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The proposed curative properties of copper(II)-non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous copper(II)-NSAID complexes with enhanced anti-inflammatory activity. In this work, the antinociceptive and toxic effects of two new coordination complexes: Cu₂(fen)₄(caf)₂ [fen: fenoprofenate anion; caf: caffeine] and Cu₂(fen)₄(dmf)₂ [dmf: N-N'-dimethylformamide] were evaluated in mice. The antinociceptive effect was evaluated with two models: acetic acid-induced writhing response and formalin test. For the sub-acute exposure, the complexes were added to the diet at different doses for 28days. Behavioral and functional nervous system parameters in a functional observational battery were assessed. Also, hematological, biochemical and histopathological studies were performed. Cu₂(fen)₄(caf)₂ and Cu₂(fen)₄(dmf)₂ significantly decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test with respect to the control and fenoprofen salt groups. The sub-acute exposure to Cu₂(fen)₄(caf)₂ complex increased the motor activity, the number of rearings and the arousal with respect to the control and fenoprofen salt groups. These impaired parameters in mice exposed to Cu₂(fen)₄(caf)₂ can be attributable to the presence of caffeine as stimulating agent. On the other hand, all exposed groups decreased the urine pools in the functional observational battery and increased the plasmatic urea. These effects could be due to the decrease in the glomerular filtration caused by NSAIDs. In conclusion, both complexes Cu₂(fen)₄(dmf)₂ and Cu₂(fen)₄(caf)₂ were more potent antinociceptive agents than fenoprofen salt. Sub-acute exposure to different doses of these complexes did not produce significant changes in the parameters that evaluate toxicity.

The purpose of this study was to develop a sensitive system for detection of crystalline drug substances in intact pharmaceutical tablets by X-ray powder diffractometry (XRPD), using synchrotron X-rays. Fenoprofen calcium dihydrate was used as a model compound. The wavelength and path length of X-rays from synchrotron radiation were optimized in order to maximize the potential of the synchrotron radiation. The optimum wavelength and path length for the measurement of fenoprofen calcium dihydrate were found to be 0.69817 A and 6.0 mm, respectively, based on theoretical calculations. Under the optimized conditions, a limit of quantification of 0.05% (RSD = 9.4%, n = 3) and a limit of detection of 0.02% (RSD = 17.3%, n = 3), results which are approximately 102 times as sensitive as those obtained using conventional XRPD instruments, were achieved. The technique was also applied to fenoprofen calcium dihydrate detection in intact film-coated tablets, which contained Ti in the coating film, and a limit of detection of 0.02% was again attained.

U radu je opisana sinteza i karakterizacija hidroksisemikarbazidnih derivata nesteroidnih protuupalnih lijekova, ibuprofena, fenoprofena i reduciranog ketoprofena.

U radu je opisana sinteza i karakterizacija semikarbazidnih derivata fenoprofena.

A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of the non-steroidal anti-inflammatory drug ibuprofen (IB) in plasma was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), samples are acidified and extracted with a mixture of isooctane-isopropanol (95:5, v/v). After evaporation of the organic layer, the drug and I.S. are derivatized with S-(-)-1(1-naphthyl)ethylamine (S-NEA) after addition of ethyl chloroformate as the coupling reagent. Ethanolamine is added 3 min after the addition of S-NEA to react with the excessive ethyl chloroformate. The resultant diastereomers corresponding to IB and I.S. were chromatographed at ambient temperature on a 100 mm x 4.6 mm I.D. C18 reversed-phase column using acetonitrile-water-acetic acid-triethylamine (60:40:0.1:0.02) as the mobile phase pumped at a flow-rate of 1.2 ml/min. Detection of the fluorescent chromophore was at 280 and 320 nm for excitation and emission, respectively. The suitability of the assay for clinical pharmacokinetic studies of IB was determined by the analysis of plasma samples obtained from a healthy volunteer, following administration of a single 400-mg oral dose of racemic IB.

For lamellar vehicles composed of lecithin, isopropyl myristate (IPM) and water, a phase transition into reversed hexagonal systems was observed on the addition of fenoprofen acid. Furthermore, the solubilization capacity for IPM was increased. An excess of oil resulted in reversed micellar solutions. The colloidal microstructure was characterized by polarized light microscopy, small-angle X-ray diffraction and transmission electron microscopy. Drug release from the systems increased with increasing content of IPM. The same trend was observed for drug permeation through excised human skin.

An equilibrium model has been developed to describe the pH and cyclodextrin concentration dependence of the electrophoretic mobilities as well as the c

High-performance frontal analysis (HPFA) and high-perfon-ance liquid chromatography (HPLC) were incorporated in an on-line coupled column system for the enantioselective determination of unbound fenoprofen (FP) concentrations in the state of a protein binding equilibrium following direct sample injection. This system consists of a “restricted access” type column for HPFA and al-acid glycoprotein-immobilized silica column for chiral separation. When a 80-μL portion of a sample solution containing 50 or 90μg/mL FP and 300 or 550,μM human serum albumin (HSA) was directly injected into the HPFA column, FP gave a trapezoidal peak exhibiting a plateau region. The concentration in the plateau range was equal to the unbound FP concentration in the initial sample solution. By the delivery of a 90-μL portion of the eluent in this plateau region into the chiral separation column, the unbound concentrations of FP enantiomers were determined. The results agreed with those obtained by the conventional ultrafil...

The separation of the enantiomers of five widely used profen-type non-steroidal anti-inflammatory agents: fenoprofen, flurbiprofen, ibuprofen, ketoprofen and naproxen was studied using four commercially available cyclodextrin silica stationary phases operated in the reversed-phase mode. The retention behavior of all profens was similar on all the cyclodextrin silica stationary phases studied, but the chiral selectivities differed significantly. Complete separation was achieved for the enantiomers of ibuprofen, flurbiprofen and naproxen.

Novel primaquine conjugates with non-steroidal anti-inflammatory drugs (PQ-NSAIDs, 4a-h) were prepared, fully chemically characterized and screened for radical scavenging and antioxidant activities. The synthetic procedure leading to twin drugs 4a-h involved two steps: i) preparation of NSAID benzotriazolides 3a-h from the corresponding NSAID (ibuprofen, ketoprofen, fenoprofen, ketoprofen hydroxy and methylene analogues, diclofenac or indomethacin) and benzotriazole carboxylic acid chloride (BtCOCl, 1), ii) reaction of intermediates 3a-h with PQ. The prepared PQ-NSAIDs exerted moderate activities in the DPPH free radical test and -carotene-linoleic acid assay. Moreover, ketoprofen derivatives 4d and 4b demonstrated a notable Fe2+ chelating ability as well. On the other hand, negligible antiproliferative and antituberculotic effects of conjugates 4a-h were observed. U radu je opisana sinteza novih konjugata primakina s nesteroidnim protuupalnim lijekovima (PQ-NSAIDs, 4a-h), njihova potpuna karakterizacija te testiranje sposobnosti hvatanja slobodnih radikala i antioksidativnog djelovanja. Sintetski postupak za pripravu dvojnih lijekova 4a-h uključuje dva koraka: i) pripravu NSAID-benzotriazolida 3a-h iz odgovarajućih nesteroidnih protuupalnih lijekova (ibuprofena, ketoprofena, fenoprofena, hidroksi i metilenskih analoga ketoprofena, diklofenaka i indometacina) i klorida 1-benzotriazol karboksilne kiseline (BtCOCl, 1), ii) reakciju intermedijera 3a-h s primakinom. Novi PQ-NSAID konjugati pokazuju umjerenu sposobnost hvatanja slobodnih radikala u DPPH testu te umjereno antioksidativno djelovanje u pokusu s -karotenom i linoleinskom kiselinom. Osim toga, derivati ketoprofena 4d i 4b imaju primjetnu sposobnost keliranja Fe2+ iona. Svi konjugati 4a-h pokazuju vrlo slabo antiproliferativno i antituberkulotsko djelovanje.

The synthesis, physicochemical characterization, anti-inflammatory properties and catecholase mimetic activity of the dinuclear complex of copper(II) with the non-steroidal anti-inflammatory drug Fenoprofen [2-(3-phenoxyphenyl)propionic acid] with formula [Cu2(fen)4(dmf)2] (fen = fenoprofenate anion, dmf = N,N-dimethylformamide) have been investigated. Results of spectroscopic analysis (FTIR and EPR) as well as thermogravimetric and differential thermal analysis data obtained for the solid complex are in good agreement with its dinuclear structure. Electronic spectra of the product are also reported and discussed. The complex was tested for anti-inflammatory properties in comparison to the parent drug, Fenoprofen calcium salt. Oral administration of the dinuclear compound inhibited development of carrageenan-induced oedema in mice; this inhibition was higher than that observed for the parent drug. The kinetic study of the catecholase mimetic activity was carried out spectrophotometrically by monitoring the oxidative transformation of 3,5-di-tert-butylcatechol into the corresponding light-absorbing o-quinone. Kinetic parameters were determined employing the Michaelis-Menten model, showing that the new complex presents catechol oxidase mimetic activity. A síntese, a caracterização físico-química, as propriedades anti-inflamatórias e a atividade mimética de catecolase do complexo de cobre(II) com a droga anti-inflamatória non-esteroidal Fenoprofeno [ácido 2-(3-fenóxifenil)propiônico] com fórmula [Cu2(fen)2(dmf)2] (fen = ânion do fenoprofenato, dmf = N,N-dimetilformamida) foram investigadas. Os resultados da análise espectroscópica (espectros de FTIR e EPR) e dados de análise termogravimétrica e térmica diferencial obtidos para o complexo sólido estão de acordo com a sua estrutura dinuclear. Os espectros eletrônicos do produto são igualmente apresentados e discutidos neste trabalho. O complexo foi testado para as suas propriedades anti-inflamatórias em comparação com a droga de referência, o sal de cálcio do Fenoprofeno. A administração oral do composto binuclear inibiu o desenvolvimento do edema induzido por carragenana em ratos; esta inibição foi mais significativa do que a obtida com a droga de referência. O estudo cinético da atividade mimética da catecolase foi realizado espectrofotometricamente, monitorando-se a transformação oxidativa do 3,5-di-terc-butilcatecol na o-quinona correspondente. Os parâmetros cinéticos foram determinados pelo emprego do modelo de Michaelis-Menten, que demonstrou que o novo complexo mimetiza a atividade da catecol oxidase.

A highly sensitive method for enantioseparation of trace fenoprofen and amino acid derivatives by capillary electrophoresis (CE) with vancomycin as the chiral selector was developed. Several CE techniques, such as the partial filling, large-volume sample stacking with EOF as pump plus anion-selective exhaustive injection (LVSEP–ASEI) were involved in the present method to improve the detection sensitivity. With on-column concentration, enantioseparation of racemic fenoprofen and six 9-fluorenylmethyl chloroformate (FMOC)-amino acid derivatives (at the concentration level of ng/mL) with the background electrolyte composed of 100 mmol/L Tris–H3PO4 (pH 6.0) and 2 mmol/L vancomycin was detected readily with the UV detection at 214 nm. Successfully performing LVSEP–ASEI needs a very low EOF that could be depressed by coating the capillary with poly(dimethylacrylamide) solution. The coating also played a role to minimize the adsorption of vancomycin onto the capillary wall. Effect of the injected sample volume and the electrokinetic injection time on the peak area of the enantiomers and their resolution factor were investigated and optimized. Under the optimized conditions, more than 1000-fold enhancement in detection sensitivity compared with the normal injection was achieved.

The rearrangement of a series of dimethylsulfonium α-substituted benzylides, e.g., 8, in ethanol has been examined. The ylides 8a, b generated in situ by treatment of the sulfonium salts 7a, b with 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) in ethanol at room temperature, afforded the o-(methylthiomethyl)phenylacetic esters 10a, b as a result of the Sommelet-Hauser rearrangement of the tautomeric ylides 9a, b. By contrast, the ylide 14 possessing a furan ring was stable at room temperature, but, on heating in ethanol, gave the rearranged product 15. The ylide 22 stabilized by an acetyl group provided three rearranged products, 23, 24, and 25, in boiling ethanol. Treatment of the sulfonium salts 30a, b with DBU at room temperature afforded the corresponding rearranged products 31a, b. The sulfonium salt 34a prepared from 33a, on treatment with sodium ethoxide, gave the rearranged product 36a, which was then S-methylated and treated with DBU to give the 1, 2, 3-trisubstituted benzene 37a. This method was applied to the synthesis of the fenoprofen analog 39 from 39 from 33b, c.

Application of the recently developed silica-adsorbed polyleucine catalysts to the enantioselective epoxidation of two enones is reported. Treatment of these epoxides with trimethylaluminium in moist dichloromethane generates the α-hydroxy-β-methyl-ketones, with inversion of configuration. Diastereoselective reduction of the ketone moiety followed by oxidative cleavage generates α-arylpropanoic acids.

Single stranded DNA aptamers that can bind to ibuprofen, a widely used anti-inflammation drug, were selected from random DNA library of 10 15 nucleotides by FluMag-SELEX process. Five different sequences were selected and their enantioselectivity and affinity were characterized. Three out of five aptamer candidates did not show any affinity to ( S )-ibuprofen, but only to racemic form of ibuprofen, suggesting that they are ( R )-ibuprofen specific aptamers. Another two aptamer candidates showed affinity to both racemic form and ( S )-ibuprofen, which were considered as ( S )-ibuprofen specific aptamers. The affinity of five ssDNA aptamers isolated was in a range of 1.5–5.2 μM. In addition, all of these five aptamers did not show any affinity to analogues of ibuprofen in its profen’s group (fenoprofen, flubiprofen, and naproxen) and the antibiotics of oxytetracycline, another control.

ATP-dependent coenzyme A (CoA) ligases catalyse the formation of the acyl-CoA thioesters of xenobiotic carboxylic acids and the formation of xenobiotic-CoAs has been implicated as being a causative factor in peroxisomal proliferation. In this study we have demonstrated using rat liver peroxisomes that the formation of palmitoyl-CoA is inhibited by a variety of xenobiotic carboxylic acids. Palmitoyl-CoA formation exhibited biphasic kinetics indicative of two isoforms, a high affinity (Km1 2.3 microM) low capacity form and a low affinity (Km2 831 microM) high capacity form. These forms were differentially inhibited by a range of xenobiotics. However, it would appear that the low affinity component may not contribute to any major extent to the formation of xenobiotic-CoAs in vivo. At a concentration of 1 mM, greater than 20% inhibition of the high affinity form was observed with the 2-arylpropionates, ibuprofen, naproxen, benoxaprofen, fenoprofen, indoprofen, ketoprofen, tiaprofenic acid and cicloprofen, the hypolipidaemics, nafenopin and ciprofibrate, and the herbicides, silvex and 2,4,5-trichlorophenoxyacetate. Valproic acid, clofibric acid, salicylic acid and 2,4-dichlorophenoxy-acetate were non-inhibitory at all concentrations studied (0.1-2.5 mM). Analysis of the type of inhibition established that only nafenopin (Ki 430 microM) and ciprofibrate (Ki 97 microM) were competitive inhibitors of palmitoyl-CoA formation suggesting that they bind at the active site and thus potentially function as alternative substrates for the peroxisomal ligase. Notably, clofibric acid which has previously been shown to form clofibroyl-CoA in peroxisomes did not interact with the palmitoyl-CoA ligase thereby suggesting that activation is mediated via an alternative peroxisomal CoA ligase. In addition, the xenobiotic inhibitors of the peroxisomal palmitoyl-CoA ligase differed from those previously reported for the equivalent microsomal enzyme suggesting that the organellar forms may be functionally distinct. This study establishes that numerous xenobiotic carboxylic acids interact with the peroxisomal palmitoyl-CoA ligase; however, it would appear that relatively few function as alternative substrates. The toxicological ramifications of peroxisomally mediated xenobiotic-CoA formation and the identification of other peroxisomal xenobiotic-CoA ligase(s) remain to be elucidated.

Summary In vitro inhibition of aromatic amino acid decarboxylase (AAD) by eight non-steroidal anti-inflammatory drugs (NSAIDs) was studied. The most potent inhibitors were fenamates (IC 50 for tolfenamate was 4.4×10 −5 m ), while fluorinated biphenylic compounds (flobufen and 2′,4′-difluorobiphenyl-4-yl acetate) and propionic acid derivatives (ibuprofen, ketoprofen, fenoprofen) were one order weaker. The in vitro inhibition of AAD by the compounds studied is probably not strong enough to contribute to their in vivo anti-inflammatory effects.

The possible contribution of pulmonary metabolism to the putative first-pass metabolism of 2-arylpropionic acid nonsteroidal antiinflammatory drugs has not been documented. Isolated perfused rabbit lungs, perfused with 4.5% bovine serum albumin or 5% dextran, were used to study the pulmonary elimination of (R)- and rac-ibuprofen, fenoprofen, and flurbiprofen. In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)-enantiomer; fraction inverted (± SE) was 0.37 ± 0.05 for (R)-ibuprofen and 0.85 ± 0.03 for (R)-fenoprofen. In the presence of protein, neither ibuprofen nor fenoprofen was metabolized. Flurbiprofen did not undergo pulmonary elimination under any condition studied. This study illustrates that even though a tissue is capable of metabolism, particularly inversion of 2-arylpropionics, the quantitative importance of such elimination pathways may be minimal in the presence of the high degree of protein binding that is characteristic of these drugs. © 1992 Wiley-Liss, Inc.

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.

A competitive inhibition mechanism is proposed to investigate the interactions among 2,3,6-tri-O-methyl-β-cyclodextrin (TM-β-CD), cationic ionic liquid (IL) type surfactants, N-undecenoxy-carbonyl-L-leucinol bromide (L-UCLB) and profens (PROFs) using affinity capillary electrophoresis. The apparent binding constant of TM-β-CD to L-UCLB was estimated by nonlinear and linear plotting methods. The binding constants of one representative PROF (e.g., fenoprofen) to TM-β-CD and to L-UCLB were estimated by a secondary plotting approach. The R- and S-fenoprofen have different binding constant values, resulting in the enantioseparation due to the synergistic effect of the two chiral selectors, TM-β-CD and L-UCLB.

In the present study, seven hydroxamic acid derivatives of nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, fenoprofen, ketoprofen, indomethacin and diclofenac) were found to possess significant antioxidant, radical scavenging and metal chelating activities. The most active antioxidant and radical scavenger was N-methylhydroxamic acid of diclofenac (ANT = 88.0 % and EC50 = 60.1 microg mL-1). The activity of the standard substance, butylated hydroxyanisole, in the two assays was ANT = 86.9 % and EC50 = 18.8 microg mL-1, respectively. Ibuproxam was the strongest iron chelator among investigated hydroxamic acids (EC50 = 255.6 microg mL-1), yet significantly weaker than the standard substance, EDTA (EC50 = 29.1 microg mL-1). It seems that different mechanism is involved in metal chelating activity than in antioxidant and radical scavenging activity. Antioxidant and radical scavenging activities may be connected with conjugation of the nitrogen lone electron pair with the carbonyl group. On the other hand, more hydrophilic substances tend to be better iron chelators. U radu je opisano antioksidativno djelovanje te sposobnost hvatanja slobodnih radikala i stvaranja kelata sedam hidroksamskih kiselina, derivata nesteroidnih protuupalnih lijekova ibuprofena, fenoprofena, ketoprofena, indometacina i diklofenaka. Najjače antioksidativno djelovanje i najjaču sposobnost hvatanja slobodnih radikala imala je N-metilhidroksamska kiselina diklofenaka (ANT = 88,0 % i EC50 = 60,1 g mL1). Vrijednosti za standardnu supstanciju, butilirani hidroksianisol, bile su: ANT = 86,9 % i EC50 = 18,8 g mL1. Derivat ibuprofena bio je najjači kelator među ispitivanim hidroksamskim kiselinama (EC50 = 255,6 g mL1), ali značajno slabiji od standardne supstancije, EDTA (EC50 = 29,1 g mL1). Pretpostavlja se da su različiti mehanizmi uključeni u keliranje metala i antioksidativno djelovanje, odnosno hvatanje slobodnih radikala. Antioksidativno djelovanje i sposobnost hvatanja slobodnih radikala moglo bi biti povezano s konjugacijom slobodnog para elektrona na dušiku s karbonilnom skupinom. S druge strane, hidrofilnije supstancije pokazale su se kao jači kelatori iona željeza.

The target phosphoramidates 5a-e were prepared in one step from 3-hydroxypropyl derivatives 3a-e of nonsteroidal anti-inflammatory drugs (fenoprofen, ketoprofen, ibuprofen, indomethacin, diclofenac). The products 3a-e and 5a-e were evaluated for their cytostatic and antiviral activity against malignant tumour cell lines and normal human fibroblasts (WI 38). All phosphoramidate derivatives 5a-e possess significantly greater inhibitory activities than the corresponding 3-hydroxypropyl derivatives 3a-e, whereby compound 5a showed the most potent inhibitory activities against cervical, pancreatic and colon carcinoma cell lines (IC(50)=5-7 microM).

This paper reports the synthesis of O-methyl and O-ethyl NSAID hydroxamic acids, their antimicrobial activities, and their ability to inhibit urease and soybean lipoxygenase activities. Ibuprofen and fenoprofen hydroxamic acids with free hydroxy groups present the highest antimicrobial activity, while indomethacin and diclofenac analogs show significantly lower antimicrobial activity. Diclofenac hydroxamic acid 4e exerts the highest anti-urease activity. Indomethacin O-ethyl hydroxamic acid 3h and ibuprofen O-benzyl hydroxamic acid 4b exert significant inhibitory activities on soybean lipoxygenase. Fenoprofen and indomethacin O-ethyl hydroxamic acids 3b and 3h and diclofenac and indomethacin O-benzyl analogs 4g and 4i highly inhibit lipid peroxidation. The highest antioxidant activity was shown by fenoprofen derivative 3b.

Ibuprofen, a chiral non-steroidal anti-inflammatory drug chemically related to fenoprofen and naproxen, has moderate but definite anti-inflammatory, analgesic and antipyretic properties, with considerably less gastrointestinal adverse effect than other drugs in the same family. Currently available in the market are preparations in which bioavailability of ibuprofen is increased by salification with various salts. We have investigated the pharmacological properties of one such salt, ibuprofen-arginine, of biological interest because l-arginine acts as substrate of the nitric oxide (NO) synthesising enzymes. Using epithelial HeLa cells expressing the endothelial NO synthase we show that ibuprofen-arginine releases NO and that this NO protects against the cytotoxic apoptogenic effects of staurosporine. We also found that ibuprofen-arginine is endowed with enhanced anti-inflammatory effects with respect to ibuprofen, as shown by reduced hind paw oedema, neutrophil infiltration and chondrocyte apoptosis in collagen-induced mouse arthritis, a model of chronic inflammation. NO has pleiotropic beneficial effects that may contribute to limit inflammation and anti-inflammatory compounds able to release NO display higher efficacy than the parent drugs in defined clinical settings. Our results open the possibility that NO generation contributes to the enhanced anti-inflammatory effects of ibuprofen-arginine vs. ibuprofen, suggesting co-administration of anti-inflammatory drugs and arginine as an additional way to exploit the beneficial effects of NO.

Calcium fenoprofen samples previously studied in powder form have been made into formulated tablets and into pure compressed discs. The wide variation in dissolution rate noted for powders is not noted in the early stages of tablet dissolution, all samples giving about the same rate in spite of variation in the disintegration rate. It is possible that smaller particles have been compressed or agglommerated to larger ones, or have been rendered hydrophobic by magnesium stearate. In later stages there is some intersample variation, apparently linked to larger particles in the parent active ingredient. Intrinsic dissolution rates from compressed discs cannot be influenced by any excipients as these are not present, or by particle size considerations as the area of the discs is constant. Rates differ only slightly after compression, and this is thought to be due to only partial retention of energetic differences following compression.

The data suggest that the 4MU-UDPGT activity of human liver microsomes probably contributes to the glucuronidation of a limited number of clinically used drugs. However, confirmation of this ultimately requires studies to be performed with purified isozymes, cDNAs expressed in cell culture, or specific inhibitory antibodies.

The diastereomeric glucuronic acid conjugates are major metabolites of the nonsteroidal anti-inflammatory drug fenoprofen (FEN). Glucuronidation of FEN enantiomers was investigated with liver microsomal preparations from different species (sheep, rabbit, rat and human). The formed R- and S-FEN conjugates can be separated and quantitated directly on a C18 reversed-phase HPLC column using a mixture of acetonitrile and tetrabutylammonium sulfate buffer, pH 2.5, as mobile phase. Applying this analytical procedure, it is possible to characterize enantioselective glucuronidation of FEN. For in vitro procedures, rates of glucuronide formation are substrate (FEN) and cosubstrate (UDP glucuronic acid, UDPGA) dependent with initial rates of glucuronide formation being higher for R- than for S-FEN. The R/S ratio of the formed products was independent of UDPGA (2.5-15 mmol/l) and substrate concentrations greater than or equal to 0.4 mmol/l. Enantioselective cleavage of the formed FEN conjugates by alkaline hydrolysis and hydrolytic enzymes (R greater than S-glucuronide) can be controlled during in vitro studies by pH adjustment and the addition of enzyme inhibitors.

Fine tuning of the biaryl and amino moieties of Feringa's phosphoramidite ligands yields structurally simpler, yet more efficient and selective, ligands for asymmetric hydrovinylation of vinylarenes and acylic 1,3-dienes. The enantioselectivities and yields observed in the formation of the 3-arylbutenes are among the highest for all asymmetric catalytic processes reported to date for the synthesis of intermediates for the widely used antiinflammatory 2-arylpropionic acids including naproxen, ibuprofen, fenoprofen, and flurbiprofen.

This study is about the preparation of an open tubular capillary column of molecularly imprinted polymer (MIP) and its application to chiral separation by microLC. A non-covalent in-situ molecular imprinting polymerization protocol was used to synthesize the S-ketoprofen MIP. A special procedure was employed to secure formation of an open tubular and rigid MIP layer in a silica capillary of 100 microm id. The capillary was filled with the reaction mixture, sealed, and placed in a water bath at 50 degrees C for 3 h. Then it was flushed with a 0.5 MPa nitrogen flow for 5 min, and was again placed in the water bath for 2 h to complete MIP formation. Methacrylic acid (MAA) has been known to be an inefficient functional monomer in preparation of MIP of an acid molecule. However, MAA was used with ethylene glycol dimethacrylate in preparation of the S-ketoprofen MIP in this study. The open tubular structure and the microLC mode of separation enabled free optimization without any restriction, thus a very good resolution (R=4.7) of ketoprofen enantiomers was achieved when a mobile phase composed of 30% acetonitrile and 70% acetate buffer at pH 4.5 was used with 5 mbar inlet pressure. This may be partially attributed to the open tubular structure of our MIP, enabling low column back-pressure and free optimization of eluent composition, as well as to the small capillary dimensions. Our MIP capillary column also showed some versatility in chiral separation, thus a good chiral separation was observed for naproxen, ibuprofen, and fenoprofen enantiomers.

We packed an ionic liquid (IL)-functionalized stationary phase – based on 1-octyl-3-propylimidazolium chloride covalently bounded to silica gel – into a 3.2 mm × 250 mm column for the simultaneous separation of acidic, basic, and neutral compounds using carbon dioxide subcritical/supercritical fluid chromatography (SFC), and examined the effects of the pressure, temperature, co-solvents, and additives on the retention behavior of the analytes. The model compounds tested for SFC separation are acetaminophen, metoprolol, fenoprofen, ibuprofen, naphthalene, and testosterone. The data indicate that hydrogen-bonding and hydrophobic interactions between the analytes and the IL-modified stationary phase seem to involve in the separation process. Simultaneous separation of acidic, basic, and neutral compounds via SFC was successful at a co-solvent content of 20% MeOH, a pressure of 110 bar, and a column temperature of 35 °C. The relative standard deviations of the retention times and peak areas at 50 ppm were all less than 4 and 8% ( n = 6), respectively.

Fine tuning of the biaryl and amino moieties of Feringa's phosphoramidite ligands yields structurally simpler, yet more efficient and selective, ligands for asymmetric hydrovinylation of vinylarenes and acylic 1,3-dienes. The enantioselectivities and yields observed in the formation of the 3-arylbutenes are among the highest for all asymmetric catalytic processes reported to date for the synthesis of intermediates for the widely used antiinflammatory 2-arylpropionic acids including naproxen, ibuprofen, fenoprofen, and flurbiprofen.

Immobilised lipase B from Candida antarctica catalyzes the enantioselective esterification of rac-fenoprofen, (±)-1. The use of orthoformates as alcohol donors permitted to synthesize the ester in irreversible manner, therefore improving the performance of the enantioselective esterification. This convenient procedure permitted to prepare (S)-fenoprofen in good yield and in high optical purity.

Samples of calcium fenoprofen crystals have been prepared on laboratory, pilot and production scales, some by conventional aqueous precipitation, others under conditions designed to increase or decrease the degree of crystallinity. They were characterized by X-ray powder diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, surface area by nitrogen sorption, agglomerate size by Coulter counter, true density, sodium content, powder dissolution rates and heats of solution. No evidence of polymorphic variation was found. Most precipitation conditions gave partially fused agglomerates of primary crystals. Relative degrees of crystallinity were assessed from heats of solution. The more perfectly crystalline samples gave relatively high endothermic heats of solution coupled with low powder dissolution rates. Lattices with high levels of disruption, or low crystallinity, gave lower heats of solution coupled with enhanced powder dissolution rates. Heats of solution make a significant contribution to the overall characterization and to understanding batch-to-batch variation, and they relate well to the observed powder dissolution rates.

In the atropine-treated rabbit, vagal stimulation, arterial infusion of ATP or vasoactive intestinal peptide (VIP) caused gastric relaxation. At the end of either vagal stimulation or ATP infusion, but not after VIP, the gastric inhibitory responses were abruptly interrupted by 'rebound contractions'. Administration of fenoprofen depressed or abolished the rebound contraction, thus transforming the brisk relaxant response, elicited by vagal stimulation or ATP, into long-lasting relaxation. Indomethacin depressed the rebound contractions only at high doses and this effect was not always reproducible.

Anecdotal and uncontrolled studies have suggested that nonsteroidal anti-inflammatory drugs produce false-positive results in immunoassay urine tests for some drugs of abuse. This study was performed in 60 volunteers who took ibuprofen as either a single 400-mg dose, or 200 mg three times a day, or 400 mg three times a day, and in 42 patients taking ibuprofen, naproxyn, or fenoprofen in therapeutic regimens for more than 30 days. Of the 510 urines collected from 102 individuals during these dosage regimens, two gave false-positive tests for cannabinoid by enzyme-mediated immunoassay (EMIA), one after 1200 mg of ibuprofen in three divided doses for one day and one in a patient taking naproxyn on a chronic basis; none was falsely positive for benzodiazepines. Two urines were false-positive for barbiturates by fluorescence polarization immunoassay (FPIA), one in a patient taking ibuprofen and one in a patient taking naproxyn. These data, collected prospectively, demonstrate the small likelihood of a false-positive immunoassay test result for cannabinoids, benzodiazepines, or barbiturates after the acute or chronic ingestion of ibuprofen, or after the chronic ingestion of naproxyn or fenoprofen.

The inversion from R- to S-enantiomer that occurs for some arylpropionic acids may have both toxicological and therapeutic implications. To characterize some properties of this inversion, arylpropionyl-CoA thioester formation was studied in rat tissue homogenates and subcellular fractions for the enantiomers of fenoprofen, ibuprofen, and flurbiprofen. Thioesters were formed from (R)-fenoprofen (64%) and (R)-ibuprofen (33%) but not from the corresponding S-enantiomers or the enantiomers of flurbiprofen. This correlates with the extensive inversion of fenoprofen and ibuprofen and lack of inversion of flurbiprofen in vivo. Subcellular fractions from rat liver showed thioester formation to occur in mitochondria and microsomes but not cytosol. Once formed, the thioesters were readily racemized by whole rat liver homogenate, mitochondria, and cytosol, but only partially inverted (S:R = 0.3) in microsomes. Thioester formation from fenoprofen and ibuprofen was studied in tissue homogenate obtained from liver, diaphragm, kidney, lung, skeletal muscle, smooth muscle, fat, caecum, and intestines. The liver was at least 50-fold more efficient than the other tissues studied and would be expected to be a major organ of enantiomeric inversion. Our data support the hypothesis that R- to S-enantiomeric inversion of arylpropionic acids proceeds via the stereoselective formation of CoA thioesters followed by enzymatic racemization and hydrolysis of the thioesters to regenerate free acid.

A high-performance liquid chromatography procedure for the determination of selected non-steroidal anti-inflammatory analgesics (acetylsalicylic acid, fenbufen, fenoprofen, ibuprofen, indomethacin, ketoprofen, naproxen, sulindac and tolmetin) from pharmaceutical dosage forms has been developed. The individual analytes are extracted from the dosage forms with 0 to 10% aqueous acetonitrile and chromatographed on a 22-cm underivatized silica column at ambient temperature (23 ± 1°C). The mobile phases consisted of 5 mM aqueous sodium phosphate—phosphoric acid buffer, pH 2.6 containing 0 to 10% acetonitrile. Accuracy and precision of the method were shown to be excellent. This study was performed to extend the applicability of underivatized silica stationary support with aqueous eluents to the analysis of acidic compounds.

Graft copolymerization of rosin-(2-acryloyloxy)ethyl ester (RAEE) onto chitosan (Cts) was carried out under microwave irradiation using potassium persulfate as an initiator. The structures, morphology, and thermal properties of the Cts graft copolymer (Cts-g-PRAEE) were characterized by means of FT-IR, XRD, SEM, and TG. Also, Cts and Cts-g-PRAEE copolymer were used as carriers of fenoprofen calcium (FC), and their controlled release behavior in artificial intestinal juice were studied. The results show that the rate of release of fenoprofen calcium from the carrier of Cts-g-PRAEE copolymer becomes very slower than that of Cts in artificial intestinal juice.

Following numerous experimental observations that various non-steroidal anti-inflammatory drugs have antitumor potentials, a series of fenoprofenamides (1a– g) and ketoprofenamides (2a– c) was tested on proliferation of different human tumor cell lines and normal human fibroblasts in vitro. Fenoprofen and ketoprofen showed modest antiproliferative activity, whereas the growth inhibitory activity of the tested amides clearly demonstrates that the substituents linked by an amide bond are essential for the significantly stronger cytostatic activity, probably because of a greater lipophilicity and/or better cell uptake. Additionally, it was shown that the most active derivatives (1d and 2a) induced cell cycle arrest at the G1 phase, as well as apoptosis.

An approach for improving the separation performance of the enantioseparation by CE with vancomycin as chiral selector is described. In the present method, a solution of poly(dimethylacrylamide) (PDMA) was used for dynamic coating of the capillary wall to minimize the adsorption of vancomycin onto the capillary wall, and to depress the EOF. Compared with the bare fused-silica capillaries and the capillaries coated with the polycationic polymer hexadimethrine bromide (HDB), the PDMA-coated capillary displayed the best separation performance. The resulting coating could withstand hundreds of runs without losing its function. Moreover, a partial filling technique was applied to avoid interference in detection caused by the presence of vancomycin in the buffer. The separation time was shortened when a short-end-injection technique was applied. Several parameters such as buffer pH, vancomycin concentration and plug length of the vancomycin solution for the separation were optimized. Under the optimal conditions, all tested enantiomers, including FMOC amino acids derivatives, ketoprofen and fenoprofen, were baseline-separated in less than 4.2 min.

A method is described for the simultaneous analysis of 14 non-steroidal anti-inflammatory drugs (NSAIDS) in human serum using negative electrospray ionization-tandem mass spectrometry (ESI-MS/MS). After addition of internal standard and protein precipitation using acetonitrile, samples were transferred to autosampler vials for direct analysis without chromatography. Injection of an air bubble with the sample and a multiple reaction monitoring (MRM) method using argon collision-induced dissociation (CID) of analyte (M-H)− ions permitted integration of the product ion peak areas to produce reproducible quantitative data over the range of concentrations expected in serum during routine use of these drugs. The method permitted the analysis of 30 samples per hour. Two hundred fifty consecutive analyses did not adversely affect instrument sensitivity.

The objective of the present study was to assess the influence of type 1 and type 2 diabetes mellitus on the enantioselective pharmacodynamics and pharmacokinetics of fenoprofen. Patients with diabetes mellitus type 1 (n = 7) or type 2 (n = 7) and healthy volunteers (n = 13) received orally a single 600-mg dose of racemic fenoprofen. Monocompartmental analysis of (+)-(S)-fenoprofen showed a significant difference (P < .05, Kruskal-Wallis test) in area under the curve (AUC) values (153.68 vs 243.50 microg x h/mL) and oral clearance (1.95 vs 1.23 L/h) only between patients with diabetes mellitus type 2 and healthy volunteers. The inhibitory activity of cyclooxygenases was evaluated indirectly by the determination of prostaglandin E2 (COX-2) and thromboxane B2 (COX-1) using the sigmoidal inhibitory Emax model. The patients with type 2 diabetes mellitus presented lower IC50 (3.29 vs 6.0 microg/mL) and g (0.73 vs 2.01) values for COX-1 activity compared to healthy volunteers (P < .05, Kruskal-Wallis test). These results show that diabetes mellitus type 2, but not type 1, influences the pharmacokinetics and pharmacodynamics of (+)-(S)-fenoprofen.

The chiral selector vancomycin was used either as mobile phase additive or bound as a chiral stationary phase (CSP) for the stereoselective separation of seven racemic nonsteroidal anti-inflammatory drugs (NSAIDs), fenoprofen, carprofen, flurbiprofen, indoprofen, flobufen, ketoprofen, and suprofen, by capillary liquid chromatography. The effect of the type of stationary phase, the chiral column Chirobiotic V or the achiral stationary phases Nucleosil 100 C8 HD and Nucleosil 100 C18 HD, and the concentration of vancomycin in the mobile phase on separation of the drug enantiomers were evaluated. All the drugs, except flobufen, were successfully enantioseparated on Nucleosil 100 C8 HD with 4 mM vancomycin present in the mobile phase (composed of methanol and buffer) in the reversed phase mode. On the vancomycin-bonded chiral stationary phase, it was difficult to get enantioseparations of the profen NSAIDs. However, flobufen gave better enantioseparation on the vancomycin CSP. The better enantioresolution of the majority of profen derivatives on the achiral columns with vancomycin added to the mobile phase can be attributed in particular to the higher separation efficiency of this capillary chromatographic system. In addition, vancomycin dimers, formed in the mobile phase, seem to offer a better steric arrangement for stereoselective interaction to these analytes than the vancomycin bonded on the CSP. These substantial differences in the CS structure significantly influence the chiral discrimination mechanism.

Three on-column preconcentration techniques were compared to analyse a group of nonsteroidal anti-inflammatory drugs (NSAIDs) using micellar electrokinetic capillary chromatography (MEKC) under pH-suppressed electroosmotic flow (EOF) in water samples. The analysed drugs were ibuprofen, fenoprofen, naproxen, ketoprofen, and diclofenac sodium. The micellar background electrolyte (BGE) solution was formed by 75 mM sodium dodecyl sulfate (SDS), 40% (v/v) acetonitrile, and 25 mM sodium phosphate at pH 2.5. When this BGE solution was used the applied voltage was reversed, -10 kV, and the drugs were separated within 20 min. The on-column preconcentration modes, characterised all of them for the sample matrix removal out of the capillary by itself under a reverse potential at the same time as the EOF was reduced, were stacking with reverse migrating micelles (SRMM), stacking with reverse migrating micelles-anion selective exhaustive injection (SRMM-ASEI), and field-enhanced sample injection with reverse migrating micelles (FESI-RMM). The sensitivity was improved up to 154-, 263-, and 63-fold, respectively when it was calculated through the peaks height. The optimised methods were validated with spiked mineral water by combining off-line solid-phase extraction (SPE) and the proposed on-line sample stacking strategies. The detection limits (LODs) of NSAIDs in mineral water were at ng/L levels.

Some aspects of both sample preparation and instrumental techniques for analysis of such acidic drugs as acetylsalicylic acid, ibuprofen, gemfibrozil, fenoprofen, naproxen, ketoprofen, and diclofenac, as well as caffeine in surface water and municipal wastewater have been studied and further developed. Water samples were filtered and target analytes were extracted by solid-phase extraction (SPE). Supelco LC-18 and Oasis HLB SPE cartridges were used to pre-concentrate samples for acidic drugs and caffeine, respectively. A methylation process was applied to acidic drugs prior to analysis while caffeine was analyzed directly. A method of gas chromatography-ion trap tandem mass spectrometry (IT-MS/MS) for analysis of the target acidic pharmaceuticals and caffeine is presented here in detail. Such parameters as collision-induced dissociation (CID) voltage, isolation time, excitation time, excitation storage level, and electron energy were adjusted in order to optimize the instrument analytical performance. After optimization, an instrument detection limit of 0.5-20 pg/microL with signal-to-noise (S/N) not less than 5 was achieved for all target analytes. It was shown that this method has good linearity within the range of 10-2000 pg/microL. The application of the optimized IT-MS/MS parameters conjointly with the sample preparation procedure resulted in method detection limits (MDLs) of 0.1-1.0 and 20 ng/L for the determination of acidic drugs and caffeine, respectively in such samples as surface water, effluent from municipal wastewater plants, as well as receiving waters.

Two types of polymer-drug conjugates were synthesized starting from styrene-maleic acid anhydride copolymer (SMA). Fenoprofen and gemfibrozil were chosen as model drugs because of their short plasma half lives. Both drugs were first converted to their 2-aminoethylamides, which possess free amino groups capable of reacting with SMA anhydride rings. By modifying the degree and type of substitution, lipophilic and hydrophilic conjugates were obtained. Drug loading in the conjugates was between 17 and 47%.

Pharmaceutical solids have generally been characterized as either three-dimensional crystals or amorphous solids based on X-ray powder diffraction and modulated temperature differential scanning calorimetry. In contrast, fewer examples of thermotropic and lyotropic liquid crystals, or mesophases, appear in the pharmaceutical literature, and that literature teaches that the aforementioned analytical techniques should be complemented with polarized light microscopy and small-angle X-ray scattering in order to effectively identify potential liquid crystalline states. Lyotropic liquid crystals are induced by the presence of solvent, and have been extensively described elsewhere in the context of emulsion technology; however, other pharmaceutical examples are emerging. Thermotropic liquid crystals are induced by a change in temperature and are essentially free of solvent, where more pharmaceutical applications appear in the literature. In the present review the general structural characteristics that favor the formation of liquid crystalline mesophases are categorized by therapeutic target and molecular size, and the analytical means of their identification are presented. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.

Terahertz pulsed spectroscopy (TPS) is a new technique that is capable of eliciting rich information when investigating pharmaceutical materials. In solids, it probes long-range crystalline lattice vibrations and low energy torsion and hydrogen bonding vibrations. These properties make TPS potentially an ideal tool to investigate crystallinity and polymorphism. In this study four drugs with different solid-state properties were analyzed using TPS and levels of polymorphism and crystallinity were quantified. Carbamazepine and enalapril maleate polymorphs, amorphous, and crystalline indomethacin, and thermotropic liquid crystalline and crystalline fenoprofen calcium mixtures were quantified using partial least-squares analysis. Root-mean-squared errors of cross validation as low as 0.349% and limits of detection as low as approximately 1% were obtained, demonstrating that TPS is an analytical technique of potential in quantifying solid-state properties of pharmaceutical compounds.