A Molecular docking study to predict enantioseparation of some chiral carboxylic acid derivatives by methyl-β-cyclodextrin

NASA Astrophysics Data System (ADS)

Nurhidayah, E. S.; Ivansyah, A. L.; Martoprawiro, M. A.; Zulfikar, M. A.

2018-05-01

A molecular docking study, using molecular mechanics calculations with Arguslab, was used to help predict the enantioseparation of some guest molecules of chiral carboxylic acid derivatives by heptakis-2,6-di-O-methyl-β-cyclodextrin (DIMEB) and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TRIMEB) as host molecules. The small differences in the binding free energy values (ΔΔG) obtained from Arguslab did not indicate any significant enantioseparation. From the molecular docking simulation results, it is predicted that in the case of DIMEB as host molecule, R-enantiomer of Etodolac, Fenoprofen, Indoprofen, Ketorolac, and Naproxen will be eluted first than S-enantiomer; However, S-enantiomer of Carprofen, Flurbiprofen, Ketoprofen, Pirprofen, Proglumide, Sulindac, Surprofen, and Zaltoprofen will be eluted first than R-enantiomer by DIMEB as host molecule. When TRIMEB is used as a host molecule, R-enantiomer of Carprofen, Flurbiprofen, Indoprofen, Ketoprofen, Naproxen, Pirprofen, and Surprofen will be eluted first than S-enantiomer; However, S-enantiomer of Etodolac, Fenoprofen, Ketorolac, Proglumide, Sulindac and Zaltoprofen will be eluted first than R-enantiomer by TRIMEB as host molecule.

Probes for narcotic receptor mediated phenomena. 42. Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

PubMed Central

Kim, Jin-Hee; Deschamps, Jeffrey R.; Rothman, Richard B.; Dersch, Christina M.; Folk, John E.; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.

2011-01-01

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan (rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest μ-opioid receptor affinity (Ki = 1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([35S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist. PMID:21570305

Liposomal Aloe vera trans-emulgel drug delivery of naproxen and nimesulide: A study

PubMed Central

Venkataharsha, Panuganti; Maheshwara, Ellutla; Raju, Y Prasanna; Reddy, Vayalpati Ashok; Rayadu, Bandugalla Sanjeev; Karisetty, Basappa

2015-01-01

Introduction: The present aim of this study was to formulate naproxen and nimesulide liposomal formulation for incorporation in Aloe vera transemulgel and to carry out in vitro and in vivo evaluation of the formulation. Material and Methods: A. vera gel was prepared and used as a gel base for formulation. Carbopol 934 is used as a gelling agent and Methyl paraben was used as a preservative for the formulation of the gel. Liposomes was formulated by using hydration method. The formulated naproxen and nimesulide liposomal formulation using A. vera trans-emul gel were evaluated for in vitro studies such as drug release, permeation study, and drug content and entrapment efficiency. Paw edema method in Wistar rats induced by carrageenan is used to study in vivo anti-inflammatory action. Result: From the in vitro studies such permeability drug release naproxen 65% (69.6), Nimesulide 65% (61.1), and commercial Nimsulide gel (60.82) at 240 min. In vivo data shows that formulated liposomal transemulgel formulation are superior in their efficacy compared to commercial and A. vera gel. The results are compared with the commercial formulations. Conclusion: From our results, it is concluded that the A. vera trans emul gel using nimesulide and naproxen liposomal formulation is stable and prepared gel base is effective for formulation with high drug release and drug content compared with commercial formulation with significant anti-inflammatory effect. PMID:25599030

Enantioselective separation of racemic juvenile hormone III by normal-phase high-performance liquid chromatography and preparation of [(2)H(3)]juvenile hormone III as an internal standard for liquid chromatography-mass spectrometry quantification.

PubMed

Ichikawa, Akio; Ono, Hiroshi; Furuta, Kenjiro; Shiotsuki, Takahiro; Shinoda, Tetsuro

2007-08-17

Juvenile hormone III (JH III) racemate was prepared from methyl (2E,6E)-farnesoate via epoxidation with 3-chloroperbenzoic acid (mCPBA). Enantioselective separation of JH III was conducted using normal-phase high-performance liquid chromatography (HPLC) on a chiral stationary phase. [(2)H(3)]Methyl (2E,6E)-farnesoate was also prepared from (2E,6E)-farnesoic acid and [(2)H(4)]methanol (methanol-d(4)) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP); the conjugated double bond underwent isomerization to some degree. Epoxidation of [(2)H(3)]methyl (2E,6E)-farnesoate with mCPBA gave a novel deuterium-substituted internal standard [(2)H(3)]JH III (JH III-d(3)). The standard curve was produced by linear regression using the peak area ratios of JH III and JH III-d(3) in liquid chromatography-mass spectrometry (LC-MS).

Probes for Narcotic Receptor Mediated Phenomena. 37.1 Synthesis and Opioid Binding Affinity of the Final Pair of Oxide-Bridged Phenylmorphans, the ortho- and para-b Isomers and Their N-Phenethyl Analogues, and the Synthesis of the N-Phenethyl Analogues of the ortho- and para-d Isomers

PubMed Central

Kurimura, Muneaki; Liu, Hehua; Sulima, Agnieszka; Hashimoto, Akihiro; Przybyl, Anna K.; Ohshima, Etsuo; Kodato, Shinichi; Deschamps, Jeffrey R.; Dersch, Christina M.; Rothman, Richard B.; Lee, Yong Sok; Jacobson, Arthur E.; Rice, Kenner C.

2008-01-01

In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphansa 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent κ-receptor antagonists in the [35S]GTPγS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d oxide-bridged phenylmorphana series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47. PMID:19053757

Geranylated flavonoids from the roots of Campylotropis hirtella and their immunosuppressive activities.

PubMed

Shou, Qing-Yao; Fu, Run-Zhong; Tan, Qing; Shen, Zheng-Wu

2009-08-12

In an effort to identify new immunosuppressive agents from natural sources, 12 new geranylated flavonoids, 5,7,4'-trihydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavone (1), a racemate of 5,7,2',4'-tetrahydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavanone (2), 2''(S)-5,7-dihydroxy-[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (3), (2''S,3''R,4''S)-5,7,3'',4''-tetrahydroxy[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (4), a racemate of 3'-geranyl-5,7,2',4'-tetrahydroxyisoflavanone (5), a racemate of 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavanone (6), 3'-geranyl-5,7,4',5'-tetrahydroxyisoflavone (8), 3'-geranyl-5,7,2',5'-tetrahydroxyisoflavone (9), 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavone (10), 2(R),3(R)-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (12), (2R,3R)-6-methyl-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (13), and 5,7-dihydroxy-4'-O-geranylisoflavone (14), were isolated from the roots of Campylotropis hirtella (Franch.) Schindl. together with three previously described flavonoids. Their structures were elucidated by spectroscopic measurements, including two-dimensional nuclear magnetic resonance (NMR) techniques. The immunosuppressive effects of these compounds were assessed using mitogen-induced splenocyte proliferation, and the cytotoxicity of the compounds was also examined. The IC50 values of the compounds were found to be in the range of 1.49-61.23 microM for T lymphocyte suppression and 1.16-73.07 microM for B lymphocyte suppression. An analysis of their structure-activity relationships revealed that an isoflavonoid carbon skeleton with a C10 substituent at the C3' position was necessary for the activity. As many of the compounds exhibited good immunosuppressive activities, they may be promising as novel immunosuppressive agents.

Functionalized β-cyclodextrin based potentiometric sensor for naproxen determination.

PubMed

Lenik, Joanna; Łyszczek, Renata

2016-04-01

Potentiometric sensors based on neutral β-cyclodextrins: (2-hydroxypropyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin and anionic β-cyclodextrin: (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin chloride for naproxen are described. Inclusion complexes of naproxen with the above-mentioned cyclodextrins were studied using IR spectroscopy. The electrode surface was made from PVC membranes doped with the appropriate β-cyclodextrin as ionophores and quaternary ammonium chlorides as positive charge additives that were dispersed in plasticizers. The optimum membrane contains heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, o-nitrophenyloctyl ether and tetraoctyl ammonium chloride as a lipophilic salt. The electrode is characterized by a Nernstian response slope of -59.0 ± 0.5 mV decade(-1) over the linear range of 5.0 × 10(-5)-1.0 × 10(-2) mol L(-1) and the detection limit 1.0 × 10(-5) mol L(-1), as well as the response time 10s. It can be used in the pH range 6.2-8.5 for 10 months without any considerable deterioration. Incorporation of β-cyclodextrins improved the electrode selectivity towards naproxen ions from several inorganic and organic interferents and some common drug excipients due to concovalent interactions (host molecule-guest molecule). The notable advantages of the naproxen-selective electrode include its high sensitivity, high selectivity, cost-effectiveness as well as accurate and comfortable application in drug analysis and milk samples. Copyright © 2015. Published by Elsevier B.V.

Additive free preparative chiral SFC separations of 2,2-dimethyl-3-aryl-propanoic acids.

PubMed

Wu, Dauh-Rurng; Yip, Shiuhang Henry; Li, Peng; Sun, Dawn; Kempson, James; Mathur, Arvind

2016-11-30

A series of racemic 2,2-dimethyl-3-aryl-propanoic acids were resolved by chiral supercritical fluid chromatography (SFC) without the use of an acidic additive, trifluoroacetic acid (TFA). The use of additive-free protic methanol as co-solvent in CO 2 was expanded to successfully resolve other series of carboxylic acid containing racemates. Large-scale SFC of racemic acid 4, 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid, in methanol without TFA as additive on both Chiralpak AD-H and Chiralcel OJ-H will be discussed, along with impact on throughput and solvent consumption. Investigation of co-solvent effect on peak sharpening of acid racemate 20, 2-(2-chloro-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid, without TFA further indicated that methanol in CO 2 provided improved peak shape compared with isopropanol (IPA) and acetonitrile. Finally, we discuss the resolution of basic aromatic chiral amines without the addition of basic additives such as diethylamine (DEA) and application of this protocol for the large-scale SFC separation of weakly basic indazole-containing racemate 14, methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate, in methanol without DEA. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and validation of an LC-ESI-MS/MS method for the simultaneous quantification of naproxen and sumatriptan in human plasma: application to a pharmacokinetic study.

PubMed

Brêtas, Juliana Machado; César, Isabela Costa; Brêtas, Camila Machado; Teixeira, Leonardo de Souza; Bellorio, Karini Bruno; Mundim, Iram Moreira; Pianetti, Gerson Antônio

2016-06-01

A sensitive and fast liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of naproxen and sumatriptan in human plasma. A simple liquid-liquid extraction procedure, with a mixture of ethyl acetate, methyl tert-butyl ether, and dichloromethane (4:3:3, v/v), was used for the cleanup of plasma. Naratriptan and aceclofenac were employed as internal standards. The analyses were carried out using an ACE C18 column (50 × 4.6 mm i.d.; particle size 5 μm) and a mobile phase consisting of 2 mM aqueous ammonium acetate with 0.025 % formic acid and methanol (38:62, v/v). A triple-quadrupole mass spectrometer equipped with an electrospray source in the positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 231.67 → m/z 185.07, m/z 296.70 → m/z 157.30, m/z 354.80 → m/z 215.00, and m/z 336.80 → m/z 97.94 for naproxen, sumatriptan, aceclofenac, and naratriptan, respectively. The method was validated and proved to be linear, accurate, precise, and selective over the ranges of 2.5-130 μg mL(-1) for naproxen and 1-50 ng mL(-1) for sumatriptan. The validated method was successfully applied to a pharmacokinetic study with simultaneous administration of naproxen sodium and sumatriptan succinate tablet formulations in healthy volunteers.

2-Methyltetrahydrofuran and cyclopentyl methyl ether for green solid-phase peptide synthesis.

PubMed

Jad, Yahya E; Acosta, Gerardo A; Khattab, Sherine N; de la Torre, Beatriz G; Govender, Thavendran; Kruger, Hendrik G; El-Faham, Ayman; Albericio, Fernando

2016-02-01

2-MeTHF and CPME were evaluated as greener alternatives for the most employed solvents in peptide synthesis. The ability of these solvents to dissolve amino acid derivatives and a range of coupling reagents were evaluated as well as the swelling of polystyrene and polyethylene glycol resins. In addition, racemization and coupling efficiencies were also determined. We concluded that the use of 2-MeTHF with combination of DIC/OxymaPure gave the lowest racemization level during stepwise synthesis of Z-Phg-Pro-NH2 and the highest purity during SPPS of Aib-enkephalin pentapeptide (H-Tyr-Aib-Aib-Phe-Leu-NH2).

Racemization of aspartic acid and phenylalanine in the sweetener aspartame at 100 degrees C.

PubMed Central

Boehm, M F; Bada, J L

1984-01-01

The racemization half-lives (i.e., the time required to reach a D/L = 0.33) at pH 6.8 for aspartic acid and phenylalanine in the sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester) were determined to be 13 and 23 hours, respectively, at 100 degrees C. Racemization at this pH does not occur in aspartame but rather in its diketopiperazine decomposition product. Our results indicate that the use of aspartame to sweeten neutral pH foods and beverages that are then heated at elevated temperature could generate D-aspartic acid and D-phenylalanine. The nutritive consequences of these D-amino acids in the human diet are not well established, and thus aspartame should probably not be used as a sweetener when the exposure of neutral pH foods and beverages to elevated temperatures is required. At pH 4, a typical pH of most foods and beverages that might be sweetened with aspartame, the half-lives are 47 hours for aspartic acid and 1200 hours for phenylalanine at 100 degrees C. Racemization at pH 4 takes place in aspartame itself. Although the racemization rates at pH 4 are slow and no appreciable racemization of aspartic acid and phenylalanine should occur during the normal use of aspartame, some food and beverage components could conceivably act as catalysts. Additional studies are required to evaluate whether the use of aspartame as a sugar substitute might not in turn result in an increased human consumption of D-aspartic acid and D-phenylalanine. PMID:6591191

Protopine hydrochloride.

PubMed

Dostál, J; Zák, Z; Necas, M; Slavík, J; Potácek, M

2001-05-01

Protopine hydrochloride (5,6,14,14a-tetrahydro-14a-hydroxy-7-methyl-8H-bis[1,3]benzodioxolo[5,6-a:4,5-g]quinolizinium chloride, C20H20NO5(+)-Cl(-)) is the salt of the isoquinoline alkaloid protopine. It is formed by the action of dilute hydrochloric acid on the protopine free base. The N-methyl and hydroxyl groups are in a trans configuration in the quinolizine ring and the central quinolizine N-C bond is unusually long [1.579 (2) A]. The crystal is a racemate.

High enantiomeric excess of the flavor relevant 4-alkyl-branched Fatty acids in milk fat and subcutaneous adipose tissue of sheep and goat.

PubMed

Kaffarnik, Stefanie; Heid, Carolina; Kayademir, Yasemin; Eibler, Dorothee; Vetter, Walter

2015-01-21

Volatile 4-alkyl-branched fatty acids are characteristic flavor compounds of sheep and goat. Due to the methyl branch, the carbon C-4 represents a stereogenic center with the possible presence of one or both enantiomers in the respective samples. In this study, we used enantioselective gas chromatography to study the enantiomeric composition of 4-methyloctanoic acid (4-Me-8:0) and 4-ethyloctanoic acid (4-Et-8:0) in milk and dairy products from sheep and goat as well as in goat subcutaneous tissue. Different columns coated with modified cyclodextrins were tested to resolve racemic 4-alkyl-branched fatty acid methyl ester standards. The best enantiomer resolution was obtained on 25% octakis(2,3,6-tri-O-ethyl)-γ-cyclodextrin (γ-TECD) diluted in OV-1701. For analysis of the food samples, the lipids were extracted and fatty acids in the extracts were converted into fatty acid methyl esters. Non-aqueous reversed-phase high-performance liquid chromatography was used to fractionate the samples in order to gain one solution enriched in 4-Me-8:0 methyl ester and one solution enriched with 4-Et-8:0 methyl ester. Subsequent analysis by enantioselective gas chromatography with mass spectrometry allowed only the detection of one enantiomer of 4-Me-8:0 and 4-Et-8:0 in the samples. By means of a non-racemic standard of 4-Me-8:0, it was found that the predominant enantiomer was (R)-4-Me-8:0.

Optical resolution by preferential crystallization of (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid and its use in synthesizing optically active 2-amino-2-methyl-3-phenylpropanoic acid.

PubMed

Shiraiwa, Tadashi; Suzuki, Masahiro; Sakai, Yoshio; Nagasawa, Hisashi; Takatani, Kazuhiro; Noshi, Daisuke; Yamanashi, Kenji

2002-10-01

To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield optically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indicated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical purities of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.

Enantio-alteration of gene transcription associated with bioconcentration in adult zebrafish (Danio rerio) exposed to chiral PCB149

NASA Astrophysics Data System (ADS)

Chai, Tingting; Cui, Feng; Mu, Pengqian; Yang, Yang; Xu, Nana; Yin, Zhiqiang; Jia, Qi; Yang, Shuming; Qiu, Jing; Wang, Chengju

2016-01-01

Enantioselective enrichment of chiral PCB149 (2,2’,3,4’,5’,6-hexachlorobiphenyl) was analysed in adult zebrafish (Danio rerio) exposed to the racemate, (-)-PCB149, and (+)-PCB149. Greater enrichment of (-)-PCB149 compared to (+) PCB149 was observed following 0.5 ng/L exposure; however, as the exposure time and concentration increased, racemic enrichment was observed in adult fish exposed to the racemate. No biotransformation between the two isomers was observed in fish exposed to single enantiomers. When zebrafish were exposed to different forms of chiral PCB149, enantioselective expression of genes associated with polychlorinated biphenyls (PCBs) was observed in brain and liver tissues and enantioselective correlations between bioconcentration and target gene expression levels were observed in brain and liver tissues. The strong positive correlations between expression levels of target genes (alox5a and alox12) and PCB149 bioconcentration suggest that prolonged exposure to the racemate of chiral PCB149 may result in inflammation-associated diseases. Prolonged exposure to (-)-PCB149 may also affect metabolic pathways such as dehydrogenation and methylation in the brain tissues of adult zebrafish. Hepatic expression levels of genes related to the antioxidant system were significantly negatively correlated with bioconcentration following exposure to (+)-PCB149.

Separation of the stereoisomers of the main metabolite of a non-steroidal anti-inflammatory drug, flobufen, by chiral high-performance liquid chromatography.

PubMed

Wsól, V; Fell, A F; Kvasnicková, E; Hais, I M

1997-02-07

The major metabolite of a novel non-steroidal anti-inflammatory drug, DL-4-(2',4'-difluorobiphenyl-4-yl)-2-oxo-2-methylbutanoic acid (flobufen, I), namely 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-gamma-butyrolactone (4-dihydroflobufen lactone, III), has four stereoisomers consisting of two racemic pairs of enantiomers. Of three chiral stationary phases tested, Cyclobond I beta-RSP (Astec) (beta-cylodextrin derivatized with R,S-hydroxypropyl) was best able to separate the (+2)(--) racemate, with a liquid phase containing acetonitrile as modifier and triethylamine acetate as buffer. Using the Box-Wilson Central Composite Design for three factors, an optimum combination of pH and concentrations of the modifier and buffer was eventually obtained. A chromatographic response function based on a combination of the Kaiser peak separation function, Pi, and retention time of the second eluting enantiomer, tRL, served as a response criterion for the process of optimization. The optimum conditions developed for the (+2)(--) racemate were also found to be suitable for separating the (+-)(-+) racemate, for which earlier studies had shown the separation to be more facile. Separation of the four stereoisomers of III, for which the chiral chromatographic system optimized in this study is proposed as the second stage, is targeted at a biochemical study of the stereoisomeric metabolism of I.

Influence of design, physico-chemical and environmental parameters on pharmaceuticals and fragrances removal by constructed wetlands.

PubMed

Hijosa-Valsero, M; Matamoros, V; Sidrach-Cardona, R; Pedescoll, A; Martín-Villacorta, J; García, J; Bayona, J M; Bécares, E

2011-01-01

The ability of several mesocosm-scale and full-scale constructed wetlands (CWs) to remove pharmaceuticals and personal care products (PPCPs) from urban wastewater was assessed. The results of three previous works were considered as a whole to find common patterns in PPCP removal. The experiment took place outdoors under winter and summer conditions. The mesocosm-scale CWs differed in some design parameters, namely the presence of plants, the vegetal species chosen (Typha angustifolia versus Phragmites australis), the flow configuration (surface flow versus subsurface flow), the primary treatment (sedimentation tank versus HUSB), the feeding regime (batch flow versus continuous saturation) and the presence of gravel bed. The full-scale CWs consisted of a combination of various subsystems (ponds, surface flow CWs and subsurface flow CWs). The studied PPCPs were ketoprofen, naproxen, ibuprofen, diclofenac, salicylic acid, carbamazepine, caffeine, methyl dihydrojasmonate, galaxolide and tonalide. The performance of the evaluated treatment systems was compound dependent and varied as a function of the CW-configuration. In addition, PPCP removal efficiencies were lower during winter. The presence of plants favoured naproxen, ibuprofen, diclofenac, salicylic acid, caffeine, methyl dihydrojasmonate, galaxolide and tonalide removal. Significant positive correlations were observed between the removal of most PPCPs and temperature or redox potential. Accordingly, microbiological pathways appear to be the most likely degradation route for the target PPCPs in the CWs studied.

Effect of release rate and enantiomeric composition on response to pheromones of Megaplatypus mutatus (Chapuis) in poplar plantations of Argentina and Italy.

PubMed

Funes, Hernán; Zerba, Eduardo; Gonzalez-Audino, Paola

2013-10-01

Megaplatypus mutatus (=Platypus sulcatus Chapuis) is an Ambrosia beetle native to South America, which was recently introduced in Italy and its presence there is causing severe damage to the local poplar plantations. The male M. mutatus pheromone is composed of (S)-(+)-6-methyl-5-hepten-2-ol [(+)-sulcatol], 6-methyl-5-hepten-2-one (sulcatone) and 3-pentanol. A series of field trials testing dose, blend and enantiomer composition performed in Argentina and Italy evaluated attraction and found that the optimal release rate of pheromone components as baits in cross vane baited traps (CIPEIN-CV) was 6, 6 and 30 mg day−1 of sulcatone, (+)-sulcatol and 3-pentanol, respectively. It was also determined that racemic sulcatol is as effective as the pure (+)-isomer for the purpose of beetle catch, due to the inert nature of the (−)-isomer allowing the usage of low cost racemic sulcatol instead of highly expensive (+)-sulcatol. The results of our work contribute to the development of pheromone-based local technologies with low environmental impact and low cost for control or monitoring of an important pest.

CHEMOPREVENTIVE EFFICACY OF NAPROXEN AND NO-NAPROXEN IN RODENT MODELS OF COLON, URINARY BLADDER, AND MAMMARY CANCERS

PubMed Central

Steele, Vernon E.; Rao, Chinthalapally V.; Zhang, Yuting; Patlolla, Jagan; Boring, Daniel; Kopelovich, Levy; Juliana, M. Margaret; Grubbs, Clinton J.; Lubet, Ronald A.

2009-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity. In the azoxymethane (AOM)-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45–60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm), and reduced total ACF by 20–40%, respectively. In the hydroxybutyl (butyl) nitrosamine (OH-BBN) rat urinary bladder cancer model, NO-naproxen was given at 183 ppm or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, while the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started three months after OH-BBN, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86–94% decreases). In the methylnitrosourea (MNU)-induced mammary cancer model in rats, NO-naproxen and naproxen showed non-significant inhibitions (12 and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis. PMID:19892664

Adsorption and Structure of Chiral Epoxides on Pd(111): Propylene Oxide and Glycidol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahapatra, Mausumi; Tysoe, Wilfred T.

Here, the adsorption of enantiopure versus racemic propylene oxide (PO) on Pd(111) is studied by temperature-programmed desorption (TPD) to explore possible differences in their saturation coverage. It is found that that the saturation coverage of enantiopure PO on Pd(111) is identical to that of racemic PO, in contrast to results on Pt(111) where significant coverage differences were found. The surface structures of enantiopure PO on Pd(111) were characterized by scanning tunneling microscopy (STM), which shows the formation of linear chains and hexagonal structures proposed to be due to freely rotating PO, in contrast to the relatively disordered PO overlayers foundmore » on Pt(111). STM experiments were carried out for enantiopure glycidol, which contains the same epoxy ring as PO, but where the methyl group of propylene oxide is replaced by a -CH 2OH group to provide a hydrogen-bonding sites. Glycidol STM images show the formation of completely different surface structures; at low coverages, glycidol forms pseudohexagonal structures which assemble from glycidol dimers, while at high coverages the surface shows extensive hydrogen-bonded networks. Density functional theory (DFT) calculations were carried out to model the enantiopure PO linear chain and the glycidol dimers that are observed by STM. Similar calculations were carried out for racemic PO and glycidol structures. The calculated interaction energies for the enantiopure and the racemic pairs reveal that there is no difference for homochiral versus heterochiral structures for both PO and glycidol on Pd(111).« less

Adsorption and Structure of Chiral Epoxides on Pd(111): Propylene Oxide and Glycidol

DOE PAGES

Mahapatra, Mausumi; Tysoe, Wilfred T.

2018-01-03

Here, the adsorption of enantiopure versus racemic propylene oxide (PO) on Pd(111) is studied by temperature-programmed desorption (TPD) to explore possible differences in their saturation coverage. It is found that that the saturation coverage of enantiopure PO on Pd(111) is identical to that of racemic PO, in contrast to results on Pt(111) where significant coverage differences were found. The surface structures of enantiopure PO on Pd(111) were characterized by scanning tunneling microscopy (STM), which shows the formation of linear chains and hexagonal structures proposed to be due to freely rotating PO, in contrast to the relatively disordered PO overlayers foundmore » on Pt(111). STM experiments were carried out for enantiopure glycidol, which contains the same epoxy ring as PO, but where the methyl group of propylene oxide is replaced by a -CH 2OH group to provide a hydrogen-bonding sites. Glycidol STM images show the formation of completely different surface structures; at low coverages, glycidol forms pseudohexagonal structures which assemble from glycidol dimers, while at high coverages the surface shows extensive hydrogen-bonded networks. Density functional theory (DFT) calculations were carried out to model the enantiopure PO linear chain and the glycidol dimers that are observed by STM. Similar calculations were carried out for racemic PO and glycidol structures. The calculated interaction energies for the enantiopure and the racemic pairs reveal that there is no difference for homochiral versus heterochiral structures for both PO and glycidol on Pd(111).« less

Synthesis, absolute configuration and antimuscarinic activity of the enantiomers of [1-(2,2-diphenyl-[1,3]dioxolan-4-yl)-ethyl]-dimethyl-amine.

PubMed

Gulini, U; Angeli, P; Marucci, G; Buccioni, M; Giardinà, D; Antolini, L; Franchini, S; Sorbi, C; Brasili, L

2001-01-22

Methylation of the carbon atom C of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2 and M3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.

Pharmacokinetic profile of extended-release versus immediate-release oral naproxen sodium after single and multiple dosing under fed and fasting conditions: two randomized, open-label trials.

PubMed

Laurora, Irene; Wang, Yuan

2016-10-01

Extended-release (ER) naproxen sodium provides pain relief for up to 24 hours with a single dose (660 mg/day). Its pharmacokinetic profile after single and multiple dosing was compared to immediate release (IR) naproxen sodium in two randomized, open-label, crossover studies, under fasting and fed conditions. Eligible healthy subjects were randomized to ER naproxen sodium 660-mg tablet once daily or IR naproxen sodium 220-mg tablet twice daily (440 mg initially, followed by 220 mg 12 hours later). Primary variables: pharmacokinetic parameters after singleday administration (day 1) and at steady state after multiple-day administration (day 6). Total exposure was comparable for both treatments under fasting and fed conditions. After fasting: peak naproxen concentrations were slightly lower with ER naproxen sodium than with IR naproxen sodium but were reached at a similar time. Fed conditions: mean peak concentrations were comparable but reached after a longer time with ER vs. IR naproxen sodium. ER naproxen sodium was well tolerated, with a similar safety profile to IR naproxen sodium. The total exposure of ER naproxen sodium (660 mg) is comparable to IR naproxen sodium (220 mg) when administered at the maximum over the counter (OTC) dose of 660-mg daily dose on a single day and over multiple days. The rate of absorption is delayed under fed conditions.

Single dose oral naproxen and naproxen sodium for acute postoperative pain (Review)

PubMed Central

Mason, L; Edwards, JE; Moore, RA; McQuay, HJ

2014-01-01

Background Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. Objectives To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. Selection criteria Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. Data collection and analysis Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. Main results Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500 patients) that compared naproxen sodium 550 mg with placebo gave a RR for at least 50% pain relief over 4 to 6 hours of 4.2 (95% confidence interval (CI) 2.9 to 6.0) and an NNT of 2.6 (95% CI 2.2 to 3.2). Three trials (334 patients) assessed naproxen 400 mg and naproxen sodium 440 mg, giving a RR of 4.8 (95% CI 2.75 to 8.38). Two small studies indicated that naproxen 200 mg and naproxen sodium 220 mg may provide effective postoperative pain relief. There was no significant difference between the number of patients experiencing any adverse event on treatment compared with placebo. Weighted mean time to remedication for naproxen sodium 550 mg was 7.6 hours compared with 2.6 hours for placebo. Authors’ conclusions Naproxen sodium 550 mg, naproxen 400 mg and naproxen sodium 440 mg administered orally are effective analgesics for the treatment of acute postoperative pain in adults. A low incidence of adverse events was found but reporting was not consistent. PMID:15495091

Separation of hydroxynorketamine stereoisomers using capillary electrophoresis with sulfated β-cyclodextrin and highly sulfated γ-cyclodextrin.

PubMed

Sandbaumhüter, Friederike A; Theurillat, Regula; Thormann, Wolfgang

2017-08-01

The racemic N-methyl-d-aspartate receptor antagonist ketamine is used in anesthesia, analgesia and the treatment of depressive disorders. It is known that interactions of hydroxylated norketamine metabolites and 5,6-dehydronorketamine (DHNK) with the α 7 -nicotinic acetylcholine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are responsible for the antidepressive effects. Ketamine and its first metabolite norketamine are not active on these receptors. As stereoselectivity plays a role in ketamine metabolism, a cationic capillary electrophoresis based method capable of resolving and analyzing the stereoisomers of four hydroxylated norketamine metabolites, norketamine and DHNK was developed. The assay is based on liquid/liquid extraction of the analytes from the biological matrix, electrokinetic sample injection across a buffer plug and analysis of the stereoisomers in a phosphate background electrolyte (BGE) at pH 3 comprising a mixture of sulfated β-cyclodextrin (5 mg/mL) and highly sulfated γ-cyclodextrin (0.1%). The method was used to analyze samples of an in vitro study in which ketamine was incubated with equine liver microsomes and in plasma samples of dogs and horses that were collected after an i.v. bolus injection of racemic ketamine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a.

PubMed

Srivatsan, Avinash; Pera, Paula; Joshi, Penny; Wang, Yanfang; Missert, Joseph R; Tracy, Erin C; Tabaczynski, Walter A; Yao, Rutao; Sajjad, Munawwar; Baumann, Heinz; Pandey, Ravindra K

2015-07-01

We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stereoselectivity of the arene epoxide pathway of mephenytoin hydroxylation in man.

PubMed

Küpfer, A; Lawson, J; Branch, R A

1984-02-01

Stereoselective metabolism of mephenytoin has been investigated in four normal subjects by comparing urinary recoveries of hydroxylated metabolites after administration of racemic RS-mephenytoin (1.4 mmol/day) and R-mephenytoin (0.7 mmol/day) on separate occasions. Gas chromatography-mass spectrometry was employed to measure the urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) and mephenytoin catechol, methylcatechol, and dihydrodiol metabolites. Following a single oral dose of racemic mephenytoin, 4-OH-M, mephenytoin catechol, and methylcatechol metabolites were identified in urine mainly as conjugates, whereas the dihydrodiol metabolite was recovered mainly in its unconjugated form. Urinary elimination of each metabolite was similar on days 1 and 10 of chronic racemic mephenytoin administration. Following R-mephenytoin administration, urinary recoveries of hydroxylated metabolites were five to 10 times smaller than after administration of the racemic drug. This implies substrate-stereoselective hydroxylation of the S-enantiomer of mephenytoin. In one subject with a genetic deficiency of aromatic mephenytoin hydroxylation deficiency, the excretion of each hydroxylated mephenytoin metabolite after RS-mephenytoin administration was decreased to 5-15% of the values found in the four extensively hydroxylating study volunteers. The impaired formation of hydroxylated mephenytoin metabolites in genetic hydroxylation deficiency, in conjunction with stereoselective hydroxylation of S-mephenytoin via an extensive NIH shift in normal man, is consistent with the hypothesis that the formation of the S-mephenytoin arene oxide is under genetic control and represents the initial enzymatic reaction of stereoselective aromatic mephenytoin hydroxylation. The formation of this potentially reactive metabolite of S-mephenytoin may have implications in mephenytoin-induced toxicity.

Optical resolution by preferential crystallization of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid.

PubMed

Shiraiwa, Tadashi; Kiyoe, Ryuuichi

2005-09-01

The racemic structure of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid [(1RS,3RS)-1] was examined based on the melting point, solubility, and IR spectrum, with the aim of optical resolution by preferential crystallization. (1RS,3RS)-1 was indicated from these results to exist as a conglomerate. The successive optical resolution by preferential crystallization of (1RS,3RS)-1 yielded (1S,3S)- and (1R,3R)-1 with optical purities of 85--95% at 66--81% degrees of resolution, which were fully purified by recrystallization.

2-Amino-2,3-dimethyl­butanamide

PubMed Central

Yin, Yongbiao

2010-01-01

The title compound, C6H14N2O, was synthesized by the reaction between 2-amino-2,3-dimethyl­butanonitrile and oil of vitriol (sulfuric acid). A racemic mixture of L- and R-2-amino-2,3-di­methyl­butanamide was characterized crystallographically. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the two enanti­omers into a three-dimensional network. PMID:21579361

Non-steroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: A molecular dynamics investigation

PubMed Central

Takeda, Takako; Kumar, Rashmi; Raman, E. Prabhu; Klimov, Dmitri K.

2010-01-01

Using implicit solvent model and replica exchange molecular dynamics we examine the propensity of non-steroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the anti-aggregation propensity of naproxen with that of ibuprofen. Naproxen anti-aggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen naproxen binding also alters the conformational ensemble of Aβ monomers by promoting β-structure. The second factor weakens naproxen anti-aggregation effect. These findings appear to explain the experimental observations, according to which naproxen binds to Aβ fibril with higher affinity than ibuprofen, yet produces weaker anti-aggregation action. PMID:20979356

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization.

PubMed

Shiraiwa, Tadashi; Kawashima, Yuka; Ikaritani, Atsushi; Suganuma, Yumiko; Saijoh, Reiichi

2006-08-01

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.

Acute toxicity and histopathological effects of naproxen in zebrafish (Danio rerio) early life stages.

PubMed

Li, Qian; Wang, Peipei; Chen, Ling; Gao, Hongwen; Wu, Lingling

2016-09-01

Zebrafish (Danio rerio) embryos and larvae were selected to investigate the potential risk and aquatic toxicity of a widely used pharmaceutical, naproxen. The acute toxicity of naproxen to embryos and larvae was measured, respectively. The histopathology was investigated in the liver of zebrafish larvae after 8-day embryo-larvae exposure to naproxen. The values of 96-h LC50 were 115.2 mg/L for embryos and 147.6 mg/L for larvae, indicating that zebrafish embryos were more sensitive than larvae to naproxen exposure. Large suites of symptoms were induced in zebrafish (D. rerio) early life stages by different dosages of naproxen, including hatching inhibition, lower heart rate, and morphological abnormalities. The most sensitive sub-lethal effect caused by naproxen was pericardial edema, the 72-h EC50 values of which for embryos and larvae were 98.3 and 149.0 mg/L, respectively. In addition, naproxen-treated zebrafish larvae exhibited histopathological liver damage, including swollen hepatocytes, vacuolar degeneration, and nuclei pycnosis. The results indicated that naproxen is a potential threat to aquatic organisms.

Functional Characterization of a Novel Marine Microbial Esterase and its Utilization in the Enantioselective Preparation of (R)-Methyl 2-Chloropropionate.

PubMed

Cao, Yingying; Deng, Dun; Sun, Aijun; Zhang, Yun; Hu, Yunfeng

2016-09-01

Chiral 2-chloropropanoic acids and their ester derivatives are crucial intermediates in the synthesis of many chemicals, especially herbicides. The enzymatic synthesis of chiral 2-chloropropanoic acids and their ester derivatives by esterases was not easily achieved, because the structural difference between the two enantiomers was too small to be recognized by esterases. Herein, we report the expression and functional characterization of one novel low temperature-resistant esterase EST12-7 identified from the genome of Pseudonocardia antitumoralis SCSIO 01299 isolated from the sediments of the South China Sea. Biocatalyst EST12-7 could hydrolyze racemic methyl 2-chloropropinate and generate optically pure (R)-methyl 2-chloropropinate with high enantiomeric excess (>99 %) and conversion (>49 %) after process optimization. Notably, the addition of different surfactants and using surfactants of different concentrations in the kinetic resolution catalyzed by EST12-7 could greatly affect the enantiomeric excess and conversion rate of product (R)-methyl 2-chloropropinate.

The Myotoxic Effects of Microencapsulated Naproxen and Carrier Polymer After Intramuscular Injection in Rats

DTIC Science & Technology

1996-10-10

THE MYOTOXIC EFFECTS OF MICROENCAPSULATED NAPROXEN AND CARRIER POLYMER AFTER INTRAMUSCULAR INJECTION IN RATS A Masters Thesis By Kevin J. Bohan... Microencapsulated Naproxen and Carrier Polymer After Intramuscular Injection in Rats" beyond brief excerpts is with the pennission of the copyright...naproxen to be microencapsulated (MEC) for parenteral use. Intramuscular MEC naproxen could provide greater pain relief than ketoralac with a longer

Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.

PubMed

Ando, Shigeru; Kikuchi, Junko; Fujimura, Yuko; Ida, Yasuo; Higashi, Kenjirou; Moribe, Kunikazu; Yamamoto, Keiji

2012-09-01

Physicochemical characterization and structural evaluation of a 2:1 naproxen-nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid-state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP)-heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-π interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid-amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons. Copyright © 2012 Wiley Periodicals, Inc.

Supra-Additive Interaction of Docosahexaenoic Acid and Naproxen and Gastric Safety on the Formalin Test in Rats.

PubMed

Arroyo-Lira, Arlette Guadalupe; Rodríguez-Ramos, Fernando; Ortiz, Mario I; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

2017-11-01

Preclinical Research The aim of this work was to evaluate the effect of docosahexaenoic acid (DHA) on the pharmacokinetics and pharmacodynamics-nociception-of naproxen in rats, as well as to determine the gastric safety resulting from this combination versus naproxen alone. Female Wistar rats were orally administered DHA, naproxen or the DHA-naproxen mixture at fixed-ratio combination of 1:3. The antinociceptive effect was evaluated using the formalin test. The gastric injury was determined 3 h after naproxen administration. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and naproxen. To determine the possibility of pharmacokinetic interactions, the oral bioavailability of naproxen was evaluated in presence and absence of oral DHA. The experimental effective dose ED 30 values (Zexp) were decreased from theoretical additive dose values (Zadd; P < 0.05). The isobolographic analysis showed that the combination exhibited supra-additive interaction. The oral administration of DHA increased the pharmacokinetic parameter AUC 0- t of naproxen (P < 0.05). Furthermore, the gastric damage induced by naproxen was abolished when this drug was combined with DHA. These data suggest that oral administration of DHA-naproxen combination induces gastric safety and supra-additive antinociceptive effect in the formalin test so that this combination could be useful to management of inflammatory pain. Drug Dev Res 78 : 332-339, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Imitating prebiotic homochirality on Earth.

PubMed

Breslow, Ronald; Levine, Mindy; Cheng, Zhan-Ling

2010-02-01

We show how the amino acids needed on prebiotic earth in their homochiral L form can be produced by a reaction of L-alpha-methyl amino acids-that have been identified in the Murchison meteorite-with alpha-keto acids under credible prebiotic conditions. When they are simply heated together they perform a process of decarboxylative transamination but with almost no chiral transfer, and that in the wrong direction, producing D-amino acids from the L-alpha-methyl amino acids. With copper ion a square planar complex with two of the reaction intermediates is formed, and now there is the desired L to L transformation, producing small enantioexcesses of the normal L-amino acids. We also show how these can be amplified, not by making more of the L form but by increasing its concentration in water solution. The process can start with a miniscule excess and in one step generate water solutions with L/D ratios in the over 90% region. Kinetic processes can exceed the results from equilibria. We have also examined such amplifications with ribonucleosides, and have shown that initial modest excesses of the D-nucleosides can be amplified to afford water solutions with D to L ratios in the high 90's. We have shown that the homochiral compound has two effects on the solubility of the racemate. On one hand it decreases the solubility of the racemate by its role in the solubility product, as a theoretical equation predicts. On the other hand, it increases the solubility of the racemate by changing the nature of the solvent, acting as a cosolvent with the water. This explains why the amplification, while large, is not as large as the simple theoretical equation predicts. Thus when credible examples are produced where small enantioexcesses of D-ribose are created under credible prebiotic conditions, the prerequisites for the RNA world will have been exemplified.

Serum concentrations of salicylate and naproxen during concurrent therapy in patients with rheumatoid arthritis.

PubMed

Furst, D E; Sarkissian, E; Blocka, K; Cassell, S; Dromgoole, S; Harris, E R; Hirschberg, J M; Josephson, N; Paulus, H E

1987-10-01

The kinetic interaction between salicylate and naproxen was investigated in 25 rheumatoid arthritis patients. Kinetic interactions were tested in serum after patients had been on each drug regimen for 1 month. Salicylate decreased serum naproxen concentration from 89.5 mg/liter to 65.9 mg/liter (P less than 0.001) and increased serum naproxen clearance by 56%. Naproxen had minimal effect on serum salicylate concentrations.

Improvement of the physicochemical properties of Co-amorphous naproxen-indomethacin by naproxen-sodium.

PubMed

Beyer, Andreas; Grohganz, Holger; Löbmann, Korbinian; Rades, Thomas; Leopold, Claudia S

2017-06-30

Improvement of the physicochemical properties of amorphous active pharmaceutical ingredients (APIs) applying the concept of co-amorphisation is a promising alternative to the use of polymer glass solutions. In co-amorphous systems, the physical stability and the dissolution rate of the involved components may be improved in comparison to the respective single amorphous phases. However, for the co-amorphous naproxen-indomethacin model system it has been reported that recrystallization could not be prevented for more than 112days regardless of the applied preparation method and blend ratio In the present study, it was thus tested if the physicochemical properties of co-amorphous naproxen-indomethacin could be optimized by incorporation of the naproxen sodium into the system. Three different co-amorphous systems in nine different molar ratios were prepared by quench-cooling: naproxen-indomethacin (NI), naproxen-sodium-naproxen-indomethacin (NSNI) and naproxen-sodium-indomethacin (NSI). The samples were analyzed by XRPD, FTIR, DSC and by intrinsic dissolution experiments to investigate the influence of naproxen-sodium on the resulting physicochemical properties of the systems. With the three systems, fully amorphous samples with single glass transition temperatures could be prepared with naproxen molar fractions up to 0.7. The NSI and NSNI systems showed up to about 40°C higher Tgs than the NI system. Furthermore, no recrystallization occurred during 270d of storage with the NSI and NSNI samples that were initially amorphous. Moreover, with the NSI system, the intrinsic dissolution rate of naproxen and indomethacin was improved by a factor of 2 compared to the unmodified NI system. In conclusion, the physical stability as well as the dissolution rate was significantly improved if partial or full exchange of naproxen by its sodium salt was performed, which may present a general optimization method to improve co-amorphous systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Naproxen Interferes with the Assembly of Aβ Oligomers Implicated in Alzheimer's Disease

PubMed Central

Kim, Seongwon; Chang, Wenling E.; Kumar, Rashmi; Klimov, Dmitri K.

2011-01-01

Experimental and epidemiological studies have shown that the nonsteroidal antiinflammatory drug naproxen may be useful in the treatment of Alzheimer's disease. To investigate the interactions of naproxen with Aβ dimers, which are the smallest cytotoxic aggregated Aβ peptide species, we use united atom implicit solvent model and exhaustive replica exchange molecular dynamics. We show that naproxen ligands bind to Aβ dimer and penetrate its volume interfering with the interpeptide interactions. As a result naproxen induces a destabilizing effect on Aβ dimer. By comparing the free-energy landscapes of naproxen interactions with Aβ dimers and fibrils, we conclude that this ligand has stronger antiaggregation potential against Aβ fibrils rather than against dimers. The analysis of naproxen binding energetics shows that the location of ligand binding sites in Aβ dimer is dictated by the Aβ amino acid sequence. Comparison of the in silico findings with experimental observations reveals potential limitations of naproxen as an effective therapeutic agent in the treatment of Alzheimer's disease. PMID:21504739

Protective Effect of 4-(3,4-Dihydroxyphenyl)-3-Buten-2-One from Phellinus linteus on Naproxen-Induced Gastric Antral Ulcers in Rats.

PubMed

Kim, Jeong-Hwan; Kwon, Hyun Ju; Kim, Byung Woo

2016-05-28

The present study investigated the protective effect of naturally purified 4-(3,4- dihydroxyphenyl)-3-buten-2-one (DHP) from Phellinus linteus against naproxen-induced gastric antral ulcers in rats. To verify the protective effect of DHP on naproxen-induced gastric antral ulcers, various doses (1, 5, and 10 μg/kg) of DHP were pretreated for 3 days, and then gastric damage was caused by 80 mg/kg naproxen applied for 3 days. DHP prevented naproxen-induced gastric antral ulcers in a dose-dependent manner. In particular, 10 μg/kg DHP showed the best protective effect against naproxen-induced gastric antral ulcers. Moreover, DHP significantly attenuated the naproxen-induced lipid peroxide level in gastric mucosa and increased the activities of radical scavenging enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in a dose-dependent manner. A histological examination clearly demonstrated that the gastric antral ulcer induced by naproxen nearly disappeared after the pretreatment of DHP. These results suggest that DHP can inhibit naproxen-induced gastric antral ulcers through prevention of lipid peroxidation and activation of radical scavenging enzymes.

Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials.

PubMed

Laurora, Irene; An, Robert

2016-01-01

To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model. Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220 mg tid (study 2). Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded. NCT00720057 (study 1), NCT01389284 (study 2). Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2-24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid. The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief. A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain.

Naproxen-PC: a GI safe and highly effective anti-inflammatory.

PubMed

Lichtenberger, L M; Romero, J J; Dial, E J; Moore, J E

2009-02-01

We have been developing a family of phosphatidylcholine (PC)-associated NSAIDs, which appear to have improved GI safety and therapeutic efficacy in both rodent model systems and pilot clinical trials. As naproxen has been demonstrated to be associated with the lowest cardiovascular adverse events in comparison with both COX-2 selective inhibitors and conventional NSAIDs, we have been developing a Naproxen-PC formulation for evaluation in animal models and clinical trials. We have determined that an oil-based formulation of naproxen and triple strength soy lecithin provides excellent GI protection in both: 1) an acute NSAID-induced intestinal bleeding model in rats pretreated with L-NAME that are intragastrically administered a single dose of naproxen (at a dose of 50 mg/kg) vs the equivalent dose of Naproxen-PC; and 2) a more chronic model (at a naproxen dose of 25 mg/kg BID) in rats that have pre-existing hindpaw inflammation (induced with a intradermal injection of Complete Freund's Adjuvant/CFA). Both models demonstrate the superior GI safety of Naproxen-PC vs naproxen while this novel formulation had significant anti-inflammatory efficacy to reduce hindpaw edema and the generation of PGE(2) in the collected joint synovial fluid. Naproxen-PC appears to induce significantly less GI injury and bleeding in two rodent model systems while maintaining anti-inflammatory and COX-inhibitory activity.

Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)

PubMed Central

Bies, Robert; Kamden, Landry K.; Desta, Zeruesenay; Flockhart, David A.

2010-01-01

The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the Km (4 μM). To test for mechanism-based inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1–1000 μM), R- or S-methadone (0.5–500 μM), or EDDP or EMDP (10 and 100 μM) followed by incubation with testosterone at a Vmax concentration (50 μM). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time- and concentration-dependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The KI and kinact values for racemic methadone were calculated to be 40.6 ± 2.8 μM and 0.061 ± 0.001 min−1, respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients. PMID:20410453

LFER and CoMFA studies on optical resolution of alpha-alkyl alpha-aryloxy acetic acid methyl esters on DACH-DNB chiral stationary phase.

PubMed

Carotti, A; Altomare, C; Cellamare, S; Monforte, A; Bettoni, G; Loiodice, F; Tangari, N; Tortorella, V

1995-04-01

The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl esters I on a pi-acid N,N'-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.

The combination of naproxen and citral reduces nociception and gastric damage in rats.

PubMed

Ortiz, Mario I; Ramírez-Montiel, Martha L; González-García, Martha P; Ponce-Monter, Héctor A; Castañeda-Hernández, Gilberto; Cariño-Cortés, Raquel

2010-10-01

It has been shown that the association of non-steroidal anti-inflammatory drugs with plant extracts can increase their antinociceptive activity, allowing the use of lower doses and, thus, limiting side effects. Therefore, the aim of this study was to examine the effects of the interaction between naproxen and citral on nociception and gastric injury in rats. Naproxen, citral, or combinations of naproxen and citral produced an antinociceptive effect. The administration of naproxen produced significant gastric damage, but this effect was not obtained with either citral or the naproxen-citral combination. The ED(50) value was estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED(50) for the antinociceptive effect (423.8 mg/kg) was not significantly different from the observed experimental value (359.0 mg/kg); hence, the interaction between naproxen and citral mediating the antinociceptive effect is additive. These data suggest that the naproxen-citral combination interacts at the systemic level, produces minor gastric damage, and potentially has therapeutic advantages for the clinical treatment of inflammatory pain.

Enzymes Involved in Naproxen Degradation by Planococcus sp. S5.

PubMed

Wojcieszyńska, Danuta; Domaradzka, Dorota; Hupert-Kocurek, Katarzyna; Guzik, Urszula

2016-01-01

Naproxen is a one of the most popular non-steroidal anti-inflammatory drugs (NSAIDs) entering the environment as a result of high consumption. For this reason, there is an emerging need to recognize mechanisms of its degradation and enzymes engaged in this process. Planococcus sp. S5 is a gram positive strain able to degrade naproxen in monosubstrate culture (27%). However, naproxen is not a sufficient growth substrate for this strain. In the presence of benzoate, 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid or vanillic acid as growth substrates, the degradation of 21.5%, 71.71%, 14.75% and 8.16% of naproxen was observed respectively. It was shown that the activity of monooxygenase, hydroxyquinol 1,2-dioxygenase, protocatechuate 3,4-dioxygenase and protocatechuate 4,5-dioxyegnase in strain S5 was induced after growth of the strain with naproxen and 4-hydroxybenzoate. Moreover, in the presence of naproxen activity of gentisate 1,2-dioxygenase, enzyme engaged in 4-hydroxybenzoate metabolism, was completely inhibited. The obtained results suggest that monooxygenase and hydroxyquinol 1,2-dioxygenase are the main enzymes in naproxen degradation by Planococcus sp. S5.

Low doses of tizanidine synergize the anti-nociceptive and anti-inflammatory effects of ketorolac or naproxen while reducing of side effects.

PubMed

Patiño-Camacho, Selene I; Déciga Campos, Myrna; Beltrán-Villalobos, Karla; Castro-Vidal, Dalia A; Montiel-Ruiz, Rosa M; Flores-Murrieta, Francisco J

2017-06-15

The aim of the present study was to determine whether tizanidine, an alpha2-adrenoceptor agonist, is able to increase the anti-inflammatory and anti-nociceptive effects of naproxen and ketorolac with a low incidence of gastric injury and spontaneous activity in rats. The anti-inflammatory effect was assayed in a carrageenan test, and oral administration of tizanidine (ED 40 =0.94±0.2mg/kg), naproxen (ED 40 =3.18±0.4mg/kg), and ketorolac (ED 40 =16.4±1.9mg/kg) showed a dose-dependent effect on inflammation. The anti-nociceptive effect was assayed in the formalin test, and administration of tizanidine (ED 40 =0.39±0.06mg/kg, p.o.), naproxen (ED 40 =33.9±3.9mg/kg, p.o.) or ketorolac (ED 40 =6.49±1mg/kg, p.o.) each showed a dose-dependent anti-nociceptive effect. The effects of combinations of tizanidine/naproxen and tizanidine/ketorolac were determined considering their ED 40 at a rate of 1:1. Additionally, the tizanidine/naproxen and tizanidine/ketorolac combinations showed anti-inflammatory and anti-nociceptive effects. The tizanidine/ketorolac combination was more potent than tizanidine/naproxen, in both inflammatory (interaction index=0.03 tizanidine/ketorolac and 0.07 tizanidine/naproxen) and nociceptive (interaction index=0.005 tizanidine/ketorolac and 0.01 tizanidine/naproxen) processes. In both cases, tizanidine improved naproxen and ketorolac gastrointestinal tolerability by 50%. Furthermore, co-administration of tizanidine with naproxen or ketorolac did not modify the spontaneous activity in the same way as individual tizanidine administration. Considering that tizanidine increases the anti-inflammatory and anti-nociceptive effects of naproxen or ketorolac, with an increase in gastric tolerability, tizanidine could provide therapeutic advantages in the clinical treatment of inflammation and pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Brief Report: Course of Active Inflammatory and Fatty Lesions in Patients With Early Axial Spondyloarthritis Treated With Infliximab Plus Naproxen as Compared to Naproxen Alone: Results From the Infliximab As First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial.

PubMed

Poddubnyy, Denis; Listing, Joachim; Sieper, Joachim

2016-08-01

To investigate the course of active inflammatory and fatty lesions seen on magnetic resonance imaging (MRI) in patients with early axial spondyloarthritis (SpA) treated with the tumor necrosis factor (TNF) inhibitor infliximab added to naproxen as compared to those treated with naproxen alone. A total of 158 patients with active axial SpA were randomized (2:1) to receive 28 weeks of treatment with either infliximab 5 mg/kg plus naproxen 1,000 mg/day or placebo plus naproxen 1,000 mg/day. MRI of the sacroiliac (SI) joints and of the spine was performed at baseline and week 28. Images were scored for active inflammation and for fatty lesions. After 28 weeks, there was a significant reduction of inflammation in the spine and in the SI joints in both treatment groups, which was, however, more prominent in the infliximab plus naproxen group (mean ± SD spine osteitis change score -2.9 ± 5.1, versus -2.0 ± 4.2 in the placebo plus naproxen group [P < 0.001]; SI joint osteitis change score -4.3 ± 5.2 in the infliximab plus naproxen group versus -3.9 ± 3.7 in the placebo plus naproxen group [P = 0.003]). Similarly, there was a significant increase in the fatty lesion score after 28 weeks in both groups; this change did not, however, differ significantly between groups (spine fatty lesion change score 0.8 ± 1.7 in the infliximab plus naproxen group versus 1.0 ± 1.8 in the placebo plus naproxen group [P = 0.72]; SI joint fatty lesion change score 1.7 ± 2.7 in the infliximab plus naproxen group versus 1.4 ± 2.6 in the placebo plus naproxen group [P = 0.86]). These findings indicate that effective antiinflammatory treatment of axial SpA is associated with an increase in fatty lesion scores, independent of concomitant treatment with or without anti-TNF. © 2016, American College of Rheumatology.

Fourth-order derivative spectrophotometric method for simultaneous determination of pseudoephedrine and naproxen in pharmaceutical dosage forms

PubMed Central

Souri, Effat; Mosafer, Amir; Tehrani, Maliheh Barazandeh

2016-01-01

Combination dosage forms of naproxen sodium and pseudoephedrine hydrochloride are used for symptomatic treatment of cold and sinus disorders. In this study, fourth-order derivative spectrophotometric method was used for simultaneous determination of naproxen sodium and pseudoephedrine hydrochloride. The method was linear over the range of 2-28 μg/ml for pseudoephedrine hydrochloride and 4-200 μg/ml for naproxen sodium. The within-day and between-day coefficient of variation values were less than 5.8% and 2.5% for pseudoephedrine hydrochloride and naproxen sodium, respectively. The application of the proposed method for simultaneous determination of naproxen and pseudoephedrine in dosage forms was demonstrated without any special pretreatment. PMID:27168748

On the reported optical activity of amino acids in the Murchison meteorite

USGS Publications Warehouse

Bada, J.L.; Cronin, J.R.; Ho, M.-S.; Kvenvolden, K.A.; Lawless, J.G.; Miller, S.L.; Oro, John; Steinberg, S.

1983-01-01

In analyses of extracts from the Murchison meteorite (a carbonaceous chondrite), Engel and Nagy1 reported an excess of L-enantiomers for several protein amino acids but found that the non-protein amino acids were racemic. They suggested that the excess of L-isomers might have resulted from an asymmetric synthesis or decomposition. Their results disagree with those obtained previously2-4 and they claim this is due to improved methodology. In fact, their extraction method and analytical procedure (gas chromatography-mass spectrometry, GC-MS) was similar to those used in the original report2 of amino acids in the Murchison meteorite except that they used specific ion monitoring in the GC-MS measurements. We found the results of Engel and Nagy odd in that likely contaminants (the protein amino acids ala, leu, glu, asp and pro) were nonracemic while unlikely contaminants (isovaline and ??-amino-n-butyric acid) were racemic. For example, Engel and Nagy report that the leucine is ???90% L-enantiomer in the water-extracted sample whereas isovaline (??-methyl-??-aminobutyric acid) is racemic. It would be most unusual for an abiotic stereoselective decomposition or synthesis of amino acids to occur with protein amino acids but not with non-protein amino acids. We now show here that the explanation of terrestrial contamination is consistent with their results and is much more probable. ?? 1983 Nature Publishing Group.

Naproxen sodium overdose

MedlinePlus

... page: //medlineplus.gov/ency/article/002507.htm Naproxen sodium overdose To use the sharing features on this page, please enable JavaScript. Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID) used ...

Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders.

PubMed

Kestur, Umesh S; Wanapun, Duangporn; Toth, Scott J; Wegiel, Lindsay A; Simpson, Garth J; Taylor, Lynne S

2012-11-01

The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug-polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to determine the response of pharmaceutical powders. Physical mixtures containing different proportions of crystalline naproxen and hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) were prepared by blending and a dispersion was produced by solvent evaporation. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the crystalline drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect crystalline drug even in the presence of 99.9 wt % HPMCAS in the binary mixtures. The calibration curve revealed a linear dynamic range with a R(2) value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%-10%. Analysis of a 75 wt % HPMCAS-naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addition, results from the crystallization kinetics experiment using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer. Copyright © 2012 Wiley-Liss, Inc.

NO-naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund's adjuvant arthritis

PubMed Central

Cicala, Carla; Ianaro, Angela; Fiorucci, Stefano; Calignano, Antonio; Bucci, Mariarosaria; Gerli, Roberto; Santucci, Luca; Wallace, John L; Cirino, Giuseppe

2000-01-01

Anti-inflammatory non steroidal drugs releasing NO (NO-NSAIDs) are a new class of anti-inflammatory drugs to which has been added an NO-releasing moiety. These compounds have been shown to retain the anti-inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity.Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 μl of mycobacterium butirricum (6 mg ml−1). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg−1) and NO-naproxen (1.5, 4.5 and 16 mg kg−1) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1–21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7–21).Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitro proliferation of T cells following stimulation with concanavalin A (0.5–5 μg ml−1) was measured using a tritiated thymidine incorporation assay. IL-2 receptor expression on T cells was measured by FACS analysis.Naproxen and NO-naproxen showed similar activity in reducing oedema formation in the non-injected (controlateral) hindpaw. Both drugs showed anti-nociceptive effect. NO-naproxen was anti-nociceptive at a dose of 4.5 mg kg−1 while naproxen showed the same extent of inhibition only at a dose of 10 mg kg−1.T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitro caused a significant increase in thymidine uptake. NO-naproxen at a dose of 4.5 mg kg−1 inhibited T cell proliferation to the same extent as 10 mg kg−1 of naproxen.Inhibition of T cell proliferation was well correlated with reduced IL-2 receptor expression on T cells. In addition, NO-naproxen reduced both IL-1β and TNFα plasma levels whilst naproxen reduced IL-1β levels only.In conclusion, both naproxen and NO-naproxen reduce inflammation and nociception associated with arthritis. In addition NO-naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structure increases the effect at the level of the immune system. PMID:10903982

Synthesis of 9,9,9-trideutero-1,4-dihydroxynonane mercapturic acid (d3-DHN-MA), a useful internal standard for DHN-MA urinalysis.

PubMed

Chantegrel, B; Deshayes, C; Doutheau, A; Steghens, J P

2002-10-01

Racemic 1,4-dihydroxynonane mercapturic acid (DHN-MA) and 9,9,9-trideutero-1,4-dihydroxynonane mercapturic acid (d3-DHN-MA) are synthesized on a 400-mg scale (overall yield approximately 40%) by a two-step sequence involving Michael addition of N-acetyl-L-cysteine to methyl 4-hydroxynon-2(E)-enoate or methyl 9,9,9-trideutero-4-hydroxynon-2 (E)-enoate, followed by reduction of the intermediate adducts with lithium borohydride. The requisite starting methyl esters are obtained, respectively, from heptanal or 7,7,7-trideuteroheptanal and methyl 4-chlorophenylsulfinylacetate via a sulfoxide piperidine and carbonyl reaction described in the literature. The 7,7,7-trideuteroheptanal is easily prepared by classical methods in four steps from 6-bromo-1-hexanol. 13C NMR data indicate that DHN-MA as well as d3-DHN-MA are obtained as mixtures of four diastereomers. Preliminary results show that d3-DHN-MA could be used as an internal standard for mass spectrometric quantification of DHN-MA in human urine.

Nonselective inhibition of prostaglandin-endoperoxide synthase by naproxen ameliorates hepatic injury in animals with acute or chronic liver injury

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev

2014-01-01

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury. PMID:24220607

Carbamazepine and naproxen: fate in wetland mesocosms planted with Scirpus validus.

PubMed

Zhang, Dong Qing; Hua, Tao; Gersberg, Richard M; Zhu, Junfei; Ng, Wun Jern; Tan, Soon Keat

2013-03-01

Scirpus validus was grown hydroponically and exposed to the pharmaceuticals, carbamazepine and naproxen at concentrations of 0.5-2.0 mg L(-1) for an exposure duration of up to 21 d. By the end of experiment, carbamazepine elimination from the nutrient solution reached to 74%, while nearly complete removal (>98%) was observed for naproxen. Photodegradation and biodegradation played only minor roles for carbamazepine elimination, while naproxen showed a high potential for both photodegradation and biodegradation. Levels of carbamazepine ranged from 3.3 to19.0 μg g(-1) (fresh weight) in the roots and 0.3-0.7 μg g(-1) (fresh weight) in the shoots, while naproxen concentrations were 0.2-2.4 μg g(-1) (fresh weight) in the roots and 0.2-2.8 μg g(-1) (fresh weight) in the shoots. Bioaccumulation factors (BAFs) for carbamazepine ranged from 5.5 to 13.0 for roots and 0.3-1.0 for shoots, and uptake by S. validus accounted for up to 22% of the total mass loss of carbamazepine in the nutrient solutions. All BAFs for naproxen were less than 4.2 and plant uptake accounted for less than 5% of the total mass loss of naproxen, implying that plant uptake was not significant in naproxen elimination. The rather limited plant uptake of naproxen was not surprising despite the fact that its log K(ow) is close to the optimal range (1.8-3.1) for maximal potential for plant uptake. Apparently, for ionizable compounds such as naproxen, the effects of pK(a) and pH partitioning might be more important than lipophilicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Two Double-Blind, Multicenter, Randomized, Placebo-Controlled, Single-Dose Studies of Sumatriptan/Naproxen Sodium in the Acute Treatment of Migraine: Function, Productivity, and Satisfaction Outcomes

PubMed Central

Landy, Stephen; DeRossett, Sarah E.; Rapoport, Alan; Rothrock, John; Ames, Michael H.; McDonald, Susan A.; Burch, Steven P.

2007-01-01

Objective To describe return to normal function, productivity, and satisfaction of patients with moderate or severe migraine attacks treated with combined sumatriptan/naproxen sodium, sumatriptan alone, naproxen sodium alone, or placebo. Patients, design, and setting Patients in 2 identical, US, phase 3, randomized, double-blind, parallel-group, placebo-controlled, single-dose, multicenter studies treated a single moderate or severe migraine attack with sumatriptan/naproxen sodium (85 mg sumatriptan formulated with RT Technology and 500 mg naproxen sodium in a single-tablet formulation), sumatriptan, naproxen sodium, or placebo. Main outcome measures Ability to function (not impaired, mildly impaired, severely impaired, or required bed rest) was collected in diary cards completed immediately prior to treatment, every 30 minutes for the first 2 hours, and hourly from 2 to 24 hours while awake. Patients completed the Productivity Assessment Questionnaire (PAQ) 24 hours after study drug administration. The Patient Perception of Migraine Questionnaire (PPMQ) was administered at screening and 24 hours post treatment to capture patient satisfaction. Results Compared with the other groups, the sumatriptan/naproxen sodium group reported significantly higher levels of normal or mildly impaired functioning as early as 2 and 4 hours after dosing. They also demonstrated greater reductions in workplace productivity loss compared with placebo in both studies, and were consistently more satisfied with their treatment compared with patients in other treatment groups and compared with their usual medications. Conclusions Treatment with sumatriptan/naproxen sodium allowed significantly more subjects to return to normal or mildly impaired functioning more quickly, and sumatriptan/naproxen sodium patients were significantly more satisfied with their treatment compared with other treatment groups. Overall productivity loss was significantly reduced following use of sumatriptan/naproxen sodium. PMID:17955107

Naproxen-induced Ca2+ movement and death in MDCK canine renal tubular cells.

PubMed

Cheng, H-H; Chou, C-T; Sun, T-K; Liang, W-Z; Cheng, J-S; Chang, H-T; Tseng, H-W; Kuo, C-C; Chen, F-A; Kuo, D-H; Shieh, P; Jan, C-R

2015-11-01

Naproxen is an anti-inflammatory drug that affects cellular calcium ion (Ca(2+)) homeostasis and viability in different cells. This study explored the effect of naproxen on [Ca(2+)](i) and viability in Madin-Darby canine kidney cells (MDCK) canine renal tubular cells. At concentrations between 50 μM and 300 μM, naproxen induced [Ca(2+)](i) rises in a concentration-dependent manner. This Ca(2+) signal was reduced partly when extracellular Ca(2+) was removed. The Ca(2+) signal was inhibited by a Ca(2+) channel blocker nifedipine but not by store-operated Ca(2+) channel inhibitors (econazole and SKF96365), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate, and a PKC inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with 2,5-di-tert-butylhydroquinone or thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+) pumps, partly inhibited naproxen-induced Ca(2+) signal. Inhibition of phospholipase C with U73122 did not alter naproxen-evoked [Ca(2+)](i) rises. At concentrations between 15 μM and 30 μM, naproxen killed cells in a concentration-dependent manner, which was not reversed by prechelating cytosolic Ca(2+) with the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl. Annexin V/propidium iodide staining data suggest that naproxen induced apoptosis. Together, in MDCK renal tubular cells, naproxen induced [Ca(2+)](i) rises by inducing Ca(2+) release from multiple stores that included the endoplasmic reticulum and Ca(2+) entry via nifedipine-sensitive Ca(2+) channels. Naproxen induced cell death that involved apoptosis. © The Author(s) 2015.

Naproxen effects on brain response to painful pressure stimulation in patients with knee osteoarthritis: a double-blind, randomized, placebo-controlled, single-dose study.

PubMed

Giménez, Mónica; Pujol, Jesús; Ali, Zahid; López-Solà, Marina; Contreras-Rodríguez, Oren; Deus, Joan; Ortiz, Héctor; Soriano-Mas, Carles; Llorente-Onaindia, Jone; Monfort, Jordi

2014-11-01

The aim of our study was to investigate the effects of naproxen, an antiinflammatory analgesic drug, on brain response to painful stimulation on the affected knee in chronic osteoarthritis (OA) using functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled study. A sample of 25 patients with knee OA received naproxen (500 mg), placebo, or no treatment in 3 separate sessions in a randomized manner. Pressure stimulation was applied to the medial articular interline of the knee during the fMRI pain sequence. We evaluated subjective pain ratings at every session and their association with brain responses to pain. An fMRI control paradigm was included to discard global brain vascular effects of naproxen. We found brain activation reductions under naproxen compared to no treatment in different cortical and subcortical core pain processing regions (p≤0.001). Compared to placebo, naproxen triggered an attenuation of amygdala activation (p=0.001). Placebo extended its attenuation effects beyond the classical pain processing network (p≤0.001). Subjective pain scores during the fMRI painful task differed between naproxen and no treatment (p=0.037). Activation attenuation under naproxen in different regions (i.e., ventral brain, cingulate gyrus) was accompanied by an improvement in the subjective pain complaints (p≤0.002). Naproxen effectively reduces pain-related brain responses involving different regions and the attenuation is related to subjective pain changes. Our current work yields further support to the utility of fMRI to objectify the acute analgesic effects of a single naproxen dose in patients affected by knee OA. The trial was registered at the EuropeanClinicalTrials Database, "EudraCT Number 2008-004501-33".

Hydrogen sulfide releasing naproxen offers better anti-inflammatory and chondroprotective effect relative to naproxen in a rat model of zymosan induced arthritis.

PubMed

Dief, A E; Mostafa, D K; Sharara, G M; Zeitoun, T H

2015-04-01

Hydrogen sulfide (H2S) is rapidly gaining ground as a physiological mediator of inflammation, but there is no clear consensus as to its precise role in inflammation. Therefore, this study was undertaken to evaluate the effects of ATB-346 as a novel H2S-releasing naproxen compared to naproxen, as a traditional non-steroidal anti-inflammatory drug on zymosan induced mono-arthritis in rats. Male Wistar rats (n=48) were randomly assigned to four main groups: normal control, untreated arthritis, Naproxen and ATB-346 treated groups. Mono-arthritis was induced by intra-articular injection of zymosan into the knee joints. Mechanical hypernociception and joint swelling were evaluated at 6 hours and 5 days. Inflammatory cellular recruitment and adherence, tumor necrosis factor alpha, nuclear factor kappa β, total sulfide levels, and histological changes were evaluated in knee lavages, blood or joint tissues at selected time points. Zymosan injection evoked knee inflammation and pain as characterized by mechanical hypernociception, impaired gait, joint swelling with inflammatory exudation and histological changes. Treatment with ATB-346 attenuated nociceptive responses, inflammatory cellular and biochemical changes in comparison to naproxen. Only ATB-346 was able to suppress neutrophil adherence and to preserve normal articular structure. H2S releasing naproxen represents an advancement over the parent drug, naproxen. Apart from the superior anti-inflammatory and anti-noceiceptive activity, ATB-346 offered a distinguished chondroprotective effect and is almost devoid from naproxen deleterious effects on articular cartilage.

Synthesis and characterization of a helicene-based imidazolium salt and its application in organic molecular electronics.

PubMed

Storch, Jan; Zadny, Jaroslav; Strasak, Tomas; Kubala, Martin; Sykora, Jan; Dusek, Michal; Cirkva, Vladimir; Matejka, Pavel; Krbal, Milos; Vacek, Jan

2015-02-02

Herein we demonstrate the synthesis of a helicene-based imidazolium salt. The salt was prepared by starting from racemic 2-methyl[6]helicene, which undergoes radical bromination to yield 2-(bromomethyl)[6]helicene. Subsequent treatment with 1-butylimidazole leads to the corresponding salt 1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide. The prepared salt was subsequently characterized by using NMR spectroscopy and X-ray analysis, various optical spectrometric techniques, and computational chemistry tools. Finally, the imidazolium salt was immobilized onto a SiO2 substrate as a crystalline or amorphous deposit. The deposited layers were used for the development of organic molecular semiconductor devices and the construction of a fully reversible humidity sensor. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crystallization of lysozyme with ( R)-, ( S)- and ( RS)-2-methyl-2,4-pentanediol

DOE PAGES

Stauber, Mark; Jakoncic, Jean; Berger, Jacob; ...

2015-03-01

Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2,4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with ( R)-MPD had the most order and produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with ( R)-MPD and ( RS)-MPD the crystal contacts are made by ( R)-MPD, demonstrating that there ismore » preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

Synergistic effect of the interaction between naproxen and citral on inflammation in rats.

PubMed

Ortiz, Mario I; González-García, Martha P; Ponce-Monter, Héctor A; Castañeda-Hernández, Gilberto; Aguilar-Robles, Paulina

2010-12-15

The combination of non-steroidal anti-inflammatory drugs with herbs having analgesic effects can increase their antinociceptive activity and limit their side effects. The aim of the present study was to examine the effects on inflammation and gastric injury in rats resulting from the interaction between naproxen and citral. Naproxen, citral, or fixed-dose naproxen-citral combinations were administered orally and their anti-inflammation (carrageenan-induced paw edema) and gastric damage were assessed in rats. The pharmacological interaction type was evaluated by the isobolographic analysis. Naproxen, citral, or combinations of naproxen and citral produced anti-inflammatory effects. The sole administration of naproxen produced significant gastric damage, but this effect was not obtained with either citral or combinations. ED(30) values were estimated for the individual drugs, and isobolograms were constructed. The derived theoretical ED(30) for the anti-inflammatory effect was 504.4 mg/kg; this was significantly higher than the observed experimental value (190.6 mg/kg). These results indicate that a synergistic interaction underlies the anti-inflammatory effect. The data suggests that the naproxen-citral combination can interact and to produce minor gastric damage and may have therapeutic advantages for the clinical treatment of inflammation. Copyright © 2010 Elsevier GmbH. All rights reserved.

¹H NMR-based metabolic profiling of naproxen-induced toxicity in rats.

PubMed

Jung, Jeeyoun; Park, Minhwa; Park, Hye Jin; Shim, Sun Bo; Cho, Yang Ha; Kim, Jinho; Lee, Ho-Sub; Ryu, Do Hyun; Choi, Donwoong; Hwang, Geum-Sook

2011-01-15

The dose-dependent perturbations in urinary metabolite concentrations caused by naproxen toxicity were investigated using ¹H NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic evaluation of naproxen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) of ¹H NMR from rat urine revealed a dose-dependent metabolic shift between the vehicle-treated control rats and rats treated with low-dose (10 mg/kg body weight), moderate-dose (50 mg/kg), and high-dose (100 mg/kg) naproxen, coinciding with their gastric damage scores after naproxen administration. The resultant metabolic profiles demonstrate that the naproxen-induced gastric damage exhibited energy metabolism perturbations that elevated their urinary levels of citrate, cis-aconitate, creatine, and creatine phosphate. In addition, naproxen administration decreased choline level and increased betaine level, indicating that it depleted the main protective constituent of the gastric mucosa. Moreover, naproxen stimulated the decomposition of tryptophan into kynurenate, which inhibits fibroblast growth factor-1 and delays ulcer healing. These findings demonstrate that ¹H NMR-based urinary metabolic profiling can facilitate noninvasive and rapid diagnosis of drug side effects and is suitable for elucidating possible biological pathways perturbed by drug toxicity. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chiral recognition of naproxen enantiomers based on fluorescence quenching of bovine serum albumin-stabilized gold nanoclusters

NASA Astrophysics Data System (ADS)

Jafari, Marzieh; Tashkhourian, Javad; Absalan, Ghodratollah

2017-10-01

A simple, fast and green method for chiral recognition of S- and R-naproxen has been introduced. The method was based on quenching of the fluorescence intensity of bovine serum albumin-stabilized gold nanoclusters in the presence of naproxen enantiomers. The quenching intensity in the presence of S-naproxen was higher than R-naproxen when phosphate buffer solution at pH 7.0 was used. The chiral recognition occurred due to steric effect between bovine serum albumin conformation and naproxen enantiomers. Two linear determination range were established as 7.4 × 10-7-9.1 × 10-6 and 9.1 × 10-6-3.1 × 10-5 mol L-1 for both enantiomers and detection limits of 7.4 × 10-8 mol L- 1 and 9.5 × 10-8 mol L-1 were obtained for S- and R-naproxen, respectively. The developed method showed good repeatability and reproducibility for the analysis of a synthetic sample. To make the procedure applicable to biological samples, the removal of heavy metals from the sample is suggested before any analytical attempt.

Massive naproxen overdose with serial serum levels.

PubMed

Al-Abri, Suad A; Anderson, Ilene B; Pedram, Fatehi; Colby, Jennifer M; Olson, Kent R

2015-03-01

Massive naproxen overdose is not commonly reported. Severe metabolic acidosis and seizure have been described, but the use of renal replacement therapy has not been studied in the context of overdose. A 28-year-old man ingested 70 g of naproxen along with an unknown amount of alcohol in a suicidal attempt. On examination in the emergency department 90 min later, he was drowsy but had normal vital signs apart from sinus tachycardia. Serum naproxen level 90 min after ingestion was 1,580 mg/L (therapeutic range 25-75 mg/L). He developed metabolic acidosis requiring renal replacement therapy using sustained low efficiency dialysis (SLED) and continuous venovenous hemofiltration (CVVH) and had recurrent seizure activity requiring intubation within 4 h from ingestion. He recovered after 48 h. Massive naproxen overdose can present with serious toxicity including seizures, altered mental status, and metabolic acidosis. Hemodialysis and renal replacement therapy may correct the acid base disturbance and provide support in cases of renal impairment in context of naproxen overdose, but further studies are needed to determine the extraction of naproxen.

Naproxen or Estradiol for Bleeding and Spotting with the Levonorgestrel Intrauterine System: A Randomized Controlled Trial

PubMed Central

MADDEN, Tessa; PROEHL, Sarah; ALLSWORTH, Jenifer E.; SECURA, Gina M.; PEIPERT, Jeffrey F.

2011-01-01

Objective To evaluate whether oral naproxen or transdermal estradiol decreases bleeding and spotting in women initiating the levonorgestrel-releasing intrauterine system (LNG-IUS). Study Design We conducted a randomized controlled trial of naproxen, estradiol, or placebo administered over the first 12 weeks of LNG-IUS use. Participants completed a written bleeding diary. We imputed missing values and performed an intention-to-treat analysis. Results There were 129 women randomized to naproxen (n=42), estradiol (n=44), or placebo (n=43). The naproxen group was more likely to be in the lowest quartile of bleeding and spotting days compared to placebo, 42.9% versus 16.3% (p=0.03). In the multivariable analysis, the naproxen group had a 10% reduction in bleeding and spotting days (RRadj 0.90, 95%CI 0.84–0.97) compared to placebo. More frequent bleeding and spotting was observed in the estradiol group (RRadj 1.25, 95%CI 1.17–1.34). Conclusions Administration of naproxen resulted in a reduction in bleeding and spotting days compared to placebo. (150 words) PMID:22055339

Microbial models of mammalian metabolism: microbial transformation of naproxen.

PubMed

el Sayed, K A

2000-12-01

Preparative-scale fermentation of S-naproxen, the known antiinflammatory, analgesic and antipyretic drug, with Cunninghamella elegans ATCC 9245 afforded S-demethylnaproxen, the known human active metabolite of naproxen, in a 90% yield. Demethylnaproxen was also detected as the major metabolite of naproxen using Cunninghamella blakesleeana ATCC 8688a. A review of the previous microbial metabolism studies using the fungi Cunninghamella species suggested that it could be a plausible in vitro predictor for mammalian metabolism.

An analysis of the 'legal high' mephedrone.

PubMed

Gibbons, Simon; Zloh, Mire

2010-07-15

'Legal highs' are compounds, plant or fungal material which can be readily bought from the internet without legal restriction and the single chemicals may be structurally related to illegal drugs of abuse such as the amphetamines. Several recent deaths in the UK have been attributed to these legal highs and unfortunately there is little chemical or biological literature on these materials or certified standards. Here, we detail the analysis of the widely consumed synthetic N-methyl-cathinone analogue known as mephedrone ((1) 2-aminomethyl-1-tolyl-propan-1-one (4'-methylmethcathinone)) and report its spectral data and molecular properties. Material was purchased from an internet site and examined by extensive one- and two-dimensional NMR studies, high-resolution mass spectrometry, elemental analysis and optical rotation, which demonstrated the sample to be of high purity and racemic in nature. Additionally, we report the molecular modelling properties of methyl-cathinones and compare them to their corresponding methyl-amphetamine series. This indicated that the methyl-cathinones are considerably more hydrophilic than the methyl-amphetamines which may account for the higher doses that are needed to demonstrate similar effects. The presence of a ketone in the side chain introduces a far more planar quality to the methyl-cathinones which is absent in the methyl-amphetamine series, and this planarity may contribute to toxicity. 2010 Elsevier Ltd. All rights reserved.

Structure-property relationships in a series of diglycerol tetraether model lipids and their lyotropic assemblies: the effect of branching topology and chirality.

PubMed

Markowski, Thomas; Drescher, Simon; Meister, Annette; Blume, Alfred; Dobner, Bodo

2014-06-14

Three novel diglycerol tetraether lipids with one membrane-spanning chain have been synthesized. These lipids contain only two or four racemic methyl branches at selected positions of the hydrophobic chains in contrast to natural lipids from archaebacterial membranes with an isoprenoid substitution pattern. The insertion of the methyl moieties was realized starting from either (RS)-citronellyl bromide or the inexpensive methyl malonic acid ethyl ester. For chain elongation the Cu-catalysed Grignard coupling reaction was used. The preparation of diglycerol tetraethers was either performed by condensing suitable blocked monoglycerol diethers by Grubbs metathesis or by reaction of the transmembrane C32-chain with blocked glycerols followed by further alkylation steps. Finally, we could show that the resulting lipids can form closed lipid vesicles comparable to the optically pure counterparts. Therefore, these much simpler lipids compared to the natural lipids from archaebacterial membranes are also suitable for preparation of stable tailored liposomes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauber, Mark; Yeshiva University, 2495 Amsterdam Avenue, New York, NY 10033-3312; Jakoncic, Jean

Crystallization of lysozyme with (R)-2-methyl-2, 4-pentanediol produces more ordered crystals and a higher resolution protein structure than crystallization with (S)-2-methyl-2, 4-pentanediol. The results suggest that chiral interactions with chiral additives are important in protein crystal formation. Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2, 4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with (R)-MPD had the most order andmore » produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with (R)-MPD and (RS)-MPD the crystal contacts are made by (R)-MPD, demonstrating that there is preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

Toxicity of naproxen sodium and its mixture with tramadol hydrochloride on fish early life stages.

PubMed

Sehonova, Pavla; Plhalova, Lucie; Blahova, Jana; Doubkova, Veronika; Prokes, Miroslav; Tichy, Frantisek; Fiorino, Emma; Faggio, Caterina; Svobodova, Zdenka

2017-12-01

Pharmaceuticals occur in water bodies as a consequence of their incomplete removal during waste water treatment processes. The occurence of pharmaceuticals in surface waters as well as their possible impact on aquatic vertebrates have received considerable attention in recent years. However, there is still a lack of informations on the chronic effects of widely used drugs as well as their possible mixture toxicity on non-target aquatic vertebrates as well as their possible mixture toxicity. The aim of this study was to assess the effects of naproxen sodium on early life stages of fish and evaluate its mixture toxicity with tramadol hydrochloride, which was assessed in our earlier study as a single substance. Two embryo-larval toxicity tests with common carp (Cyprinus carpio) were performed according to the OECD guideline 210 (Fish, Early-life Stage Toxicity Test) in order to assess the subchronic toxicity of naproxen sodium and tramadol hydrochlorid-naproxen sodium mixture at the concentrations of 10; 50; 100 and 200 μg/L. These experiments were conducted for 32 days. The subchronic exposure to naproxen sodium and naproxen sodium and tramadol hydrochloride mixture had a strong effect on the early life stages of common carp. Hatching, developmental rate, morphology, histopathology and, in the case of the naproxen sodium and tramadol hydrochloride mixture, mortality were influenced. The bioindicators of oxidative stress were also influenced. The LOEC was determined at 10 μg/L for both naproxen sodium and naproxen sodium and tramadol hydrochloride mixture. Copyright © 2017 Elsevier Ltd. All rights reserved.

Racemic DNA crystallography.

PubMed

Mandal, Pradeep K; Collie, Gavin W; Kauffmann, Brice; Huc, Ivan

2014-12-22

Racemates increase the chances of crystallization by allowing molecular contacts to be formed in a greater number of ways. With the advent of protein synthesis, the production of protein racemates and racemic-protein crystallography are now possible. Curiously, racemic DNA crystallography had not been investigated despite the commercial availability of L- and D-deoxyribo-oligonucleotides. Here, we report a study into racemic DNA crystallography showing the strong propensity of racemic DNA mixtures to form racemic crystals. We describe racemic crystal structures of various DNA sequences and folded conformations, including duplexes, quadruplexes, and a four-way junction, showing that the advantages of racemic crystallography should extend to DNA. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The design of naproxen solid lipid nanoparticles to target skin layers.

PubMed

Akbari, Jafar; Saeedi, Majid; Morteza-Semnani, Katayoun; Rostamkalaei, Seyyed Sohrab; Asadi, Masoumeh; Asare-Addo, Kofi; Nokhodchi, Ali

2016-09-01

The aim of the current investigation was to produce naproxen solid lipid nanoparticles (Nap-SLNs) by the ultrasonication method to improve its skin permeation and also to investigate the influence of Hydrophilic-lipophilic balance (HLB) changes on nanoparticles properties. The properties of obtained SLNs loaded with naproxen were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). FT-IR was also used to investigate any interaction between naproxen and the excipients used at the molecular level during the preparation of the SLNs. The performance of the formulations was investigated in terms of skin permeation and also the retention of the drug by the skin. It was found that generally, with increasing the lipid concentration, the average particle size and polydispersity index (PDI) of SLNs increased from 94.257±4.852nm to 143.90±2.685nm and from 0.293±0.037 to 0.525±0.038 respectively. The results also showed that a reduction in the HLB resulted in an increase in the PDI, particle size, zeta potential and entrapment efficiency (EE%). DSC showed that the naproxen encapsulated in the SLNs was in its amorphous form. The peaks of prominent functional groups of naproxen were found in the FT-IR spectra of naproxen-SLN, which confirmed the entrapment of naproxen in the lipid matrix. FT-IR results also ruled out any chemical interaction between drug and the chemicals used in the preparation of SLNs. The amount of naproxen detected in the receptor chamber at all the sampling times for the reference formulation (naproxen solution containing all surfactants at pH 7.4) was higher than that of the Nap-SLN8 formulation. Nap-SLN8 showed an increase in the concentration of naproxen in the skin layer with less systemic absorption. This indicates that most of the drug in Nap-SLN8 remains in the skin which can reduce the side effect of systemic absorption of the drug and increases the concentration of the drug at the site of the action. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies.

PubMed

Li, Z J; Zell, M T; Munson, E J; Grant, D J

1999-03-01

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban

PubMed Central

Frost, Charles; Shenker, Andrew; Gandhi, Mohit D; Pursley, Janice; Barrett, Yu Chen; Wang, Jessie; Zhang, Donglu; Byon, Wonkyung; Boyd, Rebecca A; LaCreta, Frank

2014-01-01

Aim To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). Method In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid–induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. Results Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml−1, consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). Conclusion Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen. PMID:24697979

S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen

PubMed Central

Bowalgaha, Kushari; Elliot, David J; Mackenzie, Peter I; Knights, Kathleen M; Swedmark, Stellan; Miners, John O

2005-01-01

Aims To characterize the kinetics of S-naproxen (‘naproxen’) acyl glucuronidation and desmethylnaproxen acyl and phenolic glucuronidation by human liver microsomes and identify the human UGT isoform(s) catalysing these reactions. Methods Naproxen and desmethylnaproxen glucuronidation were investigated using microsomes from six and five livers, respectively. Human recombinant UGTs were screened for activity towards naproxen and desmethylnaproxen. Where significant activity was observed, kinetic parameters were determined. Naproxen and desmethylnaproxen glucuronides were measured by separate high-performance liquid chromatography methods. Results Naproxen acyl glucuronidation by human liver microsomes followed biphasic kinetics. Mean apparent Km values (±SD, with 95% confidence interval in parentheses) for the high- and low-affinity components were 29 ± 13 µm (16, 43) and 473 ± 108 µm (359, 587), respectively. UGT 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10 and 2B7 glucuronidated naproxen. UGT2B7 exhibited an apparent Km (72 µm) of the same order as the high-affinity human liver microsomal activity, which was inhibited by the UGT2B7 selective ‘probe’ fluconazole. Although data for desmethylnaproxen phenolic glucuronidation by human liver microsomes were generally adequately fitted to either the single- or two-enzyme Michaelis–Menten equation, model fitting was inconclusive for desmethylnaproxen acyl glucuronidation. UGT 1A1, 1A7, 1A9 and 1A10 catalysed both the phenolic and acyl glucuronidation of desmethylnaproxen, while UGT 1A3, 1A6 and 2B7 formed only the acyl glucuronide. Atypical glucuronidation kinetics were variably observed for naproxen and desmethylnaproxen glucuronidation by the recombinant UGTs. Conclusion UGT2B7 is responsible for human hepatic naproxen acyl glucuronidation, which is the primary elimination pathway for this drug. PMID:16187975

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban.

PubMed

Frost, Charles; Shenker, Andrew; Gandhi, Mohit D; Pursley, Janice; Barrett, Yu Chen; Wang, Jessie; Zhang, Donglu; Byon, Wonkyung; Boyd, Rebecca A; LaCreta, Frank

2014-10-01

To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid-induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml(-1) , consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen. © 2014 The British Pharmacological Society.

Intravenous lipid emulsion therapy in three cases of canine naproxen overdose.

PubMed

Herring, Jennifer M; McMichael, Maureen A; Corsi, Raffaella; Wurlod, Virginie

2015-01-01

To report a case series of canine naproxen overdoses successfully treated with intravenous lipid emulsion therapy (IVLE). Three dogs were presented for acute ingestion of naproxen and were treated with IVLE. Baseline and post treatment serum naproxen concentrations were measured. The first exposure involved ingestion of 61 mg/kg of an over-the-counter naproxen formulation in a 7-month-old male intact Labrador Retriever. Pre-IVLE toxin concentration assessed by high performance liquid chromatography (HPLC) was 73 μg/mL with a one-hour post-IVLE concentration decreasing to 30 μg/mL. The second and third exposures were 3-year-old female spayed Pembroke Welsh Corgi dogs from the same family, presented for potential ingestion of up to 207 mg/kg of a prescription strength naproxen formulation. Pre-IVLE naproxen concentration by HPLC for case 2 was 30 μg/mL with a reduction to 12 μg/mL and 7.2 μg/mL 1 and 3 hours post-IVLE treatment, respectively. For case 3, pre-IVLE naproxen concentration by HPLC was 86 μg/mL with post concentrations at 21 μg/mL one hour and 10 μg/mL 3 hours post-IVLE administration. Naproxen is a nonsteroidal anti-inflammatory drug with a long half-life and narrow margin of safety in dogs. Ingestion of > 5 mg/kg has been associated with adverse gastrointestinal effects, including ulceration. At doses > 10-25 mg/kg, acute kidney failure has been reported, and at doses > 50 mg/kg, neurologic abnormalities occur. This is the first reported use of IVLE for treatment of naproxen overdose with documented decrease in serum toxin concentrations shortly after administration. No long-standing gastrointestinal, renal, or neurologic effects occurred in these dogs. © Veterinary Emergency and Critical Care Society 2015.

Naproxen or estradiol for bleeding and spotting with the levonorgestrel intrauterine system: a randomized controlled trial.

PubMed

Madden, Tessa; Proehl, Sarah; Allsworth, Jenifer E; Secura, Gina M; Peipert, Jeffrey F

2012-02-01

The purpose of this study was to evaluate whether oral naproxen or transdermal estradiol decreases bleeding and spotting in women who are initiating the levonorgestrel-releasing intrauterine system. We conducted a randomized controlled trial of naproxen, estradiol, or placebo that was administered over the first 12 weeks of levonorgestrel-releasing intrauterine system use. Participants completed a written bleeding diary. We imputed missing values and performed an intention-to-treat analysis. There were 129 women who were assigned randomly to naproxen (n = 42 women), estradiol (n = 44 women), or placebo (n = 43 women). The naproxen group was more likely to be in the lowest quartile of bleeding and spotting days compared with placebo (42.9% vs 16.3%; P = .03). In the multivariable analysis, the naproxen group had a 10% reduction in bleeding and spotting days (adjusted relative risk, 0.90; 95% confidence interval, 0.84-0.97) compared with placebo. More frequent bleeding and spotting was observed in the estradiol group (adjusted relative risk, 1.25; 95% confidence interval, 1.17-1.34). The administration of naproxen resulted in a reduction in bleeding and spotting days compared with placebo. Copyright © 2012 Mosby, Inc. All rights reserved.

Sumatriptan/Naproxen Sodium: A Review in Migraine.

PubMed

Syed, Yahiya Y

2016-01-01

Sumatriptan/naproxen sodium (Treximet®) is a fixed-dose combination of a serotonin 5-HT1B/1D receptor agonist (sumatriptan) and an NSAID (naproxen sodium), approved in the USA for the acute treatment of migraine with or without aura in adolescents and adults. In a randomized, phase 3 trial in adolescents, significantly more sumatriptan/naproxen sodium than placebo recipients were pain-free at 2 h. Similarly, in a pair of randomized phase 3 trials in adults, significantly more sumatriptan/naproxen sodium than placebo recipients had relief from migraine symptoms at 2 h, and the combination was more effective than individual components in terms of sustained (2-24 h) pain-free response rate. Sumatriptan/naproxen sodium was generally well tolerated, with ≤11 % of adolescents and ≤22 % of adults reporting treatment-related adverse events in the key clinical trials. The most common adverse reactions were nasopharyngitis, hot flushes and muscle tightness in adolescents, and dizziness, pain or pressure sensations, nausea, somnolence, dry mouth, dyspepsia and paraesthesia in adults. Based on current data, sumatriptan/naproxen sodium is a useful option for the acute treatment of migraine in adolescents and adults. The fixed-dose combination may reduce pill burden and improve adherence in some patients.

Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies.

PubMed

Milsom, Ian; Minic, Milos; Dawood, M Yusoff; Akin, Mark D; Spann, June; Niland, Nona F; Squire, R Anne

2002-09-01

Dysmenorrhea is the most common menstrual complaint in young women, with a prevalence as high as 90%. It is responsible for substantial repeated short-term absenteeism from school and work in young women. Effective treatments are available, including nonsteroidal anti-inflammatory drugs (NSAIDs). In many countries, a variety of NSAIDs have become available as over-the-counter (OTC) drugs. The goal of this study was to compare the efficacy and safety of OTC doses of naproxen (400 mg) and naproxen/naproxen sodium (200/220 mg) with acetaminophen (1000 mg), ibuprofen (200 mg), and placebo in the treatment of primary dysmenorrhea. A pooled analysis of 5 trials was performed. Efficacy was assessed by pain relief, relief of other dysmenorrheic symptoms, time to backup medication or remedication, and treatment preference. Tolerability was assessed by recording adverse events (AEs). A total of 443 women were enrolled in the combined studies. Naproxen 400 mg provided greater pain relief than acetaminophen and placebo within 30 minutes of administration (P < 0.01 and P < 0.05, respectively). Furthermore, naproxen 400 mg and 200 mg provided greater pain relief than both acetaminophen (P < 0.01 and P < 0.05, respectively) and ibuprofen (P < 0.001 and P < 0.01, respectively) at 6 hours after administration. Both doses of naproxen had higher scores than placebo for symptom relief and drug preference (all P < 0.001). The AEs and their frequency were similar among the treatment groups. No serious AEs were reported. When administered at OTC doses, naproxen was effective in the relief of pain and other symptoms of primary dysmenorrhea and had a good safety profile in the population studied.

Structure-Based Discovery of the Novel Antiviral Properties of Naproxen against the Nucleoprotein of Influenza A Virus

PubMed Central

Lejal, Nathalie; Tarus, Bogdan; Bouguyon, Edwige; Chenavas, Sylvie; Bertho, Nicolas; Delmas, Bernard; Ruigrok, Rob W. H.; Di Primo, Carmelo

2013-01-01

The nucleoprotein (NP) binds the viral RNA genome and associates with the polymerase in a ribonucleoprotein complex (RNP) required for transcription and replication of influenza A virus. NP has no cellular counterpart, and the NP sequence is highly conserved, which led to considering NP a hot target in the search for antivirals. We report here that monomeric nucleoprotein can be inhibited by a small molecule binding in its RNA binding groove, resulting in a novel antiviral against influenza A virus. We identified naproxen, an anti-inflammatory drug that targeted the nucleoprotein to inhibit NP-RNA association required for NP function, by virtual screening. Further docking and molecular dynamics (MD) simulations identified in the RNA groove two NP-naproxen complexes of similar levels of interaction energy. The predicted naproxen binding sites were tested using the Y148A, R152A, R355A, and R361A proteins carrying single-point mutations. Surface plasmon resonance, fluorescence, and other in vitro experiments supported the notion that naproxen binds at a site identified by MD simulations and showed that naproxen competed with RNA binding to wild-type (WT) NP and protected active monomers of the nucleoprotein against proteolytic cleavage. Naproxen protected Madin-Darby canine kidney (MDCK) cells against viral challenges with the H1N1 and H3N2 viral strains and was much more effective than other cyclooxygenase inhibitors in decreasing viral titers of MDCK cells. In a mouse model of intranasal infection, naproxen treatment decreased the viral titers in mice lungs. In conclusion, naproxen is a promising lead compound for novel antivirals against influenza A virus that targets the nucleoprotein in its RNA binding groove. PMID:23459490

Prevention of chemically induced urinary bladder cancers by naproxen: protocols to reduce gastric toxicity in humans do not alter preventive efficacy.

PubMed

Lubet, Ronald A; Scheiman, James M; Bode, Ann; White, Jonathan; Minasian, Lori; Juliana, M Margaret; Boring, Daniel L; Steele, Vernon E; Grubbs, Clinton J

2015-04-01

The COX inhibitors (NSAID/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2-specific inhibitors have progressed to clinical trials and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular effects. Certain NSAIDs (e.g., naproxen) have a good cardiac profile, but can cause gastric toxicity. The present study examined protocols to reduce this toxicity of naproxen. Female Fischer-344 rats were treated weekly with the urinary bladder-specific carcinogen hydroxybutyl(butyl)nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/kg body weight/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/kg body weight/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN-treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), naproxen alone or combined with omeprazole-prevented cancers, yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN -: treated rats were administered naproxen: (A) daily, (B) 1 week daily naproxen/1week vehicle, (C) 3 weeks daily naproxen/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C, and D resulted in palpable cancers in 27%, 22%, 19%, and 96% of rats (P < 0.01). Short-term naproxen treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols that should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g., naproxen) in clinical prevention trials. ©2015 American Association for Cancer Research.

Biodegradation of naproxen by freshwater algae Cymbella sp. and Scenedesmus quadricauda and the comparative toxicity.

PubMed

Ding, Tengda; Lin, Kunde; Yang, Bo; Yang, Mengting; Li, Juying; Li, Wenying; Gan, Jay

2017-08-01

Naproxen is one of the most prevalent pharmaceuticals and of great environment concern. Information about bioremediation of naproxen by algae remains limited and no study has been reported on the degradation mechanism and the toxicity of NPX on algae. In this study, both Cymbella sp. and Scenedesmus quadricauda showed complete growth inhibition (100%) at 100mgL -1 within 24h. Biochemical characteristics including chlorophyll a, carotenoid contents and enzyme activities for these two microalgae were affected by NPX at relatively high concentrations after 4d of exposure. Degradation of naproxen was accelerated by both algae species. Cymbella sp. showed a more satisfactive effect in the bioremediation of NPX with higher removal efficiency. A total of 12 metabolites were identified by LC-MS/MS and the degradation pathways of naproxen in two algae were proposed. Hydroxylation, decarboxylation, demethylation, tyrosine conjunction and glucuronidation contributed to naproxen transformation in algal cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cometabolic Degradation of Naproxen by Planococcus sp. Strain S5.

PubMed

Domaradzka, Dorota; Guzik, Urszula; Hupert-Kocurek, Katarzyna; Wojcieszyńska, Danuta

Naproxen is a non-steroidal anti-inflammatory drug frequently detected in the influent and effluent of sewage treatment plants. The Gram-positive strain Planococcus sp. S5 was able to remove approximately 30 % of naproxen after 35 days of incubation in monosubstrate culture. Under cometabolic conditions, with glucose or phenol as a growth substrate, the degradation efficiency of S5 increased. During 35 days of incubation, 75.14 ± 1.71 % and 86.27 ± 2.09 % of naproxen was degraded in the presence of glucose and phenol, respectively. The highest rate of naproxen degradation observed in the presence of phenol may be connected with the fact that phenol is known to induce enzymes responsible for aromatic ring cleavage. The activity of phenol monooxygenase, naphthalene monooxygenase, and hydroxyquinol 1,2-dioxygenase was indicated in Planococcus sp. S5 culture with glucose or phenol as a growth substrate. It is suggested that these enzymes may be engaged in naproxen degradation.

Elucidation of the naproxen sodium adsorption onto activated carbon prepared from waste apricot: kinetic, equilibrium and thermodynamic characterization.

PubMed

Onal, Y; Akmil-Başar, C; Sarici-Ozdemir, C

2007-09-30

In this study, activated carbon (WA11Zn5) was prepared from waste apricot, which is waste in apricot plants in Malatya, by chemical activation with ZnCl(2). BET surface area of activated carbon is determined as 1060 m(2)/g. The ability of WA11Zn5, to remove naproxen sodium from effluent solutions by adsorption has been studied. Equilibrium isotherms for the adsorption of naproxen sodium on activated carbon were measured experimentally. Results were analyzed by the Langmiur, Freundlich equation using linearized correlation coefficient at 298 K. The characteristic parameters for each isotherm have been determined. Langmiur equation is found to best represent the equilibrium data for naproxen sodium-WA11Zn5 systems. The monolayer adsorption capacity of WA11Zn5 for naproxen sodium was found to be 106.38 mg/g at 298 K. The process was favorable and spontaneous. The kinetics of adsorption of naproxen sodium have been discussed using three kinetic models, i.e., the pseudo first-order model, the pseudo second-order model, the intraparticle diffusion model. Kinetic parameters and correlation coefficients were determined. It was shown that the pseudo second-order kinetic equation could describe the adsorption kinetics for naproxen sodium onto WA11Zn5. The thermodynamic parameters, such as DeltaG degrees , DeltaS degrees and DeltaH degrees, were calculated. The thermodynamics of naproxen sodium-WA11Zn5 system indicates endothermic process.

Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus

PubMed Central

Tarus, Bogdan; Bertrand, Hélène; Zedda, Gloria; Di Primo, Carmelo; Quideau, Stéphane; Slama-Schwok, Anny

2015-01-01

The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function. PMID:25333630

Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus.

PubMed

Tarus, Bogdan; Bertrand, Hélène; Zedda, Gloria; Di Primo, Carmelo; Quideau, Stéphane; Slama-Schwok, Anny

2015-09-01

The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function.

Enteric protection of naproxen in a fixed-dose combination product produced by hot-melt co-extrusion.

PubMed

Vynckier, A-K; De Beer, M; Monteyne, T; Voorspoels, J; De Beer, T; Remon, J P; Vervaet, C

2015-08-01

In this study hot-melt co-extrusion is used as processing technique to manufacture a fixed-dose combination product providing enteric protection to naproxen incorporated in the core and immediate release to esomeprazole magnesium embedded in the coat. The plasticizing effect of naproxen and triethyl citrate (TEC) was tested on the enteric polymers investigated (Eudragit(®) L100-55, HPMC-AS-LF and HPMCP-HP-50). Core matrix formulations containing HPMC-AS-LF, TEC and a naproxen load of 15, 30 and 50% were processed and characterized. The in vitro naproxen release in 0.1N HCl was prevented for 2h for all formulations. The physicochemical state of the drug in the extrudates was determined and a stability study was performed. Intermolecular interactions between naproxen and polymer were identified using attenuated total reflection Fourier-transform infrared (ATR FT-IR) spectroscopy. When esomeprazole magnesium was formulated in a polyethylene oxide 100K:polyethylene glycol 4K (1:1) matrix, separated from the naproxen-containing layer, the formulation could be easily processed and complete in vitro drug release was observed after 45 min. When co-extruding the core/coat dosage form it was observed that a third layer of polymer, separating the naproxen loaded enteric formulation in the core from the coat, is required to prevent degradation of the acid-labile esomeprazole magnesium at the core/coat interface. Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical characterization of territorial marking fluid of male Bengal tiger, Panthera tigris.

PubMed

Burger, B V; Viviers, M Z; Bekker, J P I; le Roux, M; Fish, N; Fourie, W B; Weibchen, G

2008-05-01

The territorial marking fluid of the male Bengal tiger, Panthera tigris, consists of a mixture of urine and a small quantity of lipid material that may act as a controlled-release carrier for the volatile constituents of the fluid. Using gas chromatography and gas chromatography-mass spectrometry, 98 volatile compounds and elemental sulfur were identified in the marking fluid. Another 16 volatiles were tentatively identified. The majority of these compounds were alkanols, alkanals, 2-alkanones, branched and unbranched alkanoic acids, dimethyl esters of dicarboxylic acids, gamma- and delta-lactones, and compounds containing nitrogen or sulfur. Several samples of the marking fluid contained pure (R)-3-methyl-2-octanone, (R)-3-methyl-2-nonanone, and (R)-3-methyl-2-decanone, but these ketones were partly or completely racemized in other samples. The gamma-lactone (S)-(+)-(Z)-6-dodecen-4-olide and the C(8) to C(16) saturated (R)-gamma-lactones and (S)-delta-lactones were present in high enantiomeric purities. The chiral carboxylic acids, 2-methylnonanoic acid, 2-methyldecanoic acid, 2-methylundecanoic acid, and 2-ethylhexanoic acid were racemates. Cadaverine, putrescine, and 2-acetylpyrroline, previously reported as constituents of tiger urine, were not detected. The dominant contribution of some ketones, fatty acids, and lactones to the composition of the headspace of the marking fluid suggests that these compounds may be important constituents of the pheromone. Although it constitutes only a small proportion, the lipid fraction of the fluid contained larger quantities of the volatile organic compounds than the aqueous fraction (urine). The lipid derives its role as controlled-release carrier of the chemical message left by the tiger, from its affinity for the volatiles of the marking fluid. Six proteins with masses ranging from 16 to 69 kDa, inter alia, the carboxylesterase-like urinary protein known as cauxin, previously identified in the urine of the domestic cat and other felid species, were identified in the urine fraction of the marking fluid.

A computational study on the role of chiral N-oxides in enantioselective Pauson-Khand reactions.

PubMed

Fjermestad, Torstein; Pericàs, Miquel A; Maseras, Feliu

2011-08-29

Density functional calculations were carried out to ascertain the origin of enantioselectivity in the brucine N-oxide (BNO)-assisted enantioselective Pauson-Khand reaction (PKR) of norbornene with 2-methyl-3-butyn-2-ol. The computed ee value in acetone is 68 % (R), which compares well to the previously reported experimental value of 58 % (R). In DME the computed ee value of 76 % (R) is in excellent agreement with the experimentally determined value of 78 % (R). The mechanism of enantioselectivity consists of several steps. First, the dicobalt complex is activated by BNO with chirality transfer from enantiopure BNO to the dicobalt complex. Second, competition occurs between a racemization process and complexation with the olefin reagent, which leads to the products. The lower ee value in acetone is due to the lower energy barrier of the racemization process. Calculations show that replacement of BNO by a hypothetical more enantioselective chiral N-oxide will hardly increase the ee value beyond 90 %. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of a single-isomer carboxymethyl-beta-cyclodextrin in chiral capillary electrophoresis.

PubMed

Fejős, Ida; Varga, Erzsébet; Benkovics, Gábor; Malanga, Milo; Sohajda, Tamás; Szemán, Julianna; Béni, Szabolcs

2017-08-01

In this work, the synthesis, characterization, and chiral capillary electrophoretic study of heptakis-(2,3-di-O-methyl-6-O-carboxymethyl)-β-CD (HDMCM), a single-isomer carboxymethylated CD, are presented. The pH-dependent and selector concentration-dependent enantiorecognition properties of HDMCM were investigated and discussed herein. The enantioseparation was assessed applying a structurally diverse set of noncharged, basic, and zwitterionic racemates. The increase in the selector concentration and gross negative charge of HDMCM improved the enantioseparation that could be observed in the majority of the cases. HDMCM was also successfully applied as BGE additive in NACE using a methanol-based system in order to prove the separation selectivity features and to highlight the broad applicability of HDMCM. Over 25 racemates showed partial or baseline separation with HDMCM under the conditions investigated, among which optimal enantiomer migration order was found for the four stereoisomers of tadalafil, tapentadol, and dapoxetine, offering the possibility of a chiral CE method development for chiral purity profiling of these drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti-inflammatory, analgesic and ulcerogenic properties of S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin.

PubMed

Bole-Vunduk, B; Verhnjak, K; Zmitek, J

1996-11-01

The anti-inflammatory, analgesic and gastric mucosal damage-inducing activities of S-(+)-ibuproxam, and S-(+)-ibuproxam-beta-cyclodextrin, new propionic acid derivatives, and racemic ibuproxam-beta-cyclodextrin were investigated in three animal models and compared with those of racemic ibuproxam, racemic ibuprofen and its optical enantiomer S-(+)-ibuprofen. The anti-inflammatory activities of racemic ibuprofen, S-(+)-ibuprofen and racemic ibuproxam in carrageenan-induced paw oedema in rats were almost equipotent and slightly greater than those of S-(+)-ibuproxam and S-(+)-ibuproxam-beta-cyclodextrin, and significantly greater than that of racemic ibuproxam-beta-cyclodextrin. In abdominal constriction tests in mice, the analgesic effects of racemic ibuproxam, S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin were significantly less pronounced than those of racemic ibuprofen and S-(+)-ibuprofen. Ulcerogenic activity of S-(+)-ibuproxam-beta-cyclodextrin in rats was found to be significantly weaker than that of racemic ibuproxam-beta-cyclodextrin, racemic ibuproxam and S-(+)-ibuproxam and, most notably, weaker than those of racemic ibuprofen and S-(+)ibuprofen. These results indicate that S-(+)-ibuproxam-beta-cyclodextrin could be a novel potent anti-inflammatory and analgesic agent with a therapeutic index more favourable than that of the classical non-steroid anti-inflammatory drugs ibuprofen and ibuproxam.

Removal of acetaminophen and naproxen by combined coagulation and adsorption using biochar: influence of combined sewer overflow components.

PubMed

Jung, Chanil; Oh, Jeill; Yoon, Yeomin

2015-07-01

The combined coagulation and adsorption of targeted acetaminophen and naproxen using activated biochar and aluminum sulfate were studied under various synthetic "combined sewer overflow" (CSO) conditions. The biochar demonstrated better adsorption performance for both acetaminophen and naproxen (removal, 94.1 and 97.7%, respectively) than that of commercially available powdered activated carbon (removal, 81.6 and 94.1%, respectively) due to superior carbonaceous structure and surface properties examined by nuclear magnetic resonance analysis. The adsorption of naproxen was more favorable, occupying active adsorption sites on the adsorbents by naproxen due to its higher adsorption affinity compared to acetaminophen. Three classified CSO components (i.e., representing hydrophobic organics, hydrophilic organics, and inorganics) played different roles in the adsorption of both adsorbates, resulted in inhibition by humic acid complexation or metal ligands and negative electrostatic repulsion under adsorption and coagulation combined system. Adsorption alone with biochar was determined to be the most effective adsorptive condition for the removal of both acetaminophen and naproxen under various CSO conditions, while both coagulation alone and combined adsorption and coagulation failed to remove the acetaminophen and naproxen adequately due to an increase in ionic strength in the presence of spiked aluminum species derived from the coagulant.

[Physicochemical properties of suplatast tosilate racemate and enantiomers].

PubMed

Ushio, T; Endo, K; Yamamoto, K

1996-11-01

The physicochemical properties of the enantiomer and racemates of suplatast tosilate (ST) were investigated by means of infrared spectroscopy, solid-state 13C CP/MAS NMR spectroscopy, thermal analysis, and X-ray diffraction analysis, and by measuring the solubility and hygroscopy. The infrared and NMR spectra and X-ray diffraction pattern of the enantiomer were distinctly different from those of the racemate. The melting point of the enantiomer was lower than that of the racemate by 5 degrees C, while the solubility of the enantiomer was 1.3 times higher than that of the racemate. The hygroscopic rate of the enantiomer was greater than that of the racemate. These results suggested that ST was classified into a racemic compound crystal. Furthermore, by comparing the relative peak intensity ratios on X-ray diffraction patterns of the crystals with various optical purities prepared by recrystallization, it was found that a mixture of racemic compound crystals and either of racemic mixture crystals or racemic solid solutions was obtained by recrystallization of ST in the content of 0 to 64%ee, while the recrystallization of ST in the content of more than 64%ee led to the formation of racemic mixture crystals or racemic solid solutions.

Lipase-catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives.

PubMed

Łukowska-Chojnacka, Edyta; Kowalkowska, Anna; Napiórkowska, Agnieszka

2018-04-01

Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug-resistant Mycobacterium tuberculosis strains (M. tuberculosis H 37 Rv, M. tuberculosis sp. 210, M. tuberculosis sp. 192, Mycobacterium scrofulaceum, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium avium, and Mycobacterium kansasii) was evaluated. The chemical step included preparation of ketones, alcohols, and esters bearing benzoxazole moiety. All racemic mixtures of alcohols and esters were separated in Novozyme SP 435-catalyzed transesterification and hydrolysis, respectively. The transesterification reactions were carried out in various organic solvents (tert-butyl methyl ether, toluene, diethyl ether, and diisopropyl ether), and depending on the solvent, the enantioselectivity of the reactions ranged from 4 to >100. The enzymatic hydrolysis of esters was performed in 2 phase tert-butyl methyl ether/phosphate buffer (pH = 7.2) system and provided also enantiomerically enriched products (ee 88-99%). The antitubercular activity assay has shown that synthesized compounds exhibit an interesting antitubercular activity. Racemic mixtures of alcohols, (±)-4-(1,3-benzoxazol-2-ylsulfanyl)butan-2-ol ((±)-3a), (±)-4-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3b), and (±)-4-[(5,7-dibromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3c), displayed as high activity against M. scrofulaceum, M. intracellulare, M. fortuitum, and M. kansasii as commercially available antituberculosis drug-Isoniazid. Moreover, these compounds exhibited twice higher activity toward M. avium (MIC 12.5) compared with Isoniazid (MIC 50). © 2017 Wiley Periodicals, Inc.

Identification of Cytokines and Signaling Proteins Differentially Regulated by Sumatriptan/Naproxen

PubMed Central

Vause, Carrie V; Durham, Paul L

2011-01-01

Summary Objectives The goal of this study was to use protein array analysis to investigate temporal regulation of stimulated cytokine expression in trigeminal ganglia and spinal trigeminal nuclei in response to cotreatment of sumatriptan and naproxen sodium or individual drug. Background Activation of neurons and glia in trigeminal ganglia and spinal trigeminal nuclei leads to increased levels of cytokines that promote peripheral and central sensitization, which are key events in migraine pathology. While recent clinical studies have provided evidence that a combination of sumatriptan and naproxen sodium is more efficacious in treating migraine than either drug alone, it is not well understood why the combination therapy is superior to monotherapy. Methods Male Sprague Dawley rats were left untreated (control), injected with capsaicin, or pre-treated with sumatriptan/naproxen, sumatriptan, or naproxen for 1 hour prior to capsaicin. Trigeminal ganglia and spinal trigeminal nuclei were isolated 2 and 24 hours after capsaicin or drug treatment and levels of 90 proteins were determined using a RayBio® Label-Based Rat Antibody Array. Results Capsaicin stimulated a >3-fold increase in expression of the majority of cytokines in trigeminal ganglia at 2 hours that was sustained at 24 hours. Significantly, treatment with sumatriptan/naproxen almost completely abolished the stimulatory effects of capsaicin at 2 and 24 hours. Capsaicin stimulated >3-fold expression of more proteins in spinal trigeminal nuclei at 24 hours when compared to 2 hours. Similarly, sumatriptan/naproxen abolished capsaicin stimulation of proteins in spinal trigeminal nuclei at 2 hours and greatly suppressed protein expression 24 hours post capsaicin injection. Interestingly, treatment with sumatriptan alone suppressed expression of different cytokines in trigeminal ganglia and spinal trigeminal nuclei than repressed by naproxen sodium. Conclusion We found that the combination of sumatriptan/naproxen was effective in blocking capsaicin stimulation of pro-inflammatory proteins implicated in the development of peripheral and central sensitization in response to capsaicin activation of trigeminal neurons. Based on our findings that sumatriptan and naproxen regulate expression of different proteins in trigeminal ganglia and spinal trigeminal nuclei, we propose that these drugs function on therapeutically distinct cellular targets to suppress inflammation and pain associated with migraine. PMID:22150557

Improving the drug release of Naproxen Sodium tablets by preparing granules and tablets with a preferred mixing ratio of hydrates.

PubMed

Bär, David; Debus, Heiko; Grune, Christian; Tosch, Stephan; Fischer, Wolfgang; Mäder, Karsten; Imming, Peter

2017-12-01

Naproxen is a typical and well-known analgesic classified as non-steroidal anti-inflammatory drug (NSAID) and is commercialized as tablets or liquid-filled capsules. Naproxen is typically used asa sodium salt because of its better processability compared to Naproxen free acid. This entails hygroscopicity and gives rise to the existence of four different hydrates, which show polymorphic and pseudopolymorphic properties. Solid dosage forms containing Naproxen Sodium often have to be processed in an applicable dosage form by granulation and tablet compression. During granulation, Naproxen Sodium will be in contact with water and is exposed to the drop and rise in temperature and to mechanical stress. The result could be a mixture of different hydrates of Naproxen Sodium. This study showed that a modified designed fluid bed granulation was not affected by differences in the mixing ratio of hydrates when using different water contents after spraying and at the end with the finished granules. Here, X-ray diffraction combined with Rietveld refinement was used to analyze the ratio of the hydrates and its identity. All granulation batches showed a large amount of Naproxen Sodium Monohydrate (>87%) and no differences could be observed during tablet compression. Quantities of other hydrates were negligibly small. Furthermore, this study also demonstrated the influence of tablet compression by transforming the hydrates of the granules. In addition to Naproxen Sodium Monohydrate, a large quantity of amorphous structures has also been found. Rietveld evaluation combined with the preliminary studies of the raw hydrates provided conclusions on the drug release of the tablets containing hydrates of Naproxen Sodium which were influenced by tablet compression. Fast drug release was obtained when a maximum water content of about 21% was used after spraying during granulation, independently of the final water content of the finished granules. A maximum water content of less than 21% after spraying yielded a high quantity of amorphous components after tablet compression and thus worsened the drug release. Copyright © 2017 Elsevier B.V. All rights reserved.

MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice.

PubMed

Young, Richard; Glennon, Richard A

2008-01-01

Racemic MDMA (0.3-30 mg/kg), S(+)-MDMA (0.3-30 mg/kg), R(-)-MDMA (0.3-50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (+/-)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (+/-)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (+/-)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.

MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its Stereoisomers: Similarities and Differences in Behavioral Effects in an Automated Activity Apparatus in Mice

PubMed Central

Young, Richard; Glennon, Richard A.

2010-01-01

Racemic MDMA (0.3 – 30 mg/kg), S(+)-MDMA (0.3 – 30 mg/kg), R(-)-MDMA (0.3 – 50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (±)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (±)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (±)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured. PMID:17904622

Fixed Drug Eruption Due to Selective Hypersensitivity to Naproxen with Tolerance to other Propionic Acid NSAIDs.

PubMed

Noguerado-Mellado, Blanca; Gamboa, Abdonias R; Perez-Ezquerra, Patricia R; Cabeza, Cristina M; Fernandez, Roberto P; De Barrio Fernandez, Manuel

2016-01-01

Naproxen is a non-steroidal anti-inflammatory drug (NSAID), belonging to propionic acid group, and its chemical structure is a 6-metoxi-metil-2-naftalenoacetic acid. Fixed drug eruptions (FDE) have been rarely reported. A 38-year-old woman referred that after 2 hours of taking 2 tablets of naproxen for a headache, she developed several edematous and dusky-red macules, one on right forearm and the other two in both thighs and she was diagnosed with FDE probably due to naproxen. We performed patch testing (PT) (Nonweven Patch Test Strips Curatest® Lohman & Rauscher International, Rangsdorf, Germany), with ibuprofen (5% Petrolatum), ketoprofen (2.5% Petrolatum), naproxen and nabumetone (both 10% in DMSO) on the residual lesion of the forearm with naproxen and in both thighs with ibuprofen, ketoprofen and nabumetone. Readings at day 1 (D1) and day 2 (D2) showed negative results to ibuprofen, ketoprofen and nabumetone, but were positive to naproxen in D1. A single blind oral challenge test (SBOCT) with other propionic acid derivates were performed in order to check for crossreactivity between them: ibuprofen, ketoprofen and nabumetone were administered and all drugs were well tolerated. In our patient PT confirmed the diagnosis and allowed us to study the cross-reactivity between NSAIDs of the same group, and confirmed by SBOCT. Cross-reactivity between propionic acid derivatives was studied. This is a case of hypersensitivity to naproxen with good tolerance to other propionic acids NSAIDs (ibuprofen and ketoprofen) and nabumetone, confirmed by PT and SBOCT. Some relavent patents for fixed drug eruption are discussed.

Simultaneous quantification of naproxcinod and its active metabolite naproxen in rat plasma using LC-MS/MS: application to a pharmacokinetic study.

PubMed

Shi, Xiaowei; Shang, Weiding; Wang, Shuang; Xue, Na; Hao, Yanxia; Wang, Yabo; Sun, Mengmeng; Du, Yumin; Cao, Deying; Zhang, Kai; Shi, Qingwen

2015-01-26

In this study, a liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine naproxcinod and naproxen concentrations in rat plasma for the first time. Plasma samples were prepared by simple one-step extraction with methanol for protein precipitation using only 50 μL plasma. Separation was performed on a Synergi Fusion-RP C18 column with a run time of 4 min. Naproxcinod, naproxen and internal standard concentrations were detected in the positive ion mode using multiple reaction monitoring (MRM) of the transitions at m/z 348.2→302.2, 231.1→185.1 and 271.2→203.1, respectively. The calibration curves were linear, with all correlation coefficients being ≥0.9952, in the range of 1.00-400 ng/mL for naproxcinod and 20.0-8000 ng/mL for naproxen. Their accuracy was in the range of -8.1% to 8.7%, and the intra- and inter-day variations were ≤4.53%. The mean extraction recovery of all analytes was more than 93.1% efficient. Stability testing showed that naproxcinod and naproxen remained stable during the whole analytical procedure. After validation, the method was successfully applied to a pharmacokinetic study of naproxcinod and naproxen in rats. The AUC0-∞ of naproxen was 74.6 times larger than that of naproxcinod, which indicated that naproxcinod was rapidly metabolized into naproxen in rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Arylhydrazone derivatives of naproxen as new analgesic and anti-inflammatory agents: Design, synthesis and molecular docking studies.

PubMed

Azizian, Homa; Mousavi, Zahra; Faraji, Hamidreza; Tajik, Mohammad; Bagherzadeh, Kowsar; Bayat, Peyman; Shafiee, Abbas; Almasirad, Ali

2016-06-01

A series of new arylidenehydrazone derivatives of naproxen were synthesized and evaluated for their analgesic and anti-inflammatory activities. Some of the synthesized analogues showed comparable activities when compared against naproxen for their analgesic and anti-inflammatory properties. 2-(6-methoxy-2-naphthyl)-N'-[(pyridine-4-yl)methylene]propanoic acid hydrazide 4j was found to be the most active analgesic agent. 2-(6-methoxy-2-naphthyl)-N'-[4-nitrobenzylidene]propanoic acid hydrazide 4g showed highest anti-inflammatory activity in comparison to the naproxen. Molecular modeling study of the synthesized compounds suggested that the designed molecules were well located and bound to the COX-1 and COX-2 active sites. Compound 4g showed the highest selectivity for COX-2 (RCOX-2/COX-1=1.94) and higher affinity rather than naproxen in COX-2 active site (RCOX-2/naproxen=1.28). Moreover, the structural analyses confirmed that the E-ap rotamer is the preferred structure for the arylidenehydrazone derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

A practical approach to reduce interference due to in-source collision-induced dissociation of acylglucuronides in LC-MS/MS.

PubMed

Mess, Jean-Nicholas; Bérubé, Eugénie-Raphaelle; Furtado, Milton; Garofolo, Fabio

2011-08-01

In LC-MS/MS, glucuronide conjugated metabolites may convert back to the parent drug due to in-source collision-induced dissociation (CID). During the bioanalysis of naproxen, it was noticed that naproxen acylglucuronide exhibited intense in-source CID to the naproxen [M+H](+) ion under positive ESI. However, no in-source CID of the acylglucuronide to the naproxen [M+NH(4)](+) adduct was observed. Furthermore, absolutely no in-source CID was detected under negative ESI. This phenomenon was not only observed for naproxen acylglucuronide but for eight other acylglucuronides compounds. We have shown that monitoring the parent drug [M-H](-) or [M+NH(4)](+) whenever possible could be an easy approach used by bioanalytical scientists to minimize the impact of in-source CID of acylglucuronides to the parent drug.

Enthalpies of Dissolution of Crystalline Naproxen Sodium in Water and Potassium Hydroxide Aqueous Solutions at 298 K

NASA Astrophysics Data System (ADS)

Lytkin, A. I.; Chernikov, V. V.; Krutova, O. N.; Bychkova, S. A.; Volkov, A. V.; Skvortsov, I. A.

2018-03-01

The enthalpies of dissolution of crystalline naproxen sodium in water and aqueous solutions of KOH at 298.15 K are measured by direct calorimetric means in a wide range of concentrations. The acid-base properties of naproxen sodium at ionic strength I 0 and I = 0.1 (KNO3) and a temperature of 298.15 K are studied by spectrophotometric means. The concentration and thermodynamic dissociation constants are determined. The standard enthalpies of the formation of naproxen sodium and the products of its dissociation in aqueous solution are calculated.

Naproxen Induces Type X Collagen Expression in Human Bone-Marrow-Derived Mesenchymal Stem Cells Through the Upregulation of 5-Lipoxygenase

PubMed Central

Alaseem, Abdulrahman M.; Madiraju, Padma; Aldebeyan, Sultan A.; Noorwali, Hussain; Antoniou, John

2015-01-01

Several studies have shown that type X collagen (COL X), a marker of late-stage chondrocyte hypertrophy, is expressed in mesenchymal stem cells (MSCs) from osteoarthritis (OA) patients. We recently found that Naproxen, but not other nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen, Celebrex, Diclofenac), can induce type X collagen gene (COL10A1) expression in bone-marrow-derived MSCs from healthy and OA donors. In this study we determined the effect of Naproxen on COL X protein expression and investigated the intracellular signaling pathways that mediate Naproxen-induced COL10A1 expression in normal and OA hMSCs. MSCs of OA patients were isolated from aspirates from the intramedullary canal of donors (50–80 years of age) undergoing hip replacement surgery for OA and were treated with or without Naproxen (100 μg/mL). Protein expression and phosphorylation were determined by immunoblotting using specific antibodies (COL X, p38 mitogen-activated protein kinase [p38], phosphorylated-p38, c-Jun N-terminal kinase [JNK], phosphorylated-JNK, extracellular signal-regulated kinase [ERK], and phosphorylated-ERK). Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the expression of COL10A1 and Runt-related transcription factor 2 gene (Runx2). Our results show that Naproxen significantly stimulated COL X protein expression after 72 h of exposure both in normal and OA hMSCs. The basal phosphorylation of mitogen-activated protein kinases (MAPKs) (ERK, JNK, and p38) in OA hMSCs was significantly higher than in normal. Naproxen significantly increased the MAPK phosphorylation in normal and OA hMSCs. NSAID cellular effects include cyclooxygenase, 5-lipoxygenase, and p38 MAPK signaling pathways. To investigate the involvement of these pathways in the Naproxen-induced COL10A1 expression, we incubated normal and OA hMSCs with Naproxen with and without inhibitors of ERK (U0126), JNK (BI-78D3), p38 (SB203580), and 5-lipoxygenase (MK-886). Our results showed that increased basal COL10A1 expression in OA hMSCs was significantly suppressed in the presence of JNK and p38 inhibitors, whereas Naproxen-induced COL10A1 expression was suppressed by 5-lipoxygenase inhibitor. This study shows that Naproxen induces COL X both at transcriptional and translational levels in normal and OA hMSCs. Elevated basal COL10A1 expression in OA hMSCs is probably through the activation of MAPK pathway and Naproxen-induced COL10A1 expression is through the increased 5-lipoxygenase signaling. PMID:25091567

Hydrogen sulphide protects against NSAID-enteropathy through modulation of bile and the microbiota

PubMed Central

Blackler, Rory W; Motta, Jean-Paul; Manko, Anna; Workentine, Matthew; Bercik, Premysl; Surette, Michael G; Wallace, John L

2015-01-01

Background and Purpose Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID-induced enteropathy. Experimental Approach Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen-induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells. Key Results Suppression of endogenous hydrogen sulphide synthesis by β-cyano-L-alanine exacerbated naproxen-induced enteropathy. Diallyl disulphide co-administration dose-dependently reduced the severity of naproxen-induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen-induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen-induced changes in the intestinal microbiota. Conclusions and Implications Hydrogen sulphide protects against NSAID-enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID-induced dysbiosis. PMID:25297699

Comparison of the analgesic effects of oral tramadol and naproxen sodium on pain relief during IUD insertion.

PubMed

Karabayirli, Safinaz; Ayrim, Aylin Aker; Muslu, Bunyamin

2012-01-01

To compare the analgesic efficacy of oral tramadol and naproxen sodium on pain during insertion of an intrauterine device (IUD). Randomized, double-blinded, clinical trial (Canadian Task Force classification I). University-affiliated hospital. Single-center. One hundred three patients scheduled for insertion of an IUD. Patients were randomly assigned to receive oral tramadol 50 mg capsules (n = 35) or naproxen sodium 550 mg tablets (n = 34) or placebo (n = 34) 1 hour before insertion of the IUD. After insertion of the IUD, pain intensity was evaluated using a visual analog scale (VAS, 0-10). Adverse effects, patient satisfaction with the medication, and preference for using it during future insertions were also recorded. The VAS scores were significantly different during IUD insertion among the 3 groups (p = .001). Pain scores in the tramadol group were significantly lower than in the naproxen group (p = .003), and the scores in the naproxen group was significantly lower than in the control group (p = .001). Patient satisfaction with the medication and preference for its future use were significantly lower in the control group than in the other 2 groups (p = .001). Prophylactic analgesia using 50 mg tramadol and 550 mg naproxen, delivered orally, can be used to relieve pain during IUD insertion. However, tramadol capsules were found to be more effective than naproxen tablets. Copyright © 2012 AAGL. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee.

PubMed

Levy, Robert M; Khokhlov, Alexander; Kopenkin, Sergey; Bart, Boris; Ermolova, Tatiana; Kantemirova, Raiasa; Mazurov, Vadim; Bell, Marjorie; Caldron, Paul; Pillai, Lakshmi; Burnett, Bruce P

2010-10-01

Flavocoxid is a novel flavonoid-based "dual inhibitor" of the 5-lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee. In this randomized, multicenter, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. The trial was structured to show noninferiority of flavocoxid to naproxen. Primary outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subscales and a timed walk. More than 90% of the subjects in both groups noted significant reduction in the signs and symptoms of knee OA. There were no statistically significant differences in efficacy between the flavocoxid and naproxen groups when the entire intent-to-treat population was analyzed. The flavocoxid group had significantly fewer upper gastrointestinal (UGI) and renal (edema) adverse events (AEs) as well as a strong trend toward fewer respiratory AEs. Flavocoxid, a first-in-class flavonoid-based therapeutic that inhibits COX-1 and COX-2 as well as 5-LOX, was as effective as naproxen in managing the signs and symptoms of OA of the knee. Flavocoxid demonstrated better UGI, renal (edema), and respiratory safety profiles than naproxen.

Improvement of the surface hydrophilic properties of naproxen particles with addition of hydroxypropylmethyl cellulose and sodium dodecyl sulphate: In vitro and in vivo studies.

PubMed

García-Herrero, Víctor; Torrado, Carlos; García-Rodríguez, Juan José; López-Sánchez, Alicia; Torrado, Susana; Torrado-Santiago, Santiago

2017-08-30

In this study, a new surface-modified naproxen was developed to enhance brain concentration in acute migraine treatment. Fast-dissolving naproxen granules were made by mixing hydroxypropylmethylcellulose (HPMC) sodium dodecyl sulphate (SDS) and sodium croscarmellose with micronized naproxen particles. The aim of this study was to evaluate the effect of adding proportions of SDS to the HPMC film caused changes in the polymer chains of the HPMC, producing a new hydrophilic HPMC-SDS structure. These formulations with different HPMC/SDS ratios were characterised using electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). SDS 10% (w/w) produced a highly hydrophilic HPMC-SDS structure on the surface of the naproxen microparticles. The fast dissolution granules (SF-10%) showed a significant improvement in the dissolution rate of naproxen. Pharmacokinetic studies were conducted with mice, showing an improvement of Cmax (1.38 and 1.41-fold) and AUC0-2h (30% and 10% higher) for plasma and brain samples compared to the reference naproxen suspension. The faster Tmax ratio for SF-10% may be related to increased hydration in the gastrointestinal environment, enabling the drug to permeate the gastrointestinal hydration layer more easily due to the presence of the hydrophilic HPMC-SDS structure in the formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural studies of bovine, equine, and leporine serum albumin complexes with naproxen.

PubMed

Bujacz, Anna; Zielinski, Kamil; Sekula, Bartosz

2014-09-01

Serum albumin, a protein naturally abundant in blood plasma, shows remarkable ligand binding properties of numerous endogenous and exogenous compounds. Most of serum albumin binding sites are able to interact with more than one class of ligands. Determining the protein-ligand interactions among mammalian serum albumins is essential for understanding the complexity of this transporter. We present three crystal structures of serum albumins in complexes with naproxen (NPS): bovine (BSA-NPS), equine (ESA-NPS), and leporine (LSA-NPS) determined to 2.58 Å (C2), 2.42 Å (P61), and 2.73 Å (P2₁2₁2₁) resolutions, respectively. A comparison of the structurally investigated complexes with the analogous complex of human serum albumin (HSA-NPS) revealed surprising differences in the number and distribution of naproxen binding sites. Bovine and leporine serum albumins possess three NPS binding sites, but ESA has only two. All three complexes of albumins studied here have two common naproxen locations, but BSA and LSA differ in the third NPS binding site. None of these binding sites coincides with the naproxen location in the HSA-NPS complex, which was obtained in the presence of other ligands besides naproxen. Even small differences in sequences of serum albumins from various species, especially in the area of the binding pockets, influence the affinity and the binding mode of naproxen to this transport protein. © 2014 Wiley Periodicals, Inc.

Influence of chirality on vibrational and relaxational properties of (S)- and (R,S)-ibuprofen/methyl-β-cyclodextrin inclusion complexes: an INS and QENS study.

PubMed

Crupi, Vincenza; Guella, Graziano; Longeville, Stéphane; Majolino, Domenico; Mancini, Ines; Paciaroni, Alessandro; Rossi, Barbara; Venuti, Valentina

2013-10-03

In this paper, we analyze the internal picosecond dynamics of enantiomeric ((S)-) and racemic ((R,S)-) ibuprofen (IBP), when forming inclusion complexes, in solid state, with methyl-β-cyclodextrin (Me-β-CD), by inelastic and quasi elastic neutron scattering. The study was aimed at understanding, by the analysis of the vibrational and relaxational properties of the inclusion complexes also with respect to the single components, if and how the differences in the structural properties of the hydrogen bond (HB) network of (S)- and (R,S)-IBP can have influence on the complexation process triggered by "host-guest" interactions, whose detailed knowledge is retained as a prerequisite for enantiodiscrimination. From the results, a similar complexation mechanism for (S)- and (R,S)-IBP is argued, with a preferred penetration mode involving the isopropyl group of IBP.

Comparison of the postoperative analgesic effects of naproxen sodium and naproxen sodium-codeine phosphate for arthroscopic meniscus surgery.

PubMed

Bali, Cagla; Ergenoglu, Pinar; Ozmete, Ozlem; Akin, Sule; Ozyilkan, Nesrin Bozdogan; Cok, Oya Yalcin; Aribogan, Anis

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to control arthroscopic pain. Addition of oral effective opioid "codeine" to NSAIDs may be more effective and decrease parenteral opioid consumption in the postoperative period. The aim of this study was to compare the efficacy and side effects of naproxen sodium and a new preparation naproxen sodium-codeine phosphate when administered preemptively for arthroscopic meniscectomy. Sixty-one patients were randomized into two groups to receive either oral naproxen sodium (Group N) or naproxen sodium-codeine phosphate (Group NC) before surgery. The surgery was carried out under general anesthesia. Intravenous meperidine was initiated by patient-controlled analgesia (PCA) for all patients. The primary outcome measure was pain score at the first postoperative hour assessed by the Visual Analogue Scale (VAS). Sedation assessed by Ramsey Sedation Scale, first demand time of PCA, postoperative meperidine consumption, side effects and hemodynamic data were also recorded. The groups were demographically comparable. Median VAS scores both at rest and on movement were significantly lower in Group NC compared with Group N, except 18(th) hour on movement (p<0.05). The median time to the first demand of PCA was shorter in Group N compared with Group NC (p<0.001). Meperidine consumption was higher in Group N compared with Group NC (p<0.001). There was no difference between groups with respect to side effects (p>0.05). The combination of naproxen sodium-codeine phosphate provided more effective analgesia than naproxen sodium and did not increase side effects. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Effect of Naproxen Prophylaxis on Heterotopic Ossification Following Hip Arthroscopy: A Double-Blind Randomized Placebo-Controlled Trial.

PubMed

Beckmann, James T; Wylie, James D; Potter, Michael Q; Maak, Travis G; Greene, Thomas H; Aoki, Stephen K

2015-12-16

Heterotopic ossification (HO) is a known complication of hip arthroscopy. Our objective was to determine the effect of postoperative naproxen therapy on the development of HO following arthroscopic surgery for femoroacetabular impingement. Between August 2011 and April 2013, 108 eligible patients were enrolled and randomized to take naproxen or a placebo for three weeks postoperatively. Radiographs were made at routine follow-up visits for one year following surgery. The primary outcome measure was the development of HO, as classified with the Brooker criteria and two-dimensional measurements on radiographs made at least seventy-five days postoperatively (average, 322 days). The primary analysis, performed with a Fisher exact test, compared the proportion of subjects with HO between the treatment and control groups. A single a priori interim analysis was planned at the midpoint of the study. Our data safety and monitoring board stopped this study when the interim analysis showed that the stopping criterion had been met for demonstration of efficacy of the naproxen intervention. The prevalence of HO was 46% (twenty-two of the forty-eight in the final analysis) in the placebo group versus 4% (two of forty-eight) in the naproxen group (p < 0.001). Medication compliance was 69% overall, but it did not differ between the naproxen and placebo groups. Minor adverse reactions to the study medications were reported in 42% of the patients taking naproxen versus 35% of those taking the placebo (p = 0.45). In this trial, prophylaxis with naproxen was effective in reducing the prevalence of HO without medication-related morbidity. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.

Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen.

PubMed

Ekman, Evan F; Gimbel, Joseph S; Bello, Alfonso E; Smith, Michael D; Keller, David S; Annis, Karen M; Brown, Mark T; West, Christine R; Verburg, Kenneth M

2014-11-01

Two studies evaluated efficacy and safety of tanezumab versus naproxen for treatment of knee or hip osteoarthritis (OA). Randomized controlled studies [NCT00830063 (Study 1015, n=828) and NCT00863304 (Study 1018, n=840)] of subjects with hip or knee OA compared intravenous tanezumab (5 mg or 10 mg) to placebo and naproxen (500 mg twice daily). Coprimary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function (0-10 numerical rating scale), and patient's global assessment of OA at Week 16. In both studies, tanezumab reduced pain versus placebo [least squares mean differences, 95% CI, tanezumab 5 mg: -1.21 (-1.72, -0.70); -1.13 (-1.65, -0.62); tanezumab 10 mg: -0.91 (-1.42, -0.40); -0.80 (-1.32, -0.29)], and improved function and global scores. Tanezumab 5 mg produced greater pain reduction [-0.76 (-1.28, -0.25); -0.69 (-1.21, -0.17)], and favorable functional and global outcomes versus naproxen. Pain reductions with tanezumab 10 mg versus naproxen did not reach significance, unlike functional (both studies) and global (1 study) outcomes; thus, tanezumab 10 mg was not superior to naproxen, and predefined statistical testing procedures were not met, allowing for conclusion of superiority of tanezumab 5 mg over naproxen despite replicated favorable coprimary outcomes. Tanezumab was associated with greater incidence of peripheral sensory adverse events (paresthesia, hyperesthesia, hypoesthesia, burning sensation), pain in extremity, peripheral edema, and arthralgia. Overall frequency and discontinuations as a result of adverse events were similar to placebo and naproxen. Tanezumab provides efficacious treatment of knee or hip OA and may have therapeutic utility in patients with OA who experience inadequate analgesia with nonsteroidal antiinflammatory drugs.

Comparison of the effect of naproxen, etodolac and diclofenac on postoperative sequels following third molar surgery: A randomised, double-blind, crossover study

PubMed Central

Akbulut, Nihat; Atakan, Cemal; Çölok, Gülümser

2014-01-01

Objectives: To compare the three non-steroidal anti-inflammatory agents (NSAIDs) diclofenac potassium, etodolac and naproxen sodium in relation to pain, swelling and trismus following impacted third molar surgery. Study Design: The study was a randomized and a double-blinded study which included 42 healthy young individuals with impacted third molars and bone retention. Patients were randomly assigned to 3 groups (n: 14) to which diclofenac potassium, naproxen sodium and etodolac were administered orally an hour before the operation. Impacted third molars were surgically extracted with local anaesthesia. Visual analog scales (VAS) were used to assess the pain in the 6th, 12th hours and on the 1st, 2nd, 3rd, 5th, and 7th days postoperatively. Swelling was evaluated using ultrasound (US) and mouth opening (trismus) was measured with a composing stick pre and post operatively on the 2nd and 7th days respectively. Results: Regarding pain alleviation, diclofenac potassium was better than naproxen sodium and naproxen sodium was better than etodolac but these differences were not statistically significant. US measurements showed that the swelling on postoperative 2nd day was significantly lowest with diclofenac potassium as compared to others (p= 0.027) while naproxen sodium and etodolac acted similarly (p=0.747). No difference was noted regarding trismus in any of the groups. Conclusions: NSAIDs (diclofenac, naproxen and etodolac) are somehow similarly effective for controlling pain and trismus following extraction of mandibular third molars but diclofenac potassium surpasses others in reduction of swelling. Key words:Diclofenac potassium, naproxen sodium, etodolac, impacted third molar surgery, pain, swelling, trismus. PMID:24316711

[Comparison of the postoperative analgesic effects of naproxen sodium and naproxen sodium-codeine phosphate for arthroscopic meniscus surgery].

PubMed

Bali, Cagla; Ergenoglu, Pinar; Ozmete, Ozlem; Akin, Sule; Ozyilkan, Nesrin Bozdogan; Cok, Oya Yalcin; Aribogan, Anis

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to control arthroscopic pain. Addition of oral effective opioid "codeine" to NSAIDs may be more effective and decrease parenteral opioid consumption in the postoperative period. The aim of this study was to compare the efficacy and side effects of naproxen sodium and a new preparation naproxen sodium-codeine phosphate when administered preemptively for arthroscopic meniscectomy. Sixty-one patients were randomized into two groups to receive either oral naproxen sodium (Group N) or naproxen sodium-codeine phosphate (Group NC) before surgery. The surgery was carried out under general anesthesia. Intravenous meperidine was initiated by patient-controlled analgesia (PCA) for all patients. The primary outcome measure was pain score at the first postoperative hour assessed by the Visual Analogue Scale (VAS). Sedation assessed by Ramsey Sedation Scale, first demand time of PCA, postoperative meperidine consumption, side effects and hemodynamic data were also recorded. The groups were demographically comparable. Median VAS scores both at rest and on movement were significantly lower in Group NC compared with Group N, except 18(th) hour on movement (p<0.05). The median time to the first demand of PCA was shorter in Group N compared with Group NC (p<0.001). Meperidine consumption was higher in Group N compared with Group NC (p<0.001). There was no difference between groups with respect to side effects (p>0.05). The combination of naproxen sodium-codeine phosphate provided more effective analgesia than naproxen sodium and did not increase side effects. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Lipase-catalyzed enantioselective synthesis of (R,R)-lactide from alkyl lactate to produce PDLA (poly D-lactic acid) and stereocomplex PLA (poly lactic acid).

PubMed

Jeon, Byoung Wook; Lee, Jumin; Kim, Hyun Sook; Cho, Dae Haeng; Lee, Hyuk; Chang, Rakwoo; Kim, Yong Hwan

2013-10-20

R-lactide, a pivotal monomer for the production of poly (D-lactic acid) (PDLA) or stereocomplex poly (lactic acid) (PLA) was synthesized from alkyl (R)-lactate through a lipase-catalyzed reaction without racemization. From among several types of lipase, only lipase B from Candida antarctica (Novozym 435; CAL-B) was effective in the reaction that synthesized (R,R)-lactide. Enantiopure (R,R)-lactide, which consisted of over 99% enantiomeric excess, was synthesized from methyl (R)-lactate through CAL-B catalysis. Removal of the methanol by-product was critical to obtain a high level of lactide conversion. The (R,R)-lactide yield was 56% in a reaction containing 100 mg of Novozym 435, 10 mM methyl (R)-lactate and 1500 mg of molecular sieve 5A in methyl tert-butyl ether (MTBE). The important monomer (R,R)-lactide that is required for the production of the widely recognized bio-plastic PDLA and the PLA stereocomplex can be obtained using this novel synthetic method. Copyright © 2013 Elsevier B.V. All rights reserved.

Enhanced hydrogenation activity and diastereomeric interactions of methyl pyruvate co-adsorbed with R-1-(1-naphthyl)ethylamine on Pd(111)

DOE PAGES

Mahapatra, Mausumi; Burkholder, Luke; Garvey, Michael; ...

2016-08-04

Unmodified racemic sites on heterogeneous chiral catalysts reduce their overall enantioselectivity, but this effect is mitigated in the Orito reaction (methyl pyruvate (MP) hydrogenation to methyl lactate) by an increased hydrogenation reactivity. Here, this effect is explored on a R-1-(1-naphthyl)ethylamine (NEA)-modified Pd(111) model catalyst where temperature-programmed desorption experiments reveal that NEA accelerates the rates of both MP hydrogenation and H/D exchange. NEAþMP docking complexes are imaged using scanning tunneling microscopy supplemented by density functional theory calculations to allow the most stable docking complexes to be identified. The results show that diastereomeric interactions between NEA and MP occur predominantly by bindingmore » of the C=C of the enol tautomer of MP to the surface, while simultaneously optimizing C=O...H 2N hydrogen-bonding interactions. In conclusion, the combination of chiral-NEA driven diastereomeric docking with a tautomeric preference enhances the hydrogenation activity since C=C bonds hydrogenate more easily than C=O bonds thus providing a rationale for the catalytic observations.« less

(O-Methyl di-thio-carbonato-κS)tri-phenyl-tin(IV).

PubMed

Javed, Fatima; Ali, Saqib; Shah, Wajid; Tahir, M Nawaz; Ullah, Hameed

2013-06-01

In the title compound, [Sn(C6H5)3(C2H3OS2)], the Sn(IV) atom adopts a distorted SnC3S tetra-hedral coordination geometry. A short Sn⋯O contact [2.988 (4) Å] is also present. The phenyl rings are each disordered over two sets of sites with an occupancy ratio of 0.550 (8):0.450 (8). The crystal studied was found to be a racemic twin with a twin component ratio of 0.57 (18):0.43 (18).

(O-Methyl di­thio­carbonato-κS)tri­phenyl­tin(IV)

PubMed Central

Javed, Fatima; Ali, Saqib; Shah, Wajid; Tahir, M. Nawaz; Ullah, Hameed

2013-01-01

In the title compound, [Sn(C6H5)3(C2H3OS2)], the SnIV atom adopts a distorted SnC3S tetra­hedral coordination geometry. A short Sn⋯O contact [2.988 (4) Å] is also present. The phenyl rings are each disordered over two sets of sites with an occupancy ratio of 0.550 (8):0.450 (8). The crystal studied was found to be a racemic twin with a twin component ratio of 0.57 (18):0.43 (18). PMID:23794982

Solubility of Naproxen in Polyethylene Glycol 200 + Water Mixtures at Various Temperatures

PubMed Central

Panahi-Azar, Vahid; Soltanpour, Shahla; Martinez, Fleming; Jouyban, Abolghasem

2015-01-01

The solubility of naproxen in binary mixtures of polyethylene glycol 200 (PEG 200) + water at the temperature range from 298.0 K to 318.0 K were reported. The combinations of Jouyban-Acree model + van’t Hoff and Jouyban-Acree model + partial solubility parameters were used to predict the solubility of naproxen in PEG 200 + water mixtures at different temperatures. Combination of Jouyban-Acree model with van’t Hoff equation can be used to predict solubility in PEG 200 + water with only four solubility data in mono-solvents. The obtained solubility calculation errors vary from ~ 17 % up to 35 % depend on the number of required input data. Non-linear enthalpy-entropy compensation was found for naproxen in the investigated solvent system and the Jouyban−Acree model provides reasonably accurate mathematical descriptions of the thermodynamic data of naproxen in the investigated binary solvent systems. PMID:26664370

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers.

PubMed

Giuffrida, Maria Chiara; Pignatello, Rosario; Castelli, Francesco; Sarpietro, Maria Grazia

2017-09-01

Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier. © 2017 Royal Pharmaceutical Society.

Synergism between Naproxen and Rutin in a Mouse Model of Visceral Pain.

PubMed

Alonso-Castro, Angel Josabad; Rangel-Velázquez, Joceline Estefanía; Isiordia-Espinoza, Mario A; Villanueva-Solís, Luis Enrique; Aragon-Martinez, Othoniel H; Zapata-Morales, Juan Ramón

2017-08-01

Preclinical Research The aim of the present study was to evaluate the antinociceptive interaction between naproxen and the glycoside flavonoid, rutin in the acetic acid-induced writhing test in mice. Naproxen (5, 20, 50, and 100 mg/kg p.o.) or rutin (10, 25, 50, and 100mg/kg p.o.) were administered 60 min before the intraperitoneal administration with acetic acid. The dose-response curve of each individual compound and the experimental effective dose 50 (ED 50 ) value were obtained to determinate different proportions of the combinations between the two compounds (naproxen-rutin 1:1, 3:1, and 3:1) in the writhing test. The results indicated a synergistic antinociceptive interaction between two drugs with different mechanism of action, naproxen and rutin in all the combinations. Drug Dev Res 78 : 184-188, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Vitamin D-Prostaglandin Interactions and Effects in Prostate Cancer

DTIC Science & Technology

2006-10-01

combining high doses of calcitriol and naproxen in PCa patients with advanced androgen-independent disease who have failed other therapies. The initial...growth inhibitory actions of calcitriol. Potential Mediators of the Enhanced Growth Inhibition by the combined treatment with Calcitriol and Naproxen ...specific NSAIDs ( naproxen and ibuprofen). To explore the possible molecular mechanisms mediating this enhanced growth inhibition, we analyzed the

Analysis of acute naproxen administration on memory in young adults: A randomized, double-blind, placebo-controlled study.

PubMed

Wilson, Jack H; Criss, Amy H; Spangler, Sean A; Walukevich, Katherine; Hewett, Sandra

2017-10-01

Nonsteroidal anti-inflammatory drugs work by non-selectively inhibiting cyclooxygenase enzymes. Evidence indicates that metabolites of the cyclooxygenase pathway play a critical role in the process of learning and memory. We evaluated whether acute naproxen treatment impairs short-term working memory, episodic memory, or semantic memory in a young, healthy adult population. Participants received a single dose of placebo or naproxen (750 mg) in random order separated by 7-10 days. Two hours following administration, participants completed five memory tasks. The administration of acute high-dose naproxen had no effect on memory in healthy young adults.

Naproxen conjugated mPEG-PCL micelles for dual triggered drug delivery.

PubMed

Karami, Zahra; Sadighian, Somayeh; Rostamizadeh, Kobra; Parsa, Maliheh; Rezaee, Saeed

2016-04-01

A conjugate of the NSAIDs drug, naproxen, with diblock methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) copolymer was synthesized by the reaction of copolymer with naproxen in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The naproxen conjugated copolymers were characterized with different techniques including (1)HNMR, FTIR, and DSC. The naproxen conjugated mPEG-PCL copolymers were self-assembled into micelles in aqueous solution. The TEM analysis revealed that the micelles had the average size of about 80 nm. The release behavior of conjugated copolymer was investigated in two different media with the pH values of 7.4 and 5.2. In vitro release study showed that the drug release rate was dependant on pH as it was higher at lower pH compared to neutral pH. Another feature of the conjugated micelles was a more sustained release profile compared to the conjugated copolymer. The kinetic of the drug release from naproxen conjugated micelles under different values of pH was also investigated by different kinetic models such as first-order, Makoid-Banakar, Weibull, Logistic, and Gompertz. Copyright © 2015 Elsevier B.V. All rights reserved.

Synergistic Skin Penetration Enhancer and Nanoemulsion Formulations Promote the Human Epidermal Permeation of Caffeine and Naproxen.

PubMed

Abd, Eman; Namjoshi, Sarika; Mohammed, Yousuf H; Roberts, Michael S; Grice, Jeffrey E

2016-01-01

We examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterized oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum (SC), as well as the uptake of product components into the SC were measured. The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous control solutions. Caffeine maximum flux enhancement was associated with a synergistic increase in both caffeine SC solubility and skin diffusivity, whereas a formulation-increased solubility in the SC was the dominant determinant for increased naproxen fluxes. Enhancements in SC solubility were related to the uptake of the formulation excipients containing the active compounds into the SC. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into the SC with impacts on SC solubility and diffusivity.

Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen.

PubMed

Reed, Grant W; Abdallah, Mouin S; Shao, Mingyuan; Wolski, Kathy; Wisniewski, Lisa; Yeomans, Neville; Lüscher, Thomas F; Borer, Jeffrey S; Graham, David Y; Husni, M Elaine; Solomon, Daniel H; Libby, Peter; Menon, Venu; Lincoff, A Michael; Nissen, Steven E

2018-04-24

The safety of nonsteroidal anti-inflammatory drug (NSAID) and aspirin coadministration is uncertain. The aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin. This analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs stratified by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events. When taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.22 to 1.90, p <0.001; and HR: 1.81; 95% CI: 1.46 to 2.26; p <0.001, respectively). Compared with celecoxib, ibuprofen had more major adverse cardiovascular events (p < 0.05), and both ibuprofen and naproxen had more gastrointestinal (p < 0.001) and renal (p < 0.05) events. Taken with aspirin, ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (HR: 1.27; 95% CI: 1.06 to 1.51; p < 0.01); this was not significantly higher with naproxen (HR: 1.18; 95% CI: 0.98 to 1.41; p = 0.08). Among patients on aspirin, major adverse cardiovascular events were similar among NSAIDs, and compared with celecoxib, ibuprofen had more gastrointestinal and renal events (p < 0.05), while naproxen had more gastrointestinal events (p < 0.05), without a difference in renal events. Similar results were seen on adjusted Kaplan-Meier analysis. Celecoxib has a more favorable overall safety profile than naproxen or ibuprofen when taken without aspirin. Adding aspirin attenuates the safety advantage of celecoxib, although celecoxib is still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen. (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen [PRECISION]; NCT00346216). Copyright © 2018 American College of Cardiology Foundation. All rights reserved.

Periorbital edema associated with separate courses of ibuprofen and naproxen.

PubMed

Balas, Morad; Plakogiannis, Roda; Sinnett, Mark

2010-06-01

A case of periorbital edema associated with separate courses of ibuprofen and naproxen is reported. An 80-year-old African- American woman with a history of osteoarthritis and hypertension came to the clinic. Her medication regimen included fosinopril sodium 40 mg daily, which she began two years prior. She had no known drug allergies and denied consuming any over-the-counter medications or herbal substances and reported a negative atopic status. She had seen her primary care provider several days prior and reported pain in the hands, fingers, and ankles, which would escalate in the morning and progressively lessen during the course of the day. Her physician prescribed naproxen 375 mg every eight hours as needed. After ingesting two doses of naproxen, she developed itching, swelling, and erythema around the left eye that became progressively worse and spread to the right eye. She contacted her primary care physician, who instructed her to discontinue the naproxen, and the reaction resolved within three days. The patient was maintained on acetaminophen for the arthritic pain with no issues. Approximately three months prior, ibuprofen 600 mg every eight hours as needed was prescribed for the same pain. She stated that after ingesting two doses of ibuprofen, she experienced a reaction similar to that recently experienced with naproxen. At that time, she was instructed to discontinue the ibuprofen, and her symptoms resolved. An elderly woman developed periorbital edema after taking ibuprofen on one occasion and naproxen on another.

Clinical Investigation Program Report.

DTIC Science & Technology

1983-10-01

metastatic to liver. (0) H-83-63. Double-blind, randomized parallel comparison of two different dosage regimens of naproxen sodium in patients with...different dosage regimens of naproxen sodium in patients with bone pain due to m etastatic cancer. Start Date: May 83 Est Comp Date: Indefinite Principal...Investigator: Facility: LTC D Gandara, MD LAMC CPT R Mansour, MD D ept/Svc: Associate Investigators: Hematology-Oncology Key Words: naproxen sodium

A randomized, clinical trial to assess the relative efficacy and tolerability of two doses of etoricoxib versus naproxen in patients with ankylosing spondylitis.

PubMed

Balazcs, Eva; Sieper, Joachim; Bickham, Kara; Mehta, Anish; Frontera, Nancy; Stryszak, Paul; Popmihajlov, Zoran; Peloso, Paul M

2016-10-13

This study evaluated two doses of etoricoxib (60 and 90 mg) vs. naproxen 1000 mg in subjects with ankylosing spondylitis (AS). This was a 2-part, double-blind, active comparator-controlled non-inferiority study in subjects ≥18 years of age with AS. In Part I, subjects were randomized to naproxen 1000 mg; etoricoxib 60 mg, and 90 mg. In Part II, naproxen and etoricoxib 90 mg subjects continued on the same treatment; subjects on etoricoxib 60 mg either continued on 60 mg or escalated to 90 mg. Part I (6 weeks) assessed the efficacy of A) etoricoxib 60 mg vs. naproxen and B) 90 mg vs. naproxen according to the time-weighted average change from baseline in Spinal Pain Intensity (SPI; 0-100 mm VAS) (primary endpoint). The non-inferiority margin was set at 8 mm for SPI. In Part II (20 weeks) we evaluated the potential benefit of increasing from 60 to 90 mg (predefined minimum clinically important difference = 6 mm in SPI) for inadequate responders (<50 % improvement from baseline in SPI) on etoricoxib 60 mg in Part I. In total, 1015 subjects were randomized to receive etoricoxib 60 mg (N = 702), etoricoxib 90 mg (N = 156), and naproxen 1000 mg (N = 157); 70.9 % were male and the mean age was 45.2 years. There were 919 subjects who completed Part I and all continued to Part II. In Part I, SPI change was non-inferior for both etoricoxib doses vs. naproxen. In both Part I and II, the incidence of adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) were similar between the 3 treatment groups. Both doses of etoricoxib were non-inferior to naproxen. All treatments were well tolerated. Etoricoxib 60 and 90 mg effectively control pain in patients with AS, with 60 mg once daily as the lowest effective dose for most patients. Clinical Trials Registry # NCT01208207 . Registered on 22 September 2010.

The cocrystal rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphoryl)ferrocene-rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphanyl)ferrocene (0.45/0.55).

PubMed

Wei, Muh Mei; Audin, Catherine; Manoury, Eric; Deydier, Eric; Daran, Jean Claude

2014-03-01

As part of our interest in the synthesis and catalytic applications of chiral (diphenylphosphanyl)ferrocene ligands, we designed a number of P,N-containing ligands for use in asymmetric transfer hydrogenation (ATH). During the synthetic procedure to obtain rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphanyl)ferrocene, the title compound, [Fe(C5H5)(C26H25NO2PS)]0.55 · [Fe(C5H5)(C26H25NO3PS)]0.45, was obtained as a by-product. It is composed of a ferrocene group disubstituted by a partially oxidized diphenylphosphanyl group, as confirmed by (31)P NMR analysis, and an (N,4-dimethylbenzenesulfonamido)methyl substituent. Owing to the partially oxidized diphenylphosphanyl group, it is best to view the crystal as being composed of a mixture of non-oxidized and oxidized phosphane, so it can be regarded as a cocrystal. It is also a racemate. To the best of our knowledge, the P=O distance [1.344 (4) Å] is the shortest observed for related (diphenylphosphoryl)ferrocene compounds. The packing is stabilized by weak C-H...O interactions, forming R2(2)(10) hydrogen-bonding motifs, which build up a chain along the c axis.

Roles of functional groups of naproxen in its sorption to kaolinite.

PubMed

Yu, Chenglong; Bi, Erping

2015-11-01

The sorption of acidic anti-inflammatory drugs to soils is important for evaluating their fate and transformations in the water-soil environment. However, roles of functional groups of ionisable drugs onto mineral surfaces have not been sufficiently studied. In this study, batch experiments of naproxen (NPX, anti-inflammatory drug) and two kinds of competitors to kaolinite were studied. The Kd of naproxen to kaolinite is 1.30-1.62 L kg(-1). The n-π electron donor-acceptor (n-π EDA) interaction between diaromatic ring of naproxen (π-electron acceptors) and the siloxane oxygens (n-donors) of kaolinite is the dominant sorption mechanism. The carboxyl group of naproxen can contribute to the overall sorption. A conception model was put forward to elucidate to sorption mechanisms, in which the contribution of n-π EDA and hydrogen bond to overall sorption was quantified. These sorption mechanisms can be helpful for estimating the fate and mobility of acid pharmaceuticals in soil-water environment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Photodegradation of naproxen and its photoproducts in aqueous solution at 254 nm: a kinetic investigation.

PubMed

Marotta, Raffaele; Spasiano, Danilo; Di Somma, Ilaria; Andreozzi, Roberto

2013-01-01

The kinetics of photodegradation of the non steroidal anti-inflammatory drug naproxen (+)-S-2-(6-methoxynaphthalen-2-yl)propanoic acid, an emerging organic pollutant, was studied in aqueous solutions under deaerated and aerated conditions. The photolysis experiments were carried out under monochromatic irradiation (λ = 254 nm) at pH = 7.0 and T = 25 °C. Simplified reaction schemes of photodegradation of naproxen are proposed in absence and in presence of oxygen respectively. The schemes take into account the photolysis of naproxen and its photoproducts and the reactions of the measured species with oxygen dissolved in the liquid bulk. According to these schemes, two kinetic models were developed which correlate the experimental data, for runs performed in absence and in presence of oxygen, with a fair accuracy and allowed to estimate the best values for the unknown kinetic parameters. The calculated quantum yield of direct photolysis of naproxen under deaerated media is in good agreement with the one previously reported. Under aerated conditions, the generation of singlet oxygen has also been taken into account. The obtained results, under the adopted conditions, indicated a marked influence of dissolved oxygen on the photodegradation rates of naproxen and the relative distribution of the major reaction intermediates. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

PubMed

Wang, Li-Juan; Tang, Yu-Hai; Liu, Yang-Hao

2011-02-01

A novel flow injection chemiluminescence (CL) method for the determination of loxoprofen and naproxen was proposed based on the CL system of KMnO 4 , and Na 2 SO 3 in acid media. The CL intensity of KMnO 4 -Na 2 SO 3 was greatly enhaneed in the presence of loxoprofen and naproxen. The mechanism of the CL reaction was studied by the kinetic proecss 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 -5 g/mL and 2.0 × 10 -7 - 4.0 × 10 -6 g/mL with the detection limit of 2.0 × 10 -8 g/mL and 3.0 × 10 -8 g/mL (S/N = 3), respectively. Thc relative standard deviations were 2.39% and 1.37% for 5.0 × 10 -7 g/mL naproxen and 5.0 × 10 -7 g/mL loxoprofen ( n = 10), respectively. The proposed method was satisfactorily applied to thc determination of loxoprofen and naproxen in pharmaceutical preparations.

High performance liquid chromatography with photo diode array for separation and analysis of naproxen and esomeprazole in presence of their chiral impurities: Enantiomeric purity determination in tablets.

PubMed

Ragab, Marwa A A; El-Kimary, Eman I

2017-05-12

A stereoselective high performance liquid chromatographic method with diode array detection (HPLC-DAD) was introduced for S-naproxen and esomeprazole determination in tablets. The separation was achieved on a Kromasil Cellucoat chiral column using a mobile phase consisting of hexane: isopropanol: trifluoroacetic acid (TFA) (90:9.9:0.1 v/v/v). The proposed system was found to be suitable for the enantioseparation of naproxen and omeprazole biologically active isomers. After optimization of the chromatographic conditions, resolution values of 3.84 and 2.17 could be obtained for naproxen and omeprazole isomers, respectively. The method was fully validated for the determination of S-isomers of each drug in their dosage form. Also, the enentiomeric purity was determined in commercial tablet containing S-naproxen and esomeprazole. The enantiomeric purity was calculated for each drug and the chiral impurities (R-isomers) could be determined at 1% level. The method was validated and good results with respect to linearity, precision, accuracy, selectivity and robustness were obtained. The limits of detection (LOD) and quantification (LOQ) were 2.00, 6.50 and 0.10, 0.35μgmL -1 for S-naproxen and esomeprazole, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery.

PubMed

Penjuri, Subhash C B; Saritha, Damineni; Ravouru, Nagaraju; Poreddy, Srikanth R

2016-01-01

The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Characterization of the anti-inflammatory properties of NCX 429, a dual-acting compound releasing nitric oxide and naproxen.

PubMed

Amoruso, Angela; Fresu, Luigia Grazia; Dalli, Jesmond; Miglietta, Daniela; Bardelli, Claudio; Federici Canova, Donata; Perretti, Mauro; Brunelleschi, Sandra

2015-04-01

Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti-inflammatory effects. The present study was undertaken to investigate the anti-inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen. We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPARγ expression and NF-κB activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis. In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1β administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates. These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti-inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs. © 2015.

Sorption of the pharmaceuticals carbamazepine and naproxen to dissolved organic matter: role of structural fractions.

PubMed

Maoz, Adi; Chefetz, Benny

2010-02-01

Pharmaceutical compounds and dissolved organic matter (DOM) are co-introduced into the environment by irrigation with reclaimed wastewater and/or application of biosolids. In this study, we evaluate the role and mechanism of interaction of the pharmaceuticals naproxen and carbamazepine with structural fractions of biosolids-derived DOM. Sorption interactions were estimated from dialysis-bag experiments at different pHs. Sorption of naproxen and carbamazepine by the hydrophobic acid fraction exhibited strong pH-dependence. With both pharmaceuticals, the highest sorption coefficients (K(DOC)) were at pH 4. With the hydrophobic neutral fraction, pH affected only naproxen sorption (decreasing with increasing pH). Among the hydrophilic DOM fractions, the hydrophilic acid fraction exhibited the highest K(DOC) value for carbamazepine, probably due to their bipolar character. In the hydrophilic acid fraction-naproxen system, significant anionic repulsion was observed with increasing pH. The hydrophilic base fraction contains positively charged functional groups. Therefore with increasing ionization of naproxen (with increasing pH), K(DOC) to this fraction increased. The hydrophilic neutral fraction exhibited the lowest K(DOC) with both studied pharmaceuticals. The K(DOC) value of carbamazepine with the bulk DOM sample was higher than the calculated K(DOC) value based on sorption by the individual isolated fractions. The opposite trend was observed with naproxen at pH 8: the calculated K(DOC) value was higher than the value obtained for the bulk DOM. These results demonstrate that DOM fractions interact with each other and do not act as separate sorption domains. (c) 2009 Elsevier Ltd. All rights reserved.

Double-blind multicentre UK hospital studies of isoxicam vs naproxen

PubMed Central

Cardoe, N.; Hart, F. Dudley

1986-01-01

1 Two multicentre, parallel group, randomised, double-blind, double-dummy comparison studies were conducted between isoxicam in the usual dose of 200 mg once daily and naproxen 500 mg twice daily. 2 The drugs were administered for 4 weeks to 230 patients suffering from osteoarthritis of the hip and/or knee in the first trial and to 249 patients suffering from rheumatoid arthritis in the second. 3 The studies compared treatments for both safety and overall effectiveness in the relief of pain. 4 In the osteoarthritis trial, overall pain was reduced by both drugs after 2 weeks of therapy but only isoxicam produced further improvement after 4 weeks. 5 Isoxicam produced reductions comparable to those produced by naproxen in pain on standing from the sitting position, pain on walking, and pain on movement of the affected joint, after 2 and 4 weeks. 6 After 4 weeks, isoxicam given once daily in the morning was significantly more effective than naproxen given in the morning and the evening in relieving not only total pain as assessed by a visual analogue scale but, as importantly, night pain. 7 Compared to naproxen therapy, isoxicam therapy was associated with significantly more patients whose disease state was improved at 2 weeks, as assessed by physicians. 8 In the rheumatoid arthritis trial, isoxicam was equally as effective as naproxen in reducing joint tenderness, joint swelling, and pain; at 4 weeks there was a trend in favour of isoxicam in reduction of joint swelling and pain. 9 Isoxicam reduced morning stiffness significantly more than naproxen after 4 weeks; this trend was apparent at 2 weeks. 10 Patients thought that isoxicam was more effective than naproxen, to a significant difference. 11 In both trials, the two drugs were well tolerated and had similar side effects profiles, with the majority of adverse experiences being associated with the digestive system; no side effect was severe. PMID:3620277

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

PubMed

Nissen, Steven E; Yeomans, Neville D; Solomon, Daniel H; Lüscher, Thomas F; Libby, Peter; Husni, M Elaine; Graham, David Y; Borer, Jeffrey S; Wisniewski, Lisa M; Wolski, Katherine E; Wang, Qiuqing; Menon, Venu; Ruschitzka, Frank; Gaffney, Michael; Beckerman, Bruce; Berger, Manuela F; Bao, Weihang; Lincoff, A Michael

2016-12-29

The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Biomimetic syntheses of racemic natural products.

PubMed

Zask, Arie; Ellestad, George

2018-02-01

Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought. © 2017 Wiley Periodicals, Inc.

Protective effects of S+ ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs.

PubMed

Dorandeu, Frederic; Baille, Valerie; Mikler, John; Testylier, Guy; Lallement, Guy; Sawyer, Thomas; Carpentier, Pierre

2007-05-20

Soman poisoning is known to induce full-blown tonic-clonic seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Previous studies in guinea-pigs have shown that racemic ketamine (KET), with atropine sulfate (AS), is very effective in preventing death, stopping seizures and protecting sensitive brain areas when given up to 1h after a supra-lethal challenge of soman. The active ketamine isomer, S(+) ketamine (S-KET), is more potent than the racemic mixture and it also induces less side-effects. To confirm the efficacy of KET and to evaluate the potential of S-KET for delayed medical treatment of soman-induced SE, we studied different S-KET dose regimens using the same paradigm used with KET. Guinea-pigs received pyridostigmine (26 microg/kg, IM) 30min before soman (62 microg/kg, 2 LD(50), IM), followed by therapy consisting of atropine methyl nitrate (AMN) (4 mg/kg, IM) 1min following soman exposure. S-KET, with AS (10mg/kg), was then administered IM at different times after the onset of seizures, starting at 1h post-soman exposure. The protective efficacy of S-KET proved to be comparable to KET against lethality and SRBD, but at doses two to three times lower. As with KET, delaying treatment by 2h post-poisoning greatly reduced efficacy. Conditions that may have led to an increased S-KET brain concentration (increased doses or number of injections, adjunct treatment with the oxime HI-6) did not prove to be beneficial. In summary, these observations confirm that ketamine, either racemic or S-KET, in association with AS and possibly other drugs, could be highly effective in the delayed treatment of severe soman intoxication.

Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen.

PubMed

Gund, Machhindra; Gaikwad, Parikshit; Borhade, Namdev; Burhan, Aslam; Desai, Dattatraya C; Sharma, Ankur; Dhiman, Mini; Patil, Mohan; Sheikh, Javed; Thakre, Gajanan; Tipparam, Santhosh G; Sharma, Somesh; Nemmani, Kumar V S; Satyam, Apparao

2014-12-15

Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are gaining attention as potentially gastric-sparing NSAIDs. Herein, we report a novel class of '1-(nitrooxy)ethyl ester' group-containing NSAIDS as efficient NO releasing 'true' prodrugs of aspirin and naproxen. While an aspirin prodrug exhibited comparable oral bioavailability and antiplatelet activity (i.e., TXB2 inhibition) to those of aspirin, a naproxen prodrug exhibited better bioavailability than naproxen. These promising NO-NSAIDs protected experimental rats from gastric damage. We therefore believe that these promising NO-NSAIDs could represent a new class of potentially 'Safe NSAIDs' for the treatment of arthritic pain, inflammation and cardiovascular disorders in the case of NO-aspirin. Copyright © 2014 Elsevier Ltd. All rights reserved.

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

PubMed Central

Ballard, Andrew; Ahmad, Hiwa O.; Narduolo, Stefania; Rosa, Lucy; Chand, Nikki; Cosgrove, David A.; Varkonyi, Peter; Asaad, Nabil; Tomasi, Simone

2017-01-01

Abstract Racemization has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1H NMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations. Such calculations thus provide predictions of the second‐order rate constants for general‐base‐catalyzed racemization that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless. PMID:29072355

Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial.

PubMed

Yeomans, N D; Graham, D Y; Husni, M E; Solomon, D H; Stevens, T; Vargo, J; Wang, Q; Wisniewski, L M; Wolski, K E; Borer, J S; Libby, P; Lincoff, A M; Lüscher, T F; Bao, W; Walker, C; Nissen, S E

2018-06-01

To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids. © 2018 John Wiley & Sons Ltd.

Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study.

PubMed

Levy, Robert M; Saikovsky, Roman; Shmidt, Evgeniya; Khokhlov, Alexander; Burnett, Bruce P

2009-05-01

Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P < or = .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups.

Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats

PubMed Central

Suh, Nanjoo; Reddy, Bandaru S.; DeCastro, Andrew; Paul, Shiby; Lee, Hong Jin; Smolarek, Amanda K.; So, Jae Young; Simi, Barbara; Wang, Chung Xiou; Janakiram, Naveena B.; Steele, Vernon; Rao, Chinthalapally V.

2011-01-01

Evidence supports the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet and colon tumors were induced with azoxymethane (AOM). One week after the second AOM-treatment groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, p=0.005) and multiplicity (58% reduction, p=0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80–85% reduction, p<0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (p=0.001) or naproxen (p =0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1 and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and cyclooxygenase-2, phospho-p65, as well as inflammatory cytokines, TNF-α, IL-1β, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans. PMID:21764859

Journal of Special Operations Medicine, Volume 3, Edition 2

DTIC Science & Technology

2003-01-01

NREMT program. However, the overall resounding rejection was that it differed from many organic military medical tasks and sup- planted those tasks...Mobic®) · Naproxen (Naprosyn®) · Naproxen sodium (Anaprox®, Alleve®) · Nabumetone (Relafen®) · Oxaprozin (Daypro®) · Piroxicam (Feldene®) · Sulindac...to sodium naproxen and ibuprofen.18 The manufac- turer recommends against the chronic use of 50mg dosing for acute pain.19 Further studies are needed

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

PubMed Central

Wang, Li-Juan; Tang, Yu-Hai; Liu, Yang-Hao

2012-01-01

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 enhaneed in the presence of loxoprofen and naproxen. The mechanism of the CL reaction was studied by the kinetic proecss 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 × 10−5 g/mL and 2.0 × 10−7 – 4.0 × 10−6 g/mL with the detection limit of 2.0 × 10−8 g/mL and 3.0 × 10−8 g/mL (S/N = 3), respectively. Thc relative standard deviations were 2.39% and 1.37% for 5.0 × 10−7 g/mL naproxen and 5.0 × 10−7 g/mL loxoprofen (n = 10), respectively. The proposed method was satisfactorily applied to thc determination of loxoprofen and naproxen in pharmaceutical preparations. PMID:29403682

Curcumin Blocks Naproxen-Induced Gastric Antral Ulcerations through Inhibition of Lipid Peroxidation and Activation of Enzymatic Scavengers in Rats.

PubMed

Kim, Jeong-Hwan; Jin, Soojung; Kwon, Hyun Ju; Kim, Byung Woo

2016-08-28

Curcumin is a polyphenol derived from the plant Curcuma longa, which is used for the treatment of diseases associated with oxidative stress and inflammation. The present study was undertaken to determine the protective effect of curcumin against naproxen-induced gastric antral ulcerations in rats. Different doses (10, 50, and 100 mg/kg) of curcumin or vehicle (curcumin, 0 mg/kg) were pretreated for 3 days by oral gavage, and then gastric mucosal lesions were caused by 80 mg/kg naproxen applied for 3 days. Curcumin significantly inhibited the naproxen-induced gastric antral ulcer area and lipid peroxidation in a dose-dependent manner. In addition, curcumin markedly increased activities of radical scavenging enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase in a dose-dependent manner. Specifically, 100 mg/kg curcumin completely protected the gastric mucosa against the loss in the enzyme, resulting in a drastic increase of activities of radical scavenging enzymes up to more than the level of untreated normal rats. Histological examination obviously showed that curcumin prevents naproxen-induced gastric antral ulceration as a result of direct protection of the gastric mucosa. These results suggest that curcumin blocks naproxen-induced gastric antral ulcerations through prevention of lipid peroxidation and activation of radical scavenging enzymes, and it may offer a potential remedy of gastric antral ulcerations.

Effective anodic oxidation of naproxen by platinum nanoparticles coated FTO glass.

PubMed

Chin, Ching-Ju Monica; Chen, Tsan-Yao; Lee, Menshan; Chang, Chiung-Fen; Liu, Yu-Ting; Kuo, Yu-Tsun

2014-07-30

This study investigated applications of the electrochemical anodic oxidation process with Pt-FTO and Pt/MWCNTs-FTO glasses as anodes on the treatment of one of the most important emerging contaminants, naproxen. The anodes used in this study have been synthesized using commercial FTO, MWCNTs and Pt nanoparticles (PtNP). XRD patterns of Pt nanoparticles coated on FTO and MWCNTs revealed that MWCNTs can prevent the surface of PtNPs from sintering and thus provide a greater reaction sites density to interact with naproxen, which have also been confirmed by higher degradation and mineralization efficiencies in the Pt/MWCNTs-FTO system. Results from the CV analysis showed that the Pt-FTO and Pt/MWCNTs-FTO electrodes possessed dual functions of decreasing activation energy and interactions between hydroxyl radicals to effectively degrade naproxen. The lower the solution pH value, the better the degradation efficiency. The existence of humic acid indeed inhibited the degradation ability of naproxen due to the competitions in the multiple-component system. The electrochemical degradation processes were controlled by diffusion mechanism and two major intermediates of 2-acetyl-6-methoxynaphthalene and 2-(6-Hydroxy-2-naphthyl)propanoic acid were identified. This study has successfully demonstrated new, easy, flexible and effective anodic materials which can be feasibly applied to the electrochemical oxidation of naproxen. Copyright © 2014 Elsevier B.V. All rights reserved.

Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling.

PubMed

Bitterlich, A; Laabs, C; Krautstrunk, I; Dengler, M; Juhnke, M; Grandeury, A; Bunjes, H; Kwade, A

2015-05-01

The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy of naproxen with or without esomeprazole for pain and inflammation in patients after bilateral third molar extractions: A double blinded crossover study

PubMed Central

Weckwerth, Giovana M.; Simoneti, Luis F.; Zupelari-Gonçalves, Paulo; Calvo, Adriana M.; Brozoski, Daniel T.; Dionísio, Thiago J.; Torres, Elza A.; Lauris, José-Roberto P.; Faria, Flávio-Augusto C.

2017-01-01

Background Using a double-blinded randomized crossover design, this study aimed to evaluate acute postoperative pain management, swelling and trismus in 46 volunteers undergoing extractions of the two lower third molars, in similar positions, at two different appointments who consumed a tablet of either NE (naproxen 500 mg + esomepraz ole 20 mg) or only naproxen (500 mg) every 12 hours for 4 days. Material and Methods Parameters were analyzed: self-reported pain intensity using a visual analog scale (VAS) pre- and postoperative mouth opening; incidence, type and severity of adverse reactions; total quantity consumed of rescue medication; and pre- and postoperative swelling. Results Female volunteers reported significantly more postoperative pain at 1, 1.5, 2, 3 and 4hrs after surgery while also taking their first rescue medication at a time significantly earlier when consuming NE when compared to naproxen (3.7hrs and 6.7hrs). Conversely, no differences were found between each drug group in males. Conclusions In conclusion, throughout the entire study, pain was mild after using either drug in both men and women with pain scores on average well below 40mm (VAS), although in women naproxen improved acute postoperative pain management when compared to NE. Key words:Oral surgery, third molar, pain, naproxen, esomeprazole, NSAIDs. PMID:27918744

Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine

PubMed Central

Lal, Ritu; Sukbuntherng, Juthamas; Luo, Wendy; Vicente, Virna; Blumenthal, Robin; Ho, Judy; Cundy, Kenneth C

2010-01-01

AIM Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug–drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS When gabapentin enacarbil was co-administered with naproxen, gabapentin Css,max increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUCss increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine. PMID:20573085

Sonocatalytic removal of naproxen by synthesized zinc oxide nanoparticles on montmorillonite.

PubMed

Karaca, Melike; Kıranşan, Murat; Karaca, Semra; Khataee, Alireza; Karimi, Atefeh

2016-07-01

ZnO/MMT nanocomposite as sonocatalyst was prepared by immobilizing synthesized ZnO on the montmorillonite surface. The characteristics of as-prepared nanocomposite were studied by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM) and X-ray diffraction (XRD) techniques. The synthesized samples were used as a catalyst for sonocatalytic degradation of naproxen. ZnO/MMT catalyst in the presence of ultrasound irradiation was more effective compared to pure ZnO nanoparticles and MMT particles in the sonocatalysis of naproxen. The effect of different operational parameters on the sonocatalytic degradation of naproxen including initial drug concentration, sonocatalyst dosage, solution pH, ultrasonic power and the presence of organic and inorganic scavengers were evaluated. It was found that the presence of the scavengers suppressed the sonocatalytic degradation efficiency. The reusability of the nanocomposite was examined in several consecutive runs, and the degradation efficiency decreased only 2% after 5 repeated runs. The main intermediates of naproxen degradation were determined by gas chromatography-mass spectrometry (GC-Mass). Copyright © 2016 Elsevier B.V. All rights reserved.

Racemic & quasi-racemic protein crystallography enabled by chemical protein synthesis.

PubMed

Kent, Stephen Bh

2018-04-04

A racemic protein mixture can be used to form centrosymmetric crystals for structure determination by X-ray diffraction. Both the unnatural d-protein and the corresponding natural l-protein are made by total chemical synthesis based on native chemical ligation-chemoselective condensation of unprotected synthetic peptide segments. Racemic protein crystallography is important for structure determination of the many natural protein molecules that are refractory to crystallization. Racemic mixtures facilitate the crystallization of recalcitrant proteins, and give diffraction-quality crystals. Quasi-racemic crystallization, using a single d-protein molecule, can facilitate the determination of the structures of a series of l-protein analog molecules. Copyright © 2018 Elsevier Ltd. All rights reserved.

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients.

PubMed

Nuzzo, Tommaso; Sacchi, Silvia; Errico, Francesco; Keller, Simona; Palumbo, Orazio; Florio, Ermanno; Punzo, Daniela; Napolitano, Francesco; Copetti, Massimiliano; Carella, Massimo; Chiariotti, Lorenzo; Bertolino, Alessandro; Pollegioni, Loredano; Usiello, Alessandro

2017-01-01

It is long acknowledged that the N -methyl d-aspartate receptor co-agonist, d-serine, plays a crucial role in several N -methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d-serine, another free d-amino acid, d-aspartate, is involved in the activation of N -methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N -methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N -methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects. Moreover, in this cohort of post-mortem brain samples we investigated the spatiotemporal variations of d-aspartate and d-serine. Consistent with previous work, we found that d-aspartate content was selectively decreased by around 30% in the dorsolateral prefrontal cortex, but not in the hippocampus, of schizophrenia-affected patients, compared to healthy subjects. Interestingly, such selective reduction was associated to greater (around 25%) cortical activity of the enzyme responsible for d-aspartate catabolism, d-aspartate oxidase. Conversely, no significant changes were found in the methylation state and transcription of DDO gene in patients with schizophrenia, compared to control individuals, as well as in the expression levels of serine racemase, the major enzyme responsible for d-serine biosynthesis, which also catalyzes aspartate racemization. These results reveal the potential involvement of altered d-aspartate metabolism in the dorsolateral prefrontal cortex as a factor contributing to dysfunctional N -methyl d-aspartate receptor-mediated transmission in schizophrenia.

Predicting protein decomposition: the case of aspartic-acid racemization kinetics.

PubMed Central

Collins, M J; Waite, E R; van Duin, A C

1999-01-01

The increase in proportion of the non-biological (D-) isomer of aspartic acid (Asp) relative to the L-isomer has been widely used in archaeology and geochemistry as a tool for dating. the method has proved controversial, particularly when used for bones. The non-linear kinetics of Asp racemization have prompted a number of suggestions as to the underlying mechanism(s) and have led to the use of mathematical transformations which linearize the increase in D-Asp with respect to time. Using one example, a suggestion that the initial rapid phase of Asp racemization is due to a contribution from asparagine (Asn), we demonstrate how a simple model of the degradation and racemization of Asn can be used to predict the observed kinetics. A more complex model of peptide bound Asx (Asn + Asp) racemization, which occurs via the formation of a cyclic succinimide (Asu), can be used to correctly predict Asx racemization kinetics in proteins at high temperatures (95-140 degrees C). The model fails to predict racemization kinetics in dentine collagen at 37 degrees C. The reason for this is that Asu formation is highly conformation dependent and is predicted to occur extremely slowly in triple helical collagen. As conformation strongly influences the rate of Asu formation and hence Asx racemization, the use of extrapolation from high temperatures to estimate racemization kinetics of Asx in proteins below their denaturation temperature is called into question. In the case of archaeological bone, we argue that the D:L ratio of Asx reflects the proportion of non-helical to helical collagen, overlain by the effects of leaching of more soluble (and conformationally unconstrained) peptides. Thus, racemization kinetics in bone are potentially unpredictable, and the proposed use of Asx racemization to estimate the extent of DNA depurination in archaeological bones is challenged. PMID:10091247

Premenstrual Syndrome (PMS)

MedlinePlus

... headaches, backaches, and breast tenderness. These include: Ibuprofen Naproxen Aspirin Some women find that taking an over- ... headaches, backaches, and breast tenderness. These include: Ibuprofen Naproxen Aspirin Some women find that taking an over- ...

Removal of carbamazepine and naproxen by immobilized Phanerochaete chrysosporium under non-sterile condition.

PubMed

Li, Xueqing; de Toledo, Renata Alves; Wang, Shengpeng; Shim, Hojae

2015-03-25

This study explored the utilization of a white-rot fungus (WRF), Phanerochaete chrysosporium, immobilized in wood chips, to remove carbamazepine and naproxen under non-sterile condition. The removal efficiencies for both pharmaceutically active compounds (PhACs) in artificially contaminated water were improved by 4% for naproxen and 30% for carbamazepine in seven days, compared to without wood chips. Although adsorption was crucial at the early stage, bioremoval was found to be the main removal mechanism for both PhACs. The extracellular enzymes played important roles in the naproxen removal, while the intracellular enzyme system was responsible for the carbamazepine removal. The increased of intracellular enzyme activity through the immobilization of WRF cells may contribute to the significantly enhanced removal efficiency for carbamazepine. In addition, the removal of naproxen or carbamazepine slightly increased when both compounds coexisted, compared to the system where the two pharmaceuticals existed separately. Based on the batch experimental results, a fixed-bed bioreactor packed with a mixture of WRF mycelia pellets and wood chips was developed and operated with the intermittent feeding and continuous aerating mode for 28 days under non-sterile condition, with naproxen and carbamazepine spiked into the influent at 1.0 mg L(-1). Almost complete removal of naproxen and 60-80% removal of carbamazepine were obtained in the first two weeks. However, the removal efficiencies for both compounds suddenly dropped to as low as less than 20% by the 14th day, possibly due to the contamination by other microorganisms in the reactor. After the addition of 8.25% sodium hypochlorite at the ratio of 1:100 (v/v) into the influent tank on both Day 20 and Day 25, a rapid recovery (higher than 95%) was achieved in the naproxen removal, by effectively inhibiting contamination in the reactor. In comparison, the same rebounding phenomenon was not observed for carbamazepine and this difference may be associated to the various enzyme-working systems. A longer hydraulic retention time (HRT) was conducive to improve the removal of both compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

Continuous Reusability using Immobilized HasApf in Chemoenzymatic Deracemization: A New Heterogeneous Enzyme Catalysis.

PubMed

Nagaoka, Hiroyuki

2016-10-25

This study found that the calibration curve of heme acquisition system A (HasA, a new reactive active species) immobilized by a porous ceramic particle (ImHApf; immobilized HasA from Pseudomonas fluorescens ) can be constructed in the range of 1750-1450 cm -1 using Fourier transform infrared spectroscopy (FTIR) analysis, and evaluated its catalytic efficiency. In the asymmetric oxidation of rac -1-(6-methoxynaphthalen-2-yl)ethanol ( rac - 1 : a naproxen precursor), a product ketone from the ( R )-isomer is desymmetrized using NaBH₄ and continuously reused even if treated with an organic solvent in 50 mM glycine-NaOH buffer at 40 °C in the absence of nicotinamide adenine dinucleotide (NAD(P)), leading to >99% enantiomeric excess and >90% chemical yield; the activity was calculated at 0.74 ± 0.03 mU/(mg·min) and the turnover number was determined to be approximately 2 × 10⁶. It was confirmed that the other sec -alcohols such as rac -1-(2-naphthyl)ethanol ( rac - 2 ) and m - and p -substituted rac -1-phenyl ethanols ( rac - 3ab - 6ab ) using ImHApf can also yield a single stereoisomer from a racemate. Therefore, HasA immobilization can be expected to become an important tool for building an environmentally friendly system that promotes industrial sustainability.

Enantiomeric separation of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs by HPLC with hydroxypropyl-beta-cyclodextrin as chiral mobile phase additive.

PubMed

Ye, Jincui; Yu, Wenying; Chen, Guosheng; Shen, Zhengrong; Zeng, Su

2010-08-01

The enantio-separations of eight 2-arylpropionic acid nonsteroidal anti-inflammatory drugs (2-APA NSAIDs) were established using reversed-phase high-performance liquid chromatography with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral mobile phase additive for studying the stereoselective skin permeation of suprofen, ketoprofen, naproxen, indoprofen, fenoprofen, furbiprofen, ibuprofen and carprofen. The effects of the mobile phase composition, concentration of HP-beta-CD and column temperature on retention and enantioselective separation were investigated. With 2-APA NSAIDs as acidic analytes, the retention times and resolutions of the enantiomers were strongly related to the pH of the mobile phase. In addition, both the concentration of HP-beta-CD and temperature had a great effect on retention time, but only a slight or almost no effect on resolutions of the analytes. Enantioseparations were achieved on a Shimpack CLC-ODS (150 x 4.6 mm i.d., 5 microm) column. The mobile phase was a mixture of methanol and phosphate buffer (pH 4.0-5.5, 20 mM) containing 25 mM HP-beta-CD. This method was flexible, simple and economically advantageous over the use of chiral stationary phase, and was successfully applied to the enantioselective determination of the racemic 2-APA NSAIDs in an enantioselective skin permeation study.

(Di­methyl­phosphor­yl)methanaminium hydrogen oxalate–oxalic acid (2/1)

PubMed Central

Bialek, Sebastian; Clemens, Rebecca; Reiss, Guido J.

2014-01-01

The reaction of (di­methyl­phosphor­yl)methanamine (dpma) with oxalic acid in ethanol yielded the title solvated salt, C3H11NOP+·C2HO4 −·0.5C2H2O4. Its asymmetric unit consists of one dpmaH+ cation, one hydrogen oxalate anion and a half-mol­ecule of oxalic acid located around a twofold rotation axis. The H atom of the hydrogen oxalate anion is statistically disordered over two positions that are trans to each other. The hydrogen oxalate monoanion is not planar (bend angle ∼16°) whereas the oxalic acid molecule shows a significantly smaller bend angle (∼7°). In the crystal, the components are connected by strong O—H⋯O and much weaker N—H⋯O hydrogen bonds, leading to the formation of layers extending parallel to (001). The structure was refined from a racemically twinned crystal with twin components in an approximate 1:1 ratio. PMID:24765013

Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties

PubMed Central

Das, Narhari; Abdur Rahman, S. M.

2016-01-01

Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid-induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID:27478435

Comparison of rectal indomethacin, diclofenac, and naproxen for the prevention of post endoscopic retrograde cholangiopancreatography pancreatitis.

PubMed

Mohammad Alizadeh, Amir H; Abbasinazari, Mohammad; Hatami, Behzad; Abdi, Saeed; Ahmadpour, Forozan; Dabir, Shideh; Nematollahi, Aida; Fatehi, Samira; Pourhoseingholi, Mohammad A

2017-03-01

NSAIDs are commonly utilized for the prevention of post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). However, not much is known about the most effective drug in preventing this complication. This study aims to clarify which drug (indomethacin, diclofenac, or naproxen) is most effective for the prevention of post endoscopic retrograde cholangiopancreatography (ERCP). In a double-blind, randomized study, patients received a single rectal dose of one of the three drugs 30 min before undergoing ERCP: diclofenac (100 mg), indomethacin (100 mg), or naproxen (500 mg). The primary outcome measured was the development of pancreatitis. The levels of serum amylase, lipase, lipoxin A4, and resolvin E1 were measured before ERCP, and at 24 h after the procedure. Three hundred and seventy-two patients completed the study. The overall incidence of PEP was 8.6%, which occurred in five of the 124 (4%) patients who received diclofenac, seven of the 122 (5.8%) patients who received indomethacin, and 20 of the 126 (15.9%) patients who received naproxen. There were no significant differences in amylase and lipase levels among the three groups (P=0.183 and 0.597, respectively). Unlike patients in the naproxen group, patients in the diclofenac and indomethacin groups showed a significant increase in lipoxin A4 and resolvin E1 (P=0.001 and 0.02, respectively). Diclofenac and indomethacin patient groups had a lower incidence of PEP than the naproxen group.

Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression.

PubMed

Carrarelli, Patrizia; Funghi, Lucia; Bruni, Simone; Luisi, Stefano; Arcuri, Felice; Petraglia, Felice

2016-01-01

Dysmenorrhea, defined as painful cramps occurring immediately before or during the menstrual period, is a common symptom of different gynecological diseases. An acute uterine inflammatory response driven by prostaglandins (PGs) is responsible for painful symptoms. Progesterone withdrawal is responsible for activation of cyclooxygenase (COX-2) enzyme and decrease of hydroxyprostaglandin dehydrogenase (HPDG) with consequent increased secretion of PGs secretion, inducing uterine contractility and pain. The most widely used drugs for the treatment of pelvic pain associated with menstrual cycle are non steroidal anti-inflammatory drugs (NSAIDs). The uterine site of action of these drugs is still not defined and the present study evaluated the effect of naproxen sodium in cultured human endometrial stromal cells (HESC) collected from healthy women. PGE2 release was measured by ELISA; COX-2 and HPDG mRNA expression were assessed by qRT-PCR. Naproxen sodium did not affect HESC vitality. Naproxen sodium significantly decreased PGE2 secretion (p < 0.01) and COX-2 mRNA expression (p < 0.01). TNF-α induced PGE2 release was reduced in presence of naproxen sodium (p < 0.05), in association with decreased COX-2 and increased HPDG mRNAs expression. Naproxen sodium decreases endometrial PGE2 release induced by inflammatory stimulus acting on endometrial COX-2 and HPDG expression, suggesting endometrial synthesis of prostaglandins as a possible target for reduction of uterine inflammatory mechanism in dysmenorrhea.

Propagation of biochirality: crossovers and nonclassical crystallization kinetics of aspartic acid in water.

PubMed

Lee, Tu; Lin, Yu Kun; Tsai, Ya Chung; Lee, Hung Lin

2013-11-01

All experimental procedures discussed could be treated as a screening tool for probing the existence of molecular association among the chiral molecules and the solvent system. The molecular association phases of a racemic conglomerate solution (CS) and a racemic compound solution (RCS), and the templating effect of aspartic acid solid surface were observed to minimize the chance of redissolving racemic conglomerate and racemic compound aspartic acid in water and reforming an RCS in crossovers experiments. Only 1 %wt% of l-aspartic acid was adequate enough to induce a transformation from a racemic compound aspartic acid to a racemic conglomerate aspartic acid. This would make the propagation of biochirality more feasible and sound. However, tetrapeptide, (l-aspartic acid)4 , failed to induce enantioseparation as templates purely by crystallization. Nonclassical crystallization theory was needed to take into account the existence of a CS. Fundamental parameters of the crystallization kinetics such as the induction time, interfacial energy, Gibbs energetic barrier, nucleation rate, and critical size of stable nuclei of: (i) racemic compound aspartic acid, (ii) racemic compound aspartic acid seeded with 1 %wt% l-aspartic acid, (iii) racemic conglomerate aspartic acid, and (iv) l-aspartic acid were evaluated and compared with different initial supersaturation ratios. Morphological studies of crystals grown from the crystallization kinetics were also carried out. © 2013 Wiley Periodicals, Inc.

Direct enantio-convergent transformation of racemic substrates without racemization or symmetrization

NASA Astrophysics Data System (ADS)

Ito, Hajime; Kunii, Shun; Sawamura, Masaya

2010-11-01

Asymmetric reactions that transform racemic mixtures into enantio-enriched products are in high demand, but classical kinetic resolution produces enantiopure compounds in <50% yield even in an ideal case. Many deracemization processes have thus been developed including dynamic kinetic resolution and dynamic kinetic asymmetric transformation, which can provide enantio-enriched products even after complete conversion of the racemic starting materials. However, these dynamic processes require racemization or symmetrization of the substrates or intermediates. We demonstrate a direct chemical enantio-convergent transformation without a racemization or symmetrization process. Copper(I)-catalysed asymmetric allylic substitution of a racemic allylic ether afforded a single enantiomer of an α-chiral allylboronate with complete conversion and high enantioselectivity (up to 98% enantiomeric excess). One enantiomer of the substrate undergoes an anti-SN2'-type reaction whereas the other enantiomer reacts via a syn-SN2' pathway. The products, which cannot be prepared by dynamic procedures, have been used to construct all-carbon quaternary stereocentres.

Naproxen Attenuates Sensitization of Depressive-Like Behavior and Fever during Maternal Separation

PubMed Central

Hennessy, Michael B.; Stafford, Nathan P.; Yusko-Osborne, Brittany; Schiml, Patricia A.; Xanthos, Evan D.; Deak, Terrence

2014-01-01

Early life stress can increase susceptibility for later development of depressive illness though a process thought to involve inflammatory mediators. Isolated guinea pig pups exhibit a passive, depressive-like behavioral response and fever that appear mediated by proinflammatory activity, and which sensitize with repeated separations. Treatment with an anti-inflammatory can attenuate the behavioral response during the initial separation and separation the following day. Here we used the cyclooxygenase inhibitor naproxen to examine the role of prostaglandins in mediating the depressive-like behavior and core body temperature of young guinea pigs during an initial separation, separation the next day, and separation 10 days after the first. The passive, depressive-like behavior as well as fever sensitized with repeated separation. Three days of injection with 14 mg/kg of naproxen prior to the initial separation reduced depressive-like behavior during all three separations. A 28 mg/kg dose of naproxen, however, had minimal effect on behavior. Fever during the early separations was moderated by naproxen, but only at the higher dose. These results suggest a role of prostaglandins in the behavioral and febrile response to maternal separation, and particularly in the sensitization of depressive-like behavior following repeated separation. PMID:25449392

Effects of the non-steroidal anti-inflammatory drug(NSAID) naproxen on gene expression of antioxidant enzymes in zebrafish (Danio rerio).

PubMed

Stancová, V; Ziková, A; Svobodová, Z; Kloas, W

2015-09-01

The aim of this study was to investigate the effects of naproxen on the gene expression of antioxidant enzymes in adult zebrafish. Surprisingly, after 2 weeks exposure no significant effect on the mRNA expression of the target genes was found in the liver. However, mRNA levels of three genes were altered significantly in the intestine. The expression of Ucp-2 decreased at the environmental concentration of 1μg/L while mRNA expression of GST p2 increased at the concentration of 100μg/L. The mRNA level for the antioxidant enzyme CAT was up-regulated significantly at both the concentrations used. Exposure to naproxen caused only moderate effects on the expression of antioxidant genes in the intestine rather than in the liver, which demonstrates that the intestine is more sensitive to waterborne naproxen exposure than the liver. Interestingly, the adverse side effects of NSAIDs occur in the gastrointestinal tract of humans. To our knowledge, this is the first study that has focused on transcriptional effects of naproxen on zebrafish. Copyright © 2015 Elsevier B.V. All rights reserved.

Naproxen

MedlinePlus

... relieve mild pain from headaches, muscle aches, arthritis, menstrual periods, the common cold, toothaches, and backaches. Naproxen is in a class of medications called NSAIDs. It works by stopping the body's production of a substance that causes pain, fever, and inflammation.

Alteration of plasma prednisolone levels by indomethacin and naproxen.

PubMed Central

Rae, S A; Williams, I A; English, J; Baylis, E M

1982-01-01

Eleven patients with stable rheumatoid disease (RD) who were receiving regular corticosteroid therapy (CS) were investigated to discover the effect on plasma prednisolone levels of additional therapy with the non-steroidal anti-inflammatory (NSAI) drugs, indomethacin and naproxen. There was a highly significant (P less than 0.001) increase in free prednisolone levels after concurrent therapy with either indomethacin or naproxen for 2 weeks. Total prednisolone levels were unchanged. These results could provide an explanation for clinical reports that these two NSAI drugs possess a steroid-sparing effect. PMID:7126420

Racemization at the Asp 58 residue in αA-crystallin from the lens of high myopic cataract patients.

PubMed

Zhu, Xiang-Jia; Zhang, Ke-Ke; He, Wen-Wen; Du, Yu; Hooi, Michelle; Lu, Yi

2018-02-01

Post-translational modifications in lens proteins are key causal factors in cataract. As the most abundant post-translational modification in the lens, racemization may be closely related to the pathogenesis of cataract. Racemization of αA-crystallin, a crucial structural and heat shock protein in the human lens, could significantly influence its structure and function. In previous studies, elevated racemization from l-Asp 58 to d-isoAsp58 in αA-crystallin has been found in age-related cataract (ARC) lenses compared to normal aged human lenses. However, the role of racemization in high myopic cataract (HMC), which is characterized by an early onset of nuclear cataract, remains unknown. In the current study, apparently different from ARC, significantly increased racemization from l-Asp 58 to d-Asp 58 in αA-crystallin was identified in HMC lenses. The average racemization rates for each Asp isoform were calculated in ARC and HMC group. In ARC patients, the conversion of l-Asp 58 to d-isoAsp 58, up to 31.89%, accounted for the main proportion in racemization, which was in accordance with the previous studies. However, in HMC lenses, the conversion of l-Asp 58 to d-Asp 58, as high as 35.44%, accounted for the largest proportion of racemization in αA-crystallin. The different trend in the conversion of αA-crystallin by racemization, especially the elevated level of d-Asp 58 in HMC lenses, might prompt early cataractogenesis and a possible explanation of distinct phenotypes of cataract in HMC. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Molecular Designs for Enhancement of Polarity in Ferroelectric Soft Materials

NASA Astrophysics Data System (ADS)

Ohtani, Ryo; Nakaya, Manabu; Ohmagari, Hitomi; Nakamura, Masaaki; Ohta, Kazuchika; Lindoy, Leonard F.; Hayami, Shinya

2015-11-01

The racemic oxovanadium(IV) salmmen complexes, [VO((rac)-(4-X-salmmen))] (X = C12C10C5 (1), C16 (2), and C18 (3); salmmen = N,N‧-monomethylenebis-salicylideneimine) with “banana shaped” molecular structures were synthesized, and their ferroelectric properties were investigated. These complexes exhibit well-defined hysteresis loops in their viscous phases, moreover, 1 also displays liquid crystal behaviour. We observed a synergetic effect influenced by three structural aspects; the methyl substituents on the ethylene backbone, the banana shaped structure and the square pyramidal metal cores all play an important role in generating the observed ferroelectricity, pointing the way to a useful strategy for the creation of advanced ferroelectric soft materials.

Preparation and In vitro Evaluation of Naproxen Suppositories

PubMed Central

Hargoli, S.; Farid, J.; Azarmi, S. H.; Ghanbarzadeh, S.; Zakeri-Milani, P.

2013-01-01

The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository. PMID:24019561

Microenvironmental pH measurement during sodium naproxenate dissolution in acidic medium by UV/vis imaging.

PubMed

Østergaard, Jesper; Jensen, Henrik; Larsen, Susan W; Larsen, Claus; Lenke, Jim

2014-11-01

Variable dissolution from sodium salts of drugs containing a carboxylic acid group after passing the acidic environment of the stomach may affect oral bioavailability. The aim of the present proof of concept study was to investigate pH effects in relation to the dissolution of sodium naproxenate in 0.01M hydrochloric acid. For this purpose a UV/vis imaging-based approach capable of measuring microenvironmental pH in the vicinity of the solid drug compact as well as monitoring drug dissolution was developed. Using a pH indicating dye real-time spatially resolved measurement of pH was achieved. Sodium naproxenate, can significantly alter the local pH of the dissolution medium, is eventually neutralized and precipitates as the acidic species naproxen. The developed approach is considered useful for detailed studies of pH dependent dissolution phenomena in dissolution testing. Copyright © 2014 Elsevier B.V. All rights reserved.

Clinical Pharmacology and Cardiovascular Safety of Naproxen.

PubMed

Angiolillo, Dominick J; Weisman, Steven M

2017-04-01

The voluntary withdrawal of Vioxx (rofecoxib) from the market in 2004, as well as the 2005 and 2014 US FDA Advisory Committee meetings about non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, have raised questions surrounding the use of NSAIDs in at-risk populations. This paper discusses the cardiovascular safety profile of naproxen in the context of the NSAID class. The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2 selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs. The over-the-counter (OTC) use of naproxen is expected to pose minimal cardiovascular risk; however, the benefit-risk ratio and appropriate use should be considered at an individual patient level, particularly to assess underlying conditions that may increase the risk of events. Likewise, regulatory authorities should revisit label information periodically to ensure labeling reflects the current understanding of benefits and risks.

Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

PubMed Central

Zhou, Quan; Yan, Xiao-Feng; Pan, Wen-Sheng; Zeng, Su

2008-01-01

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole. PMID:18442220

Amino acid racemization on Mars: implications for the preservation of biomolecules from an extinct martian biota

NASA Technical Reports Server (NTRS)

Bada, J. L.; McDonald, G. D.; Miller, S. L. (Principal Investigator)

1995-01-01

Using kinetic data, we have estimated the racemization half-lives and times for total racemization of amino acids under conditions relevant to the surface of Mars. Amino acids from an extinct martian biota maintained in a dry, cold (<250 K) environment would not have racemized significantly over the lifetime of the planet. Racemization would have taken place in environments where liquid water was present even for time periods of only a few million years following biotic extinction. The best preservation of both amino acid homochirality and nucleic acid genetic information associated with extinct martian life would be in the polar regions.

Introduction of a methyl group in alpha- or beta-position of 1-heteroarylethyl-4-phenylpiperazines affects their dopaminergic/serotonergic properties.

PubMed

Roglic, G; Andric, D; Kostic-Rajacic, S; Dukic, S; Soskic, V

2001-12-01

1-(2-Heteroarylalkyl)-4-phenylpiperazines containing methyl group in either the alpha- or the beta-position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D1 receptor-selective), spiperone (D2 receptor-selective), and 8-OH-DPAT (5-HT1A receptor-selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D2 receptor (10b-13b), and decreased the affinity for the 5-HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8-OH-DPAT. Most potent of the newly synthesized compounds in [3H]spiperone assay were compounds (+/-)6-[1-methyl-2- (4-phenylpiperazin-1-yl)-ethyl]-1,4-dihydroquinoxaline-2,3-dione (10b), Kd = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoimidazol- 2-thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D2 receptor, while the affinity for the 5-HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds (14-17) run in the same binding assays as references.

Comparative evaluation of the chiral recognition potential of single-isomer sulfated beta-cyclodextrin synthesis intermediates in non-aqueous capillary electrophoresis.

PubMed

Fejős, Ida; Varga, Erzsébet; Benkovics, Gábor; Darcsi, András; Malanga, Milo; Fenyvesi, Éva; Sohajda, Tamás; Szente, Lajos; Béni, Szabolcs

2016-10-07

The enantioselectivity of neutral single-isomer synthetic precursors of sulfated-β-cyclodextrins was studied. Four neutral single-isomer cyclodextrins substituted on the secondary side with acetyl and/or methyl functional groups, heptakis(2-O-methyl-3,6-dihydroxy)-β-cyclodextrin (HM-β-CD), heptakis(2,3-di-O-acetyl-6-hydroxy)-β-cyclodextrin (HDA-β-CD), heptakis(2,3-di-O-methyl-6-hydroxy)-β-cyclodextrin (HDM-β-CD), heptakis(2-O-methyl-3-O-acetyl-6-hydroxy)-β-cyclodextrin (HMA-β-CD), and their sulfated analogs the negatively charged heptakis(2,3-di-O-methyl-6-sulfato)-β-cyclodextrin (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-sulfato)-β-cyclodextrin (HDAS-β-CD) were investigated by non-aqueous capillary electrophoresis in the view of enantiodiscrimination for various drugs and related pharmaceutical compounds. The focus of the present work was on the chiral selectivity studies of the neutral derivatives, which are the synthesis intermediates of the sulfated products. The chiral recognition experiments proved that among the neutral compounds the HMA-β-CD shows remarkable enantioselectivity towards chiral guests in non-aqueous capillary electrophoresis, while HM-β-CD, HDA-β-CD and HDM-β-CD failed to resolve any of the 25 studied racemates under the applied experimental conditions. In order to get deeper insight into the molecular interactions between the studied single-isomer cyclodextrin and chiral fluoroquinolones (ofloxacin, gatifloxacin and lomefloxacin) and β-blockers (propranolol), 1 H and ROESY NMR experiments were performed. The 2-O-methylation in combination with the 3-O-acetylation of the host was evidenced to exclusively carry the essential spatial arrangement for chiral recognition. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen.

PubMed

Čerpnjak, Katja; Zvonar, Alenka; Vrečer, Franc; Gašperlin, Mirjana

2015-01-01

Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement. The aim of this work was to develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire® 44/14 to improve the solubility and dissolution rate of naproxen. Various oils and co-surfactants in combination with Gelucire® 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained. The selected formulation of SMEDDS was comprised of Miglyol 812®, Peceol™, Gelucire® 44/14, and Solutol® HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen. This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms.

Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration

PubMed Central

Björnsson, Marcus A; Simonsson, Ulrika S H

2011-01-01

AIMS To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. RESULTS Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid Emax model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h−1. EC50 was 0.135 µmol l−1. A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. CONCLUSIONS This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout. PMID:21272053

Naproxen Sodium for Pain Control With Intrauterine Device Insertion: A Randomized Controlled Trial.

PubMed

Ngo, Lynn L; Braaten, Kari P; Eichen, Eva; Fortin, Jennifer; Maurer, Rie; Goldberg, Alisa B

2016-12-01

To evaluate whether 550 mg oral naproxen sodium given 1 hour before intrauterine device (IUD) insertion is effective for pain relief as compared with placebo. This was a randomized, double-blind, placebo-controlled trial. The primary outcome was pain with IUD insertion measured on a 100-mm visual analog scale (VAS). Our sample size was calculated to detect a 15-mm difference in VAS scores with 80% power (α=0.05). Secondary outcomes included pain with tenaculum placement, uterine sounding, and 5 and 15 minutes postinsertion. A total of 118 women were enrolled and analyzed (58 in the naproxen sodium arm, 60 in the placebo arm, 97% nulliparous) between May 11, 2015, and March 25, 2016. There were no differences in baseline demographics or reproductive characteristics between arms. There were no differences in median VAS pain scores for the primary outcome of pain with IUD insertion between the naproxen sodium arm compared with the placebo arm (69 compared with 66 mm, P=.89). There were no differences in the secondary outcomes of median VAS pain scores with tenaculum placement (37 compared with 32 mm, P=.97) or uterine sounding (60 compared with 58 mm, P=.66). However, median pain scores postprocedure were lower in the naproxen arm as compared with the placebo arm: 17 compared with 26 mm (P=.01) at 5 minutes and 13 compared with 24 mm (P=.01) at 15 minutes postinsertion. Oral naproxen sodium does not reduce pain with IUD insertion but does reduce pain after insertion and should be considered as a premedication. ClinicalTrials.gov, http://clinicaltrials.gov, NCT02388191.

Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis : A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.

PubMed

Song, Gwan Gyu; Seo, Young Ho; Kim, Jae-Hoon; Choi, Sung Jae; Ji, Jong Dae; Lee, Young Ho

2016-06-01

This study aimed to assess the relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen at recommended dosages in patients with osteoarthritis (OA). Randomized controlled trials (RCTs) examining the efficacy and tolerability of etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg, based on the number of patient withdrawals among those with OA, were included in this network meta-analysis. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Eight RCTs, including 5,942 patients, met the inclusion criteria. The proportion of patient withdrawals due to lack of efficacy was significantly lower in the etoricoxib 30-60 mg (OR 0.21, 95 % CrI 0.12-0.38), celecoxib 200-400 mg (OR 0.29, 95 % CrI 0.18-0.47), and naproxen 1000 mg (OR 0.31, 95 % CrI 0.18-0.51) groups than in the placebo group. The number of patient withdrawals due to lack of efficacy tended to be lower in the etoricoxib 30-60 mg group than in the naproxen 1000 mg and celecoxib 200-400 mg groups, although they did not reach statistical significance (OR 0.68, 95 % CrI 0.36-1.33 and OR 0.70, 95 % CrI 0.38-1.37, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that etoricoxib 30-60 mg had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy (SUCRA = 0.9168) followed by celecoxib 200-400 mg (SUCRA = 0.5659), naproxen 1000 mg (SUCRA = 0.5171), and placebo (SUCRA = 0.000189). With respect to tolerability, the number of withdrawals due to adverse events was not significantly different among etoricoxib, celecoxib, naproxen, and placebo, although it tended to be lower with etoricoxib and placebo. Etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg were more efficacious than placebo. However, there was no significant difference in efficacy and tolerability between the medications.

Enantiomer Ratios of Meteoritic Sugar Derivatives

NASA Technical Reports Server (NTRS)

Cooper, George

2012-01-01

Carbonaceous meteorites contain a diverse suite of soluble organic compounds. Studies of these compounds reveal the Solar System's earliest organic chemistry. Among the classes of organic compounds found in meteorites are keto acids (pyruvic acid, etc.), hydroxy tricarboxylic acids (1), amino acids, amides, purines and pyrimidines. The Murchison and Murray meteorites are the most studied for soluble and insoluble organic compounds and organic carbon phases. The majority of (indigenous) meteoritic compounds are racemic, (i.e., their D/L enantiomer ratios are 50:50). However, some of the more unusual (non-protein) amino acids contain slightly more of one enantiomer (usually the L) than the other. This presentation focuses on the enantiomer analyses of three to six-carbon (3C to 6C) meteoritic sugar acids. The molecular and enantiomer analysis of corresponding sugar alcohols will also be discussed. Detailed analytical procedures for sugar-acid enantiomers have been described. Results of several meteorite analyses show that glyceric acid is consistently racemic (or nearly so) as expected of non-biological mechanisms of synthesis. Also racemic are 4-C deoxy sugar acids: 2-methyl glyceric acid; 2,4-dihydroxybutyric acid; 2,3-dihydroxybutyric acid (two diastereomers); and 3,4-dihydroxybutyric acid. However, a 4C acid, threonic acid, has never been observed as racemic, i.e., it possesses a large D excess. In several samples of Murchison and one of GRA 95229 (possibly the most pristine carbonaceous meteorite yet analyzed) threonic acid has nearly the same D enrichment. In Murchison, preliminary isotopic measurements of individual threonic acid enantiomers point towards extraterrestrial sources of the D enrichment. Enantiomer analyses of the 5C mono-sugar acids, ribonic, arabinonic, xylonic, and lyxonic also show large D excesses. It is worth noting that all four of these acids (all of the possible straight-chained 5C sugar acids) are present in meteorites, including the rare lyxonic acid, and their relative abundances are in equilibrium proportions. In addition (in contrast to the above D-only excesses), some of the above acids are found in biology as the L enantiomer. Whether rare are common, all of the 6C sugar acids that are present in sufficient amounts to allow enantiomer analysis (Mannonic, gluconic, altronic, talonic, idonic, gulonic, and galactonic) also, apparently, possess significant D excesses.

Sumatriptan plus naproxen for the treatment of acute migraine attacks in adults.

PubMed

Law, Simon; Derry, Sheena; Moore, R Andrew

2016-04-20

This is an updated version of the original Cochrane review published in October 2013 on 'Sumatriptan plus naproxen for acute migraine attacks in adults'.Migraine is a common disabling condition and a burden for the individual, health services, and society. It affects two to three times more women than men, and is most common in the age range 30 to 50 years. Effective abortive treatments include the triptan and non-steroidal anti-inflammatory classes of drugs. These drugs have different mechanisms of action and combining them may provide better relief. Sumatriptan plus naproxen is now available in combination form for the acute treatment of migraine. To determine the efficacy and tolerability of sumatriptan plus naproxen, administered together as separate tablets or taken as a fixed-dose combination tablet, compared with placebo and other active interventions in the treatment of acute migraine attacks in adults. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Register of Studies Online (CRSO) to 28 October 2015, MEDLINE (via Ovid) from 1946 to 28 October 2015, and EMBASE (via Ovid) from 1974 to 28 October 2015, and two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov). We also searched the reference lists of included studies and relevant reviews. We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using sumatriptan plus naproxen to treat a migraine headache episode. Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat for an additional beneficial outcome (NNT) or for an additional harmful outcome (NNH) compared with placebo or a different active treatment. For this update we identified one new study (43 participants), but it did not contribute any data for analysis. The review included 13 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity. Twelve studies contributed data for analyses: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. We judged only one small study to be at high risk of bias for any of the criteria evaluated; it did not contribute to any analyses.Overall, the combination was better than placebo for the primary outcomes of pain-free and headache relief at two hours. The NNT for pain-free at two hours was 3.1 (95% confidence interval 2.9 to 3.5) when the baseline pain was mild (50% response with sumatriptan plus naproxen compared with 18% with placebo), and 4.9 (4.3 to 5.7) when baseline pain was moderate or severe (28% with sumatriptan plus naproxen compared with 8% with placebo) (high quality evidence). Using 50 mg of sumatriptan, rather than 85 mg, in the combination did not significantly change the result. Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe for pain-free responses at two hours and during the 24 hours post dose. Adverse events were mostly mild or moderate in severity and rarely led to withdrawal; they were more common with the combination than with placebo (moderate quality evidence).Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than with sumatriptan (moderate quality evidence). The conclusions of this review were not changed. Combination treatment was effective in the acute treatment of migraine headaches. The effect was greater than for the same dose of either sumatriptan or naproxen alone, but additional benefits over sumatriptan alone were not large. More participants achieved good relief when medication was taken early in the attack, when pain was still mild. Adverse events were more common with the combination and sumatriptan alone than with placebo or naproxen alone.

Recent advances in racemic protein crystallography.

PubMed

Yan, Bingjia; Ye, Linzhi; Xu, Weiliang; Liu, Lei

2017-09-15

Solution of the three-dimensional structures of proteins is a critical step in deciphering the molecular mechanisms of their bioactivities. Among the many approaches for obtaining protein crystals, racemic protein crystallography has been developed as a unique method to solve the structures of an increasing number of proteins. Exploiting unnatural protein enantiomers in crystallization and resolution, racemic protein crystallography manifests two major advantages that are 1) to increase the success rate of protein crystallization, and 2) to obviate the phase problem in X-ray diffraction. The requirement of unnatural protein enantiomers in racemic protein crystallography necessitates chemical protein synthesis, which is hitherto accomplished through solid phase peptide synthesis and chemical ligation reactions. This review highlights the fundamental ideas of racemic protein crystallography and surveys the harvests in the field of racemic protein crystallography over the last five years from early 2012 to late 2016. Copyright © 2017. Published by Elsevier Ltd.

Disappearing Enantiomorphs: Single Handedness in Racemate Crystals.

PubMed

Parschau, Manfred; Ernst, Karl-Heinz

2015-11-23

Although crystallization is the most important method for the separation of enantiomers of chiral molecules in the chemical industry, the chiral recognition involved in this process is poorly understood at the molecular level. We report on the initial steps in the formation of layered racemate crystals from a racemic mixture, as observed by STM at submolecular resolution. Grown on a copper single-crystal surface, the chiral hydrocarbon heptahelicene formed chiral racemic lattice structures within the first layer. In the second layer, enantiomerically pure domains were observed, underneath which the first layer contained exclusively the other enantiomer. Hence, the system changed from a 2D racemate into a 3D racemate with enantiomerically pure layers after exceeding monolayer-saturation coverage. A chiral bias in form of a small enantiomeric excess suppressed the crystallization of one double-layer enantiomorph so that the pure minor enantiomer crystallized only in the second layer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of grinding and humidification on the transformation of conglomerate to racemic compound in optically active drugs.

PubMed

Piyarom, S; Yonemochi, E; Oguchi, T; Yamamoto, K

1997-04-01

The effects of grinding and humidification on the transformation of conglomerate to racemic compound have been investigated by X-ray powder diffraction (XPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy for leucine, norleucine, valine, serine, tartaric acid and malic acid. Racemic physical mixtures were prepared by physical mixing of equimolar quantities of D and I. crystals using a mortar and pestle. Ground mixtures were obtained by grinding the physical mixtures with a vibrational mill. Humidification was performed by storing the physical mixtures and the ground mixtures in a desiccator containing saturated aqueous salt solutions at 40 degrees C. When physical mixtures of malic acid, tartaric acid and serine were ground, the XPD peaks of the racemic compounds were observed. The XPD patterns of humidified physical mixtures of these compounds also showed the formation of the racemic compounds. This indicated that grinding or humidification of malic acid, tartaric acid and serine induced the transformation of conglomerate to racemic compound crystals. When, on the other hand, the physical mixtures of valine, leucine and norleucine were ground, peaks of racemic compounds were not detected in the XPD pattern. After humidification of the ground mixtures of valine, leucine and norleucine, however, the XPD peaks of racemic compounds were observed. DSC and IR studies revealed consistent results. We concluded that grinding or humidification of malic acid, tartaric acid and serine could induce the transformation of a conglomerate to racemic compound. In contrast, humidifying after grinding was needed to bring about the transformation in leucine, norleucine and valine.

Distinct enantiomeric signals of ibuprofen and naproxen in treated wastewater and sewer overflow.

PubMed

Khan, Stuart J; Wang, Lili; Hashim, Nor H; McDonald, James A

2014-11-01

Ibuprofen and naproxen are commonly used members of a class of pharmaceuticals known as 2-arylpropionic acids (2-APAs). Both are chiral chemicals and can exist as either of two (R)- and (S)-enantiomers. Enantioselective analyses of effluents from municipal wastewater treatment plants (WWTPs) and from untreated sewage overflow reveal distinctly different enantiomeric fractions for both pharmaceuticals. The (S)-enantiomers of both were dominant in untreated sewage overflow, but the relative proportions of the (R)-enantiomers were shown to be increased in WWTP effluents. (R)-naproxen was below method detection limits (<1 ng.L(-1)) in sewage overflow, but measurable at higher concentrations in WWTP effluents. Accordingly, enantiomeric fractions (EF) for naproxen were consistently 1.0 in sewage overflow, but ranged from 0.7–0.9 in WWTP effluents. Ibuprofen EF ranged from 0.6–0.8 in sewage overflow and receiving waters, and was 0.5 in two WWTP effluents. Strong evidence is provided to indicate that chiral inversion of (S)-2-APAs to produce (R)-2-APAs may occur during wastewater treatment processes. It is concluded that this characterization of the enantiomeric fractions for ibuprofen and naproxen in particular effluents could facilitate the distinction of treated and untreated sources of pharmaceutical contamination in surface waters.

Effect of anthocyanins on expression of matrix metalloproteinase-2 in naproxen-induced gastric ulcers.

PubMed

Kim, Sun-Joong; Park, Young Sam; Paik, Hyun-Dong; Chang, Hyo Ihl

2011-12-01

Non-steroidal anti-inflammatory drugs cause gastric ulceration through a number of mechanisms including inhibition of PG synthesis, generation of reactive oxygen species (ROS) and induction of apoptosis. Recently, matrix metalloproteinases (MMP) have been suggested to play a crucial role in these mechanisms. The present study investigated the protective effect of anthocyanins isolated from black rice bran (Heugjinjubyeo) against naproxen-induced gastric mucosal injury in rats. The oral administration of anthocyanins (5, 25 or 50 mg/kg body weight) showed significant protection against naproxen (80 mg/kg body weight)-induced gastric ulcer and inhibited lipid peroxidation in the gastric mucosa. In addition, pretreatment with anthocyanins resulted in a significant increase in the activities of radical-scavenging enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Also biochemical and zymographic analyses suggested that the administration of anthocyanins gives a significant protection against naproxen-induced gastric antral ulcer through scavenging ROS and regulation of matrix metalloproteinase-2 (MMP-2) activity. The results of intracellular radical activation show that anthocyanins suppress the generation of intracellular ROS and attenuate the suppression of MMP-2 activity by naproxen. These results suggest that anthocyanins extracted from black rice may offer potential remedy of gastric antral ulceration.

Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction.

PubMed

Yu, Zirui; Peldszus, Sigrid; Huck, Peter M

2009-03-01

The adsorption of two representative pharmaceutically active compounds (PhACs)-naproxen and carbamazepine and one endocrine disrupting compound (EDC)-nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surface diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol.

Efficacy of naproxen with or without esomeprazole for pain and inflammation in patients after bilateral third molar extractions: A double blinded crossover study.

PubMed

Weckwerth, G-M; Simoneti, L-F; Zupelari-Gonçalves, P; Calvo, A-M; Brozoski, D-T; Dionísio, T-J; Torres, E-A; Lauris, J-R-P; Faria, F-A-C; Santos, C-F

2017-01-01

Using a double-blinded randomized crossover design, this study aimed to evaluate acute postoperative pain management, swelling and trismus in 46 volunteers undergoing extractions of the two lower third molars, in similar positions, at two different appointments who consumed a tablet of either NE (naproxen 500 mg + esomepraz ole 20 mg) or only naproxen (500 mg) every 12 hours for 4 days. Parameters were analyzed: self-reported pain intensity using a visual analog scale (VAS) pre- and postoperative mouth opening; incidence, type and severity of adverse reactions; total quantity consumed of rescue medication; and pre- and postoperative swelling. Female volunteers reported significantly more postoperative pain at 1, 1.5, 2, 3 and 4hrs after surgery while also taking their first rescue medication at a time significantly earlier when consuming NE when compared to naproxen (3.7hrs and 6.7hrs). Conversely, no differences were found between each drug group in males. In conclusion, throughout the entire study, pain was mild after using either drug in both men and women with pain scores on average well below 40mm (VAS), although in women naproxen improved acute postoperative pain management when compared to NE.

Racemic protein crystallography.

PubMed

Yeates, Todd O; Kent, Stephen B H

2012-01-01

Although natural proteins are chiral and are all of one "handedness," their mirror image forms can be prepared by chemical synthesis. This opens up new opportunities for protein crystallography. A racemic mixture of the enantiomeric forms of a protein molecule can crystallize in ways that natural proteins cannot. Recent experimental data support a theoretical prediction that this should make racemic protein mixtures highly amenable to crystallization. Crystals obtained from racemic mixtures also offer advantages in structure determination strategies. The relevance of these potential advantages is heightened by advances in synthetic methods, which are extending the size limit for proteins that can be prepared by chemical synthesis. Recent ideas and results in the area of racemic protein crystallography are reviewed.

Relating hydrogen-bonding interactions with the phase behavior of naproxen/PVP K 25 solid dispersions: evaluation of solution-cast and quench-cooled films.

PubMed

Paudel, Amrit; Nies, Erik; Van den Mooter, Guy

2012-11-05

In this work, we investigated the relationship between various intermolecular hydrogen-bonding (H-bonding) interactions and the miscibility of the model hydrophobic drug naproxen with the hydrophilic polymer polyvinylpyrrolidone (PVP) across an entire composition range of solid dispersions prepared by quasi-equilibrium film casting and nonequilibrium melt quench cooling. The binary phase behavior in solid dispersions exhibited substantial processing method dependence. The solid state solubility of crystalline naproxen in PVP to form amorphous solid dispersions was 35% and 70% w/w naproxen in solution-cast films and quench-cooled films, respectively. However, the presence of a single mixed phase glass transition indicated the amorphous miscibility to be 20% w/w naproxen for the films, beyond which amorphous-amorphous and/or crystalline phase separations were apparent. This was further supported by the solution state interactions data such as PVP globular size distribution and solution infrared spectral profiles. The borderline melt composition showed cooling rate dependence of amorphization. The glass transition and melting point depression profiles of the system were treated with the analytical expressions based on Flory-Huggins mixing theory to interpolate the equilibrium solid solubility. FTIR analysis and subsequent spectral deconvolution revealed composition and miscibility dependent variations in the strength of drug-polymer intermolecular H-bonding. Two types of H-bonded populations were evidenced from 25% w/w and 35% w/w naproxen in solution-cast films and quench-cooled films, respectively, with the higher fraction of strongly H-bonded population in the drug rich domains of phase separated amorphous film compositions and highly drug loaded amorphous quench-cooled dispersions.

Comparison of oral oxycodone and naproxen in soft tissue injury pain control: a double-blind randomized clinical trial.

PubMed

Fathi, Marzieh; Zare, Mohammad Amin; Bahmani, Hamid Reza; Zehtabchi, Shahriar

2015-09-01

This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency department (ED). Adult (>18 years old) patients with soft tissue injuries were enrolled in a teaching urban ED. Subjects were randomly allocated to receive a single dose of oral oxycodone (5 mg) or oral naproxen (250 mg). Pain scores and drugs' adverse effects were assessed before, 30 minutes, and 60 minutes after medication. efficacy in pain control (reduction in pain scale >2 points) and safety (rate of side effects). The need for additional pain medication after discharge was assessed by follow-up phone call 24 hours after discharge. A total of 150 patients were enrolled. Pain scores were similar in oxycodone vs naproxen groups before (6.21 ± 0.9 in vs 6.0 ± 1.0), 30 minutes (4.5 ± 1.4 vs 4.4 ± 1.2), and 60 minutes (2.5 ± 1.3 in vs 2.6 ± 1.3) after medication, respectively. Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in first 24 hours after ED discharge. Adverse effects were more common in oxycodone group (statistically significant difference). The most common adverse effects in oxycodone group were nausea, (13.3%); vomiting, (8.0%); dizziness, (5.3%); drowsiness, 3 (4.0%); and pruritis, (2.7%). Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile. Copyright © 2015 Elsevier Inc. All rights reserved.

The Risk of Major NSAID Toxicity with Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial.

PubMed

Solomon, Daniel H; Husni, M Elaine; Libby, Peter A; Yeomans, Neville D; Lincoff, A Michael; Lϋscher, Thomas F; Menon, Venu; Brennan, Danielle M; Wisniewski, Lisa M; Nissen, Steven E; Borer, Jeffrey S

2017-12-01

The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial. We conducted a post hoc analysis of a double-blind, randomized, controlled, multicenter trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk. Patients were randomized to receive celecoxib 100 to 200 mg twice daily, ibuprofen 600 to 800 mg thrice daily, or naproxen 375 to 500 mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major nonsteroidal anti-inflammatory drug toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events, and all-cause mortality. During follow-up, 4.1% of subjects sustained any major toxicity in the celecoxib arm, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 20% (95% CI 4-39) higher risk of major toxicity than celecoxib users and that 38% (95% CI 19-59) higher risk. These risks translate into numbers needed to harm of 135 (95% CI, 72-971) for naproxen and 82 (95% CI, 53-173) for ibuprofen, both compared with celecoxib. Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately 1 in 20 experienced a major toxicity over 1 to 2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib. Copyright © 2017 Elsevier Inc. All rights reserved.

Stereochemical investigations of a novel class of chiral phosphapalladacycle complexes derived from 1-[(2,5-dimethyl)phenyl]ethyldiphenylphosphine.

PubMed

Ng, Joseph Kok-Peng; Li, Yongxin; Tan, Geok-Kheng; Koh, Lip-Lin; Vittal, Jagadese J; Leung, Pak-Hing

2005-12-26

The phosphapalladacycle derived from 1-(2',5'-dimethylphenyl)ethyldiphenylphosphine has been prepared in the optically active and racemic forms. The phosphine was synthesized as a racemate by the treatment of 1-chloro-1-(2',5'-dimethylphenyl)ethane with sodium diphenylphosphide in THF. The racemic phosphapalladacycle was subsequently obtained as the chloro-bridged dimer by the treatment of the phosphine with palladium(II) acetate followed by anion metathesis with lithium chloride. Alternatively, the phosphine could be optically resolved via metal complexation using (R,R)-bis(mu-chloro)bis{1-[1-(N,N-dimethylamino)ethyl]naphthyl-C(2),N}dipalladium(II) as the resolving agent. An efficient separation of the resulting diastereomeric complexes was achieved by silica gel chromatography. The obtained optically resolved diastereomers were next subject to chemoselective removal of the (R)-N,N-(dimethylamino)-1-(1-naphthyl)ethylaminate auxiliary by treatment with concentrated hydrochloric acid. This process yielded the binuclear dimer complexes containing the resolved eta(1)-P ligand. Cyclopalladation of the coordinated phosphine could next be performed by treatment of its eta(1)-P binuclear dimer with silver(I) hexafluorophosphate(V) in a dichloromethane/water mixture followed by treatment with lithium chloride, giving rise to a pair of optically pure enantiomeric dimers with [alpha](D) -322 and +319 degrees in CH(2)Cl(2). Despite the possibilities of the phosphine to attain a five- membered structure by ortho-palladation or a six-membered ring formation by aliphatic C-H bond activation, only the former was observed. X-ray crystallographic data of the meso dimer and an acetylacetonate derivative indicated that the phosphapalladacycle alpha-C methyl substituent was axially located. The 2-D (1)H-(1)H ROESY spectrum of the acetylacetonate derivative further revealed that the phosphapalladacycle was conformationally rigid in CDCl(3).

Age estimation of archaeological remains using amino acid racemization in dental enamel: a comparison of morphological, biochemical, and known ages-at-death.

PubMed

Griffin, R C; Chamberlain, A T; Hotz, G; Penkman, K E H; Collins, M J

2009-10-01

The poor accuracy of most current methods for estimating age-at-death in adult human skeletal remains is among the key problems facing palaeodemography. In forensic science, this problem has been solved for unburnt remains by the development of a chemical method for age estimation, using amino acid racemization in collagen extracted from dentine. Previous application of racemization methods to archaeological material has proven problematic. This study presents the application to archaeological human remains of a new age estimation method utilizing amino acid racemization in a potentially closed system-the dental enamel. The amino acid composition and extent of racemization in enamel from two Medieval cemeteries (Newcastle Blackgate and Grantham, England) and from a documented age-at-death sample from a 19th century cemetery (Spitalfriedhof St Johann, Switzerland) were determined. Alterations in the amino acid composition were detected in all populations, indicating that diagenetic change had taken place. However, in the Medieval populations, these changes did not appear to have substantially affected the relationship between racemization and age-at-death, with a strong relationship being retained between aspartic acid racemization and the morphological age estimates. In contrast, there was a poor relationship between racemization and age in the post-medieval documented age-at-death population from Switzerland. This appears to be due to leaching of amino acids post-mortem, indicating that enamel is not functioning as a perfectly closed system. Isolation of amino acids from a fraction of enamel which is less susceptible to leaching may improve the success of amino acid racemization for archaeological age estimation.

21 CFR 520.1468 - Naproxen granules.

Code of Federal Regulations, 2010 CFR

2010-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1468 Naproxen granules. (a... musculoskeletal system of the horse. (2)(i) For oral maintenance therapy following initial intravenous dosage...

Negative Cooperativity in the Interaction of Prostaglandin H Synthase-1 with the Competitive Inhibitor Naproxen Can Be Described as the Interaction of a Non-competitive Inhibitor with Heterogeneous Enzyme Preparation.

PubMed

Filimonov, I S; Berzova, A P; Barkhatov, V I; Krivoshey, A V; Trushkin, N A; Vrzheshch, P V

2018-02-01

The kinetic mechanism of the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) with their main pharmacological target, prostaglandin H synthase (PGHS), has not yet been established. We showed that inhibition of PGHS-1 from sheep vesicular glands by naproxen (a representative of NSAIDs) demonstrates a non-competitive character with respect to arachidonic acid and cannot be described within a framework of the commonly used kinetic schemes. However, it can be described by taking into account the negative cooperativity of naproxen binding to the cyclooxygenase active sites of the PGHS-1 homodimer (the first naproxen molecule forms a more stable complex (K 1 = 0.1 µM) with the enzyme than the second naproxen molecule (K 2 = 9.2 µM)). An apparent non-competitive interaction of PGHS-1 with naproxen is due to slow dissociation of the enzyme-inhibitor complexes. The same experimental data could also be described using commonly accepted kinetic schemes, assuming that naproxen interacts was a mixture of two enzyme species with the inhibition constants K α = 0.05 µM and K β = 18.3 µM. Theoretical analysis and numerical calculations show that the phenomenon of kinetic convergence of these two models has a general nature: when K 2 > K 1 , the kinetic patterns (for transient kinetics and equilibrium state) generated by the cooperative model could be described by a scheme assuming the presence of two enzyme forms with the inhibition constants K α = K 1 /2, K β = 2·K 2 . When K 2 < K 1 , the cooperative model can be presented as a scheme with two inhibitor molecules simultaneously binding to the enzyme with the observed inhibition constant K (K = K 1 ·K 2 ). The assumption on the heterogeneity of the enzyme preparation in relation to its affinity to the inhibitor can be used instead of the assumption on the negative cooperativity of the enzyme-inhibitor interactions for convenient and easy practical description of such phenomena in enzymology, biotechnology, pharmacology, and other fields of science.

[Effects of sowing date and planting density on the seed yield and oil content of winter oilseed rape].

PubMed

Zhang, Shu-Jie; Li, Ling; Zhang, Chun-Lei

2012-05-01

A field experiment was conducted to investigate the effects of different sowing date and planting density on the seed yield and seed oil content of winter oilseed rape (Brassica napus). Sowing date mainly affected the seed yield of branch raceme, while planting density affected the seed yields of both branch raceme and main raceme. The seed oil content was less affected by sowing date. The proportion of the seed yield of main raceme to the seed yield per plant increased with increasing planting density, and the seed oil content of main raceme was about 1% higher than that of branch raceme. Consequently, the seed oil production per plot increased significantly with increasing planting density. In the experimental region, the sowing date of winter oilseed rape should be earlier than mid-October. When sowing in late October, the seed yield would be decreased significantly. A planting density of 36-48 plants x m(-2) could improve the seed yield and oil content of winter oilseed rape.

Estimation of age from teeth by amino acid racemization: influence of fixative.

PubMed

Ohtani, S; Ohhira, H; Watanabe, A; Ogasawara, A; Sugimoto, H

1997-01-01

To determine the age of a subject from teeth accurately utilizing the racemization rates of amino acids, standard samples of the same tooth species from the same jaw are necessary as controls, as well as data for identification. However, standard teeth are generally stored in fixatives such as ethanol and formalin. We investigated and compared the degree of progression of racemization of dentinal aspartic acid in teeth stored in 95% ethanol, 10% formalin, or 10% neutral formalin fixatives. The racemization rate of dentinal aspartic acid in teeth stored in 10% neutral formalin was the highest, followed by that for teeth stored in 10% formalin then that for teeth stored in 95% ethanol. Teeth stored in these fixatives at 15 degrees C showed almost no progression of racemization. The racemization ratio (D/L ratio) in teeth extracted 10 years previously was almost unchanged from that at the time of extraction, and allowed an accurate evaluation of the subjects age at tooth extraction.

21 CFR 520.1468 - Naproxen granules.

Code of Federal Regulations, 2014 CFR

2014-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the..., administer 10 milligrams naproxen per kilogram of animal body weight twice daily as top dressing in the...

21 CFR 520.1468 - Naproxen granules.

Code of Federal Regulations, 2013 CFR

2013-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the..., administer 10 milligrams naproxen per kilogram of animal body weight twice daily as top dressing in the...

21 CFR 520.1468 - Naproxen granules.

Code of Federal Regulations, 2011 CFR

2011-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the..., administer 10 milligrams naproxen per kilogram of animal body weight twice daily as top dressing in the...

21 CFR 520.1468 - Naproxen granules.

Code of Federal Regulations, 2012 CFR

2012-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the..., administer 10 milligrams naproxen per kilogram of animal body weight twice daily as top dressing in the...

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

PubMed

Mansour-Ghanaei, Fariborz; Joukar, Farahnaz; Taherzadeh, Zahra; Sokhanvar, Homayoon; Hasandokht, Tolou

2016-06-07

To determine the efficacy of rectally administered naproxen for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). 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. 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). Single dose of suppository naproxen administered immediately before ERCP reduces the incidence of PEP.

In vitro evaluation of dendrimer prodrugs for oral drug delivery.

PubMed

Najlah, Mohammad; Freeman, Sally; Attwood, David; D'Emanuele, Antony

2007-05-04

Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-lact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2)=180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2)=4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen.

Ultrasound-assisted magnetic dispersive solid-phase microextraction: A novel approach for the rapid and efficient microextraction of naproxen and ibuprofen employing experimental design with high-performance liquid chromatography.

PubMed

Ghorbani, Mahdi; Chamsaz, Mahmoud; Rounaghi, Gholam Hossein

2016-03-01

A simple, rapid, and sensitive method for the determination of naproxen and ibuprofen in complex biological and water matrices (cow milk, human urine, river, and well water samples) has been developed using ultrasound-assisted magnetic dispersive solid-phase microextraction. Magnetic ethylendiamine-functionalized graphene oxide nanocomposite was synthesized and used as a novel adsorbent for the microextraction process and showed great adsorptive ability toward these analytes. Different parameters affecting the microextraction were optimized with the aid of the experimental design approach. A Plackett-Burman screening design was used to study the main variables affecting the microextraction process, and the Box-Behnken optimization design was used to optimize the previously selected variables for extraction of naproxen and ibuprofen. The optimized technique provides good repeatability (relative standard deviations of the intraday precision 3.1 and 3.3, interday precision of 5.6 and 6.1%), linearity (0.1-500 and 0.3-650 ng/mL), low limits of detection (0.03 and 0.1 ng/mL), and a high enrichment factor (168 and 146) for naproxen and ibuprofen, respectively. The proposed method can be successfully applied in routine analysis for determination of naproxen and ibuprofen in cow milk, human urine, and real water samples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Removal of naproxen and bezafibrate by activated sludge under aerobic conditions: kinetics and effect of substrates.

PubMed

Tang, Ying; Li, Xiao-Ming; Xu, Zhen-Cheng; Guo, Qing-Wei; Hong, Cheng-Yang; Bing, Yong-Xin

2014-01-01

Naproxen and bezafibrate fall into the category of pharmaceuticals that have been widely detected in the aquatic environment, and one of the major sources is the effluent discharge from wastewater treatment plants. This study investigated the sorption and degradation kinetics of naproxen and bezafibrate in the presence of activated sludge under aerobic conditions. Experimental results indicated that the adsorption of pharmaceuticals by activated sludge was rapid, and the relative adsorbabilities of the two-target compounds were based on their log Kow and pKa values. The adsorption data could be well interpreted by the pseudo-second-order kinetic model. The degradation process could be described by the pseudo-first-order kinetic model, whereas the pseudo-second-order kinetics were also well suited to describe the degradation process of the selected compounds at low concentrations. Bezafibrate was more easily degraded by activated sludge compared with naproxen. The spiked concentration of the two-target compounds was negatively correlated with k1 and k2s , indicating that the substrate inhibition effect occurred at the range of studied concentrations. Chemical oxygen demand (COD) did not associate with naproxen degradation; thus, COD is not an alternative method that could be applied to investigate natural organic matter's impact on degradation of pharmaceuticals by activated sludge. © 2013 International Union of Biochemistry and Molecular Biology, Inc.

Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Z.; Peldszus, S.; Huck, P.M.

The adsorption of two representative pharmaceutically active compounds (PhACs) naproxen and carbamazepine and one endocrine disrupting compound (EDC) nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. The GAC adsorbents were coal-based Calgon Filtrasorb 400 and coconut shell-based PICA CTIF TE. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surfacemore » diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol. 25 refs., 4 figs., 1 tab.« less

A Sulfated-Polysaccharide Fraction from Seaweed Gracilaria birdiae Prevents Naproxen-Induced Gastrointestinal Damage in Rats

PubMed Central

Silva, Renan O.; Santana, Ana Paula M.; Carvalho, Nathalia S.; Bezerra, Talita S.; Oliveira, Camila B.; Damasceno, Samara R. B.; Chaves, Luciano S.; Freitas, Ana Lúcia P.; Soares, Pedro M. G.; Souza, Marcellus H. L. P.; Barbosa, André Luiz R.; Medeiros, Jand-Venes R.

2012-01-01

Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group—vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation. PMID:23342384

A sulfated-polysaccharide fraction from seaweed Gracilaria birdiae prevents naproxen-induced gastrointestinal damage in rats.

PubMed

Silva, Renan O; Santana, Ana Paula M; Carvalho, Nathalia S; Bezerra, Talita S; Oliveira, Camila B; Damasceno, Samara R B; Chaves, Luciano S; Freitas, Ana Lúcia P; Soares, Pedro M G; Souza, Marcellus H L P; Barbosa, André Luiz R; Medeiros, Jand-Venes R

2012-12-01

Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group-vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation.

Determination of ibuprofen, naproxen and diclofenac in aqueous samples using a multi-template molecularly imprinted polymer as selective adsorbent for solid-phase extraction.

PubMed

Madikizela, Lawrence Mzukisi; Chimuka, Luke

2016-09-05

This study describes the application of multi-template molecularly imprinted polymer (MIP) as selective sorbent in the solid-phase extraction (SPE) of naproxen, ibuprofen and diclofenac from wastewater and river water. MIP was synthesized at 70°C by employing naproxen, ibuprofen and diclofenac as multi-templates, ethylene glycol dimethacrylate, 2-vinyl pyridine and toluene as cross-linker, functional monomer and porogen, respectively. Wastewater and river water samples (pH 2.5) were percolated through SPE cartridge packed with 50mg of the MIP. The cartridge was washed with 2mL of methanol-water 10:90% (v:v) prior to elution with 2mL of acetic acid-acetonitrile 20:80% (v:v). Quantification of eluted compounds was performed with high performance liquid chromatography equipped with photo diode array detection. The detection limits were 0.15, 1.00 and 0.63μgL(-1) for naproxen, ibuprofen and diclofenac, respectively. Recoveries for naproxen, ibuprofen and diclofenac in deionized water spiked at 5 and 50μgL(-1) were greater than 80%. Ibuprofen was the most frequently detected compound with maximum concentrations of 221, 67.9 and 11.4μgL(-1) in wastewater influent, effluent and river water, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine.

PubMed

Wentz, A L; Jimenez, T B; Dixon, R M; Aurora, S K; Gold, M

2008-04-01

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

Preemptive Use of Naproxen on Tooth Sensitivity Caused by In-Office Bleaching: A Triple-Blind, Crossover, Randomized Clinical Trial.

PubMed

Fernandes, M T; Vaez, S C; Lima, C M; Nahsan, F P; Loguércio, A D; Faria-E-Silva, A L

A triple-blind, randomized, crossover clinical trial evaluated prior use of nonsteroidal anti-inflammatory naproxen on sensitivity reported by patients undergoing in-office tooth bleaching. Fifty patients were subjected to two sessions of in-office tooth bleaching with 35% hydrogen peroxide in a single application of 40 minutes for two sessions, with an interval of seven days between applications. One hour prior to the procedure, each patient randomly received a single dose of naproxen (500 mg) or placebo. The patient's sensitivity level was evaluated during and immediately after the bleaching using two scales (verbal and visual analog); the verbal scale only was repeated after 24 hours. The effectiveness of the bleaching procedures was evaluated with the Bleachedguide scale. Relative risk to sensitivity was calculated and adjusted by session, while comparison of overall risk was performed by the McNemar test. Data on the sensitivity level for both scales and shade were subjected to the Friedman, Wilcoxon, and Mann-Whitney tests (α=0.05). The use of naproxen only decreased the absolute risk and intensity of tooth sensitivity reported immediately after the second session. On the other hand, no measurable effect was observed during or 24 hours after either session. The sequence of drug administration did not affect the bleaching effectiveness. Preemptive use of naproxen only reduced tooth sensitivity reported by patients immediately after the second session of bleaching.

Differential field responses of the little fire ant, Wasmannia auropunctata (Roger), to alarm pheromone enantiomers.

PubMed

Yu, Yang; Jang, Eric B; Siderhurst, Matthew S

2014-12-01

The little fire ant, Wasmannia auropunctata (Roger) (Hymenoptera: Formicidae), is an invasive ant with negative impacts on both biodiversity and agriculture throughout the tropics and subtropics. Field experiments were conducted in order to elucidate the relative attractiveness of the enantiomers of the alarm pheromones, 2,5-dimethyl-3-(2-methylbutyl)pyrazine and 3-methyl-2-(2-methylbutyl)pyrazine. The enantiomers tested were synthesized from commercially available (S)-2-methylbutan-1-ol or kinetically resolved (R)-2-methylbutan-1-ol, prepared using Pseudomonas cepacia lipase (PCL). Bioassays conducted in a macadamia orchard on the island of Hawaii demonstrated that W. auropunctata were preferentially attracted to the (S)-enantiomers of both alkyl pyrazines over the racemic mixtures in all experiments. To our knowledge, this is the first instance of differential attraction of ants to the enantiomers of chiral pyrazine pheromones despite many examples of these compounds in the literature. In addition, using a chiral column it was determined that (S)-2,5-dimethyl-3-(2-methylbutyl)pyrazine and (S)-3-methyl-2-(2-methylbutyl)pyrazine are the only enantiomers produced by W. auropunctata.

A contact sex pheromone component of the emerald ash borer Agrilus planipennis Fairmaire (Coleoptera: Buprestidae)

NASA Astrophysics Data System (ADS)

Silk, Peter J.; Ryall, Krista; Barry Lyons, D.; Sweeney, Jon; Wu, Junping

2009-05-01

Analyses of the elytral hydrocarbons from male and female emerald ash borer, Agrilus planipennis Fairmaire, that were freshly emerged vs. sexually mature (>10 days old) revealed a female-specific compound, 9-methyl-pentacosane (9-Me-C25), only present in sexually mature females. This material was synthesized by the Wittig reaction of 2-decanone with ( n-hexadecyl)-triphenylphosphonium bromide followed by catalytic reduction to yield racemic 9-Me C25, which matched the natural compound by gas chromatography/mass spectrometry (retention time and EI mass spectrum). In field bioassays with freeze-killed sexually mature A. planipennis females, feral males spent significantly more time in contact and attempting copulation with unwashed females than with females that had been washed in n-hexane to remove the cuticular lipids. Hexane-washed females to which 9-Me-C25 had been reapplied elicited similar contact time and percentage of time attempting copulation as unwashed females, indicating that 9-methyl-pentacosane is a contact sex pheromone component of A. planipennis. This is the first contact sex pheromone identified in the Buprestidae.

Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells.

PubMed

Zhang, Cheng-Chen; Yin, Xia; Cao, Chen-Yu; Wei, Jing; Zhang, Qiang; Gao, Jin-Ming

2015-11-15

One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1-10), ergosterol peroxide (1), cerevisterol (2), 3β,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3-6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (±)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauber, Mark; Jakoncic, Jean; Berger, Jacob

Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2,4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with ( R)-MPD had the most order and produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with ( R)-MPD and ( RS)-MPD the crystal contacts are made by ( R)-MPD, demonstrating that there ismore » preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

THE ACTION OF ALKALIES ON PEPTIDES AND ON KETOPIPERAZINES

PubMed Central

Levene, P. A.; Pfaltz, M. H.

1925-01-01

1. The tripeptide glycyl-levo-alanyl-glycine in solution of either one or ten equivalents of alkali does not undergo racemization on standing. 2. The dipeptide levo-alanyl-glycine under the conditions given in (1) does not undergo racemization. 3. In ketopiperazines, levo-alanyl-glycine anhydride and in levo-prolyl-glycine anhydride under the influence of dilute alkalies, racemization takes place. 4. Racemization in the present experiments was never complete. The degree of racemization seems to depend, on the one hand, on the stability of the ketopiperazine ring; on the other, on the concentration of the alkali. 5. The significance of these observations will depend on the outcome of the work on a larger number of polypeptides and ketopiperazines. The work is now in progress in this laboratory. PMID:19872187

Formation of the racemic compound of ephedrine base from a physical mixture of its enantiomers in the solid, liquid, solution, or vapor state.

PubMed

Duddu, S P; Grant, D J

1992-08-01

Physical mixtures (conglomerates) of the two enantiomers of ephedrine base, each containing 0.5% (w/w) of water, were observed to be converted to the 1:1 racemic compound in the solid, liquid, solution, or vapor state. From a geometrically mixed racemic conglomerate of particle size 250-300 microns (50-60 mesh), the formation of the racemic compound follows second-order kinetics (first order with respect to each enantiomer), with a rate constant of 392 mol-1 hr-1 at 22 degrees C. The reaction appears to proceed via the vapor phase as indicated by the growth of the crystals of the racemic compound between diametrically separated crystals of the two enantiomers in a glass petri dish. The observed kinetics of conversion in the solid state are explained by a homogeneous reaction model via the vapor and/or liquid states. Formation of the racemic compound from the crystals of ephedrine enantiomers in the solution state may explain why Schmidt et al. (Pharm. Res. 5:391-395, 1988) observed a consistently lower aqueous solubility of the mixture than of the pure enantiomers. The solid phase in equilibrium with the solution at the end of the experiment was found to be the racemic compound, whose melting point and heat of fusion are higher than those of the enantiomers. An association reaction, of measurable rate, between the opposite enantiomers in a binary mixture in the solid, liquid, solution, or vapor state to form the racemic compound may be more common than is generally realized.

Alpha lipoic acid selectively inhibits proliferation and adhesion to fibronectin of v-H-ras-transformed 3Y1 cells.

PubMed

Yamasaki, Masao; Iwase, Masahiro; Kawano, Kazuo; Sakakibara, Yoichi; Suiko, Masahito; Nishiyama, Kazuo

2012-05-01

Here, we focused on the effects of racemic α-lipoic acid on proliferation and adhesion properties of 3Y1 rat fibroblasts and the v-H-ras-transformed derivative, HR-3Y1-2 cells. Racemic α-lipoic acid inhibited proliferation of HR-3Y1-2 but not 3Y1 cells at 0.3 and 1.0 mM. R-(+)-α-lipoic acid also inhibited proliferation of HR-3Y1-2 cells equivalent to that of racemic α-lipoic acid. In addition, racemic α-lipoic acid decreased intracellular reactive oxygen species levels in HR-3Y1 cells but not 3Y1 cells. Next, we evaluated the effects of racemic α-lipoic acid on cell adhesion to fibronectin. The results indicated that racemic α-lipoic acid decreased adhesive ability of HR-3Y1-2 cells to fibronectin-coated plates. As blocking antibody experiment revealed that β1-integrin plays a key role in cell adhesion in this experimental system, the effects of racemic α-lipoic acid on the expression of β1-integrin were examined. The results indicated that racemic α-lipoic acid selectively downregulated the expression of cell surface β1-integrin expression in HR-3Y1-2 cells. Intriguingly, exogenous hydrogen peroxide upregulated cell surface β1-integrin expression in 3Y1 cells. Taken together, these data suggest that reduction of intracellular reactive oxygen species levels by α-lipoic acid could be an effective means of ameliorating abnormal growth and adhesive properties in v-H-ras transformed cells.

Racemic crystallography of synthetic protein enantiomers used to determine the X-ray structure of plectasin by direct methods

PubMed Central

Mandal, Kalyaneswar; Pentelute, Brad L; Tereshko, Valentina; Thammavongsa, Vilasak; Schneewind, Olaf; Kossiakoff, Anthony A; Kent, Stephen B H

2009-01-01

We describe the use of racemic crystallography to determine the X-ray structure of the natural product plectasin, a potent antimicrobial protein recently isolated from fungus. The protein enantiomers l-plectasin and d-plectasin were prepared by total chemical synthesis; interestingly, l-plectasin showed the expected antimicrobial activity, while d-plectasin was devoid of such activity. The mirror image proteins were then used for racemic crystallization. Synchrotron X-ray diffraction data were collected to atomic resolution from a racemic plectasin crystal; the racemate crystallized in the achiral centrosymmetric space group with one l-plectasin molecule and one d-plectasin molecule forming the unit cell. Dimer-like intermolecular interactions between the protein enantiomers were observed, which may account for the observed extremely low solvent content (13%–15%) and more highly ordered nature of the racemic crystals. The structure of the plectasin molecule was well defined for all 40 amino acids and was generally similar to the previously determined NMR structure, suggesting minimal impact of the crystal packing on the plectasin conformation. PMID:19472324

Comparison of Levalbuterol and Racemic Albuterol Based on Cardiac Adverse Effects in Children

PubMed Central

Bio, Laura L.; Willey, Vincent J.; Poon, Cathy Y.

2011-01-01

OBJECTIVE To compare the cardiac effects of levalbuterol with those of racemic albuterol based on changes in heart rate (HR) in pediatric patients. METHODS The medical records of hospitalized children ages 1 month to 12 years, who received either levalbuterol or racemic albuterol via nebulizer for 3 consecutive doses between January 2006 and December 2008 were reviewed. The documented HR was collected prior to and after each administered dose of bronchodilator. The primary outcome was the largest percentage of change in HR between groups. Secondary outcomes of comparisons of the number of patients who had more than a 10% change in HR and incidence of tachycardia were included. RESULTS A total of 50 patients, 25 in each group, was included in the study. All patients in the racemic albuterol group received 2.5 mg per dose, while most of the patients in the levalbuterol group received 0.63 mg per dose (19 patients, 76%). Only 6 levalbuterol patients received a dose of 1.25 mg. Nineteen of 25 patients (76%) in the levalbuterol group were tachycardic prior to the first recorded dose compared to 15 patients (60%) in the racemic albuterol group (p = 0.36). The median of the largest percentage of change in HR was 4.1% (interquartile range [IQR], 1.8–8.7) in the levalbuterol group compared to 5% (IQR, 1.9–7.8) in the racemic albuterol group (p = 0.763). Four patients in the levalbuterol group experienced an HR increase of more than 10% compared to 5 patients in the racemic albuterol group (p = 1.0). CONCLUSION Levalbuterol and racemic albuterol bronchodilator therapies produced similar effects on HR. No clinically significant differences were detected in HR changes between the two treatment groups, despite administration of a larger equipotent albuterol dose in the racemic albuterol group than in the levalbuterol group. PMID:22479161

Cerium-doped -Ni(OH)2 hexagon nanosheets: an effective photocatalyst for degradation of the emerging water pollutant naproxen.

PubMed

Regmi, Chhabilal; Maya-Flores, Etel; Lee, Soo Wohn; Rodríguez-González, Vicente

2018-06-21

Nickel hydroxide β-Ni(OH)2 hexagonal nanosheets were synthetized via a hydrothermal exfoliation process. The practical microwave assisted hydrothermal method facilitated obtain layered nickel 3D nanoplates with cerium functionalization in 5h. The as-produced nanostructures were characterized by XRD, XPS, FESEM, FT-IR, PL, UV-vis, and BET techniques. The hydroxilated structures are nano-thick hexagonal plates having sides with 28 nm in length and 5 nm of average thickness. UV and PL irradiation was used to study the photoactive properties in the degradation of a pharmaceutical emerging pollutant, naproxen. UV-vis spectroscopy and high-performance liquid chromatography (HPLC) monitoring indicated that the Ni(OH)2-Ce nanostructures are an effective photocatalyst for naproxen degradation including 40 % of mineralization of this highly recalcitrant drug. The photocatalyst showed stability for two consecutive cycles, preserving its photoactive and structural characteristics. Ce3+ doped nanoplates and surface functionalized Ce4+ act as charge separators and scavenging agents for the enhanced photodegradation of naproxen. © 2018 IOP Publishing Ltd.

Degradation of naproxen by UV, VUV photolysis and their combination.

PubMed

Arany, Eszter; Szabó, Rita Katalin; Apáti, László; Alapi, Tünde; Ilisz, István; Mazellier, Patrick; Dombi, András; Gajda-Schrantz, Krisztina

2013-11-15

Naproxen is a widely used nonsteroidal anti-inflammatory drug. Recently, this medicine was detected both in natural waters (up to 1.5 μg L(-1)) and in sewage treatment plant effluents (up to 5.2 μg L(-1)). Moreover, naproxen is only partly eliminated by classical processes used in sewage treatment plants. Therefore, its degradation is of utmost interest. Advanced oxidation processes proved to be the most suitable methods for the elimination of persistent organic contaminants. In this work ultraviolet (UV, 254 nm), vacuum ultraviolet photolysis (VUV, 172 nm) and their combination (UV/VUV, 254/185 nm) were investigated. The efficiency of the methods increased in the following order: UV < VUV < UV/VUV photolysis. However, VUV irradiation was found to mineralize the contaminant molecule most effectively. The chemical structures of three out of four aromatic by-products and of some aliphatic carboxylic acids were presumed. The effects of dissolved O2 and the initial concentration of naproxen on the degradation were also investigated. Copyright © 2013 Elsevier B.V. All rights reserved.

Competitive stereocomplexation, homocrystallization, and polymorphic crystalline transition in poly(L-lactic acid)/poly(D-lactic acid) racemic blends: molecular weight effects.

PubMed

Pan, Pengju; Han, Lili; Bao, Jianna; Xie, Qing; Shan, Guorong; Bao, Yongzhong

2015-05-28

Competitive crystallization kinetics, polymorphic crystalline structure, and transition of poly(l-lactic acid)/poly(d-lactic acid) (PLLA/PDLA) racemic blends with a wide range of molecular weights (MWs) were symmetrically investigated. Stereocomplex (sc) crystallites are exclusively formed in the low-MW racemic blends. However, stereocomplexation is remarkably depressed, and homocrystallization becomes prevailing with increasing MWs of PLLA and PDLA. Suppressed stereocomplexation in high-MW (HMW) racemic blends is proposed to be due to the low chain diffusion ability and restricted intermolecular crystal nucleation/growth. Equilibrium melting point of sc crystallites first increases and then decreases as MW increases. Crystallinity and relative fraction of sc crystallites in racemic blends enhance with crystallization temperature (Tc), and the sc crystallites are merely formed at Tc > 170 °C because of their higher thermodynamic stability. In situ wide-angle X-ray diffraction (WAXD) analysis reveals that the stereocomplexation and homocrystallization are successive rather than completely simultaneous, and the stereocomplexation is preceding homocrystallization in isothermal crystallization of HMW racemic blends. Both initial crystalline structure of homocrystallites (hc) and MW influence the heating-induced hc-to-sc transition of HMW racemic blend drastically; the hc-to-sc transition becomes easier with decreasing Tc and MW. After crystallization at the same temperature, sc crystallites show smaller long period than their hc counterparts.

Features of the adsorption of naproxen enantiomers on weak chiral anion-exchangers in nonlinear chromatography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asnin, Leonid; Kaczmarski, Krzysztof; Guiochon, Georges A

The retention mechanism of the enantiomers of naproxen on a Pirkle-type chiral stationary phase (CSP) was studied. This CSP is made of a porous silica grafted with quinidine carbamate. It can interact with the weak organic electrolyte naproxen either by adsorbing it or by ion-exchange. Using frontal chromatography, we explored the adsorption equilibrium under such experimental conditions that naproxen dissociates or cannot dissociate. Under conditions preventing ionic dissociation, the adsorption isotherms were measured, the adsorption energy distributions determined, and the chromatographic profiles calculated. Three different types of the adsorption sites were found for both enantiomers. The density and the bindingmore » energy of these sites depend on the nature of the organic modifier. Different solute species, anions, neutral molecules, solvent-ion associates, and solute dimers can coexist in solution, giving rise to different forms of adsorption. This study showed the unexpected occurrence of secondary steps in the breakthrough profiles of S-naproxen in the adsorption mode at high concentrations. Being enantioselective, this phenomenon was assumed to result from the association of solute molecules involving a chiral selector moiety. A multisite Langmuir adsorption model was used to calculate band profiles. Although this model accounts excellently for the experimental adsorption isotherms, it does not explain all the features of the breakthrough profiles. A comparison between the calculated and experimental profiles allowed useful conclusions concerning the effects of the adsorbate-adsorbate and adsorbate-solvent interactions on the adsorption mechanism.« less

Naproxen Microparticulate Systems Prepared Using In Situ Crystallisation and Freeze-Drying Techniques.

PubMed

Solaiman, Amanda; Tatari, Adam Keenan; Elkordy, Amal Ali

2017-07-01

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.

Separation and enrichment of enantiopure from racemic compounds using magnetic levitation.

PubMed

Yang, Xiaochuan; Wong, Shin Yee; Bwambok, David K; Atkinson, Manza B J; Zhang, Xi; Whitesides, George M; Myerson, Allan S

2014-07-18

Crystallization of a solution with high enantiomeric excess can generate a mixture of crystals of the desired enantiomer and the racemic compound. Using a mixture of S-/RS-ibuprofen crystals as a model, we demonstrated that magnetic levitation (MagLev) is a useful technique for analysis, separation and enantioenrichment of chiral/racemic products.

X-ray Structure of Native Scorpion Toxin BmBKTx1 by Racemic Protein Crystallography Using Direct Methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mandal, Kalyaneswar; Pentelute, Brad L.; Tereshko, Valentina

2009-04-08

Racemic protein crystallography, enabled by total chemical synthesis, has allowed us to determine the X-ray structure of native scorpion toxin BmBKTx1; direct methods were used for phase determination. This is the first example of a protein racemate that crystallized in space group I41/a.

Effects of kinesiotaping versus non-steroidal anti-inflammatory drugs and physical therapy for treatment of pes anserinus tendino-bursitis: A randomized comparative clinical trial.

PubMed

Homayouni, Kaynoosh; Foruzi, Shima; Kalhori, Fereshte

2016-09-01

Pes anserinus tendino-bursitis is a condition caused by repetitive friction over the bursa or direct trauma to knee joint and it presents with proximal medial tibial pain and swelling. The aim of this study is to determine the effects of kinesiotaping in comparison with naproxen and physical therapy in treatment of pes anserinus tendino-bursitis. In a randomized comparative clinical trial 56 patients with clinical diagnosis of pes anserinus tendino-bursitis were randomly assigned to kinesiotaping and naproxen/physical therapy (28 patients in each group). Kinesiotaping on the tender area in the form of space-correction (lifting) technique was used and repeated for three times with a one-week interval. Another group received naproxen (250mg TID for 10 days) and ten sessions of daily physical therapy. The visual analog scale (VAS) was used for evaluation of pain. The depth of swelling of the area was measured with sonography before and after treatment. Wilcoxon signed ranks test has been used for determining the influence of interventions on pain (VAS) and swelling scores in each group. The ANCOVA (Analysis of covariance) test was applied for comparing the influence of interventions on VAS and swelling scores after adjustment for co-variables. At end of the study, 27 patients remained in the kinesiotaping group and 19 patients in naproxen/physical therapy group. Treatment with kinesiotaping significantly decreased the pain (P=0.0001) and swelling scores (P=0.0001) in comparison with naproxen/physical therapy after adjustment for baseline characteristics. Kinesiotaping was safe without any complications except for a mild local skin irritation in one patient. Kinesiotaping is more effective than naproxen plus physical therapy in reduction of pain and swelling in patients with pes anserinus tendino-bursitis. www.ClinicalTrials.gov identifier is NCT01680263.

Naproxen, a Nonsteroidal Anti-Inflammatory Drug, Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats.

PubMed

Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

2016-06-01

Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS.

Studying of crystal growth and overall crystallization of naproxen from binary mixtures.

PubMed

Kaminska, E; Madejczyk, O; Tarnacka, M; Jurkiewicz, K; Kaminski, K; Paluch, M

2017-04-01

Broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC) were applied to investigate the molecular dynamics and phase transitions in binary mixtures composed of naproxen (NAP) and acetylated saccharides: maltose (acMAL) and sucrose (acSUC). Moreover, the application of BDS method and optical microscopy enabled us to study both crystallization kinetics and crystal growth of naproxen from the solid dispersions with the highest content of modified carbohydrates (1:5wt ratio). It was found that the activation barriers of crystallization estimated from dielectric measurements are completely different for both studied herein mixtures. Much higher E a (=205kJ/mol) was obtained for NAP-acMAL solid dispersion. It is probably due to simultaneous crystallization of both components of the mixture. On the other hand, lower value of E a in the case of NAP-acSUC solid dispersion (81kJ/mol) indicated, that naproxen is the only crystallizing compound. This hypothesis was confirmed by X-ray diffraction studies. We also suggested that specific intermolecular dipole-dipole interactions between active substance and excipient may be an alternative explanation for the difference between activation barrier obtained for NAP-acMAL and NAP-acSUC binary mixtures. Furthermore, optical measurements showed that the activation energy for crystal growth of naproxen increases in binary mixtures. They also revealed that both excipients: acMAL and acSUC move the temperature of the maximum of crystal growth towards lower temperatures. Interestingly, this maximum occurs for nearly the same structural relaxation time, which is a good approximation of viscosity, for all samples. Finally, it was also noticed that although naproxen crystallizes to the same polymorphic form in both systems, there are some differences in morphology of obtained crystals. Thus, the observed behavior may have a significant impact on the bioavailability and dissolution rate of API produced in that way. Copyright © 2016 Elsevier B.V. All rights reserved.

Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial.

PubMed

Gagliano-Jucá, Thiago; Moreno, Ronilson A; Zaminelli, Tiago; Napolitano, Mauro; Magalhães, Antônio Frederico N; Carvalhaes, Aloísio; Trevisan, Miriam S; Wallace, John L; De Nucci, Gilberto

2016-06-04

Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. ClinicalTrials.gov, NCT02632812 . Registered 14 December 2015.

Quantifying hydrogen-deuterium exchange of meteoritic dicarboxylic acids during aqueous extraction

NASA Astrophysics Data System (ADS)

Fuller, M.; Huang, Y.

2003-03-01

Hydrogen isotope ratios of organic compounds in carbonaceous chondrites provide critical information about their origins and evolutionary history. However, because many of these compounds are obtained by aqueous extraction, the degree of hydrogen-deuterium (H/D) exchange that occurs during the process needs to be quantitatively evaluated. This study uses compound- specific hydrogen isotopic analysis to quantify the H/D exchange during aqueous extraction. Three common meteoritic dicarboxylic acids (succinic, glutaric, and 2-methyl glutaric acids) were refluxed under conditions simulating the extraction process. Changes in D values of the dicarboxylic acids were measured following the reflux experiments. A pseudo-first order rate law was used to model the H/D exchange rates which were then used to calculate the isotope exchange resulting from aqueous extraction. The degree of H/D exchange varies as a result of differences in molecular structure, the alkalinity of the extraction solution and presence/absence of meteorite powder. However, our model indicates that succinic, glutaric, and 2-methyl glutaric acids with a D of 1800 would experience isotope changes of 38, 10, and 6, respectively during the extraction process. Therefore, the overall change in D values of the dicarboxylic acids during the aqueous extraction process is negligible. We also demonstrate that H/D exchange occurs on the chiral -carbon in 2-methyl glutaric acid. The results suggest that the racemic mixture of 2-methyl glutaric acid in the Tagish Lake meteorite could result from post-synthesis aqueous alteration. The approach employed in this study can also be used to quantify H/D exchange for other important meteoritic compounds such as amino acids.

Recent advances in chirally pure proton pump inhibitors.

PubMed

Pai, Vikas; Pai, Nitin

2007-08-01

Chirality is a ubiquitous natural phenomenon resulting because of a differential spatial orientation of molecules around its chiral centre. This leads to the existence of two or more spatially dissimilar forms, known as stereoisomers or enantiomers, which are non-superimposable images of each other and may significantly differ from each other with respect to pharmacokinetic and pharmacodynamic properties and molecular interaction. Thus one isomer may offer significant pharmacokinetic and therapeutic advantages as compared to the other isomer or the racemic mixture (mixture containing both enantiomers). Proton pump inhibitors are a class of drugs which have been very effective in the management of acid-related disorders. The proton pumps currently available in the market including omeprazole, pantoprazole, rabeprazole and lansoprazole are racemic mixtures of the S and R isomers. Chirally pure forms of proton pump inhibitors show a superior metabolic and pharmacokinetic profile as compared to their racemates. The therapeutic efficacy is also superior to the parent racemate. This has been clearly demonstrated with the development of esomeprazole- the S-isomer of omeprazole. S-pantoprazole and dexrabeprazole also offer therapeutic advantages as compared to racemic pantoprazole and racemic rabeprazole respectively. This article reviews the chiral developments in the proton pump inhibitors and their clinical applications.

Occurrence of neutral and acidic drugs in the effluents of Canadian sewage treatment plants.

PubMed

Metcalfe, Chris D; Koenig, Brenda G; Bennie, Don T; Servos, Mark; Ternes, Thomas A; Hirsch, Roman

2003-12-01

Samples of influent (untreated) and effluent (treated) from 18 sewage treatment plants (STPs) in 14 municipalities in Canada were analyzed for residues of selected prescription and nonprescription drugs. Several neutral and acidic drugs were detected in effluents, including analgesic/anti-inflammatory agents, lipid regulators, and an antiepileptic drug, carbamazepine. Residues were extracted from effluents by solid-phase extraction, followed by either methylation and analysis of acidic drugs by gas chromatography/mass spectrometry or direct analysis of neutral drugs by liquid chromatography/tandem mass spectrometry. Analgesic/anti-inflammatory drugs such as ibuprofen and naproxen, as well as the metabolite of acetylsalicyclic acid, salicylic acid, were often detected in final effluents at microg/L concentrations. The acidic lipid regulator, clofibric acid, and the analgesic/anti-inflammatory drug diclofenac were not detected in any final effluent samples, which is not consistent with data from Europe. The precursor to clofibric acid, clofibrate, is not widely prescribed as a lipid regulator in Canada. However, the lipid regulators bezafibrate and gemfibrozil were detected in some samples of influent and effluent. The chemotherapy drugs ifosfamide and cyclophosphamide and the anti-inflammatory phenazone were not detected in influent or effluent samples, but the vasodilator drug pentoxyfylline was detected at ng/L concentrations in some final effluents. The widespread occurrence of carbamazepine at concentrations as high as 2.3 microg/L may be explained by use of this drug for other therapeutic purposes besides treatment of epilepsy and its resistance to elimination in STPs. The rates of elimination of ibuprofen and naproxen appeared to be elevated in STPs with hydraulic retention times for sewage greater than 12 h.

Enantiomeric excesses in meteoritic amino acids

NASA Technical Reports Server (NTRS)

Cronin, J. R.; Pizzarello, S.

1997-01-01

Gas chromatographic-mass spectral analyses of the four stereoisomers of 2-amino-2,3-dimethylpentanoic acid (dl-alpha-methylisoleucine and dl-alpha-methylalloisoleucine) obtained from the Murchison meteorite show that the L enantiomer occurs in excess (7.0 and 9.1%, respectively) in both of the enantiomeric pairs. Similar results were obtained for two other alpha-methyl amino acids, isovaline and alpha-methylnorvaline, although the alpha hydrogen analogs of these amino acids, alpha-amino-n-butyric acid and norvaline, were found to be racemates. With the exception of alpha-amino-n-butyric acid, these amino acids are either unknown or of limited occurrence in the biosphere. Because carbonaceous chondrites formed 4.5 billion years ago, the results are indicative of an asymmetric influence on organic chemical evolution before the origin of life.

Occurrence and fate of carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen in surface waters.

PubMed

Tixier, Céline; Singer, Heinz P; Oellers, Sjef; Müller, Stephan R

2003-03-15

Although various single-concentration measurements of pharmaceuticals are available in the literature, detailed information on the variation over time of the concentration and the load in wastewater effluents and rivers and on the fate of these compounds in the aquatic environment are lacking. We measured the concentrations of six pharmaceuticals, carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen, in the effluents of three wastewater treatment plants (WWTPs), in two rivers and in the water column of Lake Greifensee (Switzerland) over a time period of three months. In WWTP effluents, the concentrations reached 0.95 microg/L for carbamazepine, 0.06 microg/L for clofibric acid, 0.99 microg/L for diclofenac, 1.3 microg/L for ibuprofen, 0.18 microg/L for ketoprofen, and 2.6 microg/L for naproxen. The relative importance in terms of loads was carbamazepine, followed by diclofenac, naproxen, ibuprofen, clofibric acid, and ketoprofen. An overall removal rate of all these pharmaceuticals was estimated in surface waters, under real-world conditions (in a lake), using field measurements and modeling. Carbamazepine and clofibric acid were fairly persistent. Phototransformation was identified as the main elimination process of diclofenac in the lake water during the study period. With a relatively high sorption coefficient to particles, ibuprofen might be eliminated by sedimentation. For ketoprofen and naproxen, biodegradation and phototransformation might be elimination processes. For the first time, quantitative data regarding removal rates were determined in surface waters under real-world conditions. All these findings are important data for a risk assessment of these compounds in surface waters.

Comparison of Clinical Efficacies of Preoperatively Initiated Naproxen Sodium-Codeine Phosphate in Combination, Diclofenac Potassium, and Benzydamine Hydrochloride for Pain, Edema, and Trismus After Extraction of Impacted Lower Third Molar: A Randomized Double-Blind Study.

PubMed

Cigerim, Levent; Eroglu, Cennet Neslihan

2018-03-01

The aim of this study was to compare the clinical efficacies of naproxen sodium-codeine phosphate in combination, benzydamine hydrochloride, and diclofenac potassium for pain, edema, and trismus after lower third molar extraction. Ninety healthy volunteers in whom impacted third molar extraction was indicated were randomly distributed into 3 groups. One hour before the tooth-extraction process, patients were administered one of the following drugs: naproxen sodium, 550 mg, and codeine phosphate, 30 mg, in a tablet; diclofenac potassium, 50 mg, in a coated pill; or benzydamine hydrochloride, 50 mg, in a coated pill. Pain assessment was conducted via a visual analog scale; edema assessment, by measuring the distances between predetermined facial landmarks; and trismus assessment, by measuring interincisal distance. Regarding rescue analgesics (paracetamol, 500 mg), the number and time of use by patients were recorded. Naproxen sodium-codeine phosphate was more effective for pain, edema, and trismus than diclofenac potassium and benzydamine hydrochloride (P < .05). Benzydamine hydrochloride yielded similar clinical responses to diclofenac potassium (P > .05). No drug-related side effects were observed. Naproxen sodium-codeine phosphate constitutes the drug of choice after the extraction of a patient's impacted lower third molar. Benzydamine hydrochloride has similar efficacy to diclofenac potassium, and it can be used as a nonsteroidal anti-inflammatory analgesic drug. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Model-based analysis of thromboxane B₂ and prostaglandin E₂ as biomarkers in the safety evaluation of naproxen.

PubMed

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar

2014-08-01

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., Cmax and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B₂ and prostaglandin E₂ were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB₂ and PGE₂ was described by direct inhibition models with maximum pharmacological effects achieved at doses >7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. Copyright © 2014 Elsevier Inc. All rights reserved.

Selective inhibition by aspirin and naproxen of mainstream cigarette smoke-induced genotoxicity and lung tumors in female mice.

PubMed

Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Micale, Rosanna T; La Maestra, Sebastiano; D'Oria, Chiara; Steele, Vernon E; De Flora, Silvio

2016-05-01

The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in smoke-related lung carcinogenesis is still controversial. We have developed and validated a murine model for evaluating the tumorigenicity of mainstream cigarette smoke (MCS) and its modulation by chemopreventive agents. In the present study, the protective effects of the nonselective cyclooxygenase inhibitors aspirin and naproxen were investigated by using a total of 277 Swiss H neonatal mice of both genders. Groups of mice were exposed whole-body to MCS during the first 4 months of life, followed by an additional 3.5 months in filtered air in order to allow a better growth of tumors. Aspirin (1600 mg/kg diet) and naproxen (320 mg/kg diet) were given after weanling until the end of the experiment. After 4 months of exposure, MCS significantly enhanced the frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice, and naproxen prevented such systemic genotoxic damage in female mice. After 7.5 months, exposure of mice to MCS resulted in the formation of lung tumors, both benign and malignant, and in several other histopathological lesions detectable both in the respiratory tract and in the urinary tract. Aspirin and, even more sharply, naproxen significantly inhibited the formation of lung tumors in MCS-exposed mice, but this protective effect selectively occurred in female mice only. These results lend support to the views that estrogens are involved in smoke-related pulmonary carcinogenesis and that NSAIDs have antiestrogenic properties. The two NSAIDs proved to be safe and efficacious in the experimental model used.

Validated HPLC-UV method for determination of naproxen in human plasma with proven selectivity against ibuprofen and paracetamol.

PubMed

Filist, Monika; Szlaska, Iwona; Kaza, Michał; Pawiński, Tomasz

2016-06-01

Estimating the influence of interfering compounds present in the biological matrix on the determination of an analyte is one of the most important tasks during bioanalytical method development and validation. Interferences from endogenous components and, if necessary, from major metabolites as well as possible co-administered medications should be evaluated during a selectivity test. This paper describes a simple, rapid and cost-effective HPLC-UV method for the determination of naproxen in human plasma in the presence of two other analgesics, ibuprofen and paracetamol. Sample preparation is based on a simple liquid-liquid extraction procedure with a short, 5 s mixing time. Fenoprofen, which is characterized by a similar structure and properties to naproxen, was first used as the internal standard. The calibration curve is linear in the concentration range of 0.5-80.0 µg/mL, which is suitable for pharmacokinetic studies following a single 220 mg oral dose of naproxen sodium. The method was fully validated according to international guidelines and was successfully applied in a bioequivalence study in humans. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Fate of pharmaceutical compounds in hydroponic mesocosms planted with Scirpus validus.

PubMed

Zhang, Dong Qing; Gersberg, Richard M; Hua, Tao; Zhu, Junfei; Goyal, Manish Kumar; Ng, Wun Jern; Tan, Soon Keat

2013-10-01

A systematic approach to assess the fate of selected pharmaceuticals (carbamazepine, naproxen, diclofenac, clofibric acid and caffeine) in hydroponic mesocosms is described. The overall objective was to determine the kinetics of depletion (from solution) and plant uptake for these compounds in mesocosms planted with S. validus growing hydroponically. The potential for translocation of these pharmaceuticals from the roots to the shoots was also assessed. After 21 days of incubation, nearly all of the caffeine, naproxen and diclofenac were eliminated from solution, whereas carbamazepine and clofibric acid were recalcitrant to both photodegradation and biodegradation. The fact that the BAFs for roots for carbamazepine and clofibric acid were greater than 5, while the BAFs for naproxen, diclofenac and caffeine were less than 5, implied that the latter two compounds although recalcitrant to biodegradation, still had relatively high potential for plant uptake. Naproxen was sensitive to both photodegradation (30-42%) and biodegradation (>50%), while diclofenac was particularly sensitive (>70%) to photodegradation alone. No significant correlations (p > 0.05) were found between the rate constants of depletion or plant tissue levels of the pharmaceuticals and either log Kow or log Dow. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bioavailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol (acetaminophen): single-dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects.

PubMed

Palma-Aguirre, Jose Antonio; Villalpando-Hernández, Jorge; Novoa-Heckel, Germán; Oliva, Iván; Cariño, Lizbeth; López-Bojórquez, Ericka; Burke-Fraga, Victoria; Namur, Salvador; González-de la Parra, Mario

2009-02-01

Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities). Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events. A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol. In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.

Pharmacological synergy: the next frontier on therapeutic advancement for migraine.

PubMed

Blumenfeld, Andrew; Gennings, Chris; Cady, Roger

2012-04-01

The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population. Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours. A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs. More recently, the Food and Drug Adminstration has approved a combination product containing 85mg of sumatriptan plus 500mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism. Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT(1B) and 5-HT(1D) receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect. The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes. © 2011 American Headache Society.

Racemization in Reverse: Evidence that D-Amino Acid Toxicity on Earth Is Controlled by Bacteria with Racemases

PubMed Central

Zhang, Gaosen; Sun, Henry J.

2014-01-01

D-amino acids are toxic for life on Earth. Yet, they form constantly due to geochemical racemization and bacterial growth (the cell walls of which contain D-amino acids), raising the fundamental question of how they ultimately are recycled. This study provides evidence that bacteria use D-amino acids as a source of nitrogen by running enzymatic racemization in reverse. Consequently, when soils are inundated with racemic amino acids, resident bacteria consume D- as well as L-enantiomers, either simultaneously or sequentially depending on the level of their racemase activity. Bacteria thus protect life on Earth by keeping environments D-amino acid free. PMID:24647559

Racemization in reverse: evidence that D-amino acid toxicity on Earth is controlled by bacteria with racemases.

PubMed

Zhang, Gaosen; Sun, Henry J

2014-01-01

D-amino acids are toxic for life on Earth. Yet, they form constantly due to geochemical racemization and bacterial growth (the cell walls of which contain D-amino acids), raising the fundamental question of how they ultimately are recycled. This study provides evidence that bacteria use D-amino acids as a source of nitrogen by running enzymatic racemization in reverse. Consequently, when soils are inundated with racemic amino acids, resident bacteria consume D- as well as L-enantiomers, either simultaneously or sequentially depending on the level of their racemase activity. Bacteria thus protect life on Earth by keeping environments D-amino acid free.

Ecotoxicity of naproxen and its phototransformation products.

PubMed

Isidori, Marina; Lavorgna, Margherita; Nardelli, Angela; Parrella, Alfredo; Previtera, Lucio; Rubino, Maria

2005-09-15

The occurrence of pharmaceuticals in the environment is of great concern and only few data are available about the adverse effects of such molecules and their derivatives on non-target aquatic organisms. This study was designed to assess the toxic potential of Naproxen, a nonsteroidal anti-inflammatory, Naproxen Na, its freely water soluble sodium salt and their photoproducts in the aquatic environment. Bioassays were performed on algae, rotifers and microcrustaceans to assess acute and chronic toxicity. Furthermore, possible genotoxic effects of photoderivatives were investigated using SOS chromotest and Ames fluctuation test. The results showed that photoproducts were more toxic than the parent compounds both for acute and chronic values, while genotoxic and mutagenic effects were not found. These findings suggested the opportunity to consider derivatives in ecotoxicology assessment of drugs.

Concordance of Collagen-Based Radiocarbon and Aspartic-Acid Racemization Ages

PubMed Central

Bada, Jeffrey L.; Schroeder, Roy A.; Protsch, Reiner; Berger, Rainer

1974-01-01

By determining the extent of racemization of aspartic acid in a well-dated bone, it is possible to calculate the in situ first-order rate constant for the interconversion of the L and D enantiomers of aspartic acid. Collagen-based radiocarbon-dated bones are shown to be suitable samples for use in “calibrating” the racemization reaction. Once the aspartic-acid racemization reaction has been “calibrated” for a site, the reaction can be used to date other bones from the deposit. Ages deduced by this method are in good agreement with radiocarbon ages. These results provide evidence that the aspartic-acid racemization reaction is an important chronological tool for dating bones either too old or too small for radiocarbon dating. As an example of the potential application of the technique for dating fossil man, a piece of Rhodesian Man from Broken Hill, Zambia, was analyzed and tentatively assigned an age of about 110,000 years. PMID:4522802

Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies.

PubMed

McGettigan, Patricia; Henry, David

2011-09-01

Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary.

Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15,more » 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and humans in the effects of naproxen on TXB{sub 2}. • A biomarker-guided approach may facilitate the prediction of adverse events in humans.« less

Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy.

PubMed

Miglietta, Daniela; De Palma, Clara; Sciorati, Clara; Vergani, Barbara; Pisa, Viviana; Villa, Antonello; Ongini, Ennio; Clementi, Emilio

2015-08-22

In dystrophin-deficient muscles of Duchenne Muscular Dystrophy (DMD) patients and the mdx mouse model, nitric oxide (NO) signalling is impaired. Previous studies have shown that NO-donating drugs are beneficial in dystrophic mouse models. Recently, a long-term treatment (9 months) of mdx mice with naproxcinod, an NO-donating naproxen, has shown a significant improvement of the dystrophic phenotype with beneficial effects present throughout the disease progression. It remains however to be clearly dissected out which specific effects are due to the NO component compared with the anti-inflammatory activity associated with naproxen. Understanding the contribution of NO vs the anti-inflammatory effect is important, in view of the potential therapeutic perspective, and this is the final aim of this study. Five-week-old mdx mice received either naproxcinod (30 mg/kg) or the equimolar dose of naproxen (20 mg/kg) in the diet for 6 months. Control mdx mice were used as reference. Treatments (or vehicle for control groups) were administered daily in the diet. For the first 3 months the study was performed in sedentary animals, then all mice were subjected to exercise until the sixth month. Skeletal muscle force was assessed by measuring whole body tension in sedentary animals as well as in exercised mice and resistance to fatigue was measured after 3 months of running exercise. At the end of 6 months of treatment, animals were sacrificed for histological analysis and measurement of naproxen levels in blood and skeletal muscle. Naproxcinod significantly ameliorated skeletal muscle force and resistance to fatigue in sedentary as well as in exercised mice, reduced inflammatory infiltrates and fibrosis deposition in both cardiac and diaphragm muscles. Conversely, the equimolar dose of naproxen showed no effects on fibrosis and improved muscle function only in sedentary mice, while the beneficial effects in exercised mice were lost demonstrating a limited and short-term effect. In conclusion, this study shows that NO donation may have an important role, in addition to anti-inflammatory activity, in slowing down the progression of the disease in the mdx mouse model therefore positioning naproxcinod as a promising candidate for treatment of DMD.

Sorption and desorption of carbamazepine, naproxen and triclosan in a soil irrigated with raw wastewater: estimation of the sorption parameters by considering the initial mass of the compounds in the soil.

PubMed

Durán-Álvarez, Juan C; Prado-Pano, Blanca; Jiménez-Cisneros, Blanca

2012-06-01

In conventional sorption studies, the prior presence of contaminants in the soil is not considered when estimating the sorption parameters because this is only a transient state. However, this parameter should be considered in order to avoid the under/overestimation of the soil sorption capacity. In this study, the sorption of naproxen, carbamazepine and triclosan was determined in a wastewater irrigated soil, considering the initial mass of the compounds. Batch sorption-desorption tests were carried out at two soil depths (0-10 cm and 30-40 cm), using either 10 mM CaCl(2) solution or untreated wastewater as the liquid phase. Data were satisfactorily fitted to the initial mass model. For the two soils, release of naproxen and carbamazepine was observed when the CaCl(2) solution was used, but not in the soil/wastewater system. The compounds' release was higher in the topsoil than in the 30-40 cm soil. Sorption coefficients (K(d)) for CaCl(2) solution tests showed that in the topsoil, triclosan (64.9 L kg(-1)) is sorbed to a higher extent than carbamazepine and naproxen (5.81 and 2.39 L kg(-1), respectively). In the 30-40 cm soil, carbamazepine and naproxen K(d) values (11.4 and 4.41 L kg(-1), respectively) were higher than those obtained for the topsoil, while the triclosan K(d) value was significantly lower than in the topsoil (19.2 L kg(-1)). Differences in K(d) values were found when comparing the results obtained for the two liquid phases. Sorption of naproxen and carbamazepine was reversible for both soils, while sorption of triclosan was found to be irreversible. This study shows the sorption behavior of three pharmaceuticals in a wastewater irrigated soil, as well as the importance of considering the initial mass of target pollutants in the estimation of their sorption parameters. Copyright © 2012 Elsevier Ltd. All rights reserved.

Physical aspects of dexibuprofen and racemic ibuprofen.

PubMed

Leising, G; Resel, R; Stelzer, F; Tasch, S; Lanziner, A; Hantich, G

1996-12-01

This article presents a comparative study of ibuprofen materials in their solid state. Ibuprofen crystallizes into two different structures for the S(+) enantiomer (dexibuprofen) and racemic ibuprofen. The crystal structure of ibuprofen, its optical absorption and photoluminescence, and the thermodynamic results (melting point and heat of fusion) are discussed. From these physicochemical properties, the authors conclude that dexibuprofen, which is the most active species pharmaceutically, and racemic ibuprofen are inherently different solid-state materials.

Enantioconvergent Cross-Couplings of Racemic Alkylmetal Reagents with Unactivated Secondary Alkyl Electrophiles: Catalytic Asymmetric Negishi α-Alkylations of N-Boc-pyrrolidine

PubMed Central

Cordier, Christopher J.; Lundgren, Rylan J.; Fu, Gregory C.

2013-01-01

Although enantioconvergent alkyl-alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein, we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicate that two of the most straightforward mechanisms for enantioconvergence (a dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative. PMID:23869442

The Efficacy of Thermotherapy and Cryotherapy on Pain Relief in Patients with Acute Low Back Pain, A Clinical Trial Study

PubMed Central

Dehghan, Morteza

2014-01-01

Introduction: Acute low back pain is one of the most common health problems especially in industrialized countries where 75 per cent of the population develop it at least once during their life. This study examined the efficacy of thermotherapy and cryotherapy, alongside a routine pharmacologic treatment, on pain relief in patients with acute low back pain referring an orthopedic clinic in Shahrekord, Iran. Materials and Methods: This clinical trial study was conducted on 87 patients randomly assigned to three (thermotherapy and cryotherapy as intervention, and naproxen as control) groups of 29 each. The first (thermotherapy) group underwent treatment with hot water bag and naproxen, the second (cryotherapy) group was treated with ice and naproxen, and the naproxen group was only treated with naproxen, all for one week. All patients were examined on 0, 3rd, 8th, and 15th day after the first visit and the data gathered by McGill Pain Questionnaire. The data were analyzed by SPSS software using paired t-test, ANOVA, and chi-square. Results: In this study, mean age of the patients was 34.48 (20–50) years and 51.72 per cent were female. Thermotherapy patients reported significantly less pain compared to cryotherapy and control (p≤0.05). In thermotherapy and cryotherapy groups, mean pain in the first visit was 12.70±3.7 and 12.06±2.6, and on the 15th day after intervention 0.75±0.37 and 2.20±2.12, respectively. Conclusion: The results indicated that the application of thermo–therapy and cryotherapy accompanied with a pharmacologic treatment could relieve pain in the patients with acute low back pain. PMID:25386469

Comparison of the postoperative analgesic effects of paracetamol-codeine phosphate and naproxen sodium-codeine phosphate for lumbar disk surgery.

PubMed

Polat, Reyhan; Peker, Kevser; Gülöksüz, Çiğdem Topçu; Ergil, Julide; Akkaya, Taylan

2015-09-01

The aim of this study was to compared the efficacy of paracetamol-codeine phosphate and naproxen sodium-codeine phosphate on postoperative pain and tramadol consumption during the first 24 hours after a lumbar disk surgery. After Ethics Committee approval and informed consent had been obtained, 64 patients were allocated into three groups. Patients received oral paracetamol-codeine (300 mg + 30 mg; Group P), naproxen sodium-codeine (550 mg + 30 mg; Group N), or placebo tablets (Group C) 30 minutes prior to induction of anesthesia. Patient-controlled analgesia was supplied postoperatively using tramadol. Pain intensity, tramadol consumption, and side effects were recorded every 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after surgery. Whole study period pain intensity (visual analogue scale scores) was lower in Group P (p = 0.007) and Group N (p = 0.001), compared with Group C, however, there was no statistically significant difference between Group P and Group N regarding pain intensity (p > 0.05). Tramadol consumption was lower in Group P and Group N, compared with Group C (p < 0.001), and in turn the lowest incidence of tramadol consumption was detected in Group P compared with Group N (p < 0.001) and Group C (p < 0.001). Side effects were similar between the groups. Preemptive administration of paracetamol-codeine and naproxen sodium-codeine combination significantly reduced tramadol consumption and provided more effective analgesia compared with placebo. The paracetamol-codeine combination was superior to naproxen sodium-codeine with regard to tramadol consumption. Copyright © 2015. Published by Elsevier Taiwan.

Relief of Menstrual Symptoms and Migraine with a Single-Tablet Formulation of Sumatriptan and Naproxen Sodium

PubMed Central

Ballard, Jeanne; Diamond, Michael P.; Mannix, Lisa K.; Derosier, Frederick J.; Lener, Shelly E.; Krishen, Alok; McDonald, Susan A.

2014-01-01

Abstract Background: Dysmenorrhea and menstrual migraine may share a common pathogenic pathway. Both appear to be mediated, in part, by an excess of prostaglandin production that occurs during menstruation. Methods: Data were pooled from two replicate randomized controlled trials of 621 adult menstrual migraineurs with dysmenorrhea who treated migraine with sumatriptan-naproxen or placebo. Along with headache symptoms, nonpain menstrual symptoms (bloating, fatigue, and irritability) and menstrual pain symptoms (abdominal and back pain) were recorded at the time periods of 30 minutes and 1, 2, 4, and 4–24 hours. Relief of menstrual symptoms was compared using a Cochran-Mantel-Haenszel test. Logistic regression was used to determine the odds of a headache response with increasing numbers of moderate to severe dymenorrheic symptoms. Results: Sumatriptan-naproxen was superior to placebo for relief of tiredness, irritability, and abdominal pain at the time periods of 2, 4, and 4–24 hours (p≤0.023); back pain at the time periods of 4 and 4–24 hours (p≤0.023); and bloating at 4–24 hours endpoint (p=0.01). The odds ratios (ORs) of attaining migraine pain freedom for 2 hours and for sustained 2–24 hours decreased as moderate to severe dysmenorrhea symptoms increased with sumatriptan-naproxen versus placebo. Conclusions: Treatment with sumatriptan-naproxen may provide relief of menstrual symptoms and migraine in female migraineurs with dysmenorrhea. The presence of moderate to severe dysmenorrhea symptoms is associated with decreased response rates for menstrual migraine, suggesting that the co-occurrence of these disorders may negatively impact the results of migraine-abortive therapy. PMID:24579886

Melt extrusion vs. spray drying: The effect of processing methods on crystalline content of naproxen-povidone formulations.

PubMed

Haser, Abbe; Cao, Tu; Lubach, Joe; Listro, Tony; Acquarulo, Larry; Zhang, Feng

2017-05-01

Our hypothesis is that melt extrusion is a more suitable processing method than spray drying to prepare amorphous solid dispersions of drugs with a high crystallization tendency. Naproxen-povidone K25 was used as the model system in this study. Naproxen-povidone K25 solid dispersions at 30% and 60% drug loadings were characterized by modulated DSC, powder X-ray diffraction, FT-IR, and solid-state 13 C NMR to identify phase separation and drug recrystallization during processing and storage. At 30% drug loading, hydrogen bond (H-bond) sites of povidone K25 were not saturated and the glass transition (T g ) temperature of the formulation was higher. As a result, both melt-extruded and spray-dried materials were amorphous initially and remained so after storage at 40°C. At 60% drug loading, H-bond sites were saturated, and T g was low. We were not able to prepare amorphous materials. The initial crystallinity of the formulations was 0.4%±0.2% and 5.6%±0.6%, and increased to 2.7%±0.3% and 21.6%±1.0% for melt-extruded and spray-dried materials, respectively. Spray-dried material was more susceptible to re-crystallization during processing, due to the high diffusivity of naproxen molecules in the formulation matrix and lack of kinetic stabilization from polymer solution. A larger number of crystalline nucleation sites and high surface area made the spray-dried material more susceptible to recrystallization during storage. This study demonstrated the unique advantages of melt extrusion over spray drying for the preparation of amorphous solid dispersions of naproxen at high drug level. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial.

PubMed

Leoutsakos, Jeannie-Marie S; Muthen, Bengt O; Breitner, John C S; Lyketsos, Constantine G

2012-04-01

We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib. We identified three classes: "no decline", "slow decline", and "fast decline", and examined the effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (-2 log likelihood difference: 369.23; p < 0.001) but resulted in reversal of effects over time. Over 4 years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, whereas those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), whereas those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Our results appeared statistically robust but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then attenuated change in fast decliners. Copyright © 2011 John Wiley & Sons, Ltd.

Stereoselective Effects of Abused “Bath Salt” Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation

PubMed Central

Gannon, Brenda M.; Williamson, Adrian; Suzuki, Masaki; Rice, Kenner C.

2016-01-01

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit “bath salts” products. MDPV is a chiral molecule, but the contribution of each enantiomer to in vivo effects in mice has not been determined. To address this, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(−)-MDPV were performed. Other mice were implanted with telemetry probes to monitor core temperature and locomotor responses elicited by racemic MDPV, S(+)-MDPV, and R(−)-MDPV under a warm (28°C) or cool (20°C) ambient temperature. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(−)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(−)-MDPV did not elicit locomotor stimulant effects at any tested dose. Interestingly, significant increases in maximum core body temperature were only observed after administration of racemic MDPV in the warm ambient environment; neither MDPV enantiomer altered core temperature at any dose tested, at either ambient temperature. These studies suggest that all three forms of MDPV induce biologic effects, but R(−)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse. PMID:26769917

Racemization of aspartic acid in root dentin as a tool for age estimation in a Kuwaiti population.

PubMed

Elfawal, Mohamed Amin; Alqattan, Sahib Issa; Ghallab, Noha Ayman

2015-01-01

Estimation of age is one of the most significant tasks in forensic practice. Amino acid racemization is considered one of the most reliable and accurate methods of age estimation and aspartic acid shows a high racemization reaction rate. The present study has investigated the application of aspartic acid racemization in age estimation in a Kuwaiti population using root dentin from a total of 89 upper first premolar teeth. The D/L ratio of aspartic acid was obtained by HPLC technique in a test group of 50 subjects and a linear regression line was established between aspartic acid racemization and age. The correlation coefficient (r) was 0.97, and the standard error of estimation was ±1.26 years. The racemization age "t" of each subject was calculated by applying the following formula: ln [(1 + D/L)/(1 - D/L)] = 0.003181 t + (-0.01591). When the proposed formula "estimated age t = ln [(1 + D/L)/(1 - D/L)] + 0.01591/0.003181" was applied to a validation group of 39 subjects, the range of error was less than one year in 82.1% of the cases and the standard error of estimation was ±1.12. The current work has established a reasonably significant correlation of the D-/L-aspartic acid ratio with age, and proposed an apparently reliable formula for calculating the age in Kuwaiti populations through aspartic acid racemization. Further research is required to find out whether similar findings are applicable to other ethnic populations. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Age estimation in forensic sciences: application of combined aspartic acid racemization and radiocarbon analysis.

PubMed

Alkass, Kanar; Buchholz, Bruce A; Ohtani, Susumu; Yamamoto, Toshiharu; Druid, Henrik; Spalding, Kirsty L

2010-05-01

Age determination of unknown human bodies is important in the setting of a crime investigation or a mass disaster because the age at death, birth date, and year of death as well as gender can guide investigators to the correct identity among a large number of possible matches. Traditional morphological methods used by anthropologists to determine age are often imprecise, whereas chemical analysis of tooth dentin, such as aspartic acid racemization, has shown reproducible and more precise results. In this study, we analyzed teeth from Swedish individuals using both aspartic acid racemization and radiocarbon methodologies. The rationale behind using radiocarbon analysis is that aboveground testing of nuclear weapons during the cold war (1955-1963) caused an extreme increase in global levels of carbon-14 ((14)C), which has been carefully recorded over time. Forty-four teeth from 41 individuals were analyzed using aspartic acid racemization analysis of tooth crown dentin or radiocarbon analysis of enamel, and 10 of these were split and subjected to both radiocarbon and racemization analysis. Combined analysis showed that the two methods correlated well (R(2) = 0.66, p < 0.05). Radiocarbon analysis showed an excellent precision with an overall absolute error of 1.0 +/- 0.6 years. Aspartic acid racemization also showed a good precision with an overall absolute error of 5.4 +/- 4.2 years. Whereas radiocarbon analysis gives an estimated year of birth, racemization analysis indicates the chronological age of the individual at the time of death. We show how these methods in combination can also assist in the estimation of date of death of an unidentified victim. This strategy can be of significant assistance in forensic casework involving dead victim identification.

Stereoselective Effects of Abused "Bath Salt" Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation.

PubMed

Gannon, Brenda M; Williamson, Adrian; Suzuki, Masaki; Rice, Kenner C; Fantegrossi, William E

2016-03-01

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit "bath salts" products. MDPV is a chiral molecule, but the contribution of each enantiomer to in vivo effects in mice has not been determined. To address this, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(-)-MDPV were performed. Other mice were implanted with telemetry probes to monitor core temperature and locomotor responses elicited by racemic MDPV, S(+)-MDPV, and R(-)-MDPV under a warm (28°C) or cool (20°C) ambient temperature. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(-)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(-)-MDPV did not elicit locomotor stimulant effects at any tested dose. Interestingly, significant increases in maximum core body temperature were only observed after administration of racemic MDPV in the warm ambient environment; neither MDPV enantiomer altered core temperature at any dose tested, at either ambient temperature. These studies suggest that all three forms of MDPV induce biologic effects, but R(-)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse. U.S. Government work not protected by U.S. copyright.

Age estimation in forensic sciences: Application of combined aspartic acid racemization and radiocarbon analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alkass, K; Buchholz, B A; Ohtani, S

Age determination of unknown human bodies is important in the setting of a crime investigation or a mass disaster, since the age at death, birth date and year of death, as well as gender, can guide investigators to the correct identity among a large number of possible matches. Traditional morphological methods used by anthropologists to determine age are often imprecise, whereas chemical analysis of tooth dentin, such as aspartic acid racemization has shown reproducible and more precise results. In this paper we analyze teeth from Swedish individuals using both aspartic acid racemization and radiocarbon methodologies. The rationale behind using radiocarbonmore » analysis is that above-ground testing of nuclear weapons during the cold war (1955-1963) caused an extreme increase in global levels of carbon-14 ({sup 14}C) which have been carefully recorded over time. Forty-four teeth from 41 individuals were analyzed using aspartic acid racemization analysis of tooth crown dentin or radiocarbon analysis of enamel and ten of these were split and subjected to both radiocarbon and racemization analysis. Combined analysis showed that the two methods correlated well (R2=0.66, p < 0.05). Radiocarbon analysis showed an excellent precision with an overall absolute error of 0.6 {+-} 04 years. Aspartic acid racemization also showed a good precision with an overall absolute error of 5.4 {+-} 4.2 years. Whereas radiocarbon analysis gives an estimated year of birth, racemization analysis indicates the chronological age of the individual at the time of death. We show how these methods in combination can also assist in the estimation of date of death of an unidentified victim. This strategy can be of significant assistance in forensic casework involving dead victim identification.« less

Synthesis, Properties, and Two-Dimensional Adsorption Characteristics of [6]Hexahelicene-7-carboxylic acid.

PubMed

van der Meijden, Maarten W; Balandina, Tatyana; Ivasenko, Oleksandr; De Feyter, Steven; Wurst, Klaus; Kellogg, Richard M

2016-10-04

A convergent synthesis of racemic [6]hexahelicene-7-carboxylic acid by cross-coupling of a bicyclic and a tricyclic component is described. A metal-catalyzed ring-closure is also a fundamental component of the synthetic approach. Scanning tunneling microscopy (STM) measurements of the racemate self-assembled on Au(111) at liquid-solid interface revealed the formation of ordered racemic 2D crystals. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Racemic versus l-epinephrine aerosol in the treatment of postextubation laryngeal edema: results from a prospective, randomized, double-blind study.

PubMed

Nutman, J; Brooks, L J; Deakins, K M; Baldesare, K K; Witte, M K; Reed, M D

1994-10-01

To determine whether any advantage exists using racemic epinephrine instead of the more potent and less expensive levo(1)-epinephrine in the treatment of postextubation laryngeal edema. Prospective, double-blind, randomized study. Pediatric intensive care unit in a university teaching hospital. Twenty-eight patients with stridor during the immediate postextubation period. After extubation, patients demonstrating clinically important stridor were randomized in a double-blind fashion to receive an aerosol containing either 2.25% racemic or 1% l-epinephrine. Heart rate, respiratory rate, blood pressure, and stridor score were determined at 20, 40, and 60 mins and 4 and 8 hrs after the initial aerosol administration. Patients in both groups demonstrated significant (p < .01) reductions in stridor score after aerosol administration. No significant differences were observed between treatment groups in improvement in stridor score or the number of subsequent aerosols required. Respiratory rate decreased significantly 40 and 60 mins after l-epinephrine but not after racemic epinephrine. No significant change in heart rate or blood pressure occurred after aerosol administration in either group. These data suggest that aerosolized l-epinephrine is as effective as aerosolized racemic epinephrine in the treatment of postextubation laryngeal edema without additional adverse side effects. When dosed appropriately, l-epinephrine is a less expensive and more widely available alternative to racemic epinephrine for the treatment of postextubation laryngeal edema.

Resveratrol, 4' Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health.

PubMed

Lephart, Edwin D

2017-06-03

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4' acetoxy resveratrol (4AR), R -equol, racemic equol or S -equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R -equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S -equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R -equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4' analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R -equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin.

Fe(III)-EDDHA and -EDDHMA sorption on Ca-montmorillonite, ferrihydrite, and peat.

PubMed

Hernández-Apaolaza, L; Lucena, J J

2001-11-01

The effectiveness of Fe chelates as Fe sources and carriers in soil can be severely limited by the adsorption of Fe chelates or chelating agents in the solid phase. To study this phenomenon, well-characterized peat, Ca-montmorillonite, and ferrihydrite were used as model compounds, and the adsorption of Fe-EDDHA and Fe-EDDHMA chelates were studied. Sorption isotherms for the meso and racemic isomers of these chelates on the soil materials are described. The variability of sorption with pH in peat and ferrihydrite was also determined because both have variable surface charge at different pH values. In montmorillonite, at low concentrations, the retention of Fe from the Fe-EDDHMA chelate is greater than the one of the Fe-EDDHA chelate. As well as the concentration increased, the inverse situation occurs. The behavior of both meso and racemic isomers of chelates in contact with Ca-montmorillonite is similar. The Fe-meso-EDDHA isomer was highly adsorbed on ferrihydrite, but the racemic isomer is not significantly retained by this oxide. For Fe-EDDHMA isomers, the racemic isomer was more retained by the oxide, but a small sorption of the racemic isomer was also observed. Results suggest that Fe-EDDHA chelates were more retained in peat than Fe-EDDHMA chelates. The most retained isomer of Fe-EDDHA was the meso isomer. For Fe-EDDHMA, the adsorption was very low for both racemic and meso isomers.

Cell Cycle Target-based Therapy for Ovarian Cancer

DTIC Science & Technology

2008-09-01

induces apoptosis in quiescent ovarian cancer cells. Strong inducers of apoptosis included flufenamic acid, flurbiprofen, celebrex and finasteride ...Thus, a whole panel of NSAIDs including Aspirin, Ibuprofen, Exisulind, Acetaminophen, Naproxen, NS-398, Celecoxib, Diclofenac, Finasteride ...Naproxen, 200µM NS-398, 50µM Celecoxib, 200µM Diclofenac, 50µM Finasteride , 200µM Flufenamic acid, 40µM Meloxican, 50µM Ebselen, 20nM Flurbiprofen or

Encapsulation of Naproxen in Lipid-Based Matrix Microspheres: Characterization and Release Kinetics

PubMed Central

Bhoyar, PK; Morani, DO; Biyani, DM; Umekar, MJ; Mahure, JG; Amgaonkar, YM

2011-01-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix. PMID:21731354

Encapsulation of naproxen in lipid-based matrix microspheres: characterization and release kinetics.

PubMed

Bhoyar, P K; Morani, D O; Biyani, D M; Umekar, M J; Mahure, J G; Amgaonkar, Y M

2011-04-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix.

Vortex-assisted surfactant-enhanced emulsification microextraction based on solidification of floating organic drop combined with high performance liquid chromatography for determination of naproxen and nabumetone.

PubMed

Asadi, Mohammad; Haji Shabani, Ali Mohammad; Dadfarnia, Shayessteh; Abbasi, Bijan

2015-12-18

A novel, rapid, simple and green vortex-assisted surfactant-enhanced emulsification microextraction method based on solidification of floating organic drop was developed for simultaneous separation/preconcentration and determination of ultra trace amounts of naproxen and nabumetone with high performance liquid chromatography-fluorescence detection. Some parameters influencing the extraction efficiency of analytes such as type and volume of extractant, type and concentration of surfactant, sample pH, KCl concentration, sample volume, and vortex time were investigated and optimized. Under optimal conditions, the calibration graph exhibited linearity in the range of 3.0-300.0ngL(-1) for naproxen and 7.0-300.0ngL(-1) for nabumetone with a good coefficient of determination (R(2)>0.999). The limits of detection were 0.9 and 2.1ngL(-1). The relative standard deviations for inter- and intra-day assays were in the range of 5.8-10.1% and 3.8-6.1%, respectively. The method was applied to the determination of naproxen and nabumetone in urine, water, wastewater and milk samples and the accuracy was evaluated through recovery experiments. Copyright © 2015 Elsevier B.V. All rights reserved.

Sensitization of meningeal nociceptors: inhibition by naproxen

PubMed Central

Levy, Dan; Zhang, Xi-Chun; Jakubowski, Moshe; Burstein, Rami

2009-01-01

Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non-selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non-selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single-unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non-selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of Aδ- and C-units and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) onto the dural receptive field of Aδ- and C-unit nociceptors also reversed the neuronal hyper-responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache. PMID:18333963

Preparation and recrystallization behavior of spray-dried co-amorphous naproxen-indomethacin.

PubMed

Beyer, Andreas; Radi, Lydia; Grohganz, Holger; Löbmann, Korbinian; Rades, Thomas; Leopold, Claudia S

2016-07-01

To improve the dissolution properties and the physical stability of amorphous active pharmaceutical ingredients, small molecule stabilizing agents may be added to prepare co-amorphous systems. The objective of the study was to investigate if spray-drying allows the preparation of co-amorphous drug-drug systems such as naproxen-indomethacin and to examine the influence of the process conditions on the resulting initial sample crystallinity and the recrystallization behavior of the drug(s). For this purpose, the process parameters inlet temperature and pump feed rate were varied according to a 2(2) factorial design and the obtained samples were analyzed with X-ray powder diffractometry and Fourier-transformed infrared spectroscopy. Evaluation of the data revealed that the preparation of fully amorphous samples could be achieved depending on the process conditions. The resulting recrystallization behavior of the samples, such as the total recrystallization rate, the individual recrystallization rates of naproxen and indomethacin as well as the polymorphic form of indomethacin that was formed were influenced by these process conditions. For initially amorphous samples, it was found that naproxen and indomethacin recrystallized almost simultaneously, which supports the theory of formation of drug-drug heterodimers in the co-amorphous phase. Copyright © 2016 Elsevier B.V. All rights reserved.

Environmental fate of naproxen, carbamazepine and triclosan in wastewater, surface water and wastewater irrigated soil - Results of laboratory scale experiments.

PubMed

Durán-Álvarez, J C; Prado, B; González, D; Sánchez, Y; Jiménez-Cisneros, B

2015-12-15

Lab-scale photolysis, biodegradation and transport experiments were carried out for naproxen, carbamazepine and triclosan in soil, wastewater and surface water from a region where untreated wastewater is used for agricultural irrigation. Results showed that both photolysis and biodegradation occurred for the three emerging pollutants in the tested matrices as follows: triclosan>naproxen>carbamazepine. The highest photolysis rate for the three pollutants was obtained in experiments using surface water, while biodegradation rates were higher in wastewater and soil than in surface water. Carbamazepine showed to be recalcitrant to biodegradation both in soil and water; although photolysis occurred at a higher level than biodegradation, this compound was poorly degraded by natural processes. Transport experiments showed that naproxen was the most mobile compound through the first 30cm of the soil profile; conversely, the mobility of carbamazepine and triclosan through the soil was delayed. Biodegradation of target pollutants occurred within soil columns during transport experiments. Triclosan was not detected either in leachates or the soil in columns, suggesting its complete biodegradation. Data of these experiments can be used to develop more reliable fate-on-the-field and environmental risk assessment studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Dehalogenation Activity of Selected Fungi Toward δ-Iodo-γ-Lactone Derived from trans,trans-Farnesol.

PubMed

Gliszczyńska, Anna; Gładkowski, Witold; Świtalska, Marta; Wietrzyk, Joanna; Szumny, Antoni; Gębarowska, Elżbieta; Wawrzeńczyk, Czesław

2016-04-01

Time-course of biotransformation of racemic trans-4-((E)-4',8'-dimethylnona-3',7'-dien-1-yl)-5-iodomethyl-4-methyldihydrofuran-2-one (1) in fungal and yeast cultures was investigated. In these conditions, the substrate 1 was enantioselectively dehalogenated yielding 4-((E)-4',8'-dimethylnona-3',7'-dien-1-yl)-4-methyl-5-methylenedihydrofuran-2-one (2) and its structure was established based on the spectroscopic data. The most effective biocatalyst used was Didymosphaeria igniaria, which catalyzed the process with highest rate and enantioselectivity (ee of product = 76%). The antiproliferative activity of δ-iodo-γ-lactone 1, product of its biotransformation 2, and starting substrate (farnesol) were evaluated toward two cancer cell lines: A549 (human lung adenocarcinoma) and HL-60 (human promyelocytic leukemia). © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

Cysteine Racemization on IgG Heavy and Light Chains

PubMed Central

Zhang, Qingchun; Flynn, Gregory C.

2013-01-01

Under basic pH conditions, the heavy chain 220-light chain 214 (H220-L214) disulfide bond, found in the flexible hinge region of an IgG1, can convert to a thioether. Similar conditions also result in racemization of the H220 cysteine. Here, we report that racemization occurs on both H220 and L214 on an IgG1 with a λ light chain (IgG1λ) but almost entirely on H220 of an IgGl with a κ light chain (IgG1κ) under similar conditions. Likewise, racemization was detected at significant levels on H220 and L214 on endogenous human IgG1λ but only at the H220 position on IgG1κ. Low but measurable levels of d-cysteines were found on IgG2 cysteines in the hinge region, both with monoclonal antibodies incubated under basic pH conditions and on antibodies isolated from human serum. A simplified reaction mechanism involving reversible β-elimination on the cysteine is presented that accounts for both base-catalyzed racemization and thioether formation at the hinge disulfide. PMID:24142697

Expeditious access to unprotected racemic pyroglutamic acids.

PubMed

Isaacson, Jerry; Gilley, Cynthia B; Kobayashi, Yoshihisa

2007-05-11

A series of biologically intriguing pyroglutamic acids were synthesized in racemic form by employing indole-isonitrile and ammonium acetate in the Ugi 4-center-3-component reaction of gamma-ketoacids.

Amino Acid Racemization and the Preservation of Ancient DNA

NASA Technical Reports Server (NTRS)

Poinar, Hendrik N.; Hoss, Matthias

1996-01-01

The extent of racemization of aspartic acid, alanine, and leucine provides criteria for assessing whether ancient tissue samples contain endogenous DNA. In samples in which the D/L ratio of aspartic acid exceeds 0.08, ancient DNA sequences could not be retrieved. Paleontological finds from which DNA sequences purportedly millions of years old have been reported show extensive racemization, and the amino acids present are mainly contaminates. An exception is the amino acids in some insects preserved in amber.

Amino acid racemization dating of fossil bones, I. inter-laboratory comparison of racemization measurements

USGS Publications Warehouse

Bada, J.L.; Hoopes, E.; Darling, D.; Dungworth, G.; Kessels, H.J.; Kvenvolden, K.A.; Blunt, D.J.

1979-01-01

Enantiomeric measurements for aspartic acid, glutamic acid, and alanine in twenty-one different fossil bone samples have been carried out by three different laboratories using different analytical methods. These inter-laboratory comparisons demonstrate that D/L aspartic acid measurements are highly reproducible, whereas the enantiomeric measurements for the other amino acids show a wide variation between the three laboratories. At present, aspartic acid measurements are the most suitable for racemization dating of bone because of their superior analytical precision. ?? 1979.

Development and optimization of a new synthetic process for lorcaserin.

PubMed

Cluzeau, Jérôme; Stavber, Gaj

2018-02-15

A two-step process to synthesize racemic lorcaserin was developed from 2-(4-chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4-chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Severe toxic liver failure after acute poisoning with paracetamol, ferrous sulphate and naproxen].

PubMed

Adamek, Robert; Wilczek, Lech; Krupiński, Bogusław

2004-01-01

We present the case of 20-year-old woman intoxicated with mixed drugs, composed of paracetamol (acetaminophen), ferrous sulphate, naproxen and benzodiazepines. Acute toxic liver damage with clinical symptoms of coma resolved at the patient. Lack of the past history doesn't let to specific therapy and systemic complications. In this data we confirm, that past history, clinical symptoms and laboratory results are needed in designing a treatment strategy.

Vitamin D-Prostaglandin Interactions and Effects on Prostate Cancer

DTIC Science & Technology

2005-10-01

We propose that a combination of calcitriol and a nonselective NSAID, such as naproxen , might be a useful therapeutic and/or chemo-preventive strategy...their growth inhibitory planting clinical prostate tumors or cultured human PCa actions [25]. These results strongly suggest that the combi- cells into...flufenamnic acid, sulindac sulfide, c-fos mRNA was determined as an indicator of the biological indomethacin, naproxen , and ibuprofen. Figure 5A to D

Features of the adsoprtion of naproxen on the chiral stationary phase (S,S)-Whelk-O1 under reversed-phase conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asnin, Leonid; Gritti, Fabrice; Kaczmarski, Krzysztof

Using elution chromatography, we studied the adsorption mechanism of the Naproxen enantiomers on the chiral stationary phase (S,S)-Whelk-O1, from buffered methanol-water solutions. We propose an adsorption mechanism that assumes monolayer adsorption of the more retained enantiomer and the associative adsorption of the less retained one. The effects of the mobile phase composition on the adsorption of Naproxen are discussed. The combination of an elevated column temperature and of the use of an acidic mobile phase led to the degradation of the column and caused a major loss of its separation ability. The use of a moderately acidic mobile phase atmore » temperature slightly above ambient did not produce rapid severe damages but, nevertheless, hampered the experiments and caused a slow gradual deterioration of the column.« less

Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies

PubMed Central

McGettigan, Patricia; Henry, David

2011-01-01

Background Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. Methods and Findings We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. Conclusions This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary PMID:21980265

Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers

PubMed Central

Choi, YoonJung; Han, HyeKyung; Shin, Dongseong; Lim, Kyoung Soo; Yu, Kyung-Sang

2015-01-01

Background HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium). Subjects and methods An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO®) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration–time curve from 0 to the last measurable time (AUC0−t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study. Results Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0−t (mean ± standard deviation) for naproxen in HCP1004 were 61.67±15.16 µg/mL and 1,206.52±166.46 h·µg/mL, respectively; in VIMOVO®; these values were 61.85±14.54 µg/mL and 1,211.44±170.01 h·µg/mL, respectively. The Cmax and AUC0−t for esomeprazole in HCP1004 were 658.21±510.91 ng/mL and 1,109.11±1,111.59 h·ng/mL, respectively; for VIMOVO®, these values were 595.09±364.23 ng/mL and 1,015.12±952.98 h·ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO®) of the Cmax and AUC0−t of naproxen were 0.99 (0.94–1.06) and 1.00 (0.98–1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0−t were 0.99 (0.82–1.18) and 1.04 (0.91–1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment. Conclusion The PK of HCP1004 500/20 mg was comparable to that of VIMOVO® 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues. PMID:26257511

Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers.

PubMed

Choi, YoonJung; Han, HyeKyung; Shin, Dongseong; Lim, Kyoung Soo; Yu, Kyung-Sang

2015-01-01

HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO(®) (a marketed fixed-dose combination of naproxen and esomeprazole magnesium). An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO(®)) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration-time curve from 0 to the last measurable time (AUC0-t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study. Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0-t (mean ± standard deviation) for naproxen in HCP1004 were 61.67 ± 15.16 µg/mL and 1,206.52 ± 166.46 h · µg/mL, respectively; in VIMOVO(®); these values were 61.85 ± 14.54 µg/mL and 1,211.44 ± 170.01 h · µg/mL, respectively. The Cmax and AUC0-t for esomeprazole in HCP1004 were 658.21 ± 510.91 ng/mL and 1,109.11 ± 1,111.59 h · ng/mL, respectively; for VIMOVO(®), these values were 595.09 ± 364.23 ng/mL and 1,015.12 ± 952.98 h · ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO(®)) of the Cmax and AUC0-t of naproxen were 0.99 (0.94-1.06) and 1.00 (0.98-1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0-t were 0.99 (0.82-1.18) and 1.04 (0.91-1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment. The PK of HCP1004 500/20 mg was comparable to that of VIMOVO(®) 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

The Influence of Hydrophilic Interactions on the Sorption and Mobility of Naproxen at Environmentally-Relevant Concentrations

NASA Astrophysics Data System (ADS)

Muller, K.; Ramsburg, C. A.

2011-12-01

Managed underground storage of reclaimed wastewater is currently one viable option for meeting increasing demands on water resources, yet the attenuation of many emerging contaminants within the subsurface environment is not well understood. Pharmaceuticals are of particular concern due to the rapid increase in development and use of these compounds, observations of incomplete removal during wastewater treatment, and emerging concerns over ecosystem effects. Assessment of the subsurface attenuation of pharmaceuticals is difficult because the compounds are polar, pH-active, and present at low-concentration (ng/L). Predictions of sorption that only consider hydrophobic interactions with soil organic matter may not fully describe the extent to which reversible sequestration influences pharmaceutical attenuation. In fact, hydrophilic interactions (i.e. ion exchange, cation-induced sorption, hydrogen bonding, etc) may represent important contributions to total sorption, especially when aqueous solutes are present at low concentration. Here we assess the sorption of naproxen - an acidic pharmaceutical - to three subsurface materials using equilibrium batch experiments and 1-d column experiments. Subsurface materials evaluated include Ottawa sand (quartz with negligible organic carbon and negligible iron oxide), Aplite sand (quartz and feldspar with negligible organic carbon, 0.2% wt iron oxide), and a Hinckley series silty-sand (quartz and feldspar with 0.95% wt organic carbon, and 0.4% wt iron oxides). Sorption of naproxen to the Ottawa sand was negligible and did not result in measurable retardation when naproxen was introduced to the porous medium at a concentration of 275 ng/L. Batch experiments suggest that Aplite sand offers quantifiable interaction (52% of the mass introduced is associated with the solid phase when the aqueous concentration is 1000 ng/L and the solid to liquid ratio is 1.4:1 v/v); however, column data are indicative of markedly less interaction and retardation. Naproxen sorption to the Hinckley series material was considerable (99% of the mass introduced is associated with the solid phase when the aqueous concentration is 1000 ng/L and the solid to liquid ratio is 1:1 v/v). Predictions of naproxen sorption based upon the fraction of organic carbon and the organic-carbon partitioning coefficient (Koc) greatly underestimated the sorption observed in all experiments conducted with the Hinckley series material. Assessment of sorption under 1 mM NaH2PO4 (a sorbant with a strong affinity for hydrophilic sites) suggests that hydrophobic interactions account for approximately 45% of the total interaction. Breakthrough of naproxen (C0 ~ 20 ug/L) was substantially retarded in experiments conducted with the Hinckley material and a thermally-treated Hinckley material (negligible organic carbon). These results highlight the potential role of hydrophilic interactions during the transport and attenuation of acidic pharmaceuticals at solute concentrations typical of water reuse applications.

Oxidative kinetic resolution of racemic alcohols catalyzed by chiral ferrocenyloxazolinylphosphine-ruthenium complexes.

PubMed

Nishibayashi, Yoshiaki; Yamauchi, Akiyoshi; Onodera, Gen; Uemura, Sakae

2003-07-25

Oxidative kinetic resolution of racemic secondary alcohols by using acetone as a hydrogen acceptor in the presence of a catalytic amount of [RuCl(2)(PPh(3))(ferrocenyloxazolinylphosphine)] (2) proceeds effectively to recover the corresponding alcohols in high yields with an excellent enantioselectivity. When 1-indanol is employed as a racemic alcohol, the oxidation proceeds quite smoothly even in the presence of 0.0025 mol % of the catalyst 2 to give an optically active 1-indanol in good yield with high enantioselectivity (up to 94% ee), where turnover frequency (TOF) exceeds 80,000 h(-1). From a practical viewpoint, the kinetic resolution is investigated in a large scale, optically pure (S)-1-indanol (75 g, 56% yield, >99% ee) being obtained from racemic 1-indanol (134 g) by employing this kinetic resolution method twice.

Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

PubMed Central

Lephart, Edwin D.

2017-01-01

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4′ acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4′ analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin. PMID:28587197

Resolution of R-(-) and S-(+)- enantiomers of clenbuterol in pharmaceutical preparations and black-market products using liquid chromatography-tandem mass spectrometry.

PubMed

Velasco-Bejarano, Benjamín; Bautista, Jahir; Noguez, Ma Olivia; Camacho, Evangelina; Rodríguez, Martha E; Rodríguez, Leonardo

2017-11-01

Several banned substances are illegally used by athletes in racemic mixtures for performance enhancement. These include clenbuterol, methyl hexaneamine, methamphetamines, and amphetamines. Clenbuterol is present in a large number of doping samples from Olympic and non-Olympic athletes that have adverse analytical findings (AAFs). In some cases, the presence of these substances could be the result of consumption of meat contaminated with clenbuterol. In other cases, the origin is not clear. In this study, 27 products with racemic clenbuterol were evaluated using a new analytical methodology for the resolution of R-(-) and S-(+)-enantiomers of clenbuterol by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a chiral column in 15 min with good separation. The method developed can also be used for the analysis of other biological matrices such as urine, serum, and meat. The resolution between two peaks' (R s ) value obtained using chromatographic data was 1.03. Both clenbuterol enantiomers were present in all products analyzed and the ratio was nearly 1. The origin of the product was not important for determining the presence of one or both enantiomers. All products displayed a 50:50 ratio of clenbuterol enantiomers. To the best of our knowledge, clenbuterol ratio determination of a large number of pharmaceutical preparations and black-market products has not been reported previously. The information shown could be used by national anti-doping organizations and the athletes with AAFs attributed to clenbuterol. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Amino acids in modern and fossil woods

NASA Technical Reports Server (NTRS)

Lee, C.; Bada, J. L.; Peterson, E.

1976-01-01

The amino acid composition and the extent of racemization in several modern and fossil woods are reported. The method of analysis is described, and data are presented on the total amino acid concentration, the amino acid ratios, and the enantiomeric ratios in each sample. It is found that the amino acid concentration per gram of dry wood decreases with age of the sample, that the extent of racemization increases with increasing age, and that the amounts of aspartic acid, threonine, and serine decrease relative to valine with increasing age. The relative racemization rates of amino acids in wood, bone, and aqueous solution are compared, and it is shown that racemization in wood is much slower than in bone or aqueous solution. Racemization results for woods from the Kalambo Falls area of Zambia are used to calculate a minimum age of 110,000 years for the transition between the Sangoan and Acheulian industries at that site. This result is shown to be consistent with numerous radiometric dates for older Acheulian sites in Africa and to compare well with geologically inferred dates for the beginning of the Eemian and the end of the Acheulian industry in southern Africa.

Pharmacokinetics of ketamine and norketamine enantiomers after racemic or S-ketamine IV bolus administration in dogs during sevoflurane anaesthesia.

PubMed

Romagnoli, Noemi; Bektas, Rima N; Kutter, Annette P; Barbarossa, Andrea; Roncada, Paola; Hartnack, Sonja; Bettschart-Wolfensberger, Regula

2017-06-01

The aims of this study were to measure plasma levels of R- and S-ketamine and their major metabolites R- and S-norketamine following single intravenous bolus administration of racemic or S-ketamine in sevoflurane anaesthetised dogs and to calculate the relevant pharmacokinetic profiles. Six adult healthy beagle dogs were used in the study. An intravenous bolus of 4mg/kg racemic ketamine (RS-KET) or 2mg/kg S-ketamine (S-KET) was administered, with a three-weeks washout period between treatments. Venous blood samples were collected at fixed times until 900min and R- and S-ketamine as well as R- and S-norketamine plasma levels determined by liquid chromatography coupled with tandem mass spectrometry. Cardiovascular parameters were recorded during the anaesthesia until 240min. All dogs recovered well from anaesthesia. No statistical differences between groups were detected in any cardiovascular parameter. The pharmacokinetics of S-ketamine did not differ when injected intravenously alone or as part of the racemic mixture in dogs anaesthetised with sevoflurane. Following racemic ketamine, the area under the curve of R-norketamine was statistically higher than the one of S-norketamine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of aquatic plants for removing polar microcontaminants: a microcosm experiment.

PubMed

Matamoros, Víctor; Nguyen, Loc Xuan; Arias, Carlos A; Salvadó, Victòria; Brix, Hans

2012-08-01

Microcosm wetland systems (5 L containers) planted with Salvinia molesta, Lemna minor, Ceratophyllum demersum, and Elodea canadensis were investigated for the removal of diclofenac, triclosan, naproxen, ibuprofen, caffeine, clofibric acid and MCPA. After 38 days of incubation, 40-99% of triclosan, diclofenac, and naproxen were removed from the planted and unplanted reactors. In covered control reactors no removal was observed. Caffeine and ibuprofen were removed from 40% to 80% in planted reactors whereas removals in control reactors were much lower (2-30%). Removal of clofibric acid and MCPA were negligible in both planted and unplanted reactors. The findings suggested that triclosan, diclofenac, and naproxen were removed predominantly by photodegradation, whereas caffeine and naproxen were removed by biodegradation and/or plant uptake. Pseudo-first-order removal rate constants estimated from nonlinear regressions of time series concentration data were used to describe the contaminant removals. Removal rate constants ranged from 0.003 to 0.299 d(-1), with half-lives from 2 to 248 days. The formation of two major degradation products from ibuprofen, carboxy-ibuprofen and hydroxy-ibuprofen, and a photodegradation product from diclofenac, 1-(8-Chlorocarbazolyl)acetic acid, were followed as a function of time. This study emphasizes that plants contribute to the elimination capacity of microcontaminants in wetlands systems through biodegradation and uptake processes. Copyright © 2012 Elsevier Ltd. All rights reserved.

An efficient approach to selective electromembrane extraction of naproxen by means of molecularly imprinted polymer-coated multi-walled carbon nanotubes-reinforced hollow fibers.

PubMed

Tahmasebi, Zeinab; Davarani, Saied Saeed Hosseiny; Asgharinezhad, Ali Akbar

2016-10-28

In this work, a novel microextraction technique using molecularly imprinted polymer-coated multi-walled carbon nanotubes (MIP-MWCNTs) in electromembrane extraction (EME) procedure is described. The method in combination with HPLC-UV was utilized to determine naproxen, as an acidic model drug, in urine, plasma and wastewater samples. For this purpose, MIP-MWCNTs were placed in the pores of polypropylene hollow fiber. The MIP-MWCNTs-EME method has the advantages of high selectivity and cleanup of MIP along with high enrichment ability of the EME in a single step extraction. Continuing with the research, optimization of the factors affecting the migration of naproxen from sample solutions to MIP-MWCNTs sites and then into the lumen of hollow fiber was explored. Under the optimized conditions, the limit of detection (LOD) of the developed method was calculated to be 0.3μgL -1 . All relative standard deviations (RSDs) were lower than 3%. Linearity of the method was obtained within the range of 1-1000μgL -1 with the coefficient of determination (r 2 ) being higher than 0.999. Under the optimized conditions, an extraction recovery of 66% was obtained, which corresponded to a preconcentration factor of 88. Finally, the developed method was satisfactorily used to determine naproxen in urine, plasma and wastewater samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Age estimation of living Indian individuals based on aspartic acid racemization from tooth biopsy specimen

PubMed Central

Rastogi, Manu; Logani, Ajay; Shah, Naseem; Kumar, Abhishek; Arora, Saurabh

2017-01-01

Background: Age estimation in living individuals is imperative to amicably settle civil and criminal disputes. A biochemical method based on amino acid racemization was evaluated for age estimation of living Indian individuals. Design: Caries-free maxillary/mandibular premolar teeth (n = 90) were collected from participants with age proof documents and divided into predefined nine age groups. Materials and Methods: Dentine biopsy from the labial aspect of the tooth crown was taken with an indigenously developed microtrephine. The samples were processed and subjected to gas chromatography. Dextrorotatory:levorotatory ratios were calculated, and a regression equation was formulated. Results: Across all age groups, an error of 0 ± 4 years between protein racemization age and chronological age was observed. Conclusion: Aspartic acid racemization from dentine biopsy samples could be a viable and accurate technique for age estimation of living individuals who have attained a state of skeletal maturity. PMID:29263613

Age estimation by amino acid racemization in human teeth.

PubMed

Ohtani, Susumu; Yamamoto, Toshiharu

2010-11-01

When an unidentified body is found, it is essential to establish the personal identity of the body in addition to investigating the cause of death. Identification is one of the most important functions of forensic dentistry. Fingerprint, dental, and DNA analysis can be used to accurately identify a body. However, if no information is available for identification, age estimation can contribute to the resolution of a case. The authors have been using aspartic acid racemization rates in dentin (D-aspartic acid/L-aspartic acid: D/L Asp) as an index for age estimation and have obtained satisfactory results. We report five cases of age estimation using the racemization method. In all five cases, estimated ages were accurate within a range ±3 years. We conclude that the racemization method is a reliable and practical method for estimating age. © 2010 American Academy of Forensic Sciences.

Phosphine-Catalyzed Doubly Stereoconvergent γ-Additions of Racemic Heterocycles to Racemic Allenoates: The Catalytic Enantioselective Synthesis of Protected α,α-Disubstituted α-Amino Acid Derivatives.

PubMed

Kalek, Marcin; Fu, Gregory C

2015-07-29

Methods have recently been developed for the phosphine-catalyzed asymmetric γ-addition of nucleophiles to readily available allenoates and alkynoates to generate useful α,β-unsaturated carbonyl compounds that bear a stereogenic center in either the γ or the δ position (but not both) with high stereoselectivity. The utility of this approach would be enhanced considerably if the stereochemistry at both termini of the new bond could be controlled effectively. In this report, we describe the achievement of this objective, specifically, that a chiral phosphepine can catalyze the stereoconvergent γ-addition of a racemic nucleophile to a racemic electrophile; through the choice of an appropriate heterocycle as the nucleophilic partner, this new method enables the synthesis of protected α,α-disubstituted α-amino acid derivatives in good yield, diastereoselectivity, and enantioselectivity.

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single Enantiomer (+)-Mefloquine Compared with Racemic Mefloquine in Healthy Persons

PubMed Central

Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

2010-01-01

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (−) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (−)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted. PMID:21118921

Diazepam Is No Better Than Placebo When Added to Naproxen for Acute Low Back Pain.

PubMed

Friedman, Benjamin W; Irizarry, Eddie; Solorzano, Clemencia; Khankel, Nauman; Zapata, Jennifer; Zias, Eleftheria; Gallagher, E John

2017-08-01

Low back pain causes more than 2.5 million visits to US emergency departments (EDs) annually. Low back pain patients are often treated with nonsteroidal anti-inflammatory drugs and benzodiazepines. The former is an evidence-based intervention, whereas the efficacy of the latter has not been established. We compare pain and functional outcomes 1 week and 3 months after ED discharge among patients randomized to a 1-week course of naproxen+diazepam versus naproxen+placebo. This was a randomized, double-blind, comparative efficacy clinical trial conducted in an urban health care system. Patients presenting with acute, nontraumatic, nonradicular low back pain of no more than a duration of 2 weeks were eligible for enrollment immediately before discharge from an ED if they had a score greater than 5 on the Roland-Morris Disability Questionnaire, a validated 24-item inventory of functional impairment caused by low back pain. Higher scores on the questionnaire indicate greater functional disability. The primary outcome in the trial was improvement in the score between ED discharge and 1 week later. Secondary outcomes included pain intensity 1 week and 3 months after ED discharge, as measured on a 4-point descriptive scale (severe, moderate, mild, and none). All patients were given 20 tablets of naproxen 500 mg, to be taken twice a day as needed for low back pain. Additionally, patients were randomized to receive either 28 tablets of diazepam 5 mg or identical placebo, to be received as 1 or 2 tablets every 12 hours as needed for low back pain. All patients received a standardized 10-minute low back pain educational session before discharge. Using a between-group mean difference of 5 Roland-Morris Disability Questionnaire points, a previously validated threshold for clinical significance, we calculated the need for at least 100 patients with primary outcome data. Enrollment began in June 2015 and continued for 9 months. Five hundred forty-five patients were screened for eligibility. One hundred fourteen patients met selection criteria and were randomized. Baseline demographic characteristics were not substantially different between the 2 groups. One hundred twelve patients (98%) provided 1-week outcome data. The mean Roland-Morris Disability Questionnaire score of patients randomized to naproxen+diazepam improved by 11 (95% confidence interval [CI] 9 to 13), as did the mean score of patients randomized to naproxen+placebo (11; 95% CI 8 to 13). At 1-week follow-up, 18 of 57 diazepam patients (32%; 95% CI 21% to 45%) reported moderate or severe low back pain versus 12 of 55 placebo patients (22%; 95% CI 13% to 35%). At 3-month follow-up, 6 of 50 diazepam patients (12%; 95% CI 5% to 24%) reported moderate or severe low back pain versus 5 of 53 placebo patients (9%; 95% CI 4% to 21%). Adverse events were reported by 12 of 57 diazepam patients (21%; 95% CI 12% to 33%) and 8 of 55 placebo patients (15%; 95% CI 7% to 26%). Among ED patients with acute, nontraumatic, nonradicular low back pain, naproxen+diazepam did not improve functional outcomes or pain compared with naproxen+placebo 1 week and 3 months after ED discharge. Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Pharmaceutical-grade albumin: impaired drug-binding capacity in vitro

PubMed Central

Olsen, Harald; Andersen, Anders; Nordbø, Arve; Kongsgaard, Ulf E; Børmer, Ole P

2004-01-01

Background Albumin is the most abundant protein in blood plasma, and due to its ligand binding properties, serves as a circulating depot for endogenous and exogenous (e.g. drugs) compounds. Hence, the unbound drug is the pharmacologically active drug. Commercial human albumin preparations are frequently used during surgery and in critically ill patients. Recent studies have indicated that the use of pharmaceutical-grade albumin is controversial in critically ill patients. In this in vitro study we investigated the drug binding properties of pharmaceutical-grade albumins (Baxter/Immuno, Octapharma, and Pharmacia & Upjohn), native human serum, and commercially available human serum albumin from Sigma Chemical Company. Methods The binding properties of the various albumin solutions were tested in vitro by means of ultrafiltration. Naproxen, warfarin, and digitoxin were used as ligands. HPLC was used to quantitate the total and free drug concentrations. The data were fitted to a model of two classes of binding sites for naproxen and warfarin and one class for digitoxin, using Microsoft Excel and Graphpad Prism. Results The drugs were highly bound to albumin (95–99.5%). The highest affinity (lowest K1) was found with naproxen. Pharmaceutical-grade albumin solutions displayed significantly lower drug-binding capacity compared to native human serum and Sigma albumin. Thus, the free fraction was considerably higher, approximately 40 times for naproxen and 5 and 2 times for warfarin and digitoxin, respectively. The stabilisers caprylic acid and N-acetyl-DL-tryptophan used in the manufacturing procedure seem to be of importance. Adding the stabilisers to human serum and Sigma albumin reduced the binding affinity whereas charcoal treatment of the pharmaceutical-grade albumin from Octapharma almost restored the specific binding capacity. Conclusion This in vitro study demonstrates that the specific binding for warfarin and digitoxin is significantly reduced and for naproxen no longer detectable in pharmaceutical-grade albumin. It further shows that the addition of stabilisers may be of major importance for this effect. PMID:15046641

The use of combination therapies in the acute management of migraine.

PubMed

Krymchantowski, Abouch Valenty

2006-09-01

Migraine is a highly prevalent neurological disorder with multiple peripheral and central mechanisms. Targeting a single mechanism for treating individual attacks as well as for performing the prophylaxis has been shown to be only partially effective. Recently, the role of combining agents for acute migraine treatment has gained attention and the combination of a triptan plus a non-steroidal anti-inflammatory drug (NSAID) has demonstrated better efficacy. This review focuses on the fundamentals of treating migraine attacks with two or more agents, and emphasizes the characteristics of the recently approved fixed combination sumatriptan-naproxen. A PubMed search using the terms "migraine", "treatment", "acute", "triptans", "non-steroidal anti-inflammatory drugs", "sumatriptan", "naproxen", and "combination" was used. In addition, abstracts presented in the major meetings of the American Headache and the International Headache Societies along with the American Academy of Neurology were also evaluated. Although most of the few studies encountered were not controlled, there is a clear trend for better efficacy in combining triptans with NSAID. Additionally, the results of two recent large and controlled studies using fixed combinations of sumatriptan (50 mg and 85 mg) with 500 mg naproxen sodium confirm the initial observations of the clear superiority of this combination over the use of each agent alone. The differences in the endpoints 24-hour pain-relief response as well as pain-free and pain-relief parameters at 2-hour time-point are the most noticeable efficacy measures. Tolerability was not different between studied drugs. Combining triptans with NSAID and other agents for the acute treatment of migraine suggests better outcome efficacy measures than the use of single agents. The fixed combination of sumatriptan and naproxen sodium offers improved 2-hour and 24-hour benefits over monotherapy with each one these options. Recently issued FDA approval for marketing the combination (sumatriptan 50 mg-naproxen 500 mg) emphasizes the usefulness and safety of this new treatment for migraine attacks.

Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis.

PubMed

Levy, Robert; Khokhlov, Alexander; Kopenkin, Sergey; Bart, Boris; Ermolova, Tatiana; Kantemirova, Raiasa; Mazurov, Vadim; Bell, Marjorie; Caldron, Paul; Pillai, Lakshmi; Burnett, Bruce

2010-12-01

twice-daily flavocoxid, a cyclooxygenase and 5-lipoxygenase inhibitor with potent antioxidant activity of botanical origin, was evaluated for 12 weeks in a randomized, double-blind, active-comparator study against naproxen in 220 subjects with moderate-severe osteoarthritis (OA) of the knee. As previously reported, both groups noted a significant reduction in the signs and symptoms of OA with no detectable differences in efficacy between the groups when the entire intent-to-treat population was considered. This post-hoc analysis compares the efficacy of flavocoxid to naproxen in different subsets of patients, specifically those related to age, gender, and disease severity as reported at baseline for individual response parameters. in the original randomized, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. In this subgroup analysis, primary outcome measures including the Western Ontario and McMaster Universities OA index and subscales, timed walk, and secondary efficacy variables, including investigator global assessment for disease and global response to treatment, subject visual analog scale for discomfort, overall disease activity, global response to treatment, index joint tenderness and mobility, were evaluated for differing trends between the study groups. subset analyses revealed some statistically significant differences and some notable trends in favor of the flavocoxid group. These trends became stronger the longer the subjects continued on therapy. These observations were specifically noted in older subjects (>60 years), males and in subjects with milder disease, particularly those with lower subject global assessment of disease activity and investigator global assessment for disease and faster walking times at baseline. initial analysis of the entire intent-to-treat population revealed that flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee. Detailed analyses of subject subsets demonstrated distinct trends in favor of flavocoxid for specific groups of subjects.

Use of DMPC and DSPC lipids for verapamil and naproxen permeability studies by PAMPA.

PubMed

Alvarez-Figueroa, M J; Contreras-Garrido, B C; Soto-Arriaza, M A

2015-04-01

Verapamil and naproxen Parallel Artificial Membrane Permeability Assay (PAMPA) permeability was studied using lipids not yet reported for this model in order to facilitate the quantification of drug permeability. These lipids are 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and an equimolar mixture of DMPC/DSPC, both in the absence and in the presence of 33.3 mol% of cholesterol. PAMPA drug permeability using the lipids mentioned above was compared with lecithin-PC. The results show that verapamil permeability depends on the kind of lipid used, in the order DMPC > DMPC/DSPC > DSPC. The permeability of the drugs was between 1.3 and 3.5-times larger than those obtained in lecithin-PC for all the concentrations of the drug used. Naproxen shows similar permeability than verapamil; however, the permeability increased with respect to lecithin-PC only when DMPC and DMPC/DSPC were used. This behavior could be explained by a difference between the drug net charge at pH 7.4. On the other hand, in the presence of cholesterol, verapamil permeability increases in all lipid systems; however, the relative verapamil permeability respect to lecithin-PC did not show any significant increase. This result is likely due to the promoting effect of cholesterol, which is not able to compensate for the large increase in verapamil permeability observed in lecithin-PC. With respect to naproxen, its permeability value and relative permeability respect lecithin-PC not always increased in the presence of cholesterol. This result is probably attributed to the negative charge of naproxen rather than its molecular weight. The lipid systems studied have an advantage in drug permeability quantification, which is mainly related to the charge of the molecule and not to its molecular weight or to cholesterol used as an absorption promoter.

Influence of the cooling rate and the blend ratio on the physical stability of co-amorphous naproxen/indomethacin.

PubMed

Beyer, Andreas; Grohganz, Holger; Löbmann, Korbinian; Rades, Thomas; Leopold, Claudia S

2016-12-01

Co-amorphization represents a promising approach to increase the physical stability and dissolution rate of amorphous active pharmaceutical ingredients (APIs) as an alternative to polymer glass solutions. For amorphous and co-amorphous systems, it is reported that the preparation method and the blend ratio play major roles with regard to the resulting physical stability. Therefore, in the present study, co-amorphous naproxen-indomethacin (NAP/IND) was prepared by melt-quenching at three different cooling rates and at ten different NAP/IND blend ratios. The samples were analyzed using XRPD and FTIR, both directly after preparation and during storage to investigate their physical stabilities. All cooling methods led to fully amorphous samples, but with significantly different physical stabilities. Samples prepared by fast cooling had a higher degree of crystallinity after 300d of storage than samples prepared by intermediate cooling and slow cooling. Intermediate cooling was subsequently used to prepare co-amorphous NAP/IND at different blend ratios. In a previous study, it was postulated that the equimolar (0.5:0.5) co-amorphous blend of NAP/IND is most stable. However, in the present study the physically most stable blend was found for a NAP/IND ratio of 0.6:0.4, which also represents the eutectic composition of the crystalline NAP/γ-IND system. This indicates that the eutectic point may be of major importance for the stability of binary co-amorphous systems. Slight deviations from the optimal naproxen molar fraction led to significant recrystallization during storage. Either naproxen or γ-indomethacin recrystallized until a naproxen molar fraction of about 0.6 in the residual co-amorphous phase was reached again. In conclusion, the physical stability of co-amorphous NAP/IND may be significantly improved, if suitable preparation conditions and the optimal phase composition are chosen. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of raceme-localized supplemental light on soybean reproductive abscission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myers, R.L.; Brun, W.A.; Brenner, M.L.

The percentage of soybean (Glycine max (L.) Merr.) reproductive structures that abscise is a potentially important yield factor. To better understand the involvement of light in the abscission of reproductive structures, a series of in vitro raceme-culture and growth-chamber experiments were conducted. In the in vitro raceme-culture experiments, racemes with four to six flowers at or past anthesis were excised from the soybean plant (genotype IX93-100), embedded in a complete nutrient, solid agar medium, and subjected to various light treatments. A series of three experiments indicated that the racemes contain a photoreceptor, possibly phytochrome, capable of regulating sucrose accumulation. Inmore » each of the growth chamber studies, supplemental light was supplied directly to individual soybean flowers via fiber optic light guides. The light source increased the photon flux to the flowers by 10-fold. The first growth chamber experiment showed that flowers receiving supplemental light were more intense sinks for /sup 14/C-sucrose than were controls (intensity value of 1.0 vs 0.4 x 10/sup -7/, intensity = (dps of flower/dps of raceme)/(kg dry wt of flower)). In a second study, 42% of flowers treated with supplemental light set pods, while only 26% of control flowers set pods. A third experiment showed that red supplemental light produced 55% fruit set, compared to 41% set for far-red light, and 35% for controls. These experiments indicate that both photoassimilate accumulation and abscission in young soybean reproductive structures may be regulated by light quality.« less

Fenoterol enantiomers do not possess beneficial therapeutic properties of their racemic mixture in the rat model of post myocardial infarction dilated cardiomyopathy.

PubMed

Ahmet, Ismayil; Turner, Tia; Lakatta, Edward G; Talan, Mark I

2012-04-01

A salutary effect of β(2) adrenergic receptor (AR) agonist, fenoterol has been demonstrated in a rat model of post-myocardial infarction (MI) dilated cardiomyopathy (DCM). Recent reports on single cardiomyocyte experiments suggested that out of two enantiomers, RR and SS, that constitute a racemic mixture of fenoterol, only RR-enantiomer is an active component that might be a promising new drug for treatment of chronic heart failure. The objective of this study was to compare the efficacy of the RR enantiomer of fenoterol with efficacy of racemic fenoterol, and SS, an inactive enantiomer, in whole animal experimental models of DCM. Two weeks after induction of MI by permanent ligation of the anterior descending coronary artery early cardiac remodeling and MI size were assessed via echocardiography and rats were divided into treatment groups. Treatment (placebo, racemic fenoterol, RR- or SS-enantiomers of fenoterol) continued for 6 months while progression of DCM was followed by serial echocardiography. Compared with untreated rats, rats treated with racemic fenoterol demonstrated previously described attenuation of LV remodeling, functional decline and the arrest of the MI expansion during the first 2 months of treatment. On the contrary, the treatment with either RR-, or with SS-enantiomers of fenoterol was completely ineffective. The conclusion drawn on the basis of previous experiments with single cardiomyocytes that RR-enantiomer of fenoterol represents an active component of racemic fenoterol and can be further investigated as a new drug for treatment of chronic heart failure was not confirmed in the whole animal model of DCM.

Enantiomer fractions of chlordane components in sediment from U.S. Geological Survey sites in lakes and rivers

USGS Publications Warehouse

Ulrich, E.M.; Foreman, W.T.; Van Metre, P.C.; Wilson, J.T.; Rounds, S.A.

2009-01-01

Spatial, temporal, and sediment-type trends in enantiomer signatures were evaluated for cis- and trans-chlordane (CC, TC) in archived core, suspended, and surficial-sediment samples from six lake, reservoir, and river sites across the United States. The enantiomer fractions (EFs) measured in these samples are in good agreement with those reported for sediment, soil, and air samples in previous studies. The chlordane EFs were generally close to the racemic value of 0.5, with CC values ranging from 0.493 to 0.527 (usually >0.5) and TC values from 0.463 to 0.53 (usually <0.5). EF changes with core depth were detected for TC and CC in some cores, with the most non-racemic values near the top of the core. Surficial and suspended sediments generally have EF values similar to the top core layers but are often more non-racemic, indicating that enantioselective degradation is occurring before soils are eroded and deposited into bottom sediments. We hypothesize that rapid losses (desorption or degradation) from suspended sediments of the more bioavailable chlordane fraction during transport and initial deposition could explain the apparent shift to more racemic EF values in surficial and top core sediments. Near racemic CC and TC in the core profiles suggest minimal alteration of chlordane from biotic degradation, unless it is via non-enantioselective processes. EF values for the heptachlor degradate, heptachlor epoxide (HEPX), determined in surficial sediments from one location only were always non-racemic (EF ??? 0.66), were indicative of substantial biotic processing, and followed reported EF trends.

Resolving the Magnetic Asymmetry of the Inner Space in Self-assembled Dimeric Capsules Based on Tetraurea-calix[4]pyrrole Components.

PubMed

Espelt, Mónica; Aragay, Gemma; Ballester, Pablo

2015-01-01

The encapsulation of N,N, N',N'-tetramethyl-1,5-pentanediamine-N,N'-dioxide 2 in a non-chiral capsular assembly formed by dimerization of tetraurea-calix[4]pyrrole 1a produced the observation of the N-methyl groups of the encapsulated guest as two separated singlets resonating highly upfield in the (1)H NMR spectrum. In order to clarify the origin of the observed signal splitting we assembled and studied a series of structurally related dimeric capsules. We used the tetraurea-calix[4]pyrrole 1a , the enantiomerically pure tetraurea-calix[4] pyrrole R-1b and the tetraurea-bisloop calix[4]pyrrole 1c as components of the produced assemblies. The (1)H NMR spectra of the assembled encapsulation complexes with bis-N-oxide 2 evidenced diverse splitting patterns of the N-methyl groups. In addition, 2D EXSY/ROESY NMR experiments revealed the existence of chemical exchange processes involving the separated methyl signals of the encapsulated guest. The capsular assemblies were mainly stabilized by a belt of eight head-to-tail hydrogen-bonded urea groups. The interconversion between the two senses of rotation of the unidirectionally oriented urea groups was slow on the (1)H NMR timescale. These characteristics determined the appearance of a new asymmetry element (supramolecular conformational chirality) in the assemblies that accounted for some of the magnetic asymmetries featured by the capsule's inner space. The racemization of the supramolecular chirality element was fast on the EXSY timescale and produced the chemical exchange processes detected for the encapsulation complexes.

Enantioseparation and optical rotation of flavor-relevant 4-alkyl-branched fatty acids.

PubMed

Eibler, Dorothee; Vetter, Walter

2017-07-07

Short chain 4-alkyl-branched fatty acids are character impact compounds of the flavor of sheep and goat milk and meat. Due to their methyl or ethyl branches these volatile fatty acids are chiral, and both enantiomers are characterized by different aroma intensities. Recently, it was found that 4-methyloctanoic acid (4-Me-8:0), 4-ethyloctanoic acid (4-Et-8:0), and 4-methylnonanoic acid (4-Me-9:0) are enantiopure in goat and sheep samples, if present. Here we generated enantiopure or enantioenriched standards from racemates by means of (R)-selective esterification with lipase B and verified that 4-Me-8:0, 4-Et-8:0 and 4-Me-9:0 were (R)-enantiopure in these tissues. Determination of the optical rotation and [α] D value was carried out to show that (R)-4-Et-8:0 is dextrorotary and to verify the literature values of (R)-4-methyl-branched fatty acids. The elution order of free acids and the methyl and ethyl esters of 4-Me-8:0, 4-Et-8:0, 4-Me-9:0 and 4-methylhexanoic acid (4-Me-6:0) enantiomers was investigated on different chiral columns as well as the (-)-menthyl ester by indirect enantiomer separation on an ionic liquid phase. Different chiral recognition processes were suggested for free acid and esters of 4-Me-8:0 and 4-Me-9:0 on the one hand (decisive: 4-alkyl branch) compared to 4-Me-6:0 on the other hand (decisive: branch on antepenultimate carbon). Copyright © 2017 Elsevier B.V. All rights reserved.

An integrated experimental and computational approach for characterizing the kinetics and mechanism of triadimefon racemization.

EPA Science Inventory

Enantiomers of chiral molecules commonly exhibit differing pharmacokinetics and toxicities, which can introduce significant uncertainty when evaluating biological and environmental fates and potential risks to humans and the environment. However, racemization (the irreversible tr...

Sorption of diclofenac and naproxen onto MWCNT in model wastewater treated by H2O2 and/or UV.

PubMed

Czech, Bożena; Oleszczuk, Patryk

2016-04-01

The application of oxidation processes such as UV and/or H2O2 will change the physicochemical properties of carbon nanotubes (CNT). It may affect the sorption affinity of CNT to different contaminants and then affect their fate in the environment. In the present study the adsorption of two very common used pharmaceuticals (diclofenac and naproxen) onto CNT treated by UV, H2O2 or UV/H2O2 was investigated. Four different adsorption models (Freundlich, Langmuir, Temkin, Dubinin-Radushkevich) were tested. The best fitting of experimental data was observed for Freundlich or Langmuir model. The significant relationships between Q calculated from Langmuir model with O% and dispersity were observed. Kinetics of diclofenac and naproxen followed mainly pseudo-second order indicating for chemisorption limiting step of adsorption. The data showed that the mechanism of sorption was physical or chemical depending on the type of CNT modification. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Huiwen; Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701; Mollica, Molly Y.

A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1)more » by 20–30% and fibronectin by 25–44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (∼ 56%) the activity of β1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion. -- Highlights: ► NONO-naproxen, a novel nitric oxide-releasing NSAID, was synthesized. ► NONO-NSAIDs, but not their parent NSAIDs, reduced melanoma adhesion. ► NONO-naproxen, but not NONO-aspirin and NSAIDs, reduced activity of β1 integrin.« less

Occurrence of naproxen, ibuprofen, and diclofenac residues in wastewater and river water of KwaZulu-Natal Province in South Africa.

PubMed

Madikizela, Lawrence Mzukisi; Chimuka, Luke

2017-07-01

The present paper reports a detailed study that is based on the monitoring of naproxen, ibuprofen, and diclofenac in Mbokodweni River and wastewater treatment plants (WWTPs) located around the city of Durban in KwaZulu-Natal Province of South Africa. Target compounds were extracted from water samples using a multi-template molecularly imprinted solid-phase extraction prior to separation and quantification on a high-performance liquid chromatography equipped with photo diode array detector. The analytical method yielded the detection limits of 0.15, 1.00, and 0.63 μg/L for naproxen, ibuprofen, and diclofenac, respectively. Solid-phase extraction method was evaluated for its performance using deionized water samples that were spiked with 5 and 50 μg/L of target compounds. Recoveries were greater than 80% for all target compounds with RSD values in the range of 4.1 to 10%. Target compounds were detected in most wastewater and river water samples with ibuprofen being the most frequently detected pharmaceutical. Maximum concentrations detected in river water for naproxen, ibuprofen, and diclofenac were 6.84, 19.2, and 9.69 μg/L, respectively. The concentrations of target compounds found in effluent and river water samples compared well with some studies. The analytical method employed in this work is fast, selective, sensitive, and affordable; therefore, it can be used routinely to evaluate the occurrence of acidic pharmaceuticals in South African water resources.

Fenoterol Enantiomers do not Possess Beneficial Therapeutic Properties of Their Racemic Mixture in the Rat Model of Post Myocardial Infarction Dilated Cardiomyopathy

PubMed Central

Ahmet, Ismayil; Turner, Tia; Lakatta, Edward G.; Talan, Mark I.

2015-01-01

Purpose A salutary effect of β2 adrenergic receptor (AR) agonist, fenoterol has been demonstrated in a rat model of post-myocardial infarction (MI) dilated cardiomyopathy (DCM). Recent reports on single cardiomyocyte experiments suggested that out of two enantiomers, RR and SS, that constitute a racemic mixture of fenoterol, only RR-enantiomer is an active component that might be a promising new drug for treatment of chronic heart failure. The objective of this study was to compare the efficacy of the RR enantiomer of fenoterol with efficacy of racemic fenoterol, and SS, an inactive enantiomer, in whole animal experimental models of DCM. Methods Two weeks after induction of MI by permanent ligation of the anterior descending coronary artery early cardiac remodeling and MI size were assessed via echocardiography and rats were divided into treatment groups. Treatment (placebo, racemic fenoterol, RR- or SS-enantiomers of fenoterol) continued for 6 months while progression of DCM was followed by serial echocardiography. Results Compared with untreated rats, rats treated with racemic fenoterol demonstrated previously described attenuation of LV remodeling, functional decline and the arrest of the MI expansion during the first two months of treatment. On the contrary, the treatment with either RR-, or with SS-enantiomers of fenoterol was completely ineffective. Conclusion The conclusion drawn on the basis of previous experiments with single cardiomyocytes that RR-enantiomer of fenoterol represents an active component of racemic fenoterol and can be further investigated as a new drug for treatment of chronic heart failure was not confirmed in the whole animal model of DCM. PMID:22328006

Age Estimation in Forensic Sciences

PubMed Central

Alkass, Kanar; Buchholz, Bruce A.; Ohtani, Susumu; Yamamoto, Toshiharu; Druid, Henrik; Spalding, Kirsty L.

2010-01-01

Age determination of unknown human bodies is important in the setting of a crime investigation or a mass disaster because the age at death, birth date, and year of death as well as gender can guide investigators to the correct identity among a large number of possible matches. Traditional morphological methods used by anthropologists to determine age are often imprecise, whereas chemical analysis of tooth dentin, such as aspartic acid racemization, has shown reproducible and more precise results. In this study, we analyzed teeth from Swedish individuals using both aspartic acid racemization and radiocarbon methodologies. The rationale behind using radiocarbon analysis is that aboveground testing of nuclear weapons during the cold war (1955–1963) caused an extreme increase in global levels of carbon-14 (14C), which has been carefully recorded over time. Forty-four teeth from 41 individuals were analyzed using aspartic acid racemization analysis of tooth crown dentin or radiocarbon analysis of enamel, and 10 of these were split and subjected to both radiocarbon and racemization analysis. Combined analysis showed that the two methods correlated well (R2 = 0.66, p < 0.05). Radiocarbon analysis showed an excellent precision with an overall absolute error of 1.0 ± 0.6 years. Aspartic acid racemization also showed a good precision with an overall absolute error of 5.4 ± 4.2 years. Whereas radiocarbon analysis gives an estimated year of birth, racemization analysis indicates the chronological age of the individual at the time of death. We show how these methods in combination can also assist in the estimation of date of death of an unidentified victim. This strategy can be of significant assistance in forensic casework involving dead victim identification. PMID:19965905

Mucosal healing effect of mesalazine granules in naproxen-induced small bowel enteropathy

PubMed Central

Rácz, István; Szalai, Milán; Kovács, Valéria; Regőczi, Henriett; Kiss, Gyöngyi; Horváth, Zoltán

2013-01-01

AIM: To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE). METHODS: This was a single center, non-randomized, open-label, uncontrolled pilot study, using the PillCam SB CE system with RAPID 5 software. The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury. Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened. Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study. During this treatment period, 3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole. At the end of the 4-wk combined treatment period, a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results. The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment. RESULTS: A total of 18 patients (16 females), ranging in age from 46 to 78 years (mean age 60.3 years) were screened, all had been taking 1000 mg/d naproxen for at least one month. Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons: the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients, the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient, capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients. Ten patients (9 female, mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed. When comparing the change in LIS from baseline to end of treatment in all patients, a marked decrease was seen (mean LIS: 1236.4 ± 821.9 vs 925.2 ± 543.4, P = 0.271). Moreover, a significant difference between pre- and post-treatment mean total LIS was detected in 7 patients who had moderate-to-severe enteropathy gradings at the inclusion CE (mean LIS: 1615 ± 672 vs 1064 ± 424, P = 0.033). CONCLUSION: According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen. PMID:23431027

Toxicity of Triadimefon Racemate and Enantiomers to Black Fly Larvae

EPA Science Inventory

Triadimefon is a conazole fungicide commonly used for commercial and agricultural fungal control on trees, ornamentals and fruits. It is a chiral compound, existing as R-(-) and S-(+) enantiomers and used as the racemate. This is of interest since the triadimefon enantiomers ca...

Determination of the X-ray structure of the snake venom protein omwaprin by total chemical synthesis and racemic protein crystallography.

PubMed

Banigan, James R; Mandal, Kalyaneswar; Sawaya, Michael R; Thammavongsa, Vilasak; Hendrickx, Antoni P A; Schneewind, Olaf; Yeates, Todd O; Kent, Stephen B H

2010-10-01

The 50-residue snake venom protein L-omwaprin and its enantiomer D-omwaprin were prepared by total chemical synthesis. Radial diffusion assays were performed against Bacillus megaterium and Bacillus anthracis; both L- and D-omwaprin showed antibacterial activity against B. megaterium. The native protein enantiomer, made of L-amino acids, failed to crystallize readily. However, when a racemic mixture containing equal amounts of L- and D-omwaprin was used, diffraction quality crystals were obtained. The racemic protein sample crystallized in the centrosymmetric space group P2(1)/c and its structure was determined at atomic resolution (1.33 A) by a combination of Patterson and direct methods based on the strong scattering from the sulfur atoms in the eight cysteine residues per protein. Racemic crystallography once again proved to be a valuable method for obtaining crystals of recalcitrant proteins and for determining high-resolution X-ray structures by direct methods.

Enantioselective hydrolysis of racemic styrene oxide and its substituted derivatives using newly-isolated Sphingopyxis sp. exhibiting a novel epoxide hydrolase activity.

PubMed

Woo, Jung-Hee; Lee, Eun Yeol

2014-02-01

(S)-Styrene oxide, (S)-2-chlorostyrene oxide (CSO), (S)-3-CSO and (S)-4-CSO with 99.9 %ee were obtained with a yield of 20.6, 39.3, 28.7 and 26.8 % from 4 mM corresponding racemic substrates using 10 mg cells of a newly-isolated Sphingopyxis sp. at pH 8.0 and 25 °C in 1 ml 100 mM Tris/HCl buffer after 420, 100, 120 and 55 min, respectively. For racemic 2CSO, well-known for one of the racemates that is difficult to obtained in enantiomerically pure form, (S)-2-CSO with 99.9 %ee, 39.3 % yield (theoretical yield 50 %) and enantiomeric ratio of 42.1 was obtained. The newly-isolated strain can thus be used as whole-cell biocatalyst in the production of various (S)-CSO with a chlorine group at different positions.

Chirality-dependent friction of bulk molecular solids.

PubMed

Yang, Dian; Cohen, Adam E

2014-08-26

We show that the solid-solid friction between bulk chiral molecular solids can depend on the relative chirality of the two materials. In menthol and 1-phenyl-1-butanol, heterochiral friction is smaller than homochiral friction, while in ibuprofen, heterochiral friction is larger. Chiral asymmetries in the coefficient of sliding friction vary with temperature and can be as large as 30%. In the three compounds tested, the sign of the difference between heterochiral and homochiral friction correlated with the sign of the difference in melting point between racemate (compound or conglomerate) and pure enantiomer. Menthol and ibuprofen each form a stable racemic compound, while 1-phenyl-1-butanol forms a racemic conglomerate. Thus, a difference between heterochiral and homochiral friction does not require the formation of a stable interfacial racemic compound. Measurements of chirality-dependent friction provide a unique means to distinguish the role of short-range intermolecular forces from all other sources of dissipation in the friction of bulk molecular solids.

Improvement of age estimation using amino acid racemization in a case of pink teeth.

PubMed

Ohtani, S; Yamada, Y; Yamamoto, I

1998-03-01

Age was estimated from pink teeth using racemization of dentinal aspartic acid. Materials for identification were two lower second premolars. The body was determined to be that of a 40-year-old man; however, the age of the decedent had been estimated to be 29 and 30 years by the conventional method and 30 years from findings in the oral cavity. To clarify the cause of this difference, the powdered teeth were further washed in 0.01 mol/L hydrochloric acid. The racemization ratio (D/L ratio) of ordinary white teeth from persons of known age was slightly lower than that before washing, whereas that of the teeth used for identification was higher than before washing. The calculated age of the decedent using the racemization ratio of his teeth was between 36 and 37 years. These results suggest that age estimated from pink teeth is probably underestimated, but a more accurate age estimate can be obtained after adequate washing.

Effectiveness of Iron Ethylenediamine-N,N'-bis(hydroxyphenylacetic) Acid (o,o-EDDHA/Fe3+) Formulations with Different Ratios of Meso and d,l-Racemic Isomers as Iron Fertilizers.

PubMed

Alcañiz, Sara; Jordá, Juana D; Cerdán, Mar

2017-01-18

Two o,o-EDDHA/Fe 3+ formulations (meso, 93.5% w/w of meso isomer; and d,l-racemic, 91.3% w/w of d,l-racemic mixture) were prepared, and their efficacy to avoid or to relieve iron deficiency in Fe-sufficient and Fe-deficient tomato plants grown on hydroponic solution was compared with that of the current o,o-EDDHA/Fe 3+ formulations (50% of meso and d,l-racemic isomers). The effectiveness of the three o,o-EDDHA/Fe 3+ formulations was different depending on the iron nutritional status of plants. The three o,o-EDDHA/Fe 3+ formulations tested were effective in preventing iron chlorosis in healthy plants. However, the higher the meso concentration in the formulations, the higher the effectiveness in the recovery of iron chlorotic plants from iron deficiency. Accordingly, o,o-EDDHA/Fe 3+ formulations rich in meso isomer are recommended in hydroponic systems.

Implications of Chirality of Drugs and Excipients in Physical Pharmacy.

NASA Astrophysics Data System (ADS)

Duddu, Sarma P.

1993-01-01

The interactions of enantiomers of a chiral drug with other chemical entities, which may lead to changes and stereoselective differences in the physicochemical properties of the drug, were investigated. The various interactions described below employed ephedrine, pseudoephedrine and some of their salts, and to a minor extent, propranolol hydrochloride. The interaction of ephedrinium or pseudoephedrinium with the achiral anion, salicylate, yielded crystalline salts with the notable exception of homochiral ephedrine. Racemic ephedrinium salicylate exists as a centrosymmetric crystal (P2_1/n) whereas racemic pseudoephedrinium salicylate is a mixture of homochiral crystals (P2 _1). The inability of ephedrinium to exist as a homochiral salicylate salt is attributed to a high energy conformation of the ephedrinium cation, following conformational analysis. Arising from conformationally favorable interactions, the crystallization of racemic ephedrinium salicylate from aqueous solutions was utilized to improve the enantiomeric purity of a partially resolved mixture of ephedrine from 60% to 82% in one crystallization step. Interaction of the opposite enantiomers of ephedrine and pseudoephedrine in the solid, liquid, solution and vapor state produced the respective racemic compounds. The formation of racemic ephedrine in the solid state as predominantly second order (k = 392 mol^{-1} hr^{-1}), probably mediated by the vapor phase. The formation of racemic pseudoephedrine was predominantly diffusion-controlled in the solid state via an intermediate non-crystalline phase. The interaction with traces of the opposite enantiomer during crystallization of (RS)-(-)-ephedrinium 2-naphthalenesulfonate and (SS)-(+)-pseudoephedrinium salicylate changed pharmaceutically important solid state properties, including dissolution rate. Uptake of the enantiomeric impurity was measured by a new, sensitive HPLC method. The enantiomeric impurity, at mole fractions <= 0.0027 greatly increased the lattice disorder, i.e. entropy, measured calorimetrically. The release of propranolol hydrochloride from a sustained-release matrix containing HPMC and racemic propranolol hydrochloride was stereoselective, though variable, suggesting a differential interaction of the two enantiomers with the hydrated chiral matrix. Thus, the interaction of a chiral drug with other chemical entities leads to significant, interpretable changes in the physicochemical properties of the drug, which may have important implications in the design and development of reliable and effective solid dosage forms.

Isolation of novel biflavonoids from Cardiocrinum giganteum seeds and characterization of their antitussive activities.

PubMed

Shou, Jia-Wen; Zhang, Rong-Rong; Wu, Hoi-Yan; Xia, Xue; Nie, Hong; Jiang, Ren-Wang; Shaw, Pang-Chui

2018-08-10

Seeds of Cardiocrinum giganteum var. yunnanense (Leichtlin ex Elwes) Stearn (Liliaceae), also known as Doulingzi, have been used as a folk substitute for conventional antitussive herb "Madouling" (Aristolochia species) to treat chronic bronchitis and pertussis. The active antitussive phytochemicals in C. giganteum seeds are not known. The present work aims at isolating the active phytochemicals in C. giganteum seeds and confirming their antitussive effects. Active chemicals were isolated from C. giganteum seeds ethanol extract and identified their structures. Antitussive effects were evaluated with the cough frequency of guinea pigs exposed to citric acid. Electrical stimulation of the superior laryngeal nerve in guinea pigs was performed to differentiate the acting site of potential antitussives. Two racemic biflavonoids (CGY-1 and CGY-2) were isolated from C. giganteum seeds. CGY-1 was identified as (S)-2″R,3″R- and (R)-2″S,3″S-dihydro-3″-hydroxyamentoflavone-7- methyl ether, which are new compounds and firstly isolated from C. giganteum seeds. Racemic CGY-2 was identified as (S)-2″R,3″R- and (R)-2″S,3″S-dihydro-3″-hydroxyamentoflavone. Both CGY-1 and CGY-2 could significantly inhibit coughs induced by inhalation of citric acid. Further, they acted on the peripheral reflex pathway to inhibit cough after electrical stimulation of the superior laryngeal nerve in guinea pigs. These chemicals isolated from C. giganteum seeds showed good antitussive effects. The data provide scientific evidence to support the traditional use of C. giganteum seeds as an antitussive herbal medicine. Copyright © 2018 Elsevier B.V. All rights reserved.

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

PubMed

Peltoniemi, Marko A; Hagelberg, Nora M; Olkkola, Klaus T; Saari, Teijo I

2016-09-01

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Synthesis, Properties, and Two-Dimensional Adsorption Characteristics of 5-Amino[6]hexahelicene.

PubMed

van der Meijden, Maarten W; Gelens, Edith; Quirós, Natalia Murillo; Fuhr, Javier D; Gayone, J Esteban; Ascolani, Hugo; Wurst, Klaus; Lingenfelder, Magalí; Kellogg, Richard M

2016-01-22

A convergent synthesis of racemic 5-amino[6]hexahelicene is described. Cross-coupling reactions are used to assemble a pentacyclic framework, and a metal-catalyzed ring-closure comprises the final step. The enantiomers were separated by means of chromatography and the absolute configurations were assigned by comparison of the CD spectra with hexahelicene. The t1/2  value for racemization at 210 °C was approximately 1 hour. Scanning tunneling microscopy (STM) measurements were carried out on enantiopure and racemic samples of aminohelicene on Au(111) under ultrahigh vacuum (UHV) conditions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Asymmetric synthesis of 5-arylcyclohexenones by rhodium(I)-catalyzed conjugate arylation of racemic 5-(trimethylsilyl)cyclohexenone with arylboronic acids.

PubMed

Chen, Qian; Kuriyama, Masami; Soeta, Takahiro; Hao, Xinyu; Yamada, Ken-ichi; Tomioka, Kiyoshi

2005-09-29

[reaction: see text] A catalytic asymmetric conjugate arylation of racemic 5-(trimethylsilyl)cyclohex-2-enone with arylboronic acids was catalyzed by 3 mol % chiral amidophosphane- or BINAP-Rh(I) in dioxane-water (10:1) to afford trans- and cis-3-aryl-5-(trimethylsilyl)cyclohexanones in high enantioselectivity. Dehydrosilylation of the product mixture with cupric chloride in DMF gave 5-arylcyclohex-2-enones with up to 93% ee in good yield. Enantiofacial selectivity with chiral phosphane-Rh(I) exceeds the trans-diastereoselectivity that is maintained in the achiral or racemic phosphane-Rh(I)-catalyzed conjugate arylation of 5-(trimethylsilyl)cyclohexenone.

Iridium-Catalyzed Kinetic Asymmetric Transformations of Racemic Allylic Benzoates

PubMed Central

Stanley, Levi M.; Bai, Chen; Ueda, Mitsuhiro; Hartwig, John F.

2010-01-01

Versatile methods for iridium-catalyzed, kinetic asymmetric substitution of racemic, branched allylic esters are reported. These reactions occur with a variety of aliphatic, aryl, and heteroaryl allylic benzoates to form the corresponding allylic substitution products in high yields (74–96%) with good to excellent enantioselectivity (84–98% ee) with a scope that encompasses a range of anionic carbon and heteroatom nucleophiles. These kinetic asymmetric processes occur with distinct stereochemical courses for racemic aliphatic and aromatic allylic benzoates, and the high reactivity of branched allylic benzoates enables enantioselective allylic substitutions that are slow or poorly selective with linear allylic electrophiles. PMID:20552969

Achiral-to-chiral transition in benzil solidification: analogies with racemic conglomerates systems showing deracemization.

PubMed

El-Hachemi, Zoubir; Arteaga, Oriol; Canillas, Adolf; Crusats, Joaquim; Sorrenti, Alessandro; Veintemillas-Verdaguer, Sabino; Ribo, Josep M

2013-07-01

Experimental results show that benzil (1,2-diphenyl-1,2-ethanedione), an achiral compound that crystallizes as a racemic conglomerate, yields by solidification polycrystalline scalemic mixtures of high enantiomeric excesses. These results are related to those previously reported in this type of compounds on deracemizations of racemic mixtures of crystal enantiomorphs obtained by wet grinding. However, the present results strongly suggest that these experiments cannot be explained without taking into account chiral recognition interactions at the level of precritical clusters. The conditions that would define a general thermodynamic scenario for such deracemizations are discussed. © 2013 Wiley Periodicals, Inc.

Sorption and desorption of selected non-steroidal anti-inflammatory drugs in an agricultural loam-textured soil.

PubMed

Zhang, Y; Price, G W; Jamieson, R; Burton, D; Khosravi, K

2017-05-01

Non-steroidal, anti-inflammatory drugs (NSAIDs) are widely used pharmaceutical products with analgesic and anti-inflammatory effects that are consistently detected in municipal wastewater systems and in municipal biosolids. Land application of biosolids and irrigation with reclaimed wastewater introduces these compounds into agricultural environments, which is an emerging issue of concern for ecosystem health. In this study, the sorption-desorption behaviour of four commonly consumed NSAIDs, including naproxen (NPX), ibuprofen (IBU), ketoprofen (KTF), and diclofenac (DCF), was examined in a loam textured soil exposed to either an individual-compound or a mixture of the four NSAIDs. The proportion of NSAIDs adsorbed to the soil in the mixture-compound system was 72%, 55%, 50% and 45%, for diclofenac, naproxen, ketoprofen, and ibuprofen, respectively, and differed slightly from the individual compound adsorption. Diclofenac displayed strong sorption and low desorption in both the individual-compound and mixture-compound systems. Naproxen and ibuprofen exhibited significant differences between the adsorption isotherms of the individual-compound and mixture-compound systems. Results of this study highlight differences in the sorption behaviour of NSAIDs, when present as mixtures, possibly through multilayer bonding effects or complexation with cationic metals or organo-clays from the soil. Soil organic matter (SOM) may have played a role in determining some of the interactions between the compounds but other factors associated with the mixture-compound system, such as cation bridging or multilayer cooperative adsorption. Desorption data suggests that the mechanisms involved in binding NSAIDs to the soil surface are also influence by the presence of other compounds in a mixture. A reduction in desorption was observed for all four NSAIDs in the mixture-compound system relative to the individual-compound system, but were greatest for naproxen and ibuprofen. The sorption-desorption hysteresis increased for naproxen and ibuprofen in the mixture-compound system. This study suggests that cooperative adsorption plays a role in the interaction of NSAIDs when present as mixtures rather than as individual compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Longitudinal numbers-needed-to-treat (NNT) for achieving various levels of analgesic response and improvement with etoricoxib, naproxen, and placebo in ankylosing spondylitis.

PubMed

Peloso, Paul M; Gammaitoni, Arnold; Smugar, Steven S; Wang, Hongwei; Moore, Andrew R

2011-07-18

Clinical analgesic trials typically report response as group mean results. However, research has shown that few patients are average and most have responses at the extremes. Moreover, group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level. Responder analyses and numbers-needed-to-treat (NNT) are considered more relevant for evaluating treatment response. We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improvement and the associated NNTs. This was a post-hoc analysis of a 6-week, randomized, double-blind study (N = 387) comparing etoricoxib 90 mg, etoricoxib 120 mg, naproxen 1000 mg, and placebo in AS. Spine pain and BASDAI were measured on a 100-mm visual analog scale. The number and percentage of patients achieving ≥30% and ≥50% improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation. For etoricoxib 90 mg, etoricoxib 120 mg and naproxen 1000 mg, the NNTs at 6 weeks compared with placebo were 2.0, 2.0, and 2.7 respectively for BASDAI ≥30% improvement, and 3.2, 2.8, and 4.1 for ≥50% improvement. For spine pain, the NNTs were 1.9, 2.0, and 3.2, respectively, for ≥30% improvement, and 2.7, 2.5, and 3.7 for ≥50% improvement. The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinically meaningful difference for pain. Response rates and NNTs were generally similar and stable over 2, 4, and 6 weeks. For every 2 patients treated with etoricoxib, 1 achieved a clinically meaningful (≥30%) improvement in spine pain and BASDAI beyond that expected from placebo, whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen. Use of NNTs and responder analyses provide additional, complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies.

Native and microwave-modified Terminalia mantaly gums as sustained-release and bioadhesive excipients in naproxen matrix tablet formulations.

PubMed

Odeniyi, Michael Ayodele; Oyedokun, Babatunde Mukhtar; Bamiro, Oluyemisi Adebowale

2017-01-01

Hydrophilic polymers provide a means of sustaining drug delivery. Native gums may be limited in function, but modification may improve their activity. The aim of the study was to evaluate native and modified forms of Terminalia mantaly gum for their sustained-release and bioadhesive properties. The native gum (NTM) was modified by microwave irradiation for 20 seconds (MTM20) and 60 seconds (MTM60) and characterized using microscopy, Fourier transform infrared spectroscopy (FTIR) and packing properties. The effects of the thermally induced molecular reorientation were determined. Tablet formulations of naproxen were produced by direct compression. The mechanical, bioadhesive and release properties of the formulations were determined. Irradiation of NTM improved the gum's flow properties, resulting in Carr's Index and Hausner's ratios lower than 16% and 1.25, respectively. Swelling studies showed that MTM20 and MTM60 had lower water absorption capacity and swelling index values, while packing properties improved upon irradiation, as depicted by lower tapped density values. FTIR spectra of samples showed that the irradiated gums were distinct from the native gums and did not interact with naproxen sodium. The gum's mechanical properties improved with MTM20 and MTM60 and sustained-release action of up 12 h was obtained. Inclusion of hydroxypropyl methylcellulose (HPMC) in the tablet formulations proved critical for bioadhesion. Microwave irradiation of native Terminalia mantaly gum improved the flow, mechanical and sustained-release properties of Naproxen tablets, and the addition of HPMC increased bioadhesion properties. The tablet properties of the native gum were significantly improved after 20 s of microwave irradiation.

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling.

PubMed

Al-Rashed, Fahad; Calay, Damien; Lang, Marie; Thornton, Clare C; Bauer, Andrea; Kiprianos, Allan; Haskard, Dorian O; Seneviratne, Anusha; Boyle, Joseph J; Schönthal, Alex H; Wheeler-Jones, Caroline P; Mason, Justin C

2018-04-19

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα (Thr172) and CREB-1 (Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65 (Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.

Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double-Blind Placebo-Controlled Functional Magnetic Resonance Imaging Study Using Naproxen

PubMed Central

Sanders, Duncan; Krause, Kristina; O'Muircheartaigh, Jonathan; Thacker, Michael A; Huggins, John P; Vennart, William; Massat, Nathalie J; Choy, Ernest; Williams, Steven C R; Howard, Matthew A

2015-01-01

Objective In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint. Methods A placebo-controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity. Results Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. Conclusion This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain. PMID:25533872

Factors influencing naproxen metabolite interference in total bilirubin assays.

PubMed

Saifee, Nabiha Huq; Ranjitkar, Pratistha; Greene, Dina N

2016-04-01

The factors influencing naproxen metabolite O-desmethylnaproxen (ODMN) positive interference in diazo-based Jendrassik and Grof (JG) total bilirubin (Tbil) assays and lack of interference in direct bilirubin (Dbil) assays have not been resolved. The objective of this study was to understand the conditions causing this interference pattern. Pooled normal and ultra-filtered plasma samples spiked with ODMN and naproxen were measured on the Beckman Coulter DxC and AU instruments. Absorbance spectra were obtained for ODMN mixed with Dbil reagent at original and adjusted pH. Absorbance spectra were also obtained for ODMN and bilirubin samples mixed with Tbil assay reagents. ODMN produces a positive interference in the DxC JG Tbil assays, but not the AU Tbil or Dbil assays or the DxC Dbil assay. Neutralizing the acidic pH of AU and DxC Dbil reagents allows ODMN to react with diazo salts. ODMN samples mixed with DxC and AU Tbil reagents produce broad peaks from 450 to 560nm and 400 to 540nm, respectively. The DxC JG Tbil assay monitors a change in absorbance at 520nm close to peak absorbance wavelength of diazo-reacted ODMN, whereas the AU Tbil assay monitors a change in absorbance at 570/660nm, beyond the peak absorbance wavelengths of diazo-reacted ODMN. The acidic pH of diazo-based Dbil assay reagents inhibits the reaction of ODMN with diazo salts. The AU JG Tbil assay is a reliable method to measure Tbil in the setting of naproxen overdose. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Role of humic substances in the photodegradation of naproxen under simulated sunlight.

PubMed

Chen, Yong; Liu, Lu; Su, Jing; Liang, Jianfeng; Wu, Bo; Zuo, Jiaolan; Zuo, Yuegang

2017-11-01

Humic substances (HS) including humic acid (HA) and fulvic acid (FA) are ubiquitous in the natural waters. Although numerous studies documented their role in photodegradation of organic pollutants, the competitive effects of photosensitization and light-screening of HS on the photodegradation of pollutants are not yet clear. In this work, the role of HS in the photodegradation of the pharmaceutical naproxen (NP) was studied under simulated sunlight. The direct photodegradation quantum yield of NP in deionized water was 2.1 × 10 -2 , and the apparent quantum yields for photosensitized degradation of NP in the presence of FA and HA were 2.3 × 10 -4 and 2.6 × 10 -5 , respectively. Both direct and photosensitized photodegradation decreased with increasing pH, consistent with the trend of singlet oxygen ( 1 O 2 ) reaction rate constants of NP. HA inhibited the photodegradation of naproxen thoroughly. In contrast, FA accelerated the photodegradation of NP at lower substrate concentration and light intensity, and vice versa. Direct photodegradation of NP declined sharply with spectral radiation attenuation of UV region, when HS-mediated photosensitization predominantly accounted for the photodegradation. The direct photodegradation was ascribed to decomposition of excited triplet state of naproxen ( 3 NP ∗ ) and self-sensitization effect involving 1 O 2 . The FA-mediated photodegradation was mainly attributed to 1 O 2 oxidation in aerated solution. These findings are important for assessing the competitive effects of humic substances on the photodegradation of pollutants under various conditions in natural waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hyperbranched polyglycerol/graphene oxide nanocomposite reinforced hollow fiber solid/liquid phase microextraction for measurement of ibuprofen and naproxen in hair and waste water samples.

PubMed

Rezaeifar, Zohreh; Es'haghi, Zarrin; Rounaghi, Gholam Hossein; Chamsaz, Mahmoud

2016-09-01

A new design of hyperbranched polyglycerol/graphene oxide nanocomposite reinforced hollow fiber solid/liquid phase microextraction (HBP/GO -HF-SLPME) coupled with high performance liquid chromatography used for extraction and determination of ibuprofen and naproxen in hair and waste water samples. The graphene oxide first synthesized from graphite powders by using modified Hummers approach. The surface of graphene oxide was modified using hyperbranched polyglycerol, through direct polycondensation with thionyl chloride. The ready nanocomposite later wetted by a few microliter of an organic solvent (1-octanol), and then applied to extract the target analytes in direct immersion sampling mode.After the extraction process, the analytes were desorbed with methanol, and then detected via high performance liquid chromatography (HPLC). The experimental setup is very simple and highly affordable. The main factors influencing extraction such as; feed pH, extraction time, aqueous feed volume, agitation speed, the amount of functionalized graphene oxide and the desorption conditions have been examined in detail. Under the optimized experimental conditions, linearity was observed in the range of 5-30,000ngmL(-1) for ibuprofen and 2-10,000ngmL(-1) for naproxen with correlation coefficients of 0.9968 and 0.9925, respectively. The limits of detection were 2.95ngmL(-1) for ibuprofen and 1.51ngmL(-1) for naproxen. The relative standard deviations (RSDs) were found to be less than 5% (n=5). Copyright © 2016 Elsevier B.V. All rights reserved.

Practical Stereochemistry.

PubMed

Kellogg, Richard M

2017-04-18

The relationship between fundamental and applied is often uneasy, particularly in modern political climates. A familiar political view, aimed negatively at the scientific community, is that the former is a waste of money whereas the latter gives value for investment. The answer that fundamental is required as the basis for practical suffers from the fact that the timelines between fundamental and practical are often long and the routes contorted and unexpected. This has been my experience. In this Account, examples are given from the research in which I have been involved wherein quite fundamental considerations have led to various applications. The longer the time, the clearer and broader the relationship. Fundamental can and does lead to application. They need and depend on each other. I have seen this both from the side of academia and from small companies. In the course of the past 40 plus years, I have been involved in various aspects of stereochemistry and, in particular, chirality. It has been rewarding to see that several of the developments, most originally grounded in fundamental research considerations, have been used in the chemical community and given new dimensions and often practical applications by others. In this Account, a path-not planned deliberately by me-from orbital symmetry and Woodward-Hoffmann rules through crown ethers to conformational analysis to diastereomeric resolutions to deracemizations powered by Ostwald ripening and the Gibbs-Thomson effect to nucleation to helicenes is described. In order of discussion, the orbital symmetry aspects have via an unusual and unpredicted path has resulted in, among other things, a synthesis of hindered alkenes useful for the production of molecular motors. The crown ether aspects led to discovery of the utility of cesium salts particularly for racemization sensitive nucleophilic substitutions. Work on diastereomeric resolutions has concentrated on the mechanistic as well as practical/commercial aspects of the use of multiple resolving agents (Dutch resolution). During this work the complex relationship between nucleation and chirality in diastereomeric resolutions began to reveal itself. In general, nucleation, especially with involvement of chirality, is a topical challenge that has attracted the attention of many groups. The contribution of this knowledge to the development of attrition driven deracemizations of racemizable conglomerates is described. This remarkable technology allows, without intervention of chiral aids, conversion of certain racemates in quantitative yield and absolute enantiomeric excess to a single enantiomer. From a practical standpoint, this methodology has been used for the production in enantiomerically pure form of commercially interesting compounds like naproxen and clopidogrel (Plavix). Finally an STM investigation of the nucleation behavior of a helicene, prepared via a remarkably short and efficient route, on a metal surface is described.

An Examination of the Phase Transition Thermodynamics of (S)- and (RS)-Naproxen as a Basis for the Design of Enantioselective Crystallization Processes.

PubMed

Buchholz, Hannes; Emel'yanenko, Vladimir N; Lorenz, Heike; Verevkin, Sergey P

2016-05-01

A detailed experimental analysis of the phase transition thermodynamics of (S)-naproxen and (RS)-naproxen is reported. Vapor pressures were determined experimentally via the transpiration method. Sublimation enthalpies were obtained from the vapor pressures and from independent TGA measurements. Thermodynamics of fusion which have been well-studied in the literature were systematically remeasured by DSC. Both sublimation and fusion enthalpies were adjusted to one reference temperature, T = 298 K, using measured heat capacities of the solid and the melt phase by DSC. Average values from the measurements and from literature data were suggested for the sublimation and fusion enthalpies. In order to prove consistency of the proposed values the vaporization enthalpies obtained by combination of both were compared to vaporization enthalpies obtained by the group-additivity method and the correlation-gas chromatography method. The importance of reliable and precise phase transition data for thermochemical calculations such as the prediction of solid/liquid phase behaviour of chiral compounds is highlighted. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Characterization of naproxen-loaded solid SMEDDSs prepared by spray drying: the effect of the polysaccharide carrier and naproxen concentration.

PubMed

Čerpnjak, Katja; Zvonar, Alenka; Vrečer, Franc; Gašperlin, Mirjana

2015-05-15

The purpose of this study was to prepare solid SMEDDS (sSMEDDS) particles produced by spray-drying using maltodextrin (MD), hypromellose (HPMC), and a combination of the two as a solid carrier. Naproxen (NPX) as the model drug was dissolved (at 6% concentration) or partially suspended (at 18% concentration) in a liquid SMEDDS composed of Miglyol(®) 812, Peceol™, Gelucire(®) 44/14, and Solutol(®) HS 15. Among the sSMEDDSs tested, the MD-based sSMEDDSs (with a granular, smooth-surfaced, microspherical appearance) preserved the self-microemulsifying properties of liquid SMEDDSs and exhibited dissolution profiles similar to those of liquid SMEDDSs, irrespective of the concentration of NPX. In contrast, HPMC-based sSMEDDSs (irregular-shaped microparticles) exhibited slightly prolonged release times due to the polymeric nature of the carrier. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Raman mapping analysis confirmed molecularly dissolved NPX (at 6% of drug loading), whereas at 18% NPX loading drug is partially molecularly dissolved and partially in the crystalline state. Copyright © 2015. Published by Elsevier B.V.

Structure and physicochemical characterization of a naproxen-picolinamide cocrystal.

PubMed

Kerr, Hannah E; Softley, Lorna K; Suresh, Kuthuru; Hodgkinson, Paul; Evans, Ivana Radosavljevic

2017-03-01

Naproxen (NPX) is a nonsteroidal anti-inflammatory drug with pain- and fever-relieving properties, currently marketed in the sodium salt form to overcome solubility problems; however, alternative solutions for improving its solubility across all pH values are desirable. NPX is suitable for cocrystal formation, with hydrogen-bonding possibilities via the COOH group. The crystal structure is presented of a 1:1 cocrystal of NPX with picolinamide as a coformer [systematic name: (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid-pyridine-2-carboxamide (1/1), C 14 H 14 O 3 ·C 6 H 6 N 2 O]. The pharmaceutically relevant physical properties were investigated and the intrinsic dissolution rate was found to be essentially the same as that of commercial naproxen. An NMR crystallography approach was used to investigate the H-atom positions in the two crystallographically unique COOH-CONH hydrogen-bonded dimers. 1 H solid-state NMR distinguished the two carboxyl protons, despite the very similar crystallographic environments. The nature of the hydrogen bonding was confirmed by solid-state NMR and density functional theory calculations.

Simultaneous determination of several antalgic drugs based on their interactions with beta-cyclodextrin by capillary zone electrophoresis.

PubMed

Wei, Wei; Yu, Xiaodong; Ju, Huangxin

2004-03-01

The binding constants of beta-cyclodextrin (beta-CD) with antalgic drugs such as naproxen, ketoprofen, ibuprofen, acemetacin, and aspirin are determined by affinity capillary electrophoresis. Based on these interactions, a reliable method for the separation and simultaneous determinations of these compounds in the presence of 5.0 mM beta-CD in phosphate buffer solution is presented by capillary zone electrophoresis with UV detection at 214 nm for naproxen and 200 nm for the others. The linear ranges for naproxen, ketoprofen, ibuprofen, acemetacin, aspirin, and caffeine detections are from 2.0 to 800, 2.5 to 1000, 2.5 to 700, 2.5 to 700, 2.0 to 800, and 1.5 to 800 microg/mL, respectively. Their detection limits are 1.0, 0.5, 0.5, 1.5, 1.5, and 1.0 microg/mL at a signal to noise ratio of 3, respectively. This method has been successfully applied to the detections of these drugs in the pharmaceutical formulations (tablets or capsules) and urine samples.

The Formation of Racemic Amino Acids by UV Photolysis of Interstellar Ice Analogs

NASA Technical Reports Server (NTRS)

Bernstein, Max P.; Dworkin, Jason P.; Sandford, Scott A.; Cooper, George; Allamandola, Louis J.; DeVincenzi, Donald (Technical Monitor)

2001-01-01

Small biologically relevant organic molecules including the amino acids glycine, alanine, and marine were formed in the laboratory by the UV (Ultraviolet) photolysis of realistic interstellar ice analogs, composed primarily of H2O, and including CH3OH, NH3, and HCN, under interstellar conditions. N-formyl glycine, cycloserine (4-amino-3-isoxazolidinone), and glycerol were detected before hydrolysis, and glycine, racemic alanine, racemic marine, glycerol, ethanolamine, and glyceric acid were found after hydrolysis. This suggests that some meteoritic amino acids (and other molecules) may be the direct result of interstellar ice photochemistry, expanding the current paradigm that they formed by reactions in liquid water on meteorite parent bodies.

Racemization of amino acids in fossil bones and teeth from the Olduvai Gorge region, Tanzania, East Africa

NASA Astrophysics Data System (ADS)

Bada, Jeffrey L.

1981-10-01

Investigation of amino acid racemization in fossil bones and teeth from the Olduvai Gorge region, Tanzania, indicates that aspartic acid racemization can be used to date samples which are less than ˜80,000-100,000 years old in this area. In older samples, significant secondary aspartic acid is apparently present and thus these samples have lower than expectedD/L aspartic acid ratios. Isoleucine in older samples, however, is apparently syngenetic with the samples, so the epimerization of isoleucine to alloisoleucine can be used with certain limitations to date fossil bones and teeth from the older stratigraphic sections in the Olduvai region.

The even-handed approach: strategies for the deployment of racemic chiral catalysts.

PubMed

Evans, Louise A; Hodnett, Neil S; Lloyd-Jones, Guy C

2012-02-13

Asymmetric catalysis is predominantly associated with the use of enantiomerically pure chiral ligands and catalysts. Although racemic chiral catalysts have been employed quite extensively in polymerization, their utility in mainstream organic synthesis and catalyst development has arguably been rather overlooked. This Minireview collates various themes for the strategic application of racemic ligands and catalysts, ranging from the estimation of selectivity and determination of enantiomeric excess, through to control of regio- and stereochemical outcomes, and mechanistic studies. What emerges is a clear picture that, in isolation or in concert with enantiopure catalysts, the "even-handed" approach has much to offer. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biosynthesis of (R)-phenyl-1,2-ethanediol from racemic styrene oxide by using bacterial and marine fish epoxide hydrolases.

PubMed

Kim, Hee Sook; Lee, Ok Kyung; Hwang, Seungha; Kim, Beum Jun; Lee, Eun Yeol

2008-01-01

Enantio-convergent hydrolysis of racemic styrene oxides was achieved to prepare enantiopure (R)-phenyl-1,2-ethanediol by using two recombinant epoxide hydrolases (EHs) of a bacterium, Caulobacter crescentus, and a marine fish, Mugil cephalus. The recombinant C. crescentus EH primarily attacked the benzylic carbon of (S)-styrene oxide, while the M. cephalus EH preferentially attacked the terminal carbon of (R)-styrene oxide, thus leading to the formation of (R)-phenyl-1,2-ethanediol as the main product. (R)-Phenyl-1,2-ethanediol was obtained with 90% enantiomeric excess and yield as high as 94% from 50 mM racemic styrene oxides in a one-pot process.

Amino acid racemization in amber-entombed insects: implications for DNA preservation

NASA Technical Reports Server (NTRS)

Bada, J. L.; Wang, X. S.; Poinar, H. N.; Paabo, S.; Poinar, G. O.

1994-01-01

DNA depurination and amino acid racemization take place at similar rates in aqueous solution at neutral pH. This relationship suggests that amino acid racemization may be useful in accessing the extent of DNA chain breakage in ancient biological remains. To test this suggestion, we have investigated the amino acids in insects entombed in fossilized tree resins ranging in age from <100 years to 130 million years. The amino acids present in 40 to 130 million year old amber-entombed insects resemble those in a modern fly and are probably the most ancient, unaltered amino acids found so far on Earth. In comparison to other geochemical environments on the surface of the Earth, the amino acid racemization rate in amber insect inclusions is retarded by a factor of >10(4). These results suggest that in amber insect inclusions DNA depurination rates would also likely be retarded in comparison to aqueous solution measurements, and thus DNA fragments containing many hundreds of base pairs should be preserved. This conclusion is consistent with the reported successful retrieval of DNA sequences from amber-entombed organisms.

Concentration variations of amino acids in mammalian fossils: effects of diagenesis and the implications for amino acid racemization analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blackwell, B.; Rutter, N.W.

Detailed amino acid analysis of bones, teeth, and antler from several mammal species have shown that concentrations of several amino acids can be related to three factors: type of material analyzed, diagenetic alteration of the material, and relative age of the fossil. Concentrations of several amino acids are significantly different in enamel compared to those of dentine or cement. This can be used to check that no contamination of one material by another has occurred, which is critical for using the data for amino acid dating, since all three materials have different racemization rates for some acids. With increased inmore » growth of secondary minerals, generally reduced amino acid concentrations are observed. Interacid ratios and concentrations vary significantly the norms expected for the type of material with increasing degrees of alteration. These effects can be linked to abnormal racemization ratios observed in the same samples. Therefore, abnormal concentrations and/or interacid ratios can be used to detect samples in which the D/L amino acid ratios otherwise appear normal, thereby insuring better accuracy of amino acid racemization analysis. For unaltered fossils, with increasing sample age regardless the type of material, some amino acids steadily degrade, while others actually increase in concentration initially due to their generation as by-products of decay. Preliminary studies indicate that this progressive alteration can used to complement racemization data for determining relative stratigraphic sequences.« less

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion.

PubMed

Takahashi, Ohgi; Kirikoshi, Ryota; Manabe, Noriyoshi

2016-10-10

In proteins and peptides, d-aspartic acid (d-Asp) and d-β-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known to have relevance to aging and pathologies. Although nonenzymatic, the succinimide racemization will not occur without a catalyst at room or biological temperature. In the present study, we computationally investigated the mechanism of succinimide racemization catalyzed by dihydrogen phosphate ion, H₂PO₄ - , by B3LYP/6-31+G(d,p) density functional theory calculations, using a model compound in which an aminosuccinyl (Asu) residue is capped with acetyl (Ace) and NCH₃ (Nme) groups on the N- and C-termini, respectively (Ace-Asu-Nme). It was shown that an H₂PO₄ - ion can catalyze the enolization of the H α -C α -C=O portion of the Asu residue by acting as a proton-transfer mediator. The resulting complex between the enol form and H₂PO₄ - corresponds to a very flat intermediate region on the potential energy surface lying between the initial reactant complex and its mirror-image geometry. The calculated activation barrier (18.8 kcal·mol -1 after corrections for the zero-point energy and the Gibbs energy of hydration) for the enolization was consistent with the experimental activation energies of Asp racemization.

Fourier transform vibrational circular dichroism of small pharmaceutical molecules

NASA Astrophysics Data System (ADS)

Long, Fujin; Freedman, Teresa B.; Nafie, Laurence A.

1998-06-01

Fourier transform vibrational circular dichroism (FT-VCD) spectra of the small pharmaceutical molecules propanolol, ibuprofen and naproxen have been measured in the hydrogen stretching and mid-infrared regions to obtain information on solution conformation and to identify markers for absolute configuration determination. Ab initio molecular orbital calculations of low energy conformations, vibrational frequencies and VCD intensities for fragments of the drugs were utilized in interpreting the spectra. Features characteristic of five conformers of propranolol were identified. The weak positive CH stretching VCD signal in ibuprofen and naproxen is characteristic of the S-configuration of the chiral center common to these two analgesics.

Positionally isomeric organic gelators: structure-gelation study, racemic versus enantiomeric gelators, and solvation effects.

PubMed

Caplar, Vesna; Frkanec, Leo; Sijaković Vujicić, Natasa; Zinić, Mladen

2010-03-08

Low molecular weight gelator molecules consisting of aliphatic acid, amino acid (phenylglycine), and omega-aminoaliphatic acid units have been designed. By varying the number of methylene units in the aliphatic and omega-aminoaliphatic acid chains, as defined by descriptors m and n, respectively, a series of positionally isomeric gelators having different positions of the peptidic hydrogen-bonding unit within the gelator molecule has been obtained. The gelation properties of the positional isomers have been determined in relation to a defined set of twenty solvents of different structure and polarity and analyzed in terms of gelator versatility (G(ver)) and effectiveness (G(eff)). The results of gelation tests have shown that simple synthetic optimizations of a "lead gelator molecule" by variation of m and n, end-group polarity (carboxylic acid versus sodium carboxylate), and stereochemistry (racemate versus optically pure form) allowed the identification of gelators with tremendously improved versatility (G(ver)) and effectiveness (G(eff)). Dramatic differences in G(eff) values of up to 70 times could be observed between pure racemate/enantiomer pairs of some gelators, which were manifested even in the gelation of very similar solvents such as isomeric xylenes. The combined results of spectroscopic ((1)H NMR, FTIR), electron microscopy (TEM), and X-ray diffraction studies suggest similar organization of the positionally isomeric gelators at the molecular level, comprising parallel beta-sheet hydrogen-bonded primary assemblies that form inversed bilayers at a higher organizational level. Differential scanning calorimetry (DSC) studies of selected enantiomer/racemate gelator pairs and their o- and p-xylene gels revealed the simultaneous presence of different polymorphs in the racemate gels. The increased gelation effectiveness of the racemate compared to that of the single enantiomer is most likely a consequence of its spontaneous resolution into enantiomeric bilayers and their subsequent organization into polymorphic aggregates of different energy. The latter determine the gel fiber thickness and solvent immobilization capacity of the formed gel network.

Amino Acid Enantiomeric Ratios in Biogeochemistry: Complications and Opportunities

NASA Astrophysics Data System (ADS)

McDonald, G. D.; Sun, H. J.; Tsapin, A. I.

2003-12-01

Amino acid enantiomeric ratios have been used for many years as an indicator of the process of racemization, and thus as a method to determine the age of biological samples such as bones, shells, and teeth. Dating biological samples by this method relies on an accurate knowledge of the environmental temperatures the sample has experienced, and the racemization kinetic parameters in the sample matrix. In some environments, where an independent dating method such as radiocarbon is available, the observed amino acid D/L ratios are found to be either higher or lower than those expected due to racemization alone. The observed D/L ratios in these cases can be clues to biogeochemical processes operating in addition to, or in place of, chemical racemization. In Siberian permafrost (Brinton et al. 2002, Astrobiology 2, 77) we have found D/L ratios lower than expected, which we have interpreted as evidence for low-level D-amino acid metabolism and recycling in microorganisms previously thought to be metabolically dormant. In microbially-colonized Antarctic Dry Valley sandstones (McDonald and Sun 2002, Eos Trans. AGU 83, Fall Meet. Suppl., Abstract B11A-0720) we have found D/L ratios higher than can be accounted for by racemization alone, most likely due to the accumulation of D-amino-acid-containing peptidoglycan material from multiple bacterial generations. D/L profiles in polar ices and in ice-covered lakes (Tsapin et al. 2002, Astrobiology 2, 632) can be used to indicate the sources and histories of water or ice samples. Multiple biological and biogeochemical processes may complicate the interpretation of amino acid enantiomeric excesses in both terrestrial and extraterrestrial samples; however, amino acid racemization remains a useful tool in biogeochemistry and astrobiology. With a good knowledge of the environmental history of samples, amino acid D/L profiles can be used as a window into processes such as molecular repair and biomass turnover that are difficult to detect by other means, particularly over geological time scales.

Racemization of Isobornyl Chloride via Carbocations: A Nonclassical Look at a Classic Mechanism

ERIC Educational Resources Information Center

Rzepa, Henry S.; Allan, Charlotte S. M.

2010-01-01

Our understanding of carbonium ions as intermediates in chemical reaction mechanisms derives from the early work of Julius Stieglitz and the more famous Hans Meerwein, the latter studying the racemization of isobornyl chloride when treated with Lewis acids. This review analyzes how key mechanistic concepts for this reaction evolved and gives the…

High-yield conversion of (R)-2-octanol from the corresponding racemate by stereoinversion using Candida rugosa.

PubMed

Nie, Yao; Xu, Yan; Qing Mu, Xiao; Tang, Yan; Jiang, Juan; Hao Sun, Zhi

2005-01-01

Whole cells of Candida rugosa catalyzed the conversion of (R)-2-octanol from the corresponding racemate with the optical purity of 97% e.e. and yield of 92% in 10 h. The product was formed through a stereoinversion involving enantioselective oxidation and asymmetric reduction with 2-octanone as the intermediate.

Cocrystallization out of the blue: DL-mandelic acid/ethyl-DL-mandelate cocrystal

NASA Astrophysics Data System (ADS)

Tumanova, Natalia; Payen, Ricky; Springuel, Géraldine; Norberg, Bernadette; Robeyns, Koen; Le Duff, Cécile; Wouters, Johan; Leyssens, Tom

2017-01-01

This work focuses on a peculiar behavior of racemic mandelic acid in ethanol solution. Dissolution of racemic mandelic acid in ethanol followed by evaporation to dryness results in a DL-mandelic acid/ethyl-DL-mandelate cocrystal. This behavior indicates that racemic mandelic acid tends not only to transform into an ester in ethanol, but also to cocrystallize with untransformed acid molecules. Cocrystal formation for mandelic acid in ethanol was found to be reproducible under various conditions. DL-tropic acid and DL-phenyllactic acid that contain similar functional groups and that were tested as well, on the other hand, showed no cocrystal formation: DL-phenyllactic acid partly converted into an ester, whereas DL-tropic acid mostly recrystallized.

Enantioselective oxidation of racemic lactic acid to D-lactic acid and pyruvic acid by Pseudomonas stutzeri SDM.

PubMed

Gao, Chao; Qiu, Jianhua; Li, Jingchen; Ma, Cuiqing; Tang, Hongzhi; Xu, Ping

2009-03-01

D-lactic acid and pyruvic acid are two important building block intermediates. Production of D-lactic acid and pyruvic acid from racemic lactic acid by biotransformation is economically interesting. Biocatalyst prepared from 9 g dry cell wt l(-1) of Pseudomonas stutzeri SDM could catalyze 45.00 g l(-1)DL-lactic acid into 25.23 g l(-1)D-lactic acid and 19.70 g l(-1) pyruvic acid in 10h. Using a simple ion exchange process, D-lactic acid and pyruvic acid were effectively separated from the biotransformation system. Co-production of d-lactic acid and pyruvic acid by enantioselective oxidation of racemic lactic acid is technically feasible.

Racemic resolution of some DL-amino acids using Aspergillus fumigatus L-amino acid oxidase.

PubMed

Singh, Susmita; Gogoi, Binod K; Bezbaruah, Rajib L

2011-07-01

The ability of Aspergillus fumigatus L-amino acid oxidase (L-aao) to cause the resolution of racemic mixtures of DL-amino acids was investigated with DL-alanine, DL-phenylalanine, DL-tyrosine, and DL-aspartic acid. A chiral column, Crownpak CR+ was used for the analysis of the amino acids. The enzyme was able to cause the resolution of the three DL-amino acids resulting in the production of optically pure D-alanine (100% resolution), D-phenylalanine (80.2%), and D-tyrosine (84.1%), respectively. The optically pure D-amino acids have many uses and thus can be exploited industrially. This is the first report of the use of A. fumigatus L: -amino acid oxidase for racemic resolution of DL-amino acids.

Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage.

PubMed

Fomenko, Iryna; Sklyarov, Alexander; Bondarchuk, Tetyana; Biletska, Lilya; Panasyuk, Natalia; Wallace, John L

2014-12-01

Mechanisms of gastric defence under conditions of combined influence of acute stress and non-steroidal anti-inflammatory drugs (NSAIDs) are still poorly studied. The aim of this study was to explore the effects of different types of NSAIDs (naproxen, celecoxib and ATB-346) in producing experimental gastric lesions (induced by water-restraint stress (WRS) or by epinephrine (EPN) injection) and to determine the role of lipid peroxidation and the nitric oxide (NO) system in the pathogenesis of the damage. Male rats were used (eight per group) in this work. The NSAIDs were all administered at a dose 10 mg kg(-1) 30 min prior to WRS or EPN injection. Administration of naproxen to the control rats caused development of gastric lesions, whereas administration of a hydrogen sulfide (H2S)-releasing NSAID (ATB-346) or a selective cyclooxygenase-2 inhibitor (celecoxib) did not cause gastric damage. In contrast, lipid peroxidation processes were enhanced in all groups as was the activity of NO synthase (NOS). Pretreatment with naproxen in the WRS model caused an increase in severity of damage and a decrease in NOS activity. ATB-346 displayed beneficial effects, manifested by a decrease in the area of gastric damage, but parameters of lipid peroxidation and the NOS system did not differ substantially from those in the group treated with naproxen. Administration of different NSAIDs under conditions of EPN-induced gastric damage resulted in the decrease in NOS activity and lipid peroxidation. None of the tested NSAIDs exacerbated EPN-induced gastric mucosal injury; indeed, they all reduced the extent of damage.

Multi-Modal Preemptive Analgesia With Pregabalin, Acetaminophen, Naproxen, and Dextromethorphan in Radical Neck Dissection Surgery: A Randomized Clinical Trial

PubMed Central

Amiri, Hamid Reza; Mirzaei, Mojtaba; Beig Mohammadi, Mohammad Taghi; Tavakoli, Farhad

2016-01-01

Background Preemptive analgesia may be considered as a method not only to alleviate postoperative pain but also to decrease analgesic consumption. Different regimens are suggested, but there is currently no standard. Objectives The aim was to measure the efficacy of preemptive analgesia with pregabalin, acetaminophen, naproxen, and dextromethorphan in radical neck dissection surgery for reducing the intensity of pain and morphine consumption. Patients and Methods This study was conducted as a randomized double-blind clinical trial. Eighty adult patients (18 to 60 years of age) under the American society of anesthesiologists (ASA) physical status I and II undergoing elective radical neck dissection were enrolled. Patients were randomized into two groups of 40 with a simple randomization method. The case group received a combination of 15 mg/kg acetaminophen, 2.5 mg/kg pregabalin, 7 mg/kg naproxen, and 0.3 mg/kg dextromethorphan administered orally one hour prior to surgery. Postoperative pain was assessed with the universal pain assessment tool (UPAT) at 0, 2, 4, 6, 12, and 24 hours after surgery. Subjects received morphine based on postoperative pain control protocol. Total administered morphine doses were noted. Results Postoperative pain rates at 0, 2, 4, 6, 12, and 24 hours after surgery were significantly lower for the case group than the control group (P values = 0.014, 0.003, 0.00, 0.00, and 0.00, respectively). Total morphine doses for the preemptive analgesia group were 45% lower than those of the other group. Side effects were similar for both groups. Conclusions A single preoperative oral dose of pregabalin, acetaminophen, dextromethorphan, and naproxen one hour before surgery is an effective method for reducing postoperative pain and morphine consumption in patients undergoing radical neck dissection. PMID:27843771

Pharmaceuticals and personal care products (PPCPs) in surface and treated waters of Louisiana, USA and Ontario, Canada.

PubMed

Boyd, Glen R; Reemtsma, Helge; Grimm, Deborah A; Mitra, Siddhartha

2003-07-20

A newly developed analytical method was used to measure concentrations of nine pharmaceuticals and personal care products (PPCPs) in samples from two surface water bodies, a sewage treatment plant effluent and various stages of a drinking water treatment plant in Louisiana, USA, and from one surface water body, a drinking water treatment plant and a pilot plant in Ontario, Canada. The analytical method provides for simultaneous extraction and quantification of the following broad range of PPCPs and endocrine-disrupting chemicals: naproxen; ibuprofen; estrone; 17beta-estradiol; bisphenol A; clorophene; triclosan; fluoxetine; and clofibric acid. Naproxen was detected in Louisiana sewage treatment plant effluent at 81-106 ng/l and Louisiana and Ontario surface waters at 22-107 ng/l. Triclosan was detected in Louisiana sewage treatment plant effluent at 10-21 ng/l. Of the three surface waters sampled, clofibric acid was detected in Detroit River water at 103 ng/l, but not in Mississippi River or Lake Pontchartrain waters. None of the other target analytes were detected above their method detection limits. Based on results at various stages of treatment, conventional drinking-water treatment processes (coagulation, flocculation and sedimentation) plus continuous addition of powdered activated carbon at a dosage of 2 mg/l did not remove naproxen from Mississippi River waters. However, chlorination, ozonation and dual media filtration processes reduced the concentration of naproxen below detection in Mississippi River and Detroit River waters and reduced clofibric acid in Detroit River waters. Results of this study demonstrate that existing water treatment technologies can effectively remove certain PPCPs. In addition, our study demonstrates the importance of obtaining data on removal mechanisms and byproducts associated with PPCPs and other endocrine-disrupting chemicals in drinking water and sewage treatment processes.

The anti-inflammatory drugs diclofenac, naproxen and ibuprofen are found in the bile of wild fish caught downstream of a wastewater treatment plant.

PubMed

Brozinski, Jenny-Maria; Lahti, Marja; Meierjohann, Axel; Oikari, Aimo; Kronberg, Leif

2013-01-02

Pharmaceutical residues are ubiquitous in rivers, lakes, and at coastal waters affected by discharges from municipal wastewater treatment plants. In this study, the presence of 17 different pharmaceuticals and six different phase I metabolites was determined in the bile of two wild fish species, bream (Abramis brama) and roach (Rutilus rutilus). The fish were caught from a lake that receives treated municipal wastewater via a small river. Prior to analyses, the bile content was enzymatically hydrolyzed to convert the glucuronide metabolites into the original pharmaceuticals or phase I metabolites. The solid phase extracts of hydrolyzates were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the multiple reaction monitoring mode. The anti-inflammatory drug naproxen could be detected in all the six bream and roach bile samples. Diclofenac was found in five of the bream and roach samples, while ibuprofen was detected in three bream and two roach samples. The observed bile concentrations of diclofenac, naproxen, and ibuprofen in bream ranged from 6 to 95 ng mL(-1), 6 to 32 ng mL(-1), and 16 to 34 ng mL(-1), respectively. The corresponding values in roach samples ranged from 44 to 148 ng mL(-1), 11 to 103 ng mL(-1) and 15 to 26 ng mL(-1), respectively. None of the other studied compounds could be detected. The study shows that pharmaceuticals originating from wastewater treatment plant effluents can be traced to the bile of wild bream and roach living in a lake where diclofenac, naproxen, and ibuprofen are present as pollutants.

Cost analysis of flavocoxid compared to naproxen for management of mild to moderate OA.

PubMed

Walton, Surrey M; Schumock, Glen T; McLain, David Andrew

2010-09-01

Flavocoxid is a medical food used for the clinical dietary management of osteoarthritis (OA). The acquisition cost of flavocoxid is higher than most traditional, generic NSAIDs. However, flavocoxid may have more favorable gastrointestinal (GI) toxicity resulting in lower overall costs. These costs have not been previously examined. This study provides a decision analytic model to assess the net costs of using flavocoxid for OA from a Medicare perspective. A decision model was developed to estimate the total costs associated with flavocoxid versus naproxen for the management of Medicare patients with mild to moderate OA. Probabilities were obtained from literature and expert opinion, and costs were obtained from Medicare. Sensitivity analyses were conducted by varying probabilities and costs within clinically relevant ranges. The base case resulted in flavocoxid having lower total annual costs ($1482 per patient) compared to naproxen ($1592). Flavocoxid remained the lowest cost option when the cost inputs were varied by 25% (above and below the base case), and when the probability of GI events with flavocoxid were varied by 25%. However, when GI rates from the literature and implied relative risks from the expert panel were used, or if the cost of PPIs was $0, then naproxen was the less costly alternative, though saving less than the annual cost of flavocoxid. Key limitations were the limited outcomes in the model (only GI events), lack of consideration of adherence or combination therapy, and the reliance on expert opinion due to a lack of data for flavocoxid. In patients over 65 years of age who suffer from mild to moderate OA, flavocoxid may result in lower overall costs, despite a higher acquisition cost. Managed care organizations should consider total health care costs in the decision to include flavocoxid as a covered benefit.

Attempt to simultaneously generate three chiral centers in 4-hydroxyisoleucine with microbial carbonyl reductases.

PubMed

Hibi, Makoto; Takahashi, Koji; Kako, Junko; Wakita, Yuuta; Kodera, Tomohiro; Shimizu, Sakayu; Yokozeki, Kenzo; Ogawa, Jun

2018-04-01

A panel of microorganisms was screened for selective reduction ability towards a racemic mixture of prochiral 2-amino-3-methyl-4-ketopentanoate (rac-AMKP). Several of the microorganisms tested produced greater than 0.5mM 4-hydroxyisoleucine (HIL) from rac-AMKP, and the stereoselectivity of HIL formation was found to depend on the taxonomic category to which the microorganism belonged. The enzymes responsible for the AMKP-reducing activity, ApAR and FsAR, were identified from two of these microorganisms, Aureobasidium pullulans NBRC 4466 and Fusarium solani TG-2, respectively. Three AMKP reducing enzymes, ApAR, FsAR, and the previously reported BtHILDH, were reacted with rac-AMKP, and each enzyme selectively produced a specific composition of HIL stereoisomers. The enzymes appeared to have different characteristics in recognition of the stereostructure of the substrate AMKP and in control of the 4-hydroxyl group configuration in the HIL product. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enantiomeric composition of (3R)-(-)- and (3S)-(+)-linalool in various essential oils of Indian origin by enantioselective capillary gas chromatography-flame ionization and mass spectrometry detection methods.

PubMed

Chanotiya, Chandan S; Yadav, Anju

2009-04-01

Enantiomeric ratios of linalool have been determined in various authentic essential oils of Indian origin using 10% heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin as a chiral stationary phase. A complete enantiomeric excess (ee) for (3S)-(+)-linalool was characteristic of Lippia alba and Cinnamomum tamala leaf oils while less than 90% excess was noticed in Zanthoxylum armatum leaf, Zingiber roseum root/rhizome and Citrus sinensis leaf oils. On the contrary, an enantiomeric excess of (3R)-(-)-linalool characterizes essential oils of basil (100% for Ocimum basilicum) and bergamot mint (72 to 75% for Mentha citrata). Notably, some essential oils containing both enantiomers in equal ratios or in racemic forms are rose, geranium, lemongrass and Origanum. The enantiomeric composition studies are discussed as indicators of origin authenticity and quality of essential oil of Indian origin.

(R)-2-[(Dimethyl-amino)-meth-yl]-1,1'-bis-(diphenyl-phosphinothio-yl)ferrocene dichloromethane monsolvate.

PubMed

Philippe, Elisabeth; Manoury, Eric; Daran, Jean-Claude

2012-06-01

In the title compound, [Fe(C(20)H(21)NPS)(C(17)H(14)PS)]·CH(2)Cl(2), both cyclo-penta-dienyl (Cp) rings constituting the ferrocene unit are substituted by a sulfur-protected diphenyl-phosphine. One of the Cp ligands is additionally substituted by a dimethyl-amino-methyl group causing the chirality of the mol-ecule. Surprisingly, although the synthetic procedure yielded the title compound as a racemic mixture, the reported crystal is enanti-omerically pure with the R absolute configuration. The dimethyl-amino group is exo with respect to the Cp ring. Both diphenyl-thio-phosphine groups are trans with respect to the centroid-Fe-centroid direction. Weak intra-molecular C-H⋯S and C-H⋯π inter-actions between symmetry-related mol-ecules are observed. The contribution of the disordered solvent was removed from the refinement using SQUEEZE in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155].

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

PubMed Central

Jacques, Vincent; Czarnik, Anthony W.; Judge, Thomas M.; Van der Ploeg, Lex H. T.; DeWitt, Sheila H.

2015-01-01

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics. PMID:25775521

Racemic crystals of trolox derivatives compared to their chiral counterparts: Structural studies using solid-state NMR, DFT calculations and X-ray diffraction

NASA Astrophysics Data System (ADS)

Wałejko, P.; Paradowska, K.; Szeleszczuk, Ł.; Wojtulewski, S.; Baj, A.

2018-03-01

Trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) is a water-soluble vitamin E analogue that is available in enantiomeric forms R or S. Enantiomerically pure Trolox 1, its derivatives 2, 3 (R and S enantiomers) and racemic forms 1-3 were studied using solid-state 13C cross-polarisation (CP) magic angle spinning (MAS) NMR (13C CPMAS NMR). Gauge-including projector-augmented wave density functional theory (GIPAW DFT) calculations of the shielding constants supported the assignment of 13C resonances in the solid-state NMR spectra. For the 13C CPMAS NMR spectra of 1, resonances of pure enantiomers were significantly broader than those of the racemic R/S form. In order to explain these effects, five of the available crystal structures were analysed (1R/S, 3R/S, 2S and the newly measured 2R/S and 3S). Cyclic dimers with one R and one S enantiomer linked by two OHsbnd Odbnd C2b hydrogen bonds were formed in 1R/S. Similar hydrogen-bonded dimers were present in 3S but not in 3R/S, in which interactions are water-mediated. A comparison of X-ray diffraction, CPMAS NMR data and the DFT GIPAW calculations of racemic forms and pure enantiomers was conducted for the first time. Our results, particularly the solid-state NMR data, were discussed in relation to Wallach's rule, that the racemic crystal appears as more ordered than its chiral counterpart.

Chiral Polymers.

DTIC Science & Technology

1984-10-01

regardless of the method of polymerization. The styrene-bead copolymers were packed in HPLC columns, but none were especiall, effective in separating...enantiomers in a racemic mixture. The chiral butyrolactone polymer was coated on silica, but this material did not effect resolution of racemic mixtures in an...been effected utilizing chiral oxazolines3 prompted the initial efforts to synthesize various chiral 2-vinyl- oxazoline monomers for incorporation

Chemical synthesis of perfectly isotactic and high melting bacterial poly(3-hydroxybutyrate) from bio-sourced racemic cyclic diolide.

PubMed

Tang, Xiaoyan; Chen, Eugene Y-X

2018-06-11

Bacterial poly(3-hydroxybutyrate) (P3HB) is a perfectly isotactic, crystalline material possessing properties suitable for substituting petroleum plastics, but high costs and low volumes of its production are impractical for commodity applications. The chemical synthesis of P3HB via ring-opening polymerization (ROP) of racemic β-butyrolactone has attracted intensive efforts since the 1960s, but not yet produced P3HB with high isotacticity and molecular weight. Here, we report a route utilizing racemic cyclic diolide (rac-DL) derived from bio-sourced succinate. With stereoselective racemic catalysts, the ROP of rac-DL under ambient conditions produces rapidly P3HB with perfect isotacticity ([mm] > 99%), high melting temperature (T m  = 171 °C), and high molecular weight (M n  = 1.54 × 10 5  g mol -1 , Đ = 1.01). With enantiomeric catalysts, kinetic resolution polymerizations of rac-DL automatically stops at 50% conversion and yields enantiopure (R,R)-DL and (S,S)-DL with >99% e.e. and the corresponding poly[(S)-3HB] and poly[(R)-3HB] with high T m  = 175 °C.

Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats

PubMed Central

Uchida, Ryota; Okamoto, Hinako; Ikuta, Naoko; Terao, Keiji; Hirota, Takashi

2015-01-01

α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C0), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance. PMID:26402669

Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats.

PubMed

Uchida, Ryota; Okamoto, Hinako; Ikuta, Naoko; Terao, Keiji; Hirota, Takashi

2015-09-21

α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C₀), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance.

The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.

PubMed

Tracy, T S; Krohn, K; Jones, D R; Bradley, J D; Hall, S D; Brater, D C

1992-01-01

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.

[Treatment and prevention of erosive and ulcerative lesions in the stomach and duodenum caused by intake of non-steroidalanti-inflammatory drugs].

PubMed

Luzina, E V

2014-01-01

Therapy with non-steroidal anti-inflammatory drugs (NSAIDs) is a diffcult task. Good anti-inflammatory effect increases the risk of gastrointestinal complications with a frequency of 10-50%. The risk further increases with age (above 60-70 yr), the history of ulcer disease concomitant intake of acetylsalicylic acid, anticoagulants, and glucocorticosteroids. Long-term antisecretory therapy with proton pump inhibitors, e.g., esomeprazole, was shown to be an effective prophylactic tool. This drug maintains the intragastric pH value above 4 for 15 hr on the average. The risk of erosive and ulceraive lesions in the stomach and duodenum significantly decreases by selective cyclooxygenase-2 inhibitors, e.g., coxibs, that however increase the risk of thrombotic cardiovascular complications. The author proposes recommendations on the use of NSAIDs in the patients at risk of serious gastrointestinal and cardiovascular pathology. Naproxen in combination with proton pitmp inhibitors is the drug of choice among NSAIDs. Vimovo is a fixed combination of naproxen and esomeprazole. Results of comparative studies on the efficacy of vimovo and celecoxib are presented along with the data on the safety of this. combination compared with that of naproxen monotherapy

Adsorptive Removal of Pharmaceuticals and Personal Care Products from Water with Functionalized Metal-organic Frameworks: Remarkable Adsorbents with Hydrogen-bonding Abilities.

PubMed

Seo, Pill Won; Bhadra, Biswa Nath; Ahmed, Imteaz; Khan, Nazmul Abedin; Jhung, Sung Hwa

2016-10-03

Adsorption of typical pharmaceuticals and personal care products (PPCPs) (such as naproxen, ibuprofen and oxybenzone) from aqueous solutions was studied by using the highly porous metal-organic framework (MOF) MIL-101 with and without functionalization. Adsorption results showed that MIL-101s with H-donor functional groups such as -OH and -NH 2 were very effective for naproxen adsorption, despite a decrease in porosity, probably because of H-bonding between O atoms on naproxen and H atoms on the adsorbent. For this reason, MIL-101 with two functional groups capable of H-bonding (MIL-101-(OH) 2 ) exhibited remarkable adsorption capacity based on adsorbent surface area. The favorable contributions of -OH and -(OH) 2 on MIL-101 in the increased adsorption of ibuprofen and oxybenzone (especially based on porosity) confirmed again the importance of H-bonding mechanism. The adsorbent with the highest adsorption capacity, MIL-101-OH, was very competitive when compared with carbonaceous materials, mesoporous materials, and pristine MIL-101. Moreover, the MIL-101-OH could be recycled several times by simply washing with ethanol, suggesting potential application in the adsorptive removal of PPCPs from water.

Adsorptive Removal of Pharmaceuticals and Personal Care Products from Water with Functionalized Metal-organic Frameworks: Remarkable Adsorbents with Hydrogen-bonding Abilities

NASA Astrophysics Data System (ADS)

Seo, Pill Won; Bhadra, Biswa Nath; Ahmed, Imteaz; Khan, Nazmul Abedin; Jhung, Sung Hwa

2016-10-01

Adsorption of typical pharmaceuticals and personal care products (PPCPs) (such as naproxen, ibuprofen and oxybenzone) from aqueous solutions was studied by using the highly porous metal-organic framework (MOF) MIL-101 with and without functionalization. Adsorption results showed that MIL-101s with H-donor functional groups such as -OH and -NH2 were very effective for naproxen adsorption, despite a decrease in porosity, probably because of H-bonding between O atoms on naproxen and H atoms on the adsorbent. For this reason, MIL-101 with two functional groups capable of H-bonding (MIL-101-(OH)2) exhibited remarkable adsorption capacity based on adsorbent surface area. The favorable contributions of -OH and -(OH)2 on MIL-101 in the increased adsorption of ibuprofen and oxybenzone (especially based on porosity) confirmed again the importance of H-bonding mechanism. The adsorbent with the highest adsorption capacity, MIL-101-OH, was very competitive when compared with carbonaceous materials, mesoporous materials, and pristine MIL-101. Moreover, the MIL-101-OH could be recycled several times by simply washing with ethanol, suggesting potential application in the adsorptive removal of PPCPs from water.

Adsorptive Removal of Pharmaceuticals and Personal Care Products from Water with Functionalized Metal-organic Frameworks: Remarkable Adsorbents with Hydrogen-bonding Abilities

PubMed Central

Seo, Pill Won; Bhadra, Biswa Nath; Ahmed, Imteaz; Khan, Nazmul Abedin; Jhung, Sung Hwa

2016-01-01

Adsorption of typical pharmaceuticals and personal care products (PPCPs) (such as naproxen, ibuprofen and oxybenzone) from aqueous solutions was studied by using the highly porous metal-organic framework (MOF) MIL-101 with and without functionalization. Adsorption results showed that MIL-101s with H-donor functional groups such as –OH and –NH2 were very effective for naproxen adsorption, despite a decrease in porosity, probably because of H-bonding between O atoms on naproxen and H atoms on the adsorbent. For this reason, MIL-101 with two functional groups capable of H-bonding (MIL-101-(OH)2) exhibited remarkable adsorption capacity based on adsorbent surface area. The favorable contributions of –OH and –(OH)2 on MIL-101 in the increased adsorption of ibuprofen and oxybenzone (especially based on porosity) confirmed again the importance of H-bonding mechanism. The adsorbent with the highest adsorption capacity, MIL-101-OH, was very competitive when compared with carbonaceous materials, mesoporous materials, and pristine MIL-101. Moreover, the MIL-101-OH could be recycled several times by simply washing with ethanol, suggesting potential application in the adsorptive removal of PPCPs from water. PMID:27695005

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion-spheronization.

PubMed

Wang, Junlin; Kan, Shuling; Chen, Tong; Liu, Jianping

2015-03-01

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett-Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box-Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.

Application of London-type dispersion corrections to the solid-state density functional theory simulation of the terahertz spectra of crystalline pharmaceuticals.

PubMed

King, Matthew D; Buchanan, William D; Korter, Timothy M

2011-03-14

The effects of applying an empirical dispersion correction to solid-state density functional theory methods were evaluated in the simulation of the crystal structure and low-frequency (10 to 90 cm(-1)) terahertz spectrum of the non-steroidal anti-inflammatory drug, naproxen. The naproxen molecular crystal is bound largely by weak London force interactions, as well as by more prominent interactions such as hydrogen bonding, and thus serves as a good model for the assessment of the pair-wise dispersion correction term in systems influenced by intermolecular interactions of various strengths. Modifications to the dispersion parameters were tested in both fully optimized unit cell dimensions and those determined by X-ray crystallography, with subsequent simulations of the THz spectrum being performed. Use of the unmodified PBE density functional leads to an unrealistic expansion of the unit cell volume and the poor representation of the THz spectrum. Inclusion of a modified dispersion correction enabled a high-quality simulation of the THz spectrum and crystal structure of naproxen to be achieved without the need for artificially constraining the unit cell dimensions.

Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin.

PubMed

Beyer, Andreas; Grohganz, Holger; Löbmann, Korbinian; Rades, Thomas; Leopold, Claudia S

2015-10-27

To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co-amorphous systems are however limited to qualitative evaluations based on the corresponding X-ray powder diffractograms. Therefore, the objective of the study was to develop a quantification model based on X-ray powder diffractometry (XRPD), followed by a multivariate partial least squares regression approach that enables the simultaneous determination of up to four solid state fractions: crystalline naproxen, γ-indomethacin, α-indomethacin as well as co-amorphous naproxen-indomethacin. For this purpose, a calibration set that covers the whole range of possible combinations of the four components was prepared and analyzed by XRPD. In order to test the model performances, leave-one-out cross validation was performed and revealed root mean square errors of validation between 3.11% and 3.45% for the crystalline molar fractions and 5.57% for the co-amorphous molar fraction. In summary, even four solid state phases, involving one co-amorphous phase, can be quantified with this XRPD data-based approach.

Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs

PubMed Central

Li, Xuanwen; Fries, Susanne; Li, Ruizhi; Lawson, John A.; Propert, Kathleen J.; Diamond, Scott L.; Blair, Ian A.; FitzGerald, Garret A.; Grosser, Tilo

2014-01-01

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs—ibuprofen, naproxen, and celecoxib—to cause a drug–drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug–drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk. PMID:25385584

Biodegradation and bio-sorption of antibiotics and non-steroidal anti-inflammatory drugs using immobilized cell process.

PubMed

Yu, Tsung-Hsien; Lin, Angela Yu-Chen; Panchangam, Sri Chandana; Hong, Pui-Kwan Andy; Yang, Ping-Yi; Lin, Cheng-Fang

2011-08-01

In the present study, the removal mechanisms of four antibiotics (sulfamethoxazole, sulfadimethoxine, sulfamethazine, and trimethoprim) and four non-steroidal anti-inflammatory drugs (acetaminophen, ibuprofen, ketoprofen, and naproxen) in immobilized cell process were investigated using batch reactors. This work principally explores the individual or collective roles of biodegradation and bio-sorption as removal routes of the target pharmaceuticals and the results were validated by various experimental and analytical tools. Biodegradation and bio-sorption were found as dominant mechanisms for the drug removal, while volatilization and hydrolysis were negligible for all target pharmaceuticals. The target pharmaceuticals responded to the two observed removal mechanisms in different ways, typically: (1) strong biodegradability and bio-sorption by acetaminophen, (2) strong biodegradability and weak bio-sorption by sulfamethoxazole, sulfadimethoxine, ibuprofen and naproxen, (3) low biodegradability and weak bio-sorption by sulfamethazine and ketoprofen, and (4) low biodegradability and medium bio-sorption by trimethoprim. In the sorption/desorption experiment, acetaminophen, sulfamethoxazole and sulfadimethoxine were characterized by strong sorption and weak desorption. A phenomenon of moderate sorption and well desorption was observed for sulfamethazine, trimethoprim and naproxen. Both ibuprofen and ketoprofen were weakly sorbed and strongly desorbed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Supramolecular solid-phase extraction of ibuprofen and naproxen from sewage based on the formation of mixed supramolecular aggregates prior to their liquid chromatographic/photometric determination.

PubMed

Costi, Esther María; Goryacheva, Irina; Sicilia, María Dolores; Rubio, Soledad; Pérez-Bendito, Dolores

2008-11-07

Sorbents made up of sodium dodecyl sulphate (SDS) hemimicelles, formed onto gamma-alumina, were proposed for the quantitative and practically solvent-free solid-phase extraction (SPE) of ibuprofen and naproxen from sewage samples. The formation of drug-SDS mixed aggregates was proved by the pseudophase separation model and their composition as a function of the amount of drug was calculated. The overall hemimicellar SPE procedure consumed only 0.6 mL of methanol since non-organic solvent was required for cartridge conditioning and the drugs were completely eluted using 2 mL of a 0.3M NaOH:methanol (70:30, v/v) solution. Breakthrough volumes of around 0.75 L and above 1L were obtained for naproxen and ibuprofen, respectively. No clean-up steps were necessary for the determination of these drugs in sewage because the direct analysis of the eluates by liquid chromatography/UV was matrix effect-free. The identification of the analytes was based on retention times and UV spectra and it was confirmed by on-line fluorescence detection. The detection limits for naproxen and ibuprofen were 0.8 and 9 ng L(-1) in wastewater influents and 0.5 and 7 ng L(-1) in effluents, respectively. These limits were similar to or lower than those achieved by methods based on conventional sorbents (e.g. C(18)-silica or polymeric resins), which invariably require the evaporation of the eluates. The accuracy and precision of the proposed method were assessed by analysing influent and effluent wastewater samples spiked with 2 and 0.4 microg L(-1) of each analyte, respectively. The recoveries obtained and the corresponding standard deviations were in the ranges 93-101% and 2-9%. The method was applied to the determination of the target drugs in wastewater from three sewage treatment plants (STPs) in the south of Spain. The concentration of ibuprofen and naproxen ranged between 2.0 and 7.4 microg L(-1) and 0.9 and 3.3 microg L(-1) in influents and 0.4 and 1.4 microg L(-1) and 0.2 and 0.8 microg L(-1) in effluents, respectively.

Longitudinal Numbers-Needed-To-Treat (NNT) for Achieving Various Levels of Analgesic Response and Improvement with Etoricoxib, Naproxen, and Placebo in Ankylosing Spondylitis

PubMed Central

2011-01-01

Background Clinical analgesic trials typically report response as group mean results. However, research has shown that few patients are average and most have responses at the extremes. Moreover, group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level. Responder analyses and numbers-needed-to-treat (NNT) are considered more relevant for evaluating treatment response. We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improvement and the associated NNTs. Methods This was a post-hoc analysis of a 6-week, randomized, double-blind study (N = 387) comparing etoricoxib 90 mg, etoricoxib 120 mg, naproxen 1000 mg, and placebo in AS. Spine pain and BASDAI were measured on a 100-mm visual analog scale. The number and percentage of patients achieving ≥30% and ≥50% improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation. Results For etoricoxib 90 mg, etoricoxib 120 mg and naproxen 1000 mg, the NNTs at 6 weeks compared with placebo were 2.0, 2.0, and 2.7 respectively for BASDAI ≥30% improvement, and 3.2, 2.8, and 4.1 for ≥50% improvement. For spine pain, the NNTs were 1.9, 2.0, and 3.2, respectively, for ≥30% improvement, and 2.7, 2.5, and 3.7 for ≥50% improvement. The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinically meaningful difference for pain. Response rates and NNTs were generally similar and stable over 2, 4, and 6 weeks. Conclusions For every 2 patients treated with etoricoxib, 1 achieved a clinically meaningful (≥30%) improvement in spine pain and BASDAI beyond that expected from placebo, whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen. Use of NNTs and responder analyses provide additional, complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies. PMID:21767407

Synthesis, characterization and crystal structure of (2RS,4R)-2-(2-hydroxy-3-methoxyphenyl)thiazolidine-4-carboxylic acid

NASA Astrophysics Data System (ADS)

Muche, Simon; Müller, Matthias; Hołyńska, Małgorzata

2018-03-01

The condensation reaction of ortho-vanillin and L-cysteine leads to formation of a racemic mixture of (2RS,4R)-2-(2-hydroxy-3-methoxyphenyl)thiazolidine-4-carboxylic acid and not, as reported in the available literature, to a Schiff base. The racemic mixture was fully characterized by 1D and 2D NMR techniques, ESI-MS and X-ray diffraction. Addition of ZnCl2 led to formation of crystals in form of colorless needles, suitable for X-ray diffraction studies. The measured crystals were identified as the diastereomer (2R,4R)-2-(2-hydroxy-3-methoxyphenyl)thiazolidine-4-carboxylic acid 1. The bulk material is racemic. Thiazolidine exists as zwitterion in solid state, as indicated by the crystal structure.

Dynamic Kinetic Resolution of Allylic Sulfoxides by Rh-Catalyzed Hydrogenation: A Combined Theoretical and Experimental Mechanistic Study

PubMed Central

Dornan, Peter K.; Kou, Kevin G. M.; Houk, K. N.; Dong, Vy M.

2014-01-01

A dynamic kinetic resolution (DKR) of allylic sulfoxides has been demonstrated by combining the Mislow [2,3]-sigmatropic rearrangement with catalytic asymmetric hydrogenation. The efficiency of our DKR was optimized by using low pressures of hydrogen gas to decrease the rate of hydrogenation relative to the rate of sigmatropic rearrangement. Kinetic studies reveal that the rhodium complex acts as a dual-role catalyst and accelerates the substrate racemization while catalyzing olefin hydrogenation. Scrambling experiments and theoretical modeling support a novel mode of sulfoxide racemization which occurs via a rhodium π-allyl intermediate in polar solvents. In non-polar solvents, however, the substrate racemization is primarily uncatalyzed. Computational studies suggest that the sulfoxide binds to rhodium via O–coordination throughout the catalytic cycle for hydrogenation. PMID:24350903

Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial.

PubMed

Chan, Francis K L; Ching, Jessica Y L; Tse, Yee Kit; Lam, Kelvin; Wong, Grace L H; Ng, Siew C; Lee, Vivian; Au, Kim W L; Cheong, Pui Kuan; Suen, Bing Y; Chan, Heyson; Kee, Ka Man; Lo, Angeline; Wong, Vincent W S; Wu, Justin C Y; Kyaw, Moe H

2017-06-17

Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT00153660. Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3-9·2) in the celecoxib group and 12·3% (8·8-17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23-0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. The Research Grant Council of Hong Kong. Copyright © 2017 Elsevier Ltd. All rights reserved.

Total chemical synthesis and X-ray structure of kaliotoxin by racemic protein crystallography.

PubMed

Pentelute, Brad L; Mandal, Kalyaneswar; Gates, Zachary P; Sawaya, Michael R; Yeates, Todd O; Kent, Stephen B H

2010-11-21

Here we report the total synthesis of kaliotoxin by 'one pot' native chemical ligation of three synthetic peptides. A racemic mixture of D- and L-kaliotoxin synthetic protein molecules gave crystals in the centrosymmetric space group P1 that diffracted to atomic-resolution (0.95 Å), enabling the X-ray structure of kaliotoxin to be determined by direct methods.

Calibration of amino acid racemization (AAR) kinetics in United States mid-Atlantic Coastal Plain Quaternary mollusks using 87Sr/ 86Sr analyses: Evaluation of kinetic models and estimation of regional Late Pleistocene temperature history

USGS Publications Warehouse

Wehmiller, J.F.; Harris, W.B.; Boutin, B.S.; Farrell, K.M.

2012-01-01

The use of amino acid racemization (AAR) for estimating ages of Quaternary fossils usually requires a combination of kinetic and effective temperature modeling or independent age calibration of analyzed samples. Because of limited availability of calibration samples, age estimates are often based on model extrapolations from single calibration points over wide ranges of D/L values. Here we present paired AAR and 87Sr/ 86Sr results for Pleistocene mollusks from the North Carolina Coastal Plain, USA. 87Sr/ 86Sr age estimates, derived from the lookup table of McArthur et al. [McArthur, J.M., Howarth, R.J., Bailey, T.R., 2001. Strontium isotopic stratigraphy: LOWESS version 3: best fit to the marine Sr-isotopic curve for 0-509 Ma and accompanying Look-up table for deriving numerical age. Journal of Geology 109, 155-169], provide independent age calibration over the full range of amino acid D/L values, thereby allowing comparisons of alternative kinetic models for seven amino acids. The often-used parabolic kinetic model is found to be insufficient to explain the pattern of racemization, although the kinetic pathways for valine racemization and isoleucine epimerization can be closely approximated with this function. Logarithmic and power law regressions more accurately represent the racemization pathways for all amino acids. The reliability of a non-linear model for leucine racemization, developed and refined over the past 20 years, is confirmed by the 87Sr/ 86Sr age results. This age model indicates that the subsurface record (up to 80m thick) of the North Carolina Coastal Plain spans the entire Quaternary, back to ???2.5Ma. The calibrated kinetics derived from this age model yield an estimate of the effective temperature for the study region of 11??2??C., from which we estimate full glacial (Last Glacial Maximum - LGM) temperatures for the region on the order of 7-10??C cooler than present. These temperatures compare favorably with independent paleoclimate information for the region. ?? 2011 Elsevier B.V.

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride.

PubMed

Shehata, Mostafa A; Fawaz, Esraa M; El-Rahman, Mohamed K Abd; Abdel-Moety, Ezzat M

2017-11-30

Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm ® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and the merits of these benign real-time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described. Copyright © 2017 Elsevier B.V. All rights reserved.

Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates.

PubMed

Vouga, Alexandre; Gregg, Ryan A; Haidery, Maryah; Ramnath, Anita; Al-Hassani, Hassan K; Tallarida, Christopher S; Grizzanti, David; Raffa, Robert B; Smith, Garry R; Reitz, Allen B; Rawls, Scott M

2015-04-01

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100-1000 μM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 μM) and racemate (100 μM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 μM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 μM) produced EPC that was abolished when S-MEPH (100 μM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 μM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 μM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own. Copyright © 2014 Elsevier Ltd. All rights reserved.

Oligopeptides and copeptides of homochiral sequence, via beta-sheets, from mixtures of racemic alpha-amino acids, in a one-pot reaction in water; relevance to biochirogenesis.

PubMed

Illos, Roni A; Bisogno, Fabricio R; Clodic, Gilles; Bolbach, Gerard; Weissbuch, Isabelle; Lahav, Meir

2008-07-09

As part of our studies on the biochirogenesis of peptides of homochiral sequence during early evolution, the formation of oligopeptides composed of 14-24 residues of the same handedness in the polymerization of dl-leucine (Leu), dl-phenylalanine (Phe), and dl-valine (Val) in aqueous solutions, by activation with N, N'-carbonyldiimidazole and then initiation with a primary amine, in a one-pot reaction, was demonstrated by MALDI-TOF MS using deuterium enantio-labeled alpha-amino acids. The formation of long isotactic peptides is rationalized by the following steps occurring in tandem: (i) creation of a library of short diasteroisomeric oligopeptides containing isotactic peptides in excess in comparison to a binomial kinetics, as a result of an asymmetric induction exerted by the N-terminal residue of a given handedness; (ii) precipitation of the less soluble racemic isotactic penta- and hexapeptides in the form of beta-sheets that are delineated by homochiral rims; (iii) regio-enantiospecific chain elongation occurring heterogeneously at the beta-sheets/solution interface. Polymerization of l-Leu with l-isoleucine (Ile) or l-Phe with l- (1) N-Me-histidine yielded mixtures of copeptides containing both residues. In contrast, in the polymerization of the corresponding mixtures of l- + d-alpha-amino acids, the long oligopeptides were composed mainly from oligo- l-Leu and oligo- d-Ile in the first system and oligo- d-Phe in the second. Furthermore, in the polymerization of mixtures of hydrophobic racemic alpha-amino acids dl-Leu, dl-Val, and dl-Phe and with added racemic dl-alanine and dl-tyrosine, copeptides of homochiral sequences are most dominantly represented. Possible routes for a spontaneous "mirror-symmetry breaking" process of the racemic mixtures of homochiral peptides are presented.

Fe uptake from meso and D,L-racemic Fe(o,o-EDDHA) isomers by strategy I and II plants.

PubMed

Cerdán, Mar; Alcañiz, Sara; Juárez, Margarita; Jordá, Juana D; Bermúdez, Dolores

2006-02-22

One of the most efficient fertilizers to correct Fe deficiency in calcareous soils and waters with high bicarbonate content is based on ferric ethylenediamine-N,N'-bis(o-hydroxyphenylacetic) acid [Fe(o,o-EDDHA)]. Fe(o,o-EDDHA) forms two groups of geometric isomers known as meso and D,L-racemic. To determine the Fe uptake from meso and D,L-racemic Fe(o,o-EDDHA), four iron-efficient plants, two plants representative of strategy I (tomato and pepper) and two plants representative of strategy II (wheat and oats), were grown in hydroponic culture. Results indicated that strategy II plants took up iron from both Fe(o,o-EDDHA) isomers equally. However, strategy I plants took mainly the iron associated with the meso form (the lowest stability isomer).

Synthesis, Biological Evaluation, and Molecular Docking of (R)-2-((8-(3-aminopiperidin-1-yl)-3-methyl-7-(3-methylbut-2-en-1-yl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)benzonitrile as Dipeptidyl Peptidase IV Inhibitors.

PubMed

Ran, Yan; Pei, Heying; Shao, Mingfeng; Chen, Lijuan

2016-02-01

Type 2 diabetes (T2D) is classified as a major metabolic disorder, which has affected approximately 194 million people worldwide. DPP-IV inhibitors as a new therapy have shown several advantages over traditional antidiabetic drugs. Based on the similar binding modes of Alogliptin and Linagliptin, molecular operation was conducted via combining pharmacophore hybridization with structural optimization between the two market drugs and racemic compounds 40 and 43 were reported as DPP-IV inhibitors in our previous studies. But the majority of DPP-IV inhibitors have developed into a small molecule with certain conformation; in this study, we described the synthesis, biological evaluation, and molecular docking of corresponding enantiomers of compounds 40 and 43. The most potent inhibitor is (R)-40 (IC50  = 23.5 nm, F = 74.67%, T1/2  = 4 h), which exhibited moderate antihyperglycemic activity as compared to the standard antidiabetic drug Linagliptin in OGTT. In addition, compound (R)-40 effectively improved the pathological state of DIO mice. Molecular docking studies clarified the favorable binding affinity between compound (R)-40 and DPP-IV active site. Thus, compound (R)-40 would be entitled to further development as a drug candidate on the basis of the suitable pharmacokinetic (PK) and desirable pharmacodynamic (PD) profiles. © 2015 John Wiley & Sons A/S.

Removal of ibuprofen, naproxen and carbamazepine in aqueous solution onto natural clay: equilibrium, kinetics, and thermodynamic study

NASA Astrophysics Data System (ADS)

Khazri, Hassen; Ghorbel-Abid, Ibtissem; Kalfat, Rafik; Trabelsi-Ayadi, Malika

2017-10-01

This study aimed to describe the adsorption of three pharmaceuticals compounds (ibuprofen, naproxen and carbamazepine) onto natural clay on the basis of equilibrium parameters such as a function of time, effect of pH, varying of the concentration and the temperature. Adsorption kinetic data were modeled using the Lagergren's first-order and the pseudo-second-order kinetic equations. The kinetic results of adsorption are described better using the pseudo-second order model. The isotherm results were tested in the Langmuir, Freundlich and Dubinin-Radushkevich models. The thermodynamic parameters obtained indicate that the adsorption of pharmaceuticals on the clay is a spontaneous and endothermic process.

Silica-Immobilized Enzyme Reactors

DTIC Science & Technology

2007-08-01

relief from the symptoms of inflammation and pain Silica-IMERs 10 and is the mode of action of drugs such as aspirin and ibuprofen .[61] Serotonin...supports and using the enantiomeric selectivity of the enzyme to resolve racemic mixtures.[100] Immobilization onto supports with various pore sizes and...activity (~37%) and used as a packed- bed IMER to catalyze the racemic resolution of (S)-ketoprofen from its constituent enantiomers . The optically pure (S

Chemo-enzymatic Baeyer-Villiger oxidation of 4-methylcyclohexanone via kinetic resolution of racemic carboxylic acids: direct access to enantioenriched lactone.

PubMed

Drożdż, Agnieszka; Chrobok, Anna

2016-01-21

A new method for the asymmetric chemo-enzymatic Baeyer-Villiger oxidation of prochiral 4-methylcyclohexanone to (R)-4-methylcaprolactone in the presence of (±)-4-methyloctanoic acid, Candida Antarctica lipase B and 30% aq. H2O2 has been developed. A mechanism for the asymmetric induction based on kinetic resolution of racemic carboxylic acids is proposed.

Ipsenol, ipsdienol, ethanol, and á-pinene: trap lure blend for Cerambycidae and Buprestidae (Coleoptera) in pine forests of eastern North America

Treesearch

D. R. Miller; C. M. Crowe; K. J. Dodds; L. D. Galligan; P. de Groot; E. R. Hoebeke; A. E. Mayfield; T. M. Poland; K. F. Raffa; J. D. Sweeney

2015-01-01

In 2007-2008, we examined the flight responses of wood-boring beetles (Coleoptera: Cerambycidae and Buprestidae) to multiple-funnel traps baited with the pine volatiles, ethanol, and apinene [85% (–)], and the bark beetle pheromones, racemic ipsenol and racemic ipsdienol. Experiments were conducted in mature pine stands in Canada (Ontario and New Brunswick) and the...

Age estimation based on aspartic acid racemization in human sclera.

PubMed

Klumb, Karolin; Matzenauer, Christian; Reckert, Alexandra; Lehmann, Klaus; Ritz-Timme, Stefanie

2016-01-01

Age estimation based on racemization of aspartic acid residues (AAR) in permanent proteins has been established in forensic medicine for years. While dentine is the tissue of choice for this molecular method of age estimation, teeth are not always available which leads to the need to identify other suitable tissues. We examined the suitability of total tissue samples of human sclera for the estimation of age at death. Sixty-five samples of scleral tissue were analyzed. The samples were hydrolyzed and after derivatization, the extent of aspartic acid racemization was determined by gas chromatography. The degree of AAR increased with age. In samples from younger individuals, the correlation of age and D-aspartic acid content was closer than in samples from older individuals. The age-dependent racemization in total tissue samples proves that permanent or at least long-living proteins are present in scleral tissue. The correlation of AAR in human sclera and age at death is close enough to serve as basis for age estimation. However, the precision of age estimation by this method is lower than that of age estimation based on the analysis of dentine which is due to molecular inhomogeneities of total tissue samples of sclera. Nevertheless, the approach may serve as a valuable alternative or addition in exceptional cases.

A resolution approach of racemic phenylalanine with aqueous two-phase systems of chiral tropine ionic liquids.

PubMed

Wu, Haoran; Yao, Shun; Qian, Guofei; Yao, Tian; Song, Hang

2015-10-30

Aqueous two-phase systems (ATPS) based on tropine type chiral ionic liquids and inorganic salt solution were designed and prepared for the enantiomeric separation of racemic phenylalanine. The phase behavior of IL-based ATPS was comprehensive investigated, and phase equilibrium data were correlated by Merchuk equation. Various factors were also systematically investigated for their influence on separation efficiency. Under the appropriate conditions (0.13g/g [C8Tropine]pro, 35mg/g Cu(Ac)2, 20mg/g d,l-phenylalanine, 0.51g/g H2O and 0.30g/g K2HPO4), the enantiomeric excess value of phenylalanine in solid phase (mainly containing l-enantiomer) was 65%. Finally, the interaction mechanism was studied via 1D and 2D NMR. The results indicate that d-enantiomer of phenylalanine interacts more strongly with chiral ILs and Cu(2+) based on the chiral ion-pairs space coordination mechanism, which makes it tend to remain in the top IL-rich phase. By contrast, l-enantiomer is transferred into the solid phase. Above chiral ionic liquids aqueous two-phase systems have demonstrated obvious resolution to racemic phenylalanine and could be promising alterative resolution approach for racemic amino acids in aqueous circumstance. Copyright © 2015. Published by Elsevier B.V.

Characterization and quantification of racemic and meso-ethylenediamine-N,N'-bis(2-hydroxy-5-sulfophenylacetic) acid/iron (III) by ion-pair ultra-high performance liquid chromatography coupled with diode array detector and electrospray tandem mass spectrometry.

PubMed

Biasone, Alessandro; Cianci, Giusto; Di Tommaso, Donata; Piaggesi, Alberto; Tagliavini, Emilio; Galletti, Paola; Moretti, Fabio

2013-03-22

EDDHSA/Fe is a promising substitute of EDDHA/Fe to fight iron chlorosis. o,o-EDDHSA structure contains two chiral carbons giving the racemic and meso couples of stereoisomers. Ion-pair HPLC and UHPLC-UV/Vis-ESI-MS/MS methods were developed for the determination of racemic and meso-o,o-EDDHSA/Fe in commercial samples of chelates. The lack of a commercial EDDHSA standard was overcome by sulfonation of a commercial available o,o-EDDHA standard and subsequent quantification by (1)H-NMR. Assignment of configurations was carried out starting from racemic and meso-o,o-EDDHA/Fe by direct sulfonation to give the corresponding o,o-EDDHSA/Fe isomers. The performances of these methods were assessed in terms of intra and inter-day precision, linearity and selectivity. The high selectivity and lower detection limit (nanomolar) of the UHPLC-ESI-MS/MS method could allow to deepen the knowledge relative to meso and rac-o,o-EDDHSA/Fe interactions with plants, its fate in different soil conditions, its mobility and other environmental aspects. Copyright © 2013 Elsevier B.V. All rights reserved.

Design, development, and optimization of polymeric based-colonic drug delivery system of naproxen.

PubMed

Sharma, Pooja; Chawla, Anuj; Pawar, Pravin

2013-01-01

The aim of present investigation deals with the development of time-dependent and pH sensitive press-coated tablets for colon specific drug delivery of naproxen. The core tablets were prepared by wet granulation method then press coated with hydroxypropyl cellulose (HPC) or Eudragit RSPO : RLPO mixture and further coated with Eudragit S-100 by dip immerse method. The in vitro drug release study was conducted in different dissolution media such as pH 1.2, 6.8, and 7.4 with or without rat caecal content to simulate GIT conditions. Surface morphology and cross-sectional view of the tablets were visualized by scanning electron microscopy (SEM). All prepared batches were in compliance with the pharmacopoeial standards. The tablets which are compression coated with HPC followed by Eudragit S-100 coated showed highest in vitro drug release of 98.10% in presence of rat caecal content. The SEM of tablets suggested that the number of pores got increased in pH 7.4 medium followed by dissolution of coating layer. The tablets coat erosion study suggested that the lag time depends upon the coating concentrations of polymers. A time-dependent hydrophilic polymer and pH sensitive polymer based press-coated tablets of naproxen were promising delivery for colon targeting.

Occurrence and risk assessment of pharmaceutically active compounds in wastewater treatment plants. A case study: Seville city (Spain).

PubMed

Santos, J L; Aparicio, I; Alonso, E

2007-05-01

The occurrence of four anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen and naproxen), an antiepileptic drug (carbamazepine) and a nervous stimulant (caffeine) in influent and effluent samples from four wastewater treatment plants (WWTPs) in Seville was evaluated. Removal rates in the WWTPs and risk assessment of the pharmaceutically active compounds have been studied. Analytical determination was carried out by high performance liquid chromatography (HPLC) with diode array (DAD) and fluorescence (Fl) detectors after sample clean up and concentration by solid phase extraction. All pharmaceutically active compounds, except diclofenac, were detected not only in wastewater influents but also in wastewater effluents. Mean concentrations of caffeine, carbamazepine, ketoprofen and naproxen ranged between 0.28-11.44 microg l(-1) and 0.21-2.62 microg l(-1) in influent and effluent wastewater, respectively. Ibuprofen was present in the highest concentrations in the range 12.13-373.11 microg l(-1) and 0.78-48.24 microg l(-1) in influent and effluent wastewater, respectively. Removal rates of the pharmaceuticals ranged between 6 and 98%. Risk quotients, expressed as ratios between the measured environmental concentration (MEC) and the predicted no effect concentrations (PNEC) were higher than 1 for ibuprofen and naproxen in influent wastewater and for ibuprofen in effluent wastewater.

Removal of selected non-steroidal anti-inflammatory drugs (NSAIDs), gemfibrozil, carbamazepine, beta-blockers, trimethoprim and triclosan in conventional wastewater treatment plants in five EU countries and their discharge to the aquatic environment.

PubMed

Paxéus, N

2004-01-01

The removal of commonly used pharmaceuticals (ibuprofen, naproxen, diclofenac, gemfibrozil, carbamazepine, atenolol, metoprolol and trimethoprim) and a biocide (triclosan) in operating wastewater treatment plants in five EU countries has been studied. Under normal operating conditions the acidic drugs and triclosan were partially removed with removal rates varying from ca. 20 to >95%. The highest removal rate was found for ibuprofen and triclosan (>90%) followed by naproxen (80%), gemfibrozil (55%) and diclofenac (39%). Ibuprofen undergoes an oxidative transformation to corresponding hydroxy- and carboxy-metabolites, which contributes to its high removal rate. Disturbances in the activated sludge process resulted in lower removal rates for all acidic drugs, mostly for diclofenac (<10% removed) but also for ibuprofen (<60% removed). The treatment of wastewaters by activated sludge usually did not result in any practical removal (<10%) of neutral carbamazepine or basic atenolol, metoprolol and trimethoprim. The removal rates of the investigated drugs and triclosan are discussed in terms of mechanisms responsible for their removal. Discharges of carbamazepine, diclofenac, gemfibrozil, naproxen, triclosan and trimethoprim from WWTPs to the aquatic environment, expressed as the average concentration in the effluent and the daily discharged quantity per person served by WWTPs were assessed.

Efficacy and safety of Derris scandens Benth extracts in patients with knee osteoarthritis.

PubMed

Kuptniratsaikul, Vilai; Pinthong, Theerawut; Bunjob, Malee; Thanakhumtorn, Sunee; Chinswangwatanakul, Pornsiri; Thamlikitkul, Visanu

2011-02-01

The objectives of this study were to determine the efficacy and safety of Derris scandens Benth extracts in pain reduction and functional improvement in patients with knee osteoarthritis (OA). This was a prospective, randomized, controlled trial, single-blinded (assessor). The study was conducted at the Rehabilitation Medicine Department, Siriraj Hospital. One hundred and seven (107) patients with primary OA knee who had pain score of ≥ 5 were recruited. Patients were randomized to receive naproxen 500 mg/day or Derris 800 mg/day for 4 weeks. Western Ontario McMaster Osteoarthritis Index (WOMAC) scores and 6-minute walking distance were the outcome measurements. Fifty-five (55) and 52 patients were randomized to Derris and naproxen groups, respectively. The mean differences of all WOMAC scores between 2 groups at week 4 adjusted by week 0 were within ± 1 point. The mean scores of the aforementioned outcomes at weeks 0, 2, and 4 were significantly improved compared to the baseline values. There was no difference of WOMAC scores between groups. The gastrointestinal irritation and dyspepsia were observed more often in the naproxen than in the Derris group. Derris scandens Benth extracts were efficacious and safe for the treatment of knee OA.

Design, Development, and Optimization of Polymeric Based-Colonic Drug Delivery System of Naproxen

PubMed Central

Sharma, Pooja; Chawla, Anuj; Pawar, Pravin

2013-01-01

The aim of present investigation deals with the development of time-dependent and pH sensitive press-coated tablets for colon specific drug delivery of naproxen. The core tablets were prepared by wet granulation method then press coated with hydroxypropyl cellulose (HPC) or Eudragit RSPO : RLPO mixture and further coated with Eudragit S-100 by dip immerse method. The in vitro drug release study was conducted in different dissolution media such as pH 1.2, 6.8, and 7.4 with or without rat caecal content to simulate GIT conditions. Surface morphology and cross-sectional view of the tablets were visualized by scanning electron microscopy (SEM). All prepared batches were in compliance with the pharmacopoeial standards. The tablets which are compression coated with HPC followed by Eudragit S-100 coated showed highest in vitro drug release of 98.10% in presence of rat caecal content. The SEM of tablets suggested that the number of pores got increased in pH 7.4 medium followed by dissolution of coating layer. The tablets coat erosion study suggested that the lag time depends upon the coating concentrations of polymers. A time-dependent hydrophilic polymer and pH sensitive polymer based press-coated tablets of naproxen were promising delivery for colon targeting. PMID:24198725

Different Covalent Immobilizations Modulate Lipase Activities of Hypocrea pseudokoningii.

PubMed

Pereira, Marita G; Velasco-Lozano, Susana; Moreno-Perez, Sonia; Polizeli, Aline M; Heinen, Paulo R; Facchini, Fernanda D A; Vici, Ana C; Cereia, Mariana; Pessela, Benevides C; Fernandez-Lorente, Gloria; Guisan, Jose M; Jorge, João A; Polizeli, Maria de Lourdes T M

2017-09-04

Enzyme immobilization can promote several advantages for their industrial application. In this work, a lipase from Hypocrea pseudokoningii was efficiently linked to four chemical supports: agarose activated with cyanogen bromide (CNBr), glyoxyl-agarose (GX), MANAE-agarose activated with glutaraldehyde (GA) and GA-crosslinked with glutaraldehyde. Results showed a more stable lipase with both the GA-crosslinked and GA derivatives, compared to the control (CNBr), at 50 °C, 60 °C and 70 °C. Moreover, all derivatives were stabilized when incubated with organic solvents at 50%, such as ethanol, methanol, n -propanol and cyclohexane. Furthermore, lipase was highly activated (4-fold) in the presence of cyclohexane. GA-crosslinked and GA derivatives were more stable than the CNBr one in the presence of organic solvents. All derivatives were able to hydrolyze sardine, açaí ( Euterpe oleracea ), cotton seed and grape seed oils. However, during the hydrolysis of sardine oil, GX derivative showed to be 2.3-fold more selectivity (eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio) than the control. Additionally, the types of immobilization interfered with the lipase enantiomeric preference. Unlike the control, the other three derivatives preferably hydrolyzed the R -isomer of 2-hydroxy-4-phenylbutanoic acid ethyl ester and the S -isomer of 1-phenylethanol acetate racemic mixtures. On the other hand, GX and CNBr derivatives preferably hydrolyzed the S -isomer of butyryl-2-phenylacetic acid racemic mixture while the GA and GA-crosslink derivatives preferably hydrolyzed the R -isomer. However, all derivatives, including the control, preferably hydrolyzed the methyl mandelate S -isomer. Moreover, the derivatives could be used for eight consecutive cycles retaining more than 50% of their residual activity. This work shows the importance of immobilization as a tool to increase the lipase stability to temperature and organic solvents, thus enabling the possibility of their application at large scale processes.

Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats.

PubMed

Okada, K; Kanoh, H; Mohri, K

2011-10-01

Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA. The amounts of (S)-BOP-G in CFA+ rats were 2.7-fold larger than that in CFA- rats. Although (R)-BOP-T was excreted in CFA- rats, BOP-T could not be detected in CFA+ rats. Plasma clearance values of racemic BOP and (S)-BOP in CFA+ rats were 5-fold and 6-fold larger than those in CFA- rats, respectively. (S)-BOP-G formation activities were higher than (R)-BOP-G formation activities in both CFA+and CFA- microsomes. These findings suggest that CFA increases biliary excretion of (S)-BOP-G and facilitates plasma elimination of BOP, and further suggests that CFA predominantly induces chiral inversion to S rather than metabolic reaction to (R)-BOP-T, resulting in an increase of (S)-BOP-G.

Application and comparison of high-speed countercurrent chromatography and high performance liquid chromatography in preparative enantioseparation of α-substitution mandelic acids

PubMed Central

Tong, Shengqiang; Zhang, Hu; Shen, Mangmang; Ito, Yoichiro; Yan, Jizhong

2014-01-01

Preparative enantioseparations of α-cyclopentylmandelic acid and α-methylmandelic acid by high-speed countercurrent chromatography (HSCCC) and high performance liquid chromatography (HPLC) were compared using hydroxypropy-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as the chiral mobile phase additives. In preparative HPLC the enantioseparation was achieved on the ODS C18 reverse phase column with the mobile phase composed of a mixture of acetonitrile and 0.10 mol L−1 phosphate buffer at pH 2.68 containing 20 mmol L−1 HP-β-CD for α-cyclopentylmandelic acid and 20 mmol L−1 SBE-β-CD for α-methylmandelic acid. The maximum sample size for α-cyclopentylmandelic acid and α-methylmandelic acid was only about 10 mg and 5 mg, respectively. In preparative HSCCC the enantioseparations of these two racemates were performed with the two-phase solvent system composed of n-hexane-methyl tert.-butyl ether-0.1 molL−1 phosphate buffer solution at pH 2.67 containing 0.1 mol L−1 HP-β-CD for α-cyclopentylmandelic acid (8.5:1.5:10, v/v/v) and 0.1 mol L−1 SBE-β-CD for α-methylmandelic acid (3:7:10, v/v/v). Under the optimum separation conditions, total 250 mg of racemic α-cyclopentylmandelic acid could be completely enantioseparated by HSCCC with HP-β-CD as a chiral mobile phase additive in a single run, yielding 105-110 mg of enantiomers with 95-98% purity and 85-90% recovery. But, no complete enantioseparation of α-methylmandelic acid was achieved by preparative HSCCC with either of the chiral selectors due to their limited enantioselectivity. In this paper preparative enantioseparation by HSCCC and HPLC was compared from various aspects. PMID:25983356

Application and comparison of high-speed countercurrent chromatography and high performance liquid chromatography in preparative enantioseparation of α-substitution mandelic acids.

PubMed

Tong, Shengqiang; Zhang, Hu; Shen, Mangmang; Ito, Yoichiro; Yan, Jizhong

2015-04-01

Preparative enantioseparations of α-cyclopentylmandelic acid and α-methylmandelic acid by high-speed countercurrent chromatography (HSCCC) and high performance liquid chromatography (HPLC) were compared using hydroxypropy-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as the chiral mobile phase additives. In preparative HPLC the enantioseparation was achieved on the ODS C 18 reverse phase column with the mobile phase composed of a mixture of acetonitrile and 0.10 mol L -1 phosphate buffer at pH 2.68 containing 20 mmol L -1 HP-β-CD for α-cyclopentylmandelic acid and 20 mmol L -1 SBE-β-CD for α-methylmandelic acid. The maximum sample size for α-cyclopentylmandelic acid and α-methylmandelic acid was only about 10 mg and 5 mg, respectively. In preparative HSCCC the enantioseparations of these two racemates were performed with the two-phase solvent system composed of n -hexane-methyl tert. -butyl ether-0.1 molL -1 phosphate buffer solution at pH 2.67 containing 0.1 mol L -1 HP-β-CD for α-cyclopentylmandelic acid (8.5:1.5:10, v/v/v) and 0.1 mol L -1 SBE-β-CD for α-methylmandelic acid (3:7:10, v/v/v). Under the optimum separation conditions, total 250 mg of racemic α-cyclopentylmandelic acid could be completely enantioseparated by HSCCC with HP-β-CD as a chiral mobile phase additive in a single run, yielding 105-110 mg of enantiomers with 95-98% purity and 85-90% recovery. But, no complete enantioseparation of α-methylmandelic acid was achieved by preparative HSCCC with either of the chiral selectors due to their limited enantioselectivity. In this paper preparative enantioseparation by HSCCC and HPLC was compared from various aspects.

Synthesis and evaluation of the racemate and individual enantiomers of C-11 labeled methylphenidate as radioligands for the presynaptic dopaminergic neuron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Y.S.; Fowler, J.S.; Volkow, N.D.

1994-05-01

Methylphenidate (MP, ritalin) is a psychostimulant drug widely used to treat attention deficit hyperactivity disorder and narcolepsy. Its therapeutic properties are attributed to inhibition of the dopamine (DA) transporter enhancing synaptic DA. MP has two chiral centers and is marketed as the dl-threo racemic form. However, its pharmacological activity is believed due solely to the d-enantiomer. We have synthesized [{sup 11}C]d,l-threo-methylphenidate ([{sup 11}C]MP) in order to examine its pharmacokinetics in vivo and to examine its suitability as a radioligand for PET studies of the presynaptic DA neuron. [{sup 11}C]MP was prepared by O-{sup 11}C-alkylation of a protected derivative of ritalinicmore » acid with labeled methyl iodide. Serial studies at baseline and after treatment with methylphenidate (0.5 mg/kg, 20 min prior); GBR 12909 (1.5 mg/kg; 30 min prior); tomoxetine (1.5 mg/kg, 20 min prior) and citalopram (2.0 mg/kg, 30 min prior) were performed to assess non-specific binding and binding to the DA, norepinephrine and serotonin transporters respectively. Only MP and GBR 12909 changed the SR/CB distribution volume ratio (decrease of 38 and 37% respectively) demonstrating selectivity for DA transporters over other monoamine transporters. We then pursued the synthesis of enantiomerically pure C-{sup 11} labeled d- and l-MP by using enantiomerically pure protected d- and l-ritalinic acids as precursors. A striking difference in SR/CB ratio (3.3 and 1.1 for d- and l-respectively at 1 hr. after i.v. injections) strongly suggests that the pharmacological specificity of MP resides entirely in the d-isomer and the binding of l-isomer was mostly non-specific. Further evaluations are underway. Radioligand reversibility, selectivity and the fact that MP is an approved drug are advantages of using [{sup 11}C]MP.« less

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

Piroxicam in acute musculoskeletal disorders and sports injuries.

PubMed

Heere, L P

1988-05-20

Approximately 20 percent of athletes have an acute or chronic injury related to their sport. In acute musculoskeletal disorders, inflammation is an important component of the symptomatology. Recent clinical studies are showing that nonsteroidal anti-inflammatory drugs (NSAIDs) can significantly reduce inflammation and help speed return to full function. In an international study, the efficacy and toleration of piroxicam were compared with that of indomethacin, naproxen, and aspirin in three multicenter, double-blind, parallel studies involving a total of 1,290 patients with acute sprains and tendinitis. The centers compared piroxicam 40 mg once daily for the first two days followed by 20 mg once daily for the remainder of the studies. This regimen was compared with either indomethacin, 50 mg three times per day for two days and 25 mg three times per day for the remainder of the treatment period; naproxen 500 mg twice daily for two days followed by 250 mg in the morning and 500 mg in the evening thereafter; or aspirin 4 g per day for the duration of the study. Treatment normally lasted 14 days; the minimal duration was seven days, with a maximum of 28 days. Overall assessment of efficacy was excellent or good in more than 80 percent of patients. Statistical differences were seen favoring piroxicam over aspirin (p less than 0.05) regarding reduction in tenderness and resumption of daily activities within 16 days (p less than 0.02). The study comparing piroxicam and naproxen showed a statistically significant difference in favor of piroxicam (p less than 0.025). There was no difference between piroxicam and indomethacin in the number of patients who were able to accomplish normal daily activity within 16 days. Furthermore, although efficacy was comparable among the NSAIDs, piroxicam was significantly better-tolerated than either naproxen or indomethacin. Piroxicam was also better-tolerated than aspirin, but a statistical difference was not reached.

Naproxen, paracetamol and pamabrom versus paracetamol, pyrilamine and pamabrom in primary dysmenorrhea: a randomized, double-blind clinical trial.

PubMed

Ortiz, Mario I; Murguía-Cánovas, Gabriela; Vargas-López, Laura C; Silva, Rodolfo; González-de la Parra, Mario

2016-10-24

Dysmenorrhea is caused by the discharge of prostaglandins into the uterine tissue; therefore, non-steroidal anti-inflammatory drugs (NSAIDs) are the established initial therapy for dysmenorrhea. Dysmenorrhea therapy may include the administration of drug monotherapy or combination therapy. However, clinical scientific evidence on the efficacy of medications with two or three drugs combined is scarce or nonexistent. To evaluate and compare the efficacy and safety of two oral fixed-dose combinations for the relief of the symptoms of primary dysmenorrhea among Mexican women. One of the combinations is widely used in Mexico (paracetamol, pyrilamine and pamabrom) and the selected comparison was a medication with naproxen sodium, paracetamol and pamabrom based on the pathophysiology of primary dysmenorrhea. This was a single-centre, double blind, experimental, parallel group, randomized trial. Female patients with primary dysmenorrhea, older than 17 years and with pain intensity greater than 45 mm on a visual analogue scale, were included. The patients were then randomized to receive tablets with naproxen sodium, paracetamol and pamabrom or tablets with paracetamol, pyrilamine and pamabrom for one menstrual cycle. Patient evaluations of symptomatology and pain intensity were recorded throughout one menstrual period. Descriptive and inferential statistical analyses were utilized. An intention-to-treat population of 91 women, with a mean age of 21.3 ± 3.2 years, received paracetamol, pyrilamine and pamabrom tablets, and 98 participants, with a mean age of 21.0 ± 3.2 years, received naproxen sodium, paracetamol and pamabrom tablets. The participants’ assessments of pain on the Visual Analogue Scale during the menstrual cycle demonstrated a significant reduction in both treatment groups (p<0.05). There is no significant difference in efficacy between both groups (p>0.05). The results showed that both drug combinations were not different in reducing dysmenorrheic pain. Likewise, both treatments were well tolerated. Therefore, both treatments may be used for the treatment of primary dysmenorrhea.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

Responses of Cerambycidae and other insects to traps baited with ethanol, 2,3-hexanediol, and 3,2-hydroxyketone lures in north-central Georgia

Treesearch

Dan Miller; Christopher Crowe; P. D. Mayo; P. J. Silk; J. D. Sweeney

2015-01-01

In north-central Georgia, 13 species of woodboring beetles (Coleoptera: Cerambycidae: Cerambycinae) were attracted to multiple-funnel traps baited with ethanol and one of the following pheromones: (1) racemic 3-hydroxyhexan-2-one; (2) racemic 3-hydroxyoctan-2-one; and (3) syn-2,3-hexanediol. The following species were attracted to traps baited with ethanol and 3-...

Green chiral HPLC enantiomeric separations using high temperature liquid chromatography and subcritical water on Chiralcel OD and Chiralpak AD.

PubMed

Droux, Serge; Félix, Guy

2011-01-01

We report here the application of subcritical water in chiral separations on two popular polysaccharide chiral stationary phases (CSPs): Chiralpak AD and Chiralcel OD. The behavior of these two CSPs was studied under reversed phase conditions at room temperature to discover the maximum percentage of water in the mobile phase, which provided the separation of enantiomers of flavanone and benzoin, respectively, in a reasonable time (i.e., less than 1 h). Then, the stability of Chiralpak AD and Chiralcel OD versus temperature was investigated and discussed. Chiralcel OD separation of flavanone racemate was obtained at 120 °C with water and 2-propanol (80/20) as the mobile phase, while benzoin racemate was separated in pure water at 160 °C. Separations of several racemates were also presented, and advantages and limitations of the technique were discussed. Copyright © 2011 Wiley Periodicals, Inc.

Aminostratigraphy and faunal correlations of late Quaternary marine terraces, Pacific Coast, USA

USGS Publications Warehouse

Kennedy, G.L.; Lajoie, K.R.; Wehmiller, J.F.

1982-01-01

Recent studies using the extent of racemization of amino acids to date fossil mollusc shells in the Arctic1, the British Isles2 and on the Atlantic3,4 and Pacific5-13 coasts of North America have relied mainly on theoretical kinetic models of racemization. Ages generated in this fashion are highly model dependent and require estimates of integrated long-term diagenetic temperatures. We present here an alternative, empirical approach to aminostratigraphy in which we plot amino acid enantiomeric ratios versus latitude (for localities along the Pacific coast of the United States), and generate isochronal correlations by connecting data points of geographically proximal localities that have similar D:L ratios and zoogeographic aspect. Isochrons are calibrated at a few localities by independent radiometric dates. The diagenetic temperature effect on racemization is reflected in the slope of the isochrons, but the need to quantify temperature is eliminated. ?? 1982 Nature Publishing Group.

A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bunker, Richard D.; Mandal, Kalyaneswar; Bashiri, Ghader

Racemic protein crystallography was used to determine the X-ray structure of the predicted Mycobacterium tuberculosis protein Rv1738, which had been completely recalcitrant to crystallization in its natural L-form. Native chemical ligation was used to synthesize both L-protein and D-protein enantiomers of Rv1738. Crystallization of the racemic {D-protein + L-protein} mixture was immediately successful. The resulting crystals diffracted to high resolution and also enabled facile structure determination because of the quantized phases of the data from centrosymmetric crystals. The X-ray structure of Rv1738 revealed striking similarity with bacterial hibernation factors, despite minimal sequence similarity. As a result, we predict that Rv1738,more » which is highly up-regulated in conditions that mimic the onset of persistence, helps trigger dormancy by association with the bacterial ribosome.« less

A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography

DOE PAGES

Bunker, Richard D.; Mandal, Kalyaneswar; Bashiri, Ghader; ...

2015-04-07

Racemic protein crystallography was used to determine the X-ray structure of the predicted Mycobacterium tuberculosis protein Rv1738, which had been completely recalcitrant to crystallization in its natural L-form. Native chemical ligation was used to synthesize both L-protein and D-protein enantiomers of Rv1738. Crystallization of the racemic {D-protein + L-protein} mixture was immediately successful. The resulting crystals diffracted to high resolution and also enabled facile structure determination because of the quantized phases of the data from centrosymmetric crystals. The X-ray structure of Rv1738 revealed striking similarity with bacterial hibernation factors, despite minimal sequence similarity. As a result, we predict that Rv1738,more » which is highly up-regulated in conditions that mimic the onset of persistence, helps trigger dormancy by association with the bacterial ribosome.« less

Changes in the solid state of anhydrous and hydrated forms of sodium naproxen under different grinding and environmental conditions: Evidence of the formation of new hydrated forms.

PubMed

Censi, Roberta; Rascioni, Riccardo; Di Martino, Piera

2015-05-01

The aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability. The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

Enantioselective cyclization of racemic supramolecular polymers.

PubMed

ten Cate, A Tessa; Dankers, Patricia Y W; Kooijman, Huub; Spek, Anthony L; Sijbesma, Rint P; Meijer, E W

2003-06-11

Homochiral hydrogen-bonded cyclic assemblies are formed in dilute solutions of racemic supramolecular polymers based on the quadruple hydrogen bonding 2-ureido-4[1H]-pyrimidinone unit, as observed by 1H NMR and SEC experiments. Preorganization of the monomers and the combined binding strength of the eight hydrogen bonds result in a very high stability of the cyclic aggregates with pronounced selectivity between homochiral and heterochiral cyclic species, usually only observed in crystalline or liquid crystalline phases.

Less common applications of simulated moving bed chromatography in the pharmaceutical industry.

PubMed

Huthmann, E; Juza, M

2005-10-21

Simulated moving bed (SMB) chromatography is often perceived in the pharmaceutical industry as chromatographic method for separating binary mixtures, like racemates. However, SMB can also be used for unbalanced separations, i.e. binary mixtures of varying compositions and multi-component mixtures. These less common application modes of isocratic SMB chromatography are exemplified for four different compounds (racemates and diastereomers) and discussed in view of the so-called 'triangle theory' from an industrial perspective.

Trimeprazine is enantioselectively degraded by an activated sludge in ready biodegradability test conditions.

PubMed

Escuder-Gilabert, Laura; Martín-Biosca, Yolanda; Perez-Baeza, Mireia; Sagrado, Salvador; Medina-Hernández, María José

2018-05-09

A great number of available pharmaceuticals are chiral compounds. Although they are usually manufactured as racemic mixtures, they can be enantioselectively biodegraded as a result of microbial processes. In this paper, a biodegradability assay in similar conditions to those recommended in OECD tests of enantiomers of trimeprazine (a phenothiazine employed as a racemate) is carried out. Experiments were performed in batch mode using a minimal salts medium inoculated with an activated sludge (collected from a Valencian Waste Water Treatment Plant, WWTP) and supplemented with the racemate. The concentration of the enantiomers of trimeprazine were monitored by means of a chiral HPLC method using a cellulose-based chiral stationary phase and 0.5 M NaClO 4 /acetonitrile (60:40, v/v) mobile phases. Experiments were performed at three concentration levels of the racemate. In parallel, the optical density at 600 nm (OD600) was measured to control the biomass growth and to connect it with enantioselectivity. The calculated enantiomeric fractions (EF) offer the first evidence of enantioselective biodegradation of trimeprazine. A simplified Monod equation was used as a curve fitting approach for concentration (S), biodegradation (BD), and for the first time, EF experimental data in order to expand the usefulness of the results. Precision studies on S (repeatability conditions) and, for the first time, EF (intermediate precision conditions) were also performed. Copyright © 2018 Elsevier Ltd. All rights reserved.

Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni').

PubMed

Brandt, Simon D; Baumann, Michael H; Partilla, John S; Kavanagh, Pierce V; Power, John D; Talbot, Brian; Twamley, Brendan; Mahony, Olivia; O'Brien, John; Elliott, Simon P; Archer, Roland P; Patrick, Julian; Singh, Kuldip; Dempster, Nicola M; Cosbey, Simon H

2014-01-01

During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4'-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction. While aminorex and 4-methylaminorex (4-MAR) are known psychostimulants, nothing is known about the comparatively new para-methyl analog. Analytical characterization of two independent samples obtained from online vendors confirmed the presence of the (±)-cis isomer that also appeared to be associated with at least 18 of the 26 deaths. Extensive characterizations included crystal structure analysis, single, tandem, and high-resolution mass spectrometry, liquid and gas chromatography, and nuclear magnetic resonance spectroscopy. For the work described here, both the (±)-cis and (±)-trans racemates were also synthesized, confirming that the differentiation between these two forms was straight-forward. Monoamine transporter activity was studied using rat brain synaptosomes which included the comparison with d-amphetamine, aminorex and (±)-cis-4-MAR. (±)-cis-4,4'-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 ± 1.1 nM (DAT), 26.9 ± 5.9 nM (NET) and 18.5 ± 2.8 nM (SERT), respectively. The potency of (±)-cis-4,4'-DMAR at DAT and NET rivalled that of other psychomotor stimulant drugs like d-amphetamine and aminorex. However, (±)-cis-4,4'-DMAR had much more potent actions at SERT and activity at SERT varied more than 100-fold across the four drugs. The potent releasing activity of (±)-cis-4,4'-DMAR at all three monoamine transporters predicts a potential for serious side-effects such as psychotic symptoms, agitation, hyperthermia and cardiovascular stimulation, especially after high-dose exposure or following combination with other psychostimulants. Copyright © 2014 John Wiley & Sons, Ltd.

Production of natural antioxidants from vegetable oil deodorizer distillates: effect of catalytic hydrogenation.

PubMed

Pagani, María Ayelén; Baltanás, Miguel A

2010-02-01

Natural tocopherols are one of the main types of antioxidants found in living creatures, but they also have other critical biological functions. The biopotency of natural (+)-alpha-tocopherol (RRR) is 36% higher than that of the synthetic racemic mixture and 300% higher than the SRR stereoisomer. Vegetable oil deodorizer distillates (DD) are an excellent source of natural tocopherols. Catalytic hydrogenation of DD preconcentrates has been suggested as a feasible route for recovery of tocopherols in high yield. However, it is important to know whether the hydrogenation operation, as applied to these tocopherol-rich mixtures, is capable of preserving the chiral (RRR) character, which is critical to its biopotency. Fortified (i.e., (+)-alpha-tocopherol enriched) sunflower oil and methyl stearate, as well as sunflower oil DD, were fully hydrogenated using commercial Ni and Pd catalysts (120-180 degrees C; 20-60 psig). Products were analyzed by chiral HPLC. Results show that the desired chiral configuration (RRR) is fully retained. Thus, the hydrogenation route can be safely considered as a valid alternative for increasing the efficiency of tocopherol recovery processes from DDs while preserving their natural characteristics.

L-Altruronic acid formed by epimerization of D-galacturonic acid methyl esters during saponification of citrus pectin.

PubMed

Zhan, D; Qiu, F; Mort, A J

2001-02-15

While searching for oligosaccharides containing rhamnose residues in the endopolygalacturonase (EPG) digest of saponified citrus pectin, we found several oligomers containing, in addition to galacturonic acid, a sugar previously unreported in pectin. The 1- and 2-D 1H NMR spectra of the oligosaccharides were consistent with the sugar being a uronic acid with its 2- and 3-hydroxyls being axial and 4-hydroxyl being equatorial. MALDI-TOF mass spectrometry indicated that the oligomers consisted solely of uronic acids. Reduction of the uronic acids in the oligosaccharides converted them to galactose and altrose. The altrose was found to be the L enantiomer by comparison of its trimethylsilyl (-)-2-butyl glycosides to those of authentic D-altrose and a racemic mixture. The sugar was not found in oligosaccharides prepared from EPG digestion of citrus pectin deesterified with pectin methylesterase rather than saponification. Thus, it appears that during saponification, a small proportion of the methylesterified galacturonic acid residues in pectins is epimerized at C-5 leading to formation of L-altruronic acid residues.

C-H bond activation of hydrocarbons by an imidozirconocene complex.

PubMed

Hoyt, Helen M; Michael, Forrest E; Bergman, Robert G

2004-02-04

Monomeric imidozirconocene complexes of the type Cp2(L)Zr=NCMe3 (Cp = cyclopentadienyl, L = Lewis base) have been shown to activate the carbon-hydrogen bonds of benzene, but not the C-H bonds of saturated hydrocarbons. To our knowledge, this singularly important class of C-H activation reactions has heretofore not been observed in imidometallocene systems. The M=NR bond formed on heating the racemic ethylenebis(tetrahydro)indenyl methyl tert-butyl amide complex, however, cleanly and quantitatively activates a wide range of n-alkane, alkene, and arene C-H bonds. Mechanistic experiments support the proposal of intramolecular elimination of methane followed by a concerted addition of the hydrocarbon C-H bond. Products formed by activation of sp2 C-H bonds are generally more thermodynamically stable than those formed by activation of sp3 C-H bonds, and those resulting from reaction at primary C-H bonds are preferred over secondary sp3 C-H activation products. There is also evidence that thermodynamic selectivity among C-H bonds is sterically rather than electronically controlled.

(R)-2-[(Dimethyl­amino)­meth­yl]-1,1′-bis­(diphenyl­phosphinothio­yl)ferrocene dichloromethane monsolvate

PubMed Central

Philippe, Elisabeth; Manoury, Eric; Daran, Jean-Claude

2012-01-01

In the title compound, [Fe(C20H21NPS)(C17H14PS)]·CH2Cl2, both cyclo­penta­dienyl (Cp) rings constituting the ferrocene unit are substituted by a sulfur-protected diphenyl­phosphine. One of the Cp ligands is additionally substituted by a dimethyl­amino­methyl group causing the chirality of the mol­ecule. Surprisingly, although the synthetic procedure yielded the title compound as a racemic mixture, the reported crystal is enanti­omerically pure with the R absolute configuration. The dimethyl­amino group is exo with respect to the Cp ring. Both diphenyl­thio­phosphine groups are trans with respect to the centroid–Fe–centroid direction. Weak intra­molecular C—H⋯S and C—H⋯π inter­actions between symmetry-related mol­ecules are observed. The contribution of the disordered solvent was removed from the refinement using SQUEEZE in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148–155]. PMID:22719348

Determination by HPLC fluorescence analysis of the natural enantiomers of sex pheromones in the New World screwworm fly, Cochliomyia hominivorax.

PubMed

Akasaka, K; Carlson, D A; Ohtaka, T; Ohrui, H; Mori, K; Berkebile, D R

2009-06-01

Bioassays of six racemic synthesized candidate sex pheromone compounds against male New World screwworm Cochliomyia hominivorax (Coquerel) flies showed that the most potent bioactivity was found with 6-acetoxy-19-methylnonacosane and 7-acetoxy-15-methylnonacosane compared with four other isomeric acetoxy nonacosanes and a larger aliphatic ketone. As all these methyl-branched compounds have two asymmetric carbons and four possible enantiomers, characterization of the natural enantiomers was essential. All four enantiomers for the two most bioactive isomers of the natural sex pheromone were synthesized for bioassay. Hydrolysis and derivatization of these enantiomers with different fluorescent reagents was followed by column-switched high-performance liquid chromatography. The use of two linked, reversed-phase columns of different polarity held at sub-ambient temperatures allowed good separation of each enantiomer. This analysis applied to natural material was successful, as (6R,19R)-6-acetoxy-19-methylnonanocosane, and (7R,15R)- and (7R,15S)-7-acetoxy-15-methylnonanocosane were detected in extracts of recently colonized female flies.

Screening of Microorganisms Producing Cold-Active Oxidoreductases to Be Applied in Enantioselective Alcohol Oxidation. An Antarctic Survey

PubMed Central

Araújo, Lidiane S.; Kagohara, Edna; Garcia, Thaís P.; Pellizari, Vivian H.; Andrade, Leandro H.

2011-01-01

Several microorganisms were isolated from soil/sediment samples of Antarctic Peninsula. The enrichment technique using (RS)-1-(phenyl)ethanol as a carbon source allowed us to isolate 232 psychrophile/psychrotroph microorganisms. We also evaluated the enzyme activity (oxidoreductases) for enantioselective oxidation reactions, by using derivatives of (RS)-1-(phenyl)ethanol as substrates. Among the studied microorganisms, 15 psychrophile/psychrotroph strains contain oxidoreductases that catalyze the (S)-enantiomer oxidation from racemic alcohols to their corresponding ketones. Among the identified microorganisms, Flavobacterium sp. and Arthrobacter sp. showed excellent enzymatic activity. These new bacteria strains were selected for optimization study, in which the (RS)-1-(4-methyl-phenyl)ethanol oxidation was evaluated in several reaction conditions. From these studies, it was observed that Flavobacterium sp. has an excellent enzymatic activity at 10 °C and Arthrobacter sp. at 15 and 25 °C. We have also determined the growth curves of these bacteria, and both strains showed optimum growth at 25 °C, indicating that these bacteria are psychrotroph. PMID:21673897

Buyid Silk and the Tale of Bibi Shahrbanu: Identification of Biomarkers of Artificial Aging (Forgery) of Silk.

PubMed

Moini, Mehdi; Rollman, Christopher M

2017-10-03

Buyid silk forgery is one of the most famous silk forgeries in the world. In 1924-1925, excavation of the Bibi Shahrbanu site in Iran unearthed several silk textiles. The silks were thought to be of the Buyid period (934-1062 BCE) of the Persian Empire and have since been known as the "Buyid silks". In the 1930s, more silk appeared and was reported as being from the Buyid period as well. Controversy over the authenticity of these silks escalated after the purchase of the silks by museums throughout the world. Extensive investigations of several of these silks have been conducted over the years with respect to iconography, weaving patterns, dyes/mordant, style, and even radiocarbon dating. It was found that most of the silks are not from Buyid period. To test the authenticity of these silk fabrics, the recently developed silk dating technique using amino acid racemization (AAR) in conjunction with capillary electrophoresis mass spectrometry was applied to 13 Buyid silk specimens from the Textile Museum collections. Among these silk specimens, the AAR ratios of only one specimen were consistent with authentic silk fabrics collected from various museums. In addition, the aspartic acid racemization ratio of this specimen was also consistent with its 14 C dating. The other "Buyid silks" showed excessive levels of amino acid racemization not only for aspartic acid, but also for phenylalanine and tyrosine, inconsistent with racemization rates of these amino acids in authentic historical silk fabrics. Treatment of modern silk with a base at different pH and temperature reproduced the AAR pattern of the Buyid silks, implying that chemical treatment with a base at relatively high temperatures was perhaps the method used to artificially age these fabrics. The results imply that the racemization ratios of aspartic acid, phenylalanine, and tyrosine can be used as biomarkers for identification of naturally versus artificially aged silk.

Binding of long-lasting local anesthetics to lipid emulsions.

PubMed

Mazoit, Jean-Xavier; Le Guen, Régine; Beloeil, Hélène; Benhamou, Dan

2009-02-01

Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 +/- 3.8 to 46 +/- 2.8 for bupivacaine, and to a lesser extent from 51 +/- 4.0 to 31 +/- 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 microM for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 microM for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37 degrees C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics. The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.

D:L-AMINO Acids and the Turnover of Microbial Biomass

NASA Astrophysics Data System (ADS)

Lomstein, B. A.; Braun, S.; Mhatre, S. S.; Jørgensen, B. B.

2015-12-01

Decades of ocean drilling have demonstrated wide spread microbial life in deep sub-seafloor sediment, and surprisingly high microbial cell numbers. Despite the ubiquity of life in the deep biosphere, the large community sizes and the low energy fluxes in the vast buried ecosystem are still poorly understood. It is not know whether organisms of the deep biosphere are specifically adapted to extremely low energy fluxes or whether most of the observed cells are in a maintenance state. Recently we developed and applied a new culture independent approach - the D:L-amino acid model - to quantify the turnover times of living microbial biomass, microbial necromass and mean metabolic rates. This approach is based on the built-in molecular clock in amino acids that very slowly undergo chemical racemization until they reach an even mixture of L- and D- forms, unless microorganisms spend energy to keep them in the L-form that dominates in living organisms. The approach combines sensitive analyses of amino acids, the unique bacterial endospore marker (dipicolinic acid) with racemization dynamics of stereo-isomeric amino acids. Based on a heating experiment, we recently reported kinetic parameters for racemization of aspartic acid, glutamic acid, serine and alanine in bulk sediment from Aarhus Bay, Denmark. The obtained racemization rate constants were faster than the racemization rate constants of free amino acids, which we have previously applied in Holocene sediment from Aarhus Bay and in up to 10 mio yr old sediment from ODP Leg 201. Another important input parameter for the D:L-amino acid model is the cellular carbon content. It has recently been suggested that the cellular carbon content most likely is lower than previously thought. In recognition of these new findings, previously published data based on the D:L-amino acid model were recalculated and will be presented together with new data from an Arctic Holocene setting with constant sub-zero temperatures.

Aspartic acid racemization in dentin of the third molar for age estimation of the Chaoshan population in South China.

PubMed

Chen, Shisheng; Lv, Yanyi; Wang, Dian; Yu, Xiaojun

2016-09-01

Aspartic acid racemization in teeth has been increasingly used to estimate chronological age with a considerably high accuracy in forensic practice. The Chaoshan population in South China is relatively isolated in geography, and has specific lifestyle and dietary inhibits. It is still unknown whether this method is suitable for this population. The aim of this study was to analyze the relationship between chronological age and the d/l aspartic acid ratio in dentin in the third molar tooth of the Chaoshan population. Fifty-eight non-carious third molar teeth (31 mandibles and 27 maxillae), from 58 living individuals of known age (24 males and 34 females), were retrieved. Dentin was extracted from these teeth. The d- and l-aspartic acids in dentins were separated and detected by high performance liquid chromatography (HPLC). Linear regression was performed between the d/l aspartic acid ratio of dentins and chronological age. Results showed that the correlation coefficient (r) was 0.969, and the mean absolute error (MAE) was 2.19 years, its standard deviation (SD) was ±1.53 years, indicating excellent correlation. There was no significant difference in racemization rates of dentin between sexes (P=0.113, F=2.6), or between mandibles and maxillae (P=0.964, F=0.000). Results indicate that the ratio of the d and l forms of aspartic acid of dentins, in the third molar, is closely correlated with chronological age, special lifestyle do no obviously affect the accuracy of the age estimations by aspartic acid racemization of the dentin in the third molar and that aspartic acid racemization in the third molar dentin can be used as an accurate method to estimate chronological age in the Chaoshan population in South China. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Assessment of the use of racemic ketamine and its S(+) isomer, associated or not with low doses of fentanyl, in balneotherapy for major burn patients].

PubMed

Cantinho, Fernando Antônio de Freitas; Silva, Antonio Carlos Pereira da

2009-01-01

The care of the wounds of major burn patients triggers severe painful stimuli. The objective of this study was to assess the safety and efficacy of different drug combinations in anesthesia for balneotherapy. After approval by the Ethics Commission, 200 procedures of balneotherapy in 87 major burn adult patients were evaluated. Midazolam was used in all cases. The vials of ketamine were numbered and, therefore, at the time of the use, one did not know whether racemic or S(+)ketamine was being used. Each morning it was decided by drawing lots whether fentanyl would be used or not in the procedures of that day. Patients were included in one of four groups: ISO/sf (S(+) isomer without fentanyl), ISO/cf (S(+) isomer with fentanyl), RAC/sf (racemic ketamine without fentanyl), and RAC/cf (racemic ketamine with fentanyl). The initial doses proposed were as follows: midazolam, 0.06 mg.kg-1; ketamine, 1.0 to 1.1 mg.kg-1; and fentanyl, 0.8 (1/4)g.kg1-1; additional doses were administered as needed. Only one patient recalled the pain of balneotherapy. In the group that received S(+)ketamine, the use of fentanyl did not bring additional advantages; however, when associated with racemic ketamine, fentanyl reduced the total dose and the number of ketamine boluses. The extension of body surface burned was the main determinant of the severity of post-procedure pain. Reduced pain severity was the main factor considered by patients when grading their satisfaction with the anesthesia. The four different drug combinations proved to be safe and guaranteed the absence of pain during balneotherapy. Characteristics not directly related to the anesthetics proved to be more important in the incidence of post-procedure pain, which was the main factor considered by major burn patient to define their satisfaction with the anesthesia used.

[Study of selegiline and related compounds with x-ray diffraction].

PubMed

Simon, K; Böcskei, Z; Török, Z

1992-09-01

Selegiline and its parent compounds were studied by X-ray diffraction. It was established that the racemates of primary and secondary amines (p-fluoro-amphetamine, methamphetamine, p-fluoro-methamphetamine) hydrochloride do not form racemic compounds but crystalline as conglomerates, at the same time tertiary amines like selegiline and p-fluoro-selegiline hydrochlorides do. The crystalline structure of five enantiomeric hydrochlorides were determined, the CPhe-C-C-N torsion angle is anti-periplanar in all cases but in p-fluoro-amphetamine where it is gauche.

Absolute configuration and crystal packing for three chiral drugs prone to spontaneous resolution: Guaifenesin, methocarbamol and mephenesin

NASA Astrophysics Data System (ADS)

Bredikhin, Alexander A.; Gubaidullin, Aidar T.; Bredikhina, Zemfira A.; Krivolapov, Dmitry B.; Pashagin, Alexander V.; Litvinov, Igor A.

2009-02-01

Popular chiral drugs, guaifenesin, methocarbamol, and mephenesin were investigated by single-crystal X-ray analysis both for enantiopure and racemic samples. The absolute configurations for all substances were established through Flack parameter method. The conglomerate-forming nature for the compounds was confirmed by equivalence of crystal characteristics of enantiopure and racemic samples. The molecular structures and crystal packing details were evaluated and compared with one another for all three investigated substances.

Dynamic Kinetic Asymmetric Transformations of β-Stereogenic-α-Keto Esters via Direct Aldolization

PubMed Central

Corbett, Michael T.; Johnson, Jeffrey S.

2014-01-01

Dynamic kinetic asymmetric transformations (DyKAT) of racemic β-bromo-α-keto esters via direct aldolization of nitromethane and acetone provide access to fully substituted α-glycolic acid derivatives bearing a β-stereocenter. The aldol adducts are obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions. Mechanistic studies determined that the reactions proceed through a facile catalyst-mediated racemization of the β-bromo-α-keto esters under a DyKAT Type I manifold. PMID:24222195

Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process.

PubMed

Ji, Yue; Shi, Lei; Chen, Mu-Wang; Feng, Guang-Shou; Zhou, Yong-Gui

2015-08-26

A concise deracemization of racemic secondary and tertiary amines with a tetrahydroisoquinoline core has been successfully realized by orchestrating a redox process consisted of N-bromosuccinimide oxidation and iridum-catalyzed asymmetric hydrogenation. This compatible redox combination enables one-pot, single-operation deracemization to generate chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 98% ee in 93% yield, offering a simple and scalable synthetic technique for chiral amines directly from racemic starting materials.

Interactions between ethanol, syn-2,3-hexanediol, 3-hydroxyhexan-2-one, and 3-hydroxyoctan-2-one lures on trap catches of hardwood longhorn beetles in southeastern united states

Treesearch

D R Miller; C M Crowe; P D Mayo; L S Reid; P J Silk; J D Sweeney

2017-01-01

The effectiveness of a four-component “super lure” consisting of ethanol (E) and the cerambycid pheromones syn-2,3-hexanediol (D6), racemic 3-hydroxyhexan-2-one (K6), and racemic 3-hydroxyoctan-2-one (K8) on trap catches of Cerambycidae (Coleoptera) was determined in southeast United States with seven trapping experiments in 2011–2013. We captured...

Stereoselective oxidation of racemic 1-arylethanols by basil cultured cells of Ocimum basilicum cv. Purpurascens.

PubMed

Itoh, Ken-ichi; Nakamura, Kaoru; Utsukihara, Takamitsu; Sakamaki, Hiroshi; Horiuchi, C Akira

2008-05-01

The biotransformation of racemic 1-phenylethanol (30 mg) with plant cultured cells of basil (Ocimum basilicum cv. Purpurascens, 5 g wet wt) by shaking 120 rpm at 25 degrees C for 7 days in the dark gave (R)-(+)-1-phenylethanol and acetophenone in 34 and 24% yields, respectively. The biotransformation can be applied to other 1-arylethanols and basil cells oxidized the (S)-alcohols to the corresponding ketones remaining the (R)-alcohols in excellent ee.

Direct Conjugation of Emerging Contaminants in Arabidopsis: Indication for an Overlooked Risk in Plants?

PubMed

Fu, Qiuguo; Zhang, Jianbo; Borchardt, Dan; Schlenk, Daniel; Gan, Jay

2017-06-06

Agricultural use of treated wastewater, biosolids, and animal wastes introduces a multitude of contaminants of emerging concerns (CECs) into the soil-plant system. The potential for food crops to accumulate CECs depends largely on their metabolism in plants, which at present is poorly understood. Here, we evaluated the metabolism of naproxen and ibuprofen, two of the most-used human drugs from the Profen family, in Arabidopsis thaliana cells and the Arabidopsis plant. The complementary use of high-resolution mass spectrometry and 14 C labeling allowed the characterization of both free and conjugated metabolites, as well as nonextractable residues. Naproxen and ibuprofen, in their parent form, were conjugated quickly and directly with glutamic acid and glutamine, and further with peptides, in A. thaliana cells. For example, after 120 h, the metabolites of naproxen accounted for >90% of the extractable chemical mass, while the intact parent itself was negligible. The structures of glutamate and glutamine conjugates were confirmed using synthesized standards and further verified in whole plants. Amino acid conjugates may easily deconjugate, releasing the parent molecule. This finding highlights the possibility that the bioactivity of such CECs may be effectively preserved through direct conjugation, a previously overlooked risk. Many other CECs are also carboxylic acids, such as the profens. Therefore, direct conjugation may be a common route for plant metabolism of these CECs, making it imperative to consider conjugates when assessing their risks.

Biodegradation of pharmaceuticals and endocrine disruptors with oxygen, nitrate, manganese (IV), iron (III) and sulfate as electron acceptors

NASA Astrophysics Data System (ADS)

Schmidt, Natalie; Page, Declan; Tiehm, Andreas

2017-08-01

Biodegradation of pharmaceuticals and endocrine disrupting compounds was examined in long term batch experiments for a period of two and a half years to obtain more insight into the effects of redox conditions. A mix including lipid lowering agents (e.g. clofibric acid, gemfibrozil), analgesics (e.g. diclofenac, naproxen), beta blockers (e.g. atenolol, propranolol), X-ray contrast media (e.g. diatrizoic acid, iomeprol) as well as the antiepileptic carbamazepine and endocrine disruptors (e.g. bisphenol A, 17α-ethinylestradiol) was analyzed in batch tests in the presence of oxygen, nitrate, manganese (IV), iron (III), and sulfate. Out of the 23 selected substances, 14 showed a degradation of > 50% of their initial concentrations under aerobic conditions. The beta blockers propranolol and atenolol and the analgesics pentoxifylline and naproxen showed a removal of > 50% under anaerobic conditions. In particular naproxen proved to be degradable with oxygen and under most anaerobic conditions, i.e. with manganese (IV), iron (III), or sulfate. The natural estrogens estriol, estrone and 17β-estradiol showed complete biodegradation under aerobic and nitrate-reducing conditions, with a temporary increase of estrone during transformation of estriol and 17β-estradiol. Transformation of 17β-estradiol under Fe(III)-reducing conditions resulted in an increase of estriol as well. Concentrations of clofibric acid, carbamazepine, iopamidol and diatrizoic acid, known for their recalcitrance in the environment, remained unchanged.

Synthesis of high surface area carbon adsorbents prepared from pine sawdust-Onopordum acanthium L. for nonsteroidal anti-inflammatory drugs adsorption.

PubMed

Álvarez-Torrellas, S; Muñoz, M; Zazo, J A; Casas, J A; García, J

2016-12-01

Chemically activated carbon materials prepared from pine sawdust-Onopordum acanthium L. were studied for the removal of diclofenac and naproxen from aqueous solution. Several carbons, using different proportions of precursors were obtained (carbon C1 to carbon C5) and the chemical modification by liquid acid and basic treatments of C1 were carried out. The textural properties of the carbons, evaluated by N2 adsorption-desorption isotherms, revealed that the treatments with nitric acid and potassium hydroxide dramatically reduced the specific surface area and the pore volume of the carbon samples. The surface chemistry characterization, made by thermal programmed decomposition studies, determination of isoelectric point and Boehm's titration, showed the major presence of lactone and phenol groups on the activated carbons surface, being higher the content when the acidic strength of the carbon increased. Diclofenac and naproxen kinetic data onto C1 carbon followed pseudo-second order model. The adsorption equilibrium isotherms of C1 and the modified carbons were well described by both Sips and GAB isotherm equations. The highest adsorption capacity was found for naproxen onto C1 activated carbon, 325 mg g(-1), since the liquid acid and basic functionalization of the carbon led to a severe decreasing in the adsorption removal of the target compounds. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endometriosis

MedlinePlus

... ibuprofen (Advil), naproxen (Aleve), and acetaminophen (Tylenol). Prescription painkillers, if needed, for more severe pain. Regular exams ... or injections -- This treatment helps shrink growths. Side effects may include weight gain and depression. Gonadotropin-agonist ...

Grape

MedlinePlus

... fruit, skin, leaves and seed of the grape plant are used as medicine. Grape seeds are by- ... haloperidol (Haldol), imipramine (Tofranil), mexiletine (Mexitil), mirtazapine (Remeron), naproxen (Naprosyn), nortriptyline (Pamelor), olanzapine (Zyprexa), ondansetron (Zofran), propafenone ( ...

Migraines

MedlinePlus

... name: Excedrin Migraine); ibuprofen (one brand name: Motrin); naproxen (brand name: Aleve); and ketoprofen (brand name: Orudis ... and leaf and root extracts of the butterbur plant. What else can I do to prevent migraines? ...

In vitro metabolism of [14C]-benalaxyl in hepatocytes of rats, dogs and humans.

PubMed

Nallani, Gopinath C; ElNaggar, Shaaban F; Shen, Li; Chandrasekaran, Appavu

2017-03-01

The in vitro comparative animal metabolism study is now a data requirement under EU Directive 1107/2009 for registration of plant protection products. This type of study helps determine the extent of metabolism of a chemical in each surrogate species and whether any unique human metabolite(s) are formed. In the present study, metabolism of racemic [ 14 C]-benalaxyl, a fungicide was investigated in cryopreserved rat, dog and human hepatocytes. The metabolites generated were identified/characterized by LC/MS/MS with radiometric detection and comparison with reference standards. [ 14 C]-glucuronide conjugates of benalaxyl metabolites in rat, dog and human hepatocytes were confirmed via additional experiments in which known reference standards were incubated with dog liver microsomes in the presence of UDPGA. After 4 h of incubation, benalaxyl was extensively metabolized in all the species with the following trend: dog (100%) > human (86%) > rat (75%). In all species, the major metabolic pathways consisted of hydroxylation of the methyl group in the xylene moiety to 2-hydroxymethyl-benalaxyl, further oxidation to its carboxylic acid analogue (benalaxyl-2-benzoic acid), and hydrolysis of the methyl ester to yield benalaxyl acid or 2-hydroxymethyl benalaxyl acid. In addition, glucuronidation of phase I metabolites occurred in all species, to a higher extent in dog hepatocytes in which 2-hydroxymethyl-benalaxyl-glucuronide conjugate constituted the most significant metabolite. No major unique metabolite was observed in human hepatocytes. Also, benalaxyl did not undergo stereo-selective metabolism in rat or human hepatocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of Sex Pheromones and Sex Pheromone Mimics for Two North American Click Beetle Species (Coleoptera: Elateridae) in the Genus Cardiophorus Esch.

PubMed

Serrano, Jacqueline M; Collignon, R Maxwell; Zou, Yunfan; Millar, Jocelyn G

2018-04-01

To date, all known or suspected pheromones of click beetles (Coleoptera: Elateridae) have been identified solely from species native to Europe and Asia; reports of identifications from North American species dating from the 1970s have since proven to be incorrect. While conducting bioassays of pheromones of a longhorned beetle (Coleoptera: Cerambycidae), we serendipitously discovered that males of Cardiophorus tenebrosus L. and Cardiophorus edwardsi Horn were specifically attracted to the cerambycid pheromone fuscumol acetate, (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate, suggesting that this compound might also be a sex pheromone for the two Cardiophorus species. Further field bioassays and electrophysiological assays with the enantiomers of fuscumol acetate determined that males were specifically attracted by the (R)-enantiomer. However, subsequent analyses of extracts of volatiles from female C. tenebrosus and C. edwardsi showed that the females actually produced a different compound, which was identified as (3R,6E)-3,7,11-trimethyl-6,10-dodecadienoic acid methyl ester (methyl (3R,6E)-2,3-dihydrofarnesoate). In field trials, both the racemate and the (R)-enantiomer of the pheromone attracted similar numbers of male beetles, suggesting that the (S)-enantiomer was not interfering with responses to the insect-produced (R)-enantiomer. This report constitutes the first conclusive identification of sex pheromones for any North American click beetle species. Possible reasons for the strong and specific attraction of males to fuscumol acetate, which is markedly different in structure to the actual pheromone, are discussed.

Fucus Vesiculosus

MedlinePlus

... type of brown seaweed. People use the whole plant to make medicine. People use Fucus vesiculosus for ... diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ...

Peptic ulcer

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... ulcers: Drinking too much alcohol Regular use of aspirin, ibuprofen, naproxen, or other nonsteroidal anti-inflammatory drugs ( ... pylori infection. Your ulcer is caused by taking aspirin or NSAIDs. Your doctor may also prescribe this ...

Green Synthesis of Novel Polyaniline Nanofibers: Application in pH Sensing.

PubMed

Tanwar, Shivani; Ho, Ja-an Annie

2015-10-13

An optically active polyaniline nanomaterial (PANI-Nap), doped with (S)-naproxen, was developed and evaluated as a potent pH sensor. We synthesized the material in one pot by the addition of the dopant, (S)-naproxen, prior to polymerization, followed by the addition of the oxidizing agent (ammonium persulfate) that causes polymerization of the aniline. This green chemistry approach allowed us to take only 1 h to produce a water-soluble and stable nanomaterial. UV-visible spectroscopy, fluorescence spectroscopy, FT-IR spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS) were used to characterize the designed nanomaterial. This nanomaterial exhibited excellent pH sensing properties and showed long term stability (up to one month) without loss of sensor performance.

Adsorptive removal of naproxen and clofibric acid from water using metal-organic frameworks.

PubMed

Hasan, Zubair; Jeon, Jaewoo; Jhung, Sung Hwa

2012-03-30

Adsorptive removal of naproxen and clofibric acid, two typical PPCPs (pharmaceuticals and personal care products), has been studied using metal-organic frameworks (MOFs) for the first time. The removal efficiency decreases in the order of MIL-101>MIL-100-Fe>activated carbon both in adsorption rate and adsorption capacity. The adsorption kinetics and capacity of PPCPs generally depend on the average pore size and surface area (or pore volume), respectively, of the adsorbents. The adsorption mechanism may be explained with a simple electrostatic interaction between PPCPs and the adsorbent. Finally, it can be suggested that MOFs having high porosity and large pore size can be potential adsorbents to remove harmful PPCPs in contaminated water. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular docking and panicolytic effect of 8-prenylnaringenin in the elevated T-maze.

PubMed

Bagatin, Mariane Cristovão; Tozatti, Camila Santos Suniga; Abiko, Layara Akemi; Yamazaki, Diego Alberto dos Santos; Silva, Priscila Rebeca Alves; Perego, Leonardo Martins; Audi, Elisabeth Aparecida; Seixas, Flavio Augusto Vicente; Basso, Ernani Abicht; Gauze, Gisele de Freitas

2014-01-01

The purpose of this study was to investigate the effects of the chronic administration of a racemic mixture of 8-prenylnaringenin (8-PN) on rats submitted to the elevated T-maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (SERT) reuptake inhibitor fluoxetine was used as a positive control. Rat locomotion was assessed in a circular arena following each drug treatment. The administration of racemic 8-PN for 21 d in rats increased one-way escape latencies from the ETM open arm, indicating a panicolytic effect. To evaluate the interactions of 8-PN with monoamine transporters, a docking study was performed for both the R and S configurations of 8-PN towards SERT, norepinephrine (NET) and dopamine transporters (DAT). The application of the docking protocol showed that (R)-8-PN provides greater affinity to all transporters than does the S enantiomer. This result suggests that enantiomer (R)-8-PN is the active form in the in vivo test of the racemic mixture.

Separation of non-racemic mixtures of enantiomers: an essential part of optical resolution.

PubMed

Faigl, Ferenc; Fogassy, Elemér; Nógrádi, Mihály; Pálovics, Emese; Schindler, József

2010-03-07

Non-racemic enantiomeric mixtures form homochiral and heterochiral aggregates in melt or suspension, during adsorption or recrystallization, and these diastereomeric associations determine the distribution of the enantiomers between the solid and other (liquid or vapour) phases. That distribution depends on the stability order of the homo- and heterochiral aggregates (conglomerate or racemate formation). Therefore, there is a correlation between the binary melting point phase diagrams and the experimental ee(I)vs. ee(0) curves (ee(I) refers to the crystallized enantiomeric mixtures, ee(0) is the composition of the starting ones). Accordingly, distribution of the enantiomeric mixtures between two phases is characteristic and usually significant enrichment can be achieved. There are two exceptions: no enrichment could be observed under thermodynamically controlled conditions when the starting enantiomer composition corresponded to the eutectic composition, or when the method used was unsuitable for separation. In several cases, when kinetic control governed the crystallization, the character of the ee(0)-ee(I) curve did not correlate with the melting point binary phase diagram.

Characterization of Crystal Chirality in Amino Acids Using Low-Frequency Raman Spectroscopy.

PubMed

Aviv, Hagit; Nemtsov, Irena; Mastai, Yitzhak; Tischler, Yaakov R

2017-10-19

We present a new method for differentiating racemic crystals from enantiopure crystals. Recently, developments in optical filters have enabled the facile use of Raman spectroscopy to detect low-frequency vibrational (LFV) modes. Here, for the first time, we use Raman spectroscopy to characterize the LFV modes for crystalline organic materials composed of chiral molecules. The LF-Raman spectra of racemic and enantiopure crystals exhibit a significant variation, which we attribute to different hydrogen-bond networks in the chiral crystal structures. Across a representative set of amino acids, we observed that when comparing racemic versus enantiopure crystals, the available LFV modes and their relative scattering intensity are strong functions of side chain polarity. Thus, LF-Raman can be used as a method that is complementary to the currently used methods for characterizing crystal chirality due to simpler, faster, and more sensitive measurements, along with the small sample size required, which is limited by the laser-beam diameter in the focus.

Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids

NASA Astrophysics Data System (ADS)

Sidera, Mireia; Fletcher, Stephen P.

2015-11-01

Csp2-Csp2 cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp2-Csp3 cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective Csp2-Csp3 bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or ortho-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis.

Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography.

PubMed

Johnstone, Timothy C; Nolan, Elizabeth M

2017-10-25

Enterobactin is a secondary metabolite produced by Enterobacteriaceae for acquiring iron, an essential metal nutrient. The biosynthesis and utilization of enterobactin permits many Gram-negative bacteria to thrive in environments where low soluble iron concentrations would otherwise preclude survival. Despite extensive work carried out on this celebrated molecule since its discovery over 40 years ago, the ferric enterobactin complex has eluded crystallographic structural characterization. We report the successful growth of single crystals containing ferric enterobactin using racemic crystallization, a method that involves cocrystallization of a chiral molecule with its mirror image. The structures of ferric enterobactin and ferric enantioenterobactin obtained in this work provide a definitive assignment of the stereochemistry at the metal center and reveal secondary coordination sphere interactions. The structures were employed in computational investigations of the interactions of these complexes with two enterobactin-binding proteins, which illuminate the influence of metal-centered chirality on these interactions. This work highlights the utility of small-molecule racemic crystallography for obtaining elusive structures of coordination complexes.

Racemization and the origin of optically active organic compounds in living organisms

NASA Technical Reports Server (NTRS)

Bada, J. L.; Miller, S. L.

1987-01-01

The organic compounds synthesized in prebiotic experiments are racemic mixtures. A number of proposals have been offered to explain how asymmetric organic compounds formed on the Earth before life arose, with the influence of chiral weak nuclear interactions being the most frequent proposal. This and other proposed asymmetric syntheses give only sight enantiomeric excess and any slight excess will be degraded by racemization. This applies particularly to amino acids where half-lives of 10(5)-10(6) years are to be expected at temperatures characteristic of the Earth's surface. Since the generation of chiral molecules could not have been a significant process under geological conditions, the origins of this asymmetry must have occurred at the time of the origin of life or shortly thereafter. It is possible that the compounds in the first living organisms were prochiral rather than chiral; this is unlikely for amino acids, but it is possible for the monomers of RNA-like molecules.

Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography.

PubMed

Mandal, Kalyaneswar; Uppalapati, Maruti; Ault-Riché, Dana; Kenney, John; Lowitz, Joshua; Sidhu, Sachdev S; Kent, Stephen B H

2012-09-11

Total chemical synthesis was used to prepare the mirror image (D-protein) form of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage display against D-VEGF-A was used to screen designed libraries based on a unique small protein scaffold in order to identify a high affinity ligand. Chemically synthesized D- and L- forms of the protein ligand showed reciprocal chiral specificity in surface plasmon resonance binding experiments: The L-protein ligand bound only to D-VEGF-A, whereas the D-protein ligand bound only to L-VEGF-A. The D-protein ligand, but not the L-protein ligand, inhibited the binding of natural VEGF(165) to the VEGFR1 receptor. Racemic protein crystallography was used to determine the high resolution X-ray structure of the heterochiral complex consisting of {D-protein antagonist + L-protein form of VEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in appropriate stoichiometry gave a racemic protein complex of more than 73 kDa containing six synthetic protein molecules. The structure of the complex was determined to a resolution of 1.6 Å. Detailed analysis of the interaction between the D-protein antagonist and the VEGF-A protein molecule showed that the binding interface comprised a contact surface area of approximately 800 Å(2) in accord with our design objectives, and that the D-protein antagonist binds to the same region of VEGF-A that interacts with VEGFR1-domain 2.

Chiral separation of 3,4-methylenedioxymethamphetamine (MDMA) enantiomers using batch chromatography with peak shaving recycling and its effects on oxidative stress status in rat liver.

PubMed

Lourenço, Tiago C; Bósio, Graziela C; Cassiano, Neila M; Cass, Quezia B; Moreau, Regina L M

2013-01-25

This work reports the multimiligram separation of 3,4-methylenedioxy-methamphetamine (MDMA) enantiomers using batch chromatography with peak shaving recycling. The effect of both enantiomers compared to the racemic mixture was examined on the oxidative stress status of rat liver. The enantiomeric purification was performed using a based cyclodextrin chiral selector and methanol:ammonium acetate buffer (pH 6.0, 100mM) (30:70, v/v) as mobile phase. The average mass rate obtained was 40.0mg/day, providing 45.0mg of the (R)-(-)-MDMA (e.r. 99.0%) and 75.0mg (e.r. 96.0%) of (S)-(+)-MDMA. Racemic MDMA and both enantiomers were administered per orally to Wistar rats and oxidative stress status parameters, as liver total glutathione levels and malondialdehyde (MDA) production in liver were evaluated. There was a significant decrease in hepatic glutathione content in the racemic MDMA and the (R)-(-)-MDMA-treated rats when compared to the control and to (S)-(+)-MDMA. These results demonstrate that the R-enantiomer is the enantiomer that contributes to the depletion of hepatic glutathione induced by the racemic mixture. The high reactivity of the R-enantiomer of MDMA in the liver can also be observed in animals treated with (R)-(-)-MDMA. The production of malondialdehyde (MDA) by (R)-(-)-MDMA was significantly higher when compared to the other treated groups and control. Copyright © 2012 Elsevier B.V. All rights reserved.

Azilsartan

MedlinePlus

... It works by blocking the action of certain natural substances that tighten the blood vessels, allowing the ... Advil, Motrin) and naproxen (Aleve, Naprosyn) and selective COX-2 inhibitors such as celecoxib (Celebrex); diuretics ('water pills'); lithium ( ...

Carotid artery surgery

MedlinePlus

... of stroke. Some of these medicines are aspirin, clopidogrel (Plavix), and warfarin (Coumadin). Carotid angioplasty and stenting is ... thinner drugs. These include aspirin, ibuprofen (Advil, Motrin), ... (Plavix), naprosyn (Aleve, Naproxen), and other drugs like ...

Plantar Fasciitis

MedlinePlus

... medicine help? Aspirin, acetaminophen (one brand name: Tylenol), naproxen (brand name: Aleve), or ibuprofen (some brand names: ... Kids and Teens, Men, WomenTags: fasciitis, foot, heel, plant, soreness September 1, 2000 Copyright © American Academy of ...

[Problems of cardiovascular toxicity of coxibs and non-selective NSA].

PubMed

Forejtová, S

2006-01-01

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.

Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial.

PubMed

Fields, Cynthia; Drye, Lea; Vaidya, Vijay; Lyketsos, Constantine

2012-06-01

Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late-life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. The Alzheimer's Disease Anti-inflammatory Prevention Trial was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers age 70 and older with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score greater than 5 at baseline were classified as depressed. Of 2,528 participants enrolled, 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using generalized estimating equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late-life depression, these results do not support the hypothesis that inhibition of the COX pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults.

Celecoxib or naproxen treatment does not benefit depressive symptoms in persons aged 70 and over: findings from a randomized controlled trial

PubMed Central

Fields, Cynthia; Drye, Lea; Vaidya, Vijay; Lyketsos, Constantine

2011-01-01

Background Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. Objective To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. Methods The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers aged 70 and over with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200mg BID, naproxen sodium 220mg BID, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score >5 at baseline were classified as depressed. Results Of 2,528 participants enrolled 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using Generalized Estimating Equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Conclusions Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late life depression, these results do not support the hypothesis that inhibition of the cyclooxygenase pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults. PMID:21775876

Correlation between in vitro and in vivo concentration–effect relationships of naproxen in rats and healthy volunteers

PubMed Central

Huntjens, Dymphy R H; Spalding, David J M; Danhof, Meindert; Della Pasqua, Oscar E

2006-01-01

Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. The current investigation characterises the inhibition of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE2 in the absence or presence of increasing concentrations of naproxen (10−8–10−1 M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB2 was measured in serum following blood clotting. In further experiments, inhibition of PGE2 and TXB2 levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg−1). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). Inhibition of PGE2 and TXB2 was characterised by a sigmoid Emax model. The exposure–response relationships in vitro and in vivo were of the same order of magnitude in both species. IC80 estimates obtained in vitro were similar for PGE2 inhibition (130.8±11 and 131.9±19 10−6 M, mean±s.d. for humans and rats, respectively), but slightly different for TXB2 inhibition (103.9±15 and 151.4±40 10−6 M, mean±s.d. for humans and rats, respectively, P< 0.05). These differences, however, may not be biologically relevant. The results confirm the value of exposure–effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration–effect relationships in early drug development, as indicated by the estimates of IC80 for PGE2 and TXB2 inhibition. PMID:16682968

Mimicking natural systems: Changes in behavior as a result of dynamic exposure to naproxen.

PubMed

Neal, Alexandra E; Moore, Paul A

2017-01-01

Animals living in aquatic habitats regularly encounter anthropogenic chemical pollution. Typically, the toxicity of a chemical toxicant is determined by the median lethal concentration (LC 50 ) through a static exposure test. However, LC 50 values and static tests do not provide an accurate representation of exposure to pollutants within natural stream systems. In their native habitats, animals experience exposure as a fluctuating concentration due to turbulent mixing, temporal variations of contamination (seasonal inputs), and contaminant input type (point vs. non-point). Research has shown that turbulent environments produce exposures with a high degree of fluctuation in frequency, duration, and intensity. In order to more effectively evaluate the effects of pollutants, we created a dynamic exposure paradigm, utilizing both flow and substrate within a small mesocosm. A commonly used pharmaceutical, naproxen, was used as the toxicant and female crayfish (Orconectes virilis) as the target organism to investigate changes in fighting behavior as a result of dynamic exposure. Crayfish underwent either a 23h long static or a dynamic exposure to naproxen. Following exposure, the target crayfish and an unexposed size matched opponent underwent a 15min fight trial. These fight trials were recorded and later analyzed using a standard ethogram. Results indicate that exposure to sublethal concentrations of naproxen, in both static and flowing conditions, negatively impact aggressive behavior. Results also indicate that a dynamic exposure paradigm has a greater negative impact on behavior than a static exposure. Turbulence and habitat structure play important roles in shaping chemical exposure. Future research should incorporate features of dynamic chemical exposure in order to form a more comprehensive image of chemical exposure and predict the resulting sublethal effects from exposure. Possible techniques for assessment include utilizing flow-through experimental set-ups in tandem with behavioral or physiological endpoints as opposed to acute toxicity. Other possibilities of assessment could involve utilizing fine-scale chemical measurements of pollutants to determine the actual concentrations animals encounter during an exposure event. Copyright © 2016 Elsevier Inc. All rights reserved.