED(PIN)transporters in plants.Physiological experiments indicate that exogenous naproxen treatment affects pleiotropic auxin-regulated developmental processes.Additional cellular and biochemical evidence indicates that naproxen suppresses auxin transport,specifically PIN-mediated auxin efflux.Moreover,biochemical and structural analyses confirm that naproxen binds directly to PIN1 protein via the same binding cavity as the indole-3-acetic acid substrate.Thus,by combining cellular,biochemical,and structural approaches,this study clearly establishes that naproxen is a PIN inhibitor and elucidates the underlying mechanisms.Further use of this compound may advance our understanding of the molecular mechanisms of PIN-mediated auxin transport and expand our toolkit in auxin biology and agriculture.

Modeling multiple chemical equilibrium for reactive extraction of naproxen enantiomers with HP-β-CD as hydrophilic selector

Reactive extraction is an emerging technology for large-scale continuous resolution of drug enantiomers. The enantioselective extraction of R,S-naproxen by hydrophilic HP-β-CD in 1,2-dichloroethane was studied at 5℃. The experimental data were described by a reactive extraction model with a homogeneous aqueous phase reaction of R,S-naproxen with HP-β-CD which couples a complete description of chemical equilibria in aqueous phase with the overall phase equilibria of the system. Important parameters of this model were determined experimentally. The physical distribution coefficients for molecular and ionic NAP were 0.041 and 1.730, respectively. Here we show that the efficiency of extraction depends strongly on two process variables including pH and HP-β-CD concentration. The model predictions are compared graphically with the results of pre- vious experiments and there is a good agreement between each other. By the use of modeling and experiment, an optimized extraction condition with pH of 2.5 and HP-β-CD concentration of 0.1 mol/L was obtained with high enantioselectivity （a） of 1.59 and performance factor （pf） of 0,049. The model gives a good means of predicting enantiomers partitioning over a range of experimental conditions.

Enantioselective hydrolysis of naproxen ethyl ester catalyzed by polyclonal antibodies

BASED on the hypothesis of Pauling on enzyme action that free energy difference between theground and transition state is reduced by the specific binding of active center of enzyme to theintermediate,a large number of antibodies with catalytic power have been obtained successive-

Polyclonal antibody-catalyzed hydrolysis of naproxen ethyl ester

In 1986 two monumental reports appearing on antibody catalysis which combined the tremendous diversity of antibody with catalytic power of enzyme opened new horizons of chemical and immunogical fields. Since then, a large number of catalytic antibodies have been prepared successively by using designed organic molecules as haptens conjugated to carrier proteins to immunize the animals and screening out the desired monoclonal antibodies through hybridoma technology. So far more than fifty examples

Comparative analyses/evaluation of the textural properties of naproxen sodium tablets and powders prepared using microwave and other drying techniques

The properties of oral tablets are normally related to the properties of the powders they contain.Characterization of oral tablets is important for the development of tablets with rapid and safe release of the active ingredient.In this study,a new formulation of naproxen sodium was prepared and dried using microwave drying (MWD) and the following conventional drying techniques:freeze-drying (FD),vacuum drying (VD),and convective drying (CD).The reference drug powder (RDP) and dry granules MWG,CDG,VDG,and FDG,which were dried using MWD,CD,VD,and FD,respectively were compressed to form tablets labeled RF-TAB,MW-TAB,CD-TAB,VD-TAB,and FD-TAB,respectively.The dry granules and prepared tablets were characterized using Fourier transform infrared spectrometry,scanning electron microscopy,and X-ray diffraction.This study aimed to explore the correlation between the textural characteristics of the tablets and their respective powders for different drying methods.Although the morphologies of the dry particles were irregular,the prepared tablets were smooth and flat with few cracks.Drying increased the amorphous nature of the granules but decreased their crystallinity.The crystallinities of all tablets,except those prepared by VD,decreased after compression.In summary,the characteristics of the prepared tablets were acquired from their respective powders.