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Scott A White - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of prostaglandin d 2 11 ketoreductase akr1c3 in complex with the nonsteroidal anti inflammatory drugs Flufenamic Acid and indomethacin
Cancer Research, 2004Co-Authors: Andrew L Lovering, Jon P Ride, Christopher M Bunce, Julian C Desmond, Stephen M Cummings, Scott A WhiteAbstract:It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or Flufenamic Acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas Flufenamic Acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
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crystal structures of prostaglandin d 2 11 ketoreductase akr1c3 in complex with the nonsteroidal anti inflammatory drugs Flufenamic Acid and indomethacin
Cancer Research, 2004Co-Authors: Andrew L Lovering, Jon P Ride, Christopher M Bunce, Julian C Desmond, Stephen M Cummings, Scott A WhiteAbstract:It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or Flufenamic Acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas Flufenamic Acid binds to both the active site and the β-hairpin loop, at the opposite end of the central β-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
Stephen R Byrn - One of the best experts on this subject based on the ideXlab platform.
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stabilization of metastable Flufenamic Acid by inclusion of mefenamic Acid solid solution or epilayer
Journal of Pharmaceutical Sciences, 2010Co-Authors: Eun Hee Lee, Stephen R ByrnAbstract:The physical stability of metastable form I of Flufenamic Acid (FFA) increased by using mefenamic Acid (MFA) as an inclusion compound. We studied the extent of this effect and explained the mechanism by investigating the effect of the presence of MFA on nucleation and crystal growth of the mixed crystals and the effects it has on the surface morphology. We conclude that the polymorphic transformation of FFA was inhibited in the presence of MFA both by lowering the difference in free energy of the MFA/FFA I and MFA/FFA III solid solution crystals, and also by forming an epilayer, thus affecting the kinetics of the polymorphic transformation. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4013–4022, 2010
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crystal quality and physical reactivity in the case of Flufenamic Acid ffa
Journal of Pharmaceutical Sciences, 2010Co-Authors: Hong Wen, Kenneth R Morris, Joseph G Stowell, Stephen R ByrnAbstract:ABSTRACT In reality, no crystal is perfect. Crystals bear defects both in the bulk and on the surface. The purpose of this project is to study the correlation between crystal defect density and reactivity of physical transformation. The hypothesis is that larger crystals have the opportunity to pick up more defects during crystal growth than smaller crystals, therefore, have higher reactivity. Flufenamic Acid (FFA) was used as a model compound. Phase transformation of crystal Form I (white) to Form III (yellow) of FFA was studied, and observed that larger crystals of FFA Form I transform faster. Furthermore, the etching pits identified on the major crystal faces (1 0 0) using atomic form microscopy (AFM) also showed that larger crystals had higher surface defect density than smaller ones, which correlates with the finding that larger crystals transforms faster than smaller ones. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3839–3848, 2010
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epitaxy of a structurally related compound on the 100 faces of Flufenamic Acid form i and iii single crystals
Crystal Growth & Design, 2010Co-Authors: Eun Hee Lee, Stephan X M Boerrigter, Stephen R ByrnAbstract:Epitaxy is a form of two-dimensional heterogeneous nucleation in which the substrate induces a particular crystal phase of another compound. Here we describe the epitaxial sublimation behavior of a structurally related compound, mefenamic Acid on the (100) faces of Flufenamic Acid form I and III single crystals. Raman microscopy, powder X-ray diffraction, and morphology analysis demonstrated that the epitaxial crystals of mefenamic Acid were the most stable form. The mefenamic Acid crystals showed a specific orientation with respect to the substrate, which was explained by lattice matching of the epitaxial crystal with respect to the host crystal.
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formation and solid state characterization of a salt induced metastable polymorph of Flufenamic Acid
Crystal Growth & Design, 2008Co-Authors: Eun Hee Lee, Stephan X M Boerrigter, Alfred C F Rumondor, Sai Prasanth Chamarthy, Stephen R ByrnAbstract:Using additives is one of more recent and special methods to obtain a desirable polymorph. However, for pharmaceuticals, additives are usually limited to structurally related organic compounds. In this study, we have shown the potential of using a salt additive to induce crystallization of the metastable polymorph V of Flufenamic Acid (FFA). Additionally, it was found that FFA V undergoes a rapid interface mediated polymorphic transformation. Therefore, the slow evaporation method which can decrease the contact of the solvent during crystallization was chosen to delay the polymorphic transformation. It can be concluded that understanding the system is a prerequisite for using additives to obtain the desired polymorph.
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crystal packing and chemical reactivity of two polymorphs of Flufenamic Acid with ammonia
Molecular Crystals and Liquid Crystals, 2002Co-Authors: Xiaoming Chen, Kenneth R Morris, Stephen R ByrnAbstract:The objective of this study is to compare the reactivity of two polymorphs of Flufenamic Acid with ammonia and relate it to crystal packing. Forms I and III of Flufenamic Acid were exposed to dry ammonia vapor. Optical microscopy, microscopic Raman, and XRPD were used to characterize the possible changes. The different reactivity of Forms I and III was clearly observed under dry ammonia vapor from 12% ammonium hydroxide. Single crystals of Form I gradually became opaque within 180 min, whereas single crystals of Form III retained transparent. FT-Raman analysis revealed that significant ammonium salt was formed at the major face of Form I, while the reaction of Form III was undetectable. So Form I is more reactive than Form III at ambient temperature, which agrees with their thermodynamic order. At 60°C, the thermodynamic order switches and Form I is the stable form. However, Form I is still more reactive with ammonia than Form III at 60°C. The reaction rate is likely to be determined more by kinetic facto...
Jean Ducobu - One of the best experts on this subject based on the ideXlab platform.
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conception of myeloperoxidase inhibitors derived from Flufenamic Acid by computational docking and structure modification
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Pierre Van Antwerpen, Martine Prevost, Karim Zouaouiboudjeltia, Sajida Babar, Ilham Legssyer, Patrick Moreau, N Moguilevsky, Michel Vanhaeverbeek, Jean Ducobu, Jean NeveAbstract:The development of myeloperoxidase (MPO) inhibitors has been conducted using Flufenamic Acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA. Most of the synthesized molecules had an activity in the same range as Flufenamic Acid but none of them were able to inhibit the MPO-dependent LDL oxidation. The experiments however gave some useful indications for a rational conception of MPO inhibitors.
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inhibition of the myeloperoxidase chlorinating activity by non steroidal anti inflammatory drugs Flufenamic Acid and its 5 chloro derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous Acid
European Journal of Pharmacology, 2007Co-Authors: Pierre Van Antwerpen, Sajida Babar, Patrick Moreau, N Moguilevsky, Michel Vanhaeverbeek, Francois Dufrasne, Mathieu Lequeux, Karim Zouaoui Boudjeltia, Ilham Lessgyer, Jean DucobuAbstract:The present in vitro study was designed to assess the inhibition of the myeloperoxidase (MPO)/H(2)O(2)/Cl(-) system by several non steroidal anti-inflammatory drugs (NSAIDs) of the oxicam family and of nimesulide and to compare their effect with Flufenamic Acid in order to investigate their influence on the chlorinating activity of MPO as a protective mechanism during chronic inflammatory syndromes. The inhibition of the system was assessed by measurement of the taurine chlorination while the accumulation of compound II was used to investigate the mechanism of inhibition. The oxidation products of NSAIDs by the MPO/H(2)O(2)/Cl(-) system were identified and Flufenamic Acid and derivatives were also assessed in the inhibition of LDL oxidation in two models. Flufenamic Acid (IC(50) = 1.1+/-0.3 microM) is the most efficient inhibitor of the MPO/H(2)O(2)/Cl(-) system and nimesulide (IC(50) = 2.1+/-0.3 microM) is more active than the other NSAIDs of the oxicam family (IC(50) = 8-12 microM). The accumulation of compound II revealed that Flufenamic Acid acts as an electron donor while the other NSAIDs are antagonists of chloride anions. The identification of the oxidation products confirms that Flufenamic behaves like an electron donor and is directly oxidized in the 5-hydroxy-derivative but gives also the 5-chloro-derivative which similarly inhibits the MPO/H(2)O(2)/Cl(-) system. Flufenamic Acid has the best inhibiting activity towards the MPO/H(2)O(2)/Cl(-) system. However, in models that assess the LDL oxidation, Flufenamic Acid and its derivatives were unable to properly inhibit MPO activity as the enzyme is adsorbed on macrostructures such as LDL molecules.
Andrew L Lovering - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of prostaglandin d 2 11 ketoreductase akr1c3 in complex with the nonsteroidal anti inflammatory drugs Flufenamic Acid and indomethacin
Cancer Research, 2004Co-Authors: Andrew L Lovering, Jon P Ride, Christopher M Bunce, Julian C Desmond, Stephen M Cummings, Scott A WhiteAbstract:It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or Flufenamic Acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas Flufenamic Acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
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crystal structures of prostaglandin d 2 11 ketoreductase akr1c3 in complex with the nonsteroidal anti inflammatory drugs Flufenamic Acid and indomethacin
Cancer Research, 2004Co-Authors: Andrew L Lovering, Jon P Ride, Christopher M Bunce, Julian C Desmond, Stephen M Cummings, Scott A WhiteAbstract:It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or Flufenamic Acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas Flufenamic Acid binds to both the active site and the β-hairpin loop, at the opposite end of the central β-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
Ulrich F Schaefer - One of the best experts on this subject based on the ideXlab platform.
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influence of nanoencapsulation on human skin transport of Flufenamic Acid
Skin Pharmacology and Physiology, 2006Co-Authors: J Luengo, Barbara Weiss, Marc Schneider, Alexander Ehlers, Frank Stracke, Karsten Konig, Karlheinz Kostka, Clausmichael Lehr, Ulrich F SchaeferAbstract:The effect of the inclusion of Flufenamic Acid in poly(lactide-co-glycolide) nanoparticles on the transport of Flufenamic Acid into excised human skin was investigated. Penetration and permeation data were acquired using two different in vitro test systems: the Saarbrucken penetration model, where the skin acts as its own receptor medium, and the Franz diffusion cell, where the receptor medium is a buffer solution. For the stratum corneum, no differences were found between nanoencapsulated and free drug. Drug accumulation in the deeper skin layers and drug transport across human epidermis were slightly delayed for the nanoencapsulated drug compared to the free drug after shorter incubation times ( 12 h), the nanoencapsulated drug showed a statistically significantly enhanced transport and accumulation (p < 0.05). Additionally, nanoencapsulated Flufenamic Acid was visualized by multiphoton fluorescence microscopy. Particles were found homogeneously distributed on the skin surface and within the dermatoglyphs, but no nanoparticles were detected within or between the corneocytes.
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correlation between stratum corneum water partition coefficient and amounts of Flufenamic Acid penetrated into the stratum corneum
Journal of Pharmaceutical Sciences, 2002Co-Authors: Heike Wagner, Karlheinz Kostka, Clausmichael Lehr, Ulrich F SchaeferAbstract:The stratum corneum of various donors differs in particular in the composition of the lipoidal phase. Considering the drug amounts penetrating into the stratum corneum a simple methodology to correlate these differences in the stratum corneum composition with the drug amounts detectable within the stratum corneum is desirable. Penetration experiments investigating several incubation times were carried out with three different skin flaps using the Saarbruecken penetration model and the lipophilic model drug Flufenamic Acid. The drug amounts within the stratum corneum were obtained with the tape-stripping technique, while the drug amounts present in the deeper skin layers were achieved by cryosectioning. The stratum corneum/water-partition coefficient was determined with the same three skin flaps to characterize the lipoidal stratum corneum phase in general, and the differences were attributed to the different amounts of ceramides and sterols. In addition, for the lipophilic drug Flufenamic Acid, a direct linear correlation was found between the stratum corneum/water-partition coefficients and the drug amounts penetrated into the stratum corneum for all investigated time intervals (correlation coefficients of r(30 min) = 0.998, r(60 min) = 0.998 and r(180 min) = 0.987). In contrast to the stratum corneum/water-partition coefficients, the determination of a corresponding relationship for the stratum corneum and the deeper skin layers failed due to the reason that steady-state conditions could not be achieved for the deeper skin layers during the investigated time intervals. In summary, the stratum corneum/water-partition coefficients offer the possibility to predict drug amounts within the stratum corneum of different donor skin flaps without a time consuming determination of the lipid composition of the stratum corneum.