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1. Simulation model of quarter milk flowrates to estimate quarter and cow milking duration and automated milking system's box duration

Author

P. Silva Boloña, J. Upton, V. Cabrera, T. Erker, and D.J. Reinemann

Subjects
quarter milk flowrate, simulation model, milking duration, box time, automatic milking system, Dairy processing. Dairy products, SF250.5-275, Dairying, SF221-250
Abstract

ABSTRACT: The aims of this research were (1) to develop a model to simulate a herd of cows and quarter milk flowrates for a milking and derive quarter and udder milking durations and box duration (i.e., the time a cow spends inside the robot) for a group of cows milked with an automatic milking system (AMS); (2) to validate the simulation by comparing the model outcomes with empirical data from a commercial AMS dairy farm; and (3) to apply teatcup removal settings to the simulation to predict their effect on quarter and cow milking duration and box duration in an AMS. For model development, a data set from an AMS farm with 32 robots milking over 1,500 cows was used to fit the parameters to the variables days in milk, parity, and milking interval, which were subsequently used to create a herd of cows. A second data set from 2019 from an AMS farm with 1 robot milking 60 cows that contained quarter milk flowrates (at 2-s intervals) was used to extract the parameters necessary to simulate quarter milk flowrates for a milking. We simulated a herd of cows, and each was assigned a parity, days in milk, milking interval, and milk production rate. We also simulated milk flowrates every 1 s for each quarter of each cow. We estimated quarter milking duration as the total time that flowrate was greater than 0.1 kg/min after a minimum of 1 min of milk flow. We incorporated a randomly sampled attachment time for each quarter and calculated cow milking duration as the time from the first quarter attached to the last quarter detached. We included a randomly sampled preparation time which, added to cow milking duration, represented box duration. For simulation application, we tested the effect of quarter teatcup removal settings on quarter and cow milking duration. The settings were based on absolute flowrate (0.2, 0.4, and 0.6 kg/min) or a percentage of the quarter's 30-s rolling average milk flowrate (20, 30, and 50%). We simulated over 84,000 quarter milkings and found that quarter milking duration (average 212 s) had a mean absolute percent error (MAPE) of 7.5% when compared with actual data. Simulated cow milking duration (average 415 s) had a MAPE of 8%, and box duration (average 510 s) had a MAPE of 12%. From simulation application, we determined that quarter milking duration and box duration were reduced by 19% (209 vs. 170 s) and 6.5% (512 vs. 479 s), respectively, when increasing the teatcup removal flowrate from 0.2 to 0.6 kg/min. Quarter milking duration and box duration were 7% (259 vs. 241 s) and 3% (590 vs. 573 s) longer respectively by using a teatcup removal setting of 20% of the quarter's rolling average milk flowrate, compared with 30%. Both results agree with previous research. This simulation model is useful for predicting quarter and cow milking and box duration in a group of cows and to analyze the effect of milking management practices on milking efficiency.

Published
2022
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2. Disposal of Arsenic-Laden Adsorptive Media: Economic Analysis for California

Author

Benjamin T. Erker, Masakazu Kanematsu, Wei-Hsiang Chen, and Jeannie L. Darby

Subjects
Engineering, Environmental Engineering, Waste management, business.industry, Environmental engineering, chemistry.chemical_element, Potable water, Tap water, chemistry, Hazardous waste, Environmental Chemistry, Economic analysis, Water pollution, business, Arsenic, Average cost, General Environmental Science, Civil and Structural Engineering, Waste disposal
Abstract

Due to California’s stringent hazardous waste (HW) classification regulations, high-capacity adsorptive media (AM) used for the removal of arsenic from potable water are likely to be classified as HW if operated to breakthrough. An alternative is to prematurely retire the AM, avoiding generation of HW. The impact of waste classification of spent AM on annual costs for arsenic systems was investigated. For a typical small water system (SWS), the media replacement cost alone was predicted to range from $0.80 to $2.00 per 1,000 L treated, in comparison to the average cost of tap water in the U.S. of $0.53 per 1,000 L treated, highlighting the financial burden for SWS. The costs of media replacement dominated over costs for transport and disposal regardless of whether spent media were designated as HW or non-HW. Media costs and influent arsenic concentration were more significant factors than transport distance or disposal fees. Under typical conditions for SWS, it was found to be cost effective to load the m...

Published
2010
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3. Trapping and dissociation of propafenone derivatives in HERG channels

Author

A, Windisch, En, Timin, T, Schwarz, D, Stork-Riedler, T, Erker, Gf, Ecker, and S, Hering

Subjects
Molecular Weight, ERG1 Potassium Channel, Kinetics, Xenopus laevis, Patch-Clamp Techniques, Propafenone, Protein Conformation, Potassium, Action Potentials, Animals, Humans, Research Papers, Ether-A-Go-Go Potassium Channels
Abstract

Human ether-a-go-go related gene (HERG) channel inhibitors may be subdivided into compounds that are trapped in the closed channel conformation and others that dissociate at rest. The structural peculiarities promoting resting state dissociation from HERG channels are currently unknown. A small molecule-like propafenone is efficiently trapped in the closed HERG channel conformation. The aim of this study was to identify structural moieties that would promote dissociation of propafenone derivatives.Human ether-a-go-go related gene channels were heterologously expressed in Xenopus oocytes and potassium currents were recorded using the two-microelectrode voltage clamp technique. Recovery from block by 10 propafenone derivatives with variable side chains, but a conserved putative pharmacophore, was analysed.We have identified structural determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with 'short' side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H-bond acceptor in this region was trapped. Correlations were observed between molecular weight and onset of channel block as well as between pK(a) and recovery at rest.The data show that extending the size of a trapped HERG blocker-like propafenone by adding a bulky side chain may impede channel closure and thereby facilitate drug dissociation at rest. The presence of an H-bond acceptor in the bulky side chain is, however, essential.

Published
2010

4. Interaction of diltiazem with an intracellularly accessible binding site on Ca(V)1.2

Author

W, Shabbir, S, Beyl, E N, Timin, D, Schellmann, T, Erker, A, Hohaus, G H, Hockerman, and S, Hering

Subjects
Binding Sites, Cell Membrane Permeability, Patch-Clamp Techniques, Calcium Channels, L-Type, Cell Membrane, Molecular Sequence Data, binding pocket, Calcium Channel Blockers, Research Papers, Recombinant Proteins, Cell Line, Diltiazem, Kinetics, Protein Subunits, calcium antagonists, calcium channels, use-dependent block, Humans, Mutant Proteins, Amino Acid Sequence, quaternary diltiazem, Hydrophobic and Hydrophilic Interactions, Ion Channel Gating
Abstract

BACKGROUND AND PURPOSE Diltiazem inhibits CaV1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments IIIS6, IVS6 and the selectivity filter of the pore forming α1 subunit of CaV1.2. The aim of the present study was to clarify the location of the diltiazem binding site making use of its membrane-impermeable quaternary derivative d-cis-diltiazem (qDil) and mutant α1 subunits. EXPERIMENTAL APPROACH CaV1.2 composed of α1, α2-δ and β2a subunits were expressed in tsA-201 cells and barium currents through CaV1.2 channels were recorded using the patch clamp method in the whole cell configuration. qDil was synthesized and applied to the intracellular side (via the patch pipette) or to the extracellular side of the membrane (by bath perfusion). KEY RESULTS Quaternary derivative d-cis-diltiazem inhibited CaV1.2 when applied to the intracellular side of the membrane in a use-dependent manner (59 ± 4% at 300 µM) and induced only a low level of tonic (non-use-dependent) block (16 ± 2% at 300 µM) when applied to the extracellular side of the membrane. Mutations in IIIS6 and IVS6 that have previously been shown to reduce the sensitivity of CaV1.2 to tertiary diltiazem also had reduced sensitivity to intracellularly applied qDil. CONCLUSION AND IMPLICATIONS The data show that use-dependent block of in CaV1.2 by diltiazem occurs by interaction with a binding site accessible via a hydrophilic route from the intracellular side of the membrane.

Published
2010

19. Synthese von einigen potentiellen NO-Synthase-Inhibitoren mit Thieno[2,3-b] [1,4l thiazin-Grundgerüst

Author

M. E. Galanski, N. Böhler, and T. Erker

Subjects
chemistry.chemical_compound, Chemistry, Thiazine, Reagent, No synthase, NO Synthase Inhibitors, Pharmaceutical Science, Thieno[2.3-b][1,4]thiazines, Medicinal chemistry, Saponification
Abstract

The synthesis of thiolactime 4 and first studies on the syntheses of other thiolactimes with different substituted thieno[2,3-b][1,4]thiazine moieties are described as well as the syntheses of structurally modified amidines 10 - 14 with the same basic structure. The thieno[2,3-b][1,4]thiazine derivatives were prepared by reacting methyl 5-chloro-4-nitro-2-thiophencarboxylate with ethyl thioglycolate followed by reductive cyclisation to 6, which was either first saponified and then treated with Lawesson reagent to obtain thiolactame 8 or directly reacted to thiolactame 9. Reaction of 9 with various amines led to the desired products 10 - 14. which will undergo pharmacological testing on NO synthase inhibiting activities.

Published
2001
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20. Studies on the chemistry of thienoannelated O,N- and S,N-containing heterocycles. Part 19: thieno[2,3-b][1,4]thiazines with calcium antagonistic and potassium opening activities

Author

T, Erker, M E, Schreder, and C, Studenik

Subjects
Magnetic Resonance Spectroscopy, Potassium Channels, Ileum, Guinea Pigs, Thiazines, Animals, Heart Atria, In Vitro Techniques, Papillary Muscles, Calcium Channel Blockers, Aorta
Abstract

In this study novel substituted 6-benzyl-thieno[2,3-b][1,4]thiazines with an urea moiety were synthesized. Structural modifications of the amino side chain were carried out with the aim of finding tissue specific compounds. The effects on papillary muscles, right atria, aortic strips, and terminal ilea were investigated. Compounds 10c and 10d showed the most potent negative inotropic effect. The calcium antagonism of all derivatives occurred in a non-competitive manner, which may indicate that they also have potassium channel opening activities.

Published
2000

21. D

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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22. A

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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23. H

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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24. I

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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25. C

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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26. G

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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27. F

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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28. B

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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29. K

Author

Franz von Bruchhausen, Eberhard Hackenthal, Siegfried Ebel, Ulrike Holzgrabe, August Wilhelm Frahm, M. Albinus, G. Amschler, E. von Angerer, null Arras-Reiter, P. Barth, W. Barthel, K. Bauer, P. Bauer, I. Baumann, J. Beckmann, W. Beil, J. Reitz, K. Binder, F. Bossle, F. Bracher, H. Bräunlich, E. Bretschneider, R. Brigelius-Flohé, K. Brinkmann, F. von Bruchhausen, A. Rüge, W. Christ, M. Cimbollek, R. Daniels, G. Dannhardt, H. Duchstein, S. Ebel, K. Eger, P. Eichhorn, U. Eiben, T. Erker, P. Felfe, A. Frahm, M. Frahm, V. Franke, K. Freundt, D. Geffken, U. Geis, E. Glusa, B. Göber, P. Gobina, W. Golder, M. Goppelt­Strübe, K. Götte, E. Gottstein, G. Greif, A. Grisk, M. Grosam, H. Gustmann, M. Gütschow, E. Hackenthal, A. Häfner, B. Haluszczynski, A. Harder, H. Häusler, D. Heber, M. Heidenreich, G. Heinemeyer, E. Heller, D. von Herrath, J. Hilfenhaus, H. Hoffmann, U. Hoffmann-Schollmayer, B. Hofmann, C. Holpert, U. Holzgrabe, U. Hübner-Steiner, M. Hug, E. Inkmann, A. Jördens, J. Jürgens, B. Kaiser, D. Kalbhen, H. Kemmler, P. Kisser, D. Kleinsorge, C. Klett, S. Klett, M. Klingmüller, H. Klöcking, A. Kramer, B. Krammer, M. Kreher, M. Krüger, M. Kuhn, D. Landsiedel-Maier, P. Lauven, J. Lehmann, M. Lehner, D. Leopoldt, A. Maurer, W. Meindl, K. Menges, P. Mes­singer, F. Meyer, W. Meyerhof, R. Morgenstern, U. Mühlhans, A. Müller, C. Müller, K. Müller, A. Mülsch, C. Nachtsheim, M. Neugebauer, W. Neupert, P. Nickel, P. Nuhn, B. Nürnberg, H. Oelschläger, J. Oertel, M. Oettel, R. Ott, T. Ott, T. Otzen, P. Pachaly, H. Pelzer, K. Petersen, R. Pick, M. Pickert, A. Pies, H. Priewer, O. Queckenberg, G. Radau, E. Reimann, J. Remien, M. Reuß, W. Reuß, J. Richter, P. Richter, K. Riecke, H. Rommelspacher, U. Rose, G. Roth, D. Rothley, G. Rücker, J. Schäfer, J. Schantl, H. Schlager, H. Schleinitz, W. Schlichter, M. Schmauß, H. Schmidhammer, G. Schmidt, T. Schmidt, H. Schmitt, J. Sehräder, T. Schulz, H. Schwilden, M. Serke, G. Skopp, G. Skorka, K. Smolinka, U. Speck, M. Spohn, R. Stahlmann, J. Stasch, C. Steffen, H. Stein, J. Steinmeyer, K. Stiefvater, G. Strippel, K. Surborg, U. Stürig, H. Szelényi, I. Szelényi, A. Täufel, R. Thieroff-Ekerdt, R. Troschütz, H. Ungeheuer, B. Unterhalt, E. Verspohl, S. Vogel, F. Volk, T. Vorwerk, J. Wallmann, H. Weber, M. Wenzel, M. Weyandt-Spangenberg, S. Wich, R. Wintersteiger, B. Wüst, and D. Youssef

Published
1999
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31. P543: TARGETING SAMHD1 WITH HYDROXYUREA IN FIRST-LINE CYTARABINE-BASED THERAPY OF NEWLY DIAGNOSED ACUTE MYELOID LEUKAEMIA: RESULTS FROM THE HEAT-AML TRIAL

Author

M. Jädersten, I. Lilienthal, N. Tsesmetzis, M. Lourda, S. Bengtzén, A. Bohlin, C. Arnroth, T. Erkers, B. Seashore-Ludlow, G. Giraud, G. S. Barkhordar, S. Tao, L. Fogelstrand, L. Saft, P. Östling, R. Schinazi, B. Kim, T. Schaller, G. Juliusson, S. Deneberg, S. Lehmann, G. Rassidakis, M. Höglund, J.-I. Henter, and N. Herold

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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32. [Studies on the chemistry of O,N- and S,N-containing heterocylics. 10. Synthesis and biologic activity of 2-substituted 2-ethylbenzoxazoles]

Author

H, Bartsch and T, Erker

Subjects
Analgesics, Benzoxazoles, Insecticides, Mice, Antifungal Agents, Antinematodal Agents, Animals, Microbial Sensitivity Tests
Abstract

2-Vinylbenzoxazole (3) is obtained by condensation of acrylic acid with 2-aminophenol in a mixture of phosphorus pentoxide/methansulfonic acid. Interaction of 3 with N-, O-, and C-nucleophiles yields 2-substituted 2-ethyl-benzoxazoles. Compounds 8a, 8b and 8e show analgetic activity in mice. Moreover, fungicide, insecticide and nematocide activity of some compounds is found.

Published
1991

41. Role of NKCC1 Activity in Glioma K + Homeostasis and Cell Growth: New Insights With the Bumetanide-Derivative STS66.

Author

Luo L, Wang J, Ding D, Hasan MN, Yang SS, Lin SH, Schreppel P, Sun B, Yin Y, Erker T, and Sun D

Abstract

Introduction: Na + -K + -2Cl - cotransporter isoform 1 (NKCC1) is important in regulating intracellular K + and Cl - homeostasis and cell volume. In this study, we investigated a role of NKCC1 in regulating glioma K + influx and proliferation in response to apoptosis inducing chemotherapeutic drug temozolomide (TMZ). The efficacy of a new bumetanide (BMT)-derivative NKCC1 inhibitor STS66 [3-(butylamino)-2-phenoxy-5-[(2, 2, 2-trifluoroethylamino) methyl] benzenesulfonamide] in blocking NKCC1 activity was compared with well-established NKCC1 inhibitor BMT. Methods: NKCC1 activity in cultured mouse GL26 and SB28-GFP glioma cells was measured by Rb + (K + ) influx. The WNK1-SPAK/OSR1-NKCC1 signaling and AKT/ERK-mTOR signaling protein expression and activation were assessed by immunoblotting. Cell growth was determined by bromodeoxyuridine (BrdU) incorporation assay, MTT proliferation assay, and cell cycle analysis. Impact of STS66 and BMT on cell Rb + influx and growth was measured in glioma cells treated with or without TMZ. Results: Rb + influx assay showed that 10 μM BMT markedly decreased the total Rb + influx and no additional inhibition detected at >10 μM BMT. In contrast, the maximum effects of STS66 on Rb + influx inhibition were at 40-60 μM. Both BMT and STS66 reduced TMZ-mediated NKCC1 activation and protein upregulation. Glioma cell growth can be reduced by STS66. The most robust inhibition of glioma growth, cell cycle, and AKT/ERK signaling was achieved by the TMZ + STS66 treatment. Conclusion: The new BMT-derivative NKCC1 inhibitor STS66 is more effective than BMT in reducing glioma cell growth in part by inhibiting NKCC1-mediated K + influx. TMZ + STS66 combination treatment reduces glioma cell growth via inhibiting cell cycle and AKT-ERK signaling., (Copyright © 2020 Luo, Wang, Ding, Hasan, Yang, Lin, Schreppel, Sun, Yin, Erker and Sun.)

Published
2020
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42. Functional characterization of novel bumetanide derivatives for epilepsy treatment.

Author

Auer T, Schreppel P, Erker T, and Schwarzer C

Subjects
Animals, Brain metabolism, Brain physiopathology, Bumetanide pharmacology, Convulsants, Disease Models, Animal, Diuretics adverse effects, Dose-Response Relationship, Drug, Drug Resistant Epilepsy chemically induced, Drug Resistant Epilepsy physiopathology, Electroencephalography, Epilepsy, Temporal Lobe chemically induced, Epilepsy, Temporal Lobe physiopathology, Excitatory Amino Acid Agonists toxicity, Kainic Acid toxicity, Mice, Pentylenetetrazole, Phenobarbital pharmacology, Seizures physiopathology, Seizures prevention & control, Solute Carrier Family 12, Member 2 genetics, Solute Carrier Family 12, Member 2 metabolism, Anticonvulsants pharmacology, Blood-Brain Barrier metabolism, Brain drug effects, Bumetanide analogs & derivatives, Drug Resistant Epilepsy drug therapy, Epilepsy, Temporal Lobe drug therapy, Sodium Potassium Chloride Symporter Inhibitors pharmacology
Abstract

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsies, affecting approximately 35 million people worldwide. Despite the introduction of numerous novel antiepileptic drugs during the last decades, the proportion of patients with therapy-resistant TLE is still high. As an impaired cellular chloride homeostasis appears involved in disease pathophysiology, bumetanide, an antagonist to Na-K-Cl cotransporters, gained interest as potential therapeutic option. However, bumetanide induces a strong diuretic effect and displays poor penetration across the blood-brain barrier (BBB). To reduce these unwanted effects, we modified the already described BUM690 by exchanging the allyl-into a trifluoro-ethyl group to yield BUM532. Furthermore, we exchanged the nitrogen for oxygen in the trifluoro-ethyl group to yield BUM97. In the intrahippocampal kainic acid mouse model of TLE BUM532 ± phenobarbital (PB), bumetanide ± PB and PB alone significantly reduced hippocampal paroxysmal discharges (HPDs) but not spike trains. By contrast, treatment with BUM97 suppressed HPDs as well as spike trains dose-dependently, more pronounced compared to the other tested compounds and exerted a synergistic anticonvulsant effect with PB. Moreover, at higher doses BUM97 achieved long-lasting reduction of spike trains. In pentylenetetrazole-induced acute seizures only BUM532 combined with a sub-effective dose of PB increased the seizure threshold. No diuretic effects were observed at any dose of the three derivatives. Our data demonstrate the successful optimization of the pharmacological profile of bumetanide and the potential of the improved derivative BUM97 for the treatment of therapy-resistant TLE, in particular in combinatorial drug regimens with a GABA mimetic., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2020
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43. Impaired chloride homeostasis in epilepsy: Molecular basis, impact on treatment, and current treatment approaches.

Author

Auer T, Schreppel P, Erker T, and Schwarzer C

Subjects
Animals, Anticonvulsants adverse effects, Blood-Brain Barrier, Bumetanide adverse effects, Bumetanide pharmacokinetics, Bumetanide pharmacology, Diuretics adverse effects, Diuretics pharmacokinetics, Diuretics pharmacology, Drug Development, Epilepsy physiopathology, Humans, Sodium Potassium Chloride Symporter Inhibitors adverse effects, Sodium Potassium Chloride Symporter Inhibitors pharmacokinetics, Sodium Potassium Chloride Symporter Inhibitors pharmacology, Tissue Distribution, Anticonvulsants pharmacology, Chlorides metabolism, Epilepsy drug therapy
Abstract

Epilepsies represent one of the most common neurological diseases worldwide. They are characterized by recurrent spontaneous seizures with severe impact on a patient's life. An imbalance in excitatory and inhibitory signalling is considered the main underlying pathophysiological mechanism. Therefore, GABA-mimetic drugs, strengthening the main inhibitory signalling system in the CNS, are frequently used as antiepileptic or anticonvulsant drugs. However, the therapeutic effect of such treatment depends on the chloride gradient along the plasma membrane. Impairment of chloride homeostasis, caused by alterations in the functional balance of chloride transporters, was implicated in the pathophysiology of epilepsy and numerous other diseases. Breakdown or even inversion of the chloride gradient may result in ineffective or in worst cases proconvulsant effects of GABA-mimetics. Unfortunately, such situations are reported in considerable number. Consequently, bumetanide, an inhibitor of Na-K-Cl cotransporters gained interest as potential add-on therapy re-establishing the chloride gradient and thereby the hyperpolarizing effects of GABA-mimetic drugs. Indeed, preclinical studies yielded encouraging results, especially when applied in combination with GABA-mimetics in epilepsy models. However, bumetanide induces a strong diuretic effect and displays poor penetration across the blood-brain barrier, two adverse features for chronic antiepileptic treatment. Therefore, new compounds overcoming these limitations are under development. This review focuses on alterations in chloride homeostasis and its underlying molecular mechanisms in epilepsy, on the potential impact of impaired chloride homeostasis on the treatment of epilepsy and on concepts to overcome this problem including recent development of bumetanide derivatives with improved pharmacological profile., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2020
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44. The role of oxidative stress in 63 T-induced cytotoxicity against human lung cancer and normal lung fibroblast cell lines.

Author

Kucinska M, Mieszczak H, Piotrowska-Kempisty H, Kaczmarek M, Granig W, Murias M, and Erker T

Subjects
Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung metabolism, Apoptosis, Cell Proliferation, Cells, Cultured, DNA Damage drug effects, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Lipid Peroxidation drug effects, Lung drug effects, Lung metabolism, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Reactive Oxygen Species metabolism, Adenocarcinoma of Lung pathology, Antineoplastic Agents pharmacology, Benzene Derivatives pharmacology, Fibroblasts pathology, Lung pathology, Lung Neoplasms pathology, Oxidative Stress drug effects, Thioamides pharmacology
Abstract

It has been shown previously that molecules built on benzanilide and thiobenzanilide scaffolds possess differential biological properties including selective anticancer activity. In our previous study, we examined the cytotoxic activity and mechanism of action of the thiobenzanilide derivative N,N'-(1,2-phenylene)bis3,4,5-trifluorobenzothioamide (63 T) as a potential chemotherapeutic compound in an experimental model employing A549 lung adenocarcinoma cells and CCD39Lu non-tumorigenic lung fibroblasts. Since the results suggested oxidative stress as a co-existing mechanism of the cytotoxic effect exerted by 63 T on tested cells, studies involving the analysis of reactive oxygen species (ROS) generation and markers of oxidative stress in cells incubated with 63 T were carried out. It may be concluded that the selective activity of 63 T against cancer cells shown in our experiments is caused, at least in part, by the response of the tested cells to 63 T mediated oxidative stress in both tested cell lines.

Published
2019
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45. A Novel Na + -K + -Cl - Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke.

Author

Huang H, Bhuiyan MIH, Jiang T, Song S, Shankar S, Taheri T, Li E, Schreppel P, Hintersteininger M, Yang SS, Lin SH, Molyneaux BJ, Zhang Z, Erker T, and Sun D

Subjects
Animals, Brain pathology, Brain Ischemia pathology, Disease Models, Animal, Female, Male, Mice, Rotarod Performance Test, Sodium Potassium Chloride Symporter Inhibitors pharmacology, Stroke pathology, Treatment Outcome, Brain drug effects, Brain Ischemia drug therapy, Recovery of Function drug effects, Sodium Potassium Chloride Symporter Inhibitors therapeutic use, Solute Carrier Family 12, Member 2, Stroke drug therapy
Abstract

Background and Purpose- Inhibition of brain NKCC1 (Na + -K + -Cl - cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

Published
2019
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46. Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.

Author

Römermann K, Fedrowitz M, Hampel P, Kaczmarek E, Töllner K, Erker T, Sweet DH, and Löscher W

Subjects
Animals, Biological Transport drug effects, Blood-Brain Barrier drug effects, Brain drug effects, Bumetanide analogs & derivatives, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Diffusion, Female, Membrane Transport Modulators pharmacology, Mice, Organic Anion Transporters antagonists & inhibitors, Organic Anion Transporters genetics, Organic Anion Transporters, Sodium-Independent antagonists & inhibitors, Organic Anion Transporters, Sodium-Independent metabolism, Probenecid pharmacology, Blood-Brain Barrier physiology, Brain metabolism, Bumetanide pharmacokinetics, Multidrug Resistance-Associated Proteins physiology, Organic Anion Transporters, Sodium-Independent physiology, Organic Cation Transport Proteins physiology
Abstract

There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, but it is presently not clear which transporters are involved. Understanding the processes explaining the poor brain penetration of bumetanide is needed for developing strategies to improve the brain delivery of this drug. In the present study, we administered probenecid and more selective inhibitors of active transport carriers at the BBB directly into the brain of mice to minimize the contribution of peripheral effects on the brain penetration of bumetanide. Furthermore, in vitro experiments with mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster ovary cells were performed to study the interaction of bumetanide, bumetanide derivatives, and several known inhibitors of Oats on Oat3-mediated transport. The in vivo experiments demonstrated that the uptake and efflux of bumetanide at the BBB is much more complex than previously thought. It seems that both restricted passive diffusion and active efflux transport, mediated by Oat3 but also organic anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance protein 4 explain the extremely low brain concentrations that are achieved after systemic administration of bumetanide, limiting the use of this drug for targeting abnormal expression of neuronal NKCC1 in brain diseases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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47. Selective anticancer activity of the novel thiobenzanilide 63T against human lung adenocarcinoma cells.

Author

Kucinska M, Piotrowska-Kempisty H, Lisiak N, Kaczmarek M, Dams-Kozlowska H, Granig WH, Höferl M, Jäger W, Zehl M, Murias M, and Erker T

Subjects
A549 Cells, Adenocarcinoma, Adenocarcinoma of Lung, Apoptosis drug effects, Caspases metabolism, Cell Cycle drug effects, Cell Line, Cell Survival drug effects, DNA Fragmentation, Humans, Lung Neoplasms, Necrosis chemically induced, Antineoplastic Agents pharmacology, Benzene Derivatives pharmacology, Thioamides pharmacology
Abstract

Previously, it has been reported that molecules built on the benzanilide and thiobenzanilide scaffold are the promising groups of compounds with several biological activities including antifungal, antimycotic, antibacterial, spasmolytic, and anticancer ones. In this study the mechanism of action of one selected thiobenzanilide derivative N,N'-(1,2-phenylene)bis3,4,5-trifluorobenzothioamide (63T) with strongest cytotoxic activity has been investigated for the first time in human lung adenocarcinoma (A549) and normal lung derived fibroblast (CCD39Lu) in a cell culture model. The results demonstrated, that 63T can be considered a selective anticancer compound. Based on these results, several experiments including the analysis of cellular morphology, cell phase distribution, cytoplasmic histone-associated DNA fragmentation, apoptosis, necrosis, and autophagy detection were performed to understand better the mechanism underlying the anticancer activity. The data showed that 63T is a small molecule compound, which selectively induces cancer cell death in a caspase independent pathway; moreover, the autophagic dose-dependent processes may be involved in the mechanism of cell death., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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48. A Novel Genistein Prodrug: Design, Synthesis and Bioactivity on Mouse RAW264.7 Macrophages.

Author

Kloesch B, Loebsch S, Breitenbach J, Goldhahn K, Handler N, Schreppel P, and Erker T

Subjects
Animals, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Cell Survival, Cytokines biosynthesis, Drug Design, Genistein chemistry, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mice, Prodrugs chemistry, Prodrugs pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, RAW 264.7 Cells, Antineoplastic Agents, Phytogenic chemical synthesis, Genistein analogs & derivatives, Genistein chemical synthesis, Prodrugs chemical synthesis
Abstract

Genistein, a naturally occurring isoflavone, possesses many beneficial health effects. To improve the bioactivity of the natural compound, we designed and synthesized the genistein prodrug FEHH6-1. In the present study, we evaluated the biological effects of FEHH6-I on mouse RAW264.7 macrophages and compared them with those obtained with the parent drug genistein. The characteristics of FEHH6-1 were determined by melting point, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometric analysis. The effects of FEHH6-I on cell proliferation, apoptosis, and pro-inflammatory cytokine expression were monitored by XTT-assay, Annexin-V/7-AAD staining, Western blotting, and ELISA. FEHH6-1 showed NMR spectra and relative molecular mass in agreement with the designed structure. In mouse RAW264.7 macrophages, FEHH6-1 inhibited proliferation, induced apoptotic cell death and blocked interleukin 6 and tumor necrosis factor alpha synthesis. At low concentrations, FEHH6-1 induced phosphorylation of AKT1, a kinase involved in cell proliferation and survival. Our data demonstrate that the genistein prodrug FEHH6-1 is a bioactive molecule but its solubility and therefore also its efficacy was significantly lower compared with genistein.

Published
2016

49. The search for NKCC1-selective drugs for the treatment of epilepsy: Structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A.

Author

Lykke K, Töllner K, Feit PW, Erker T, MacAulay N, and Löscher W

Subjects
Animals, Humans, Oocytes, Solute Carrier Family 12, Member 2 genetics, Structure-Activity Relationship, Xenopus, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Bumetanide analogs & derivatives, Bumetanide pharmacology, Diuretics pharmacology, Epilepsy drug therapy, Solute Carrier Family 12, Member 2 drug effects
Abstract

The Na(+)-K(+)-Cl(-) cotransporter NKCC1 plays a major role in the regulation of intraneuronal Cl(-) concentration. Abnormal functionality of NKCC1 has been implicated in several brain disorders, including epilepsy. Bumetanide is the only available selective NKCC1 inhibitor, but also inhibits NKCC2, which can cause severe adverse effects during treatment of brain disorders. A NKCC1-selective bumetanide derivative would therefore be a desirable option. In the present study, we used the Xenopus oocyte heterologous expression system to compare the effects of bumetanide and several derivatives on the two major human splice variants of NKCCs, hNKCC1A and hNKCC2A. The derivatives were selected from a series of ~5000 3-amino-5-sulfamoylbenzoic acid derivatives, covering a wide range of structural modifications and diuretic potencies. To our knowledge, such structure-function relationships have not been performed before for NKCC1. Half maximal inhibitory concentrations (IC50s) of bumetanide were 0.68 (hNKCC1A) and 4.0μM (hNKCC2A), respectively, indicating that this drug is 6-times more potent to inhibit hNKCC1A than hNKCC2A. Side chain substitutions in the bumetanide molecule variably affected the potency to inhibit hNKCC1A. This allowed defining the minimal structural requirements necessary for ligand interaction. Unexpectedly, only a few of the bumetanide derivatives examined were more potent than bumetanide to inhibit hNKCC1A, and most of them also inhibited hNKCC2A, with a highly significant correlation between IC50s for the two NKCC isoforms. These data indicate that the structural requirements for inhibition of NKCC1 and NKCC2 are similar, which complicates development of bumetanide-related compounds with high selectivity for NKCC1., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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50. The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice.

Author

Erker T, Brandt C, Töllner K, Schreppel P, Twele F, Schidlitzki A, and Löscher W

Subjects
Animals, Convulsants toxicity, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Synergism, Electroencephalography drug effects, Electroshock adverse effects, Epilepsy, Temporal Lobe etiology, Mice, Pentylenetetrazole toxicity, Pilocarpine toxicity, Anticonvulsants therapeutic use, Bumetanide therapeutic use, Epilepsy, Temporal Lobe drug therapy, Phenobarbital therapeutic use, Prodrugs therapeutic use
Abstract

Objective: The loop diuretic bumetanide has been reported to potentiate the antiseizure activity of phenobarbital in rodent models of neonatal seizures, most likely as a result of inhibition of the chloride importer Na-K-Cl cotransporter isoform 1 (NKCC1) in the brain. In view of the intractability of neonatal seizures, the preclinical findings prompted a clinical trial in neonates on bumetanide as an add-on to phenobarbital, which, however, had to be terminated because of ototoxicity and lack of efficacy. We have recently shown that bumetanide penetrates only poorly into the brain, so that we developed lipophilic prodrugs such as BUM5, the N,N-dimethylaminoethylester of bumetanide, which penetrate more easily into the brain and are converted to bumetanide., Methods: In the present study, we used a new strategy to test whether BUM5 is more potent than bumetanide in potentiating the antiseizure effect of phenobarbital. Adult mice were made epileptic by pilocarpine, and the antiseizure effects of bumetanide, BUM5, and phenobarbital alone or in combination were determined by the maximal electroshock seizure threshold test., Results: In nonepileptic mice, only phenobarbital exerted seizure threshold-increasing activity, and this was not potentiated by the NKCC1 inhibitors. In contrast, a marked potentiation of phenobarbital by BUM5, but not bumetanide, was determined in epileptic mice., Significance: Thus, bumetanide is not capable of potentiating phenobarbital's antiseizure effect in an adult mouse model, which, however, can be overcome by using the prodrug BUM5. These data substantiate that BUM5 is a promising tool compound for target validation and proof-of-concept studies on the role of NKCC1 in brain diseases., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Published
2016
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