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2. Treatment with Ataluren for Duchene Muscular Dystrophy

Author

Mercuri, E, Muntoni, F, Osorio, An, Tulinius, M, Buccella, F, Morgenroth, Lp, Gordish-Dressman, H, Jiang, J, Trifillis, P, Zhu, J, Kristensen, A, Santos, Cl, Henricson, Ek, Mcdonald, Cm, Desguerre, I, Bernert, G, Gosk-Tomek, M, Ille, A, Kellersmann, A, Weiss, S, Pilshofer, V, Balintovà, Z, Danhofer, P, Fabulovà, P, Jurıkovà, L, Fuchsovà, P, Haberlovà, J, Laffargue, F, Sarret, C, Pontier, B, Bellance, R, Sarrazin, E, Sabouraud, P, Magot, A, Mercier, S, Péréon, Y, Cuisset, J-M, Coopman-Degryse, S, Enaud, E, Jacquemont, M-L, Perville, A, Renouil, M, Trommsdorff, V, Verheulpen, D, Fontaine-Carbonnel, S, Vuillerot, C, Peudenier, S, Ropars, J, Audic, F, Chabrol, B, Chabrier, S, Gousse, G, Lagrue, E, Aragon, K, Barnerias, C, Brande, Lv, De Lucia, S, Gidaro, T, Seferian, A, Servais, L, Laugel, V, Espil-Taris, C, Mecili, H, Raffo, E, Ragot-Mandry, S, Borrell, S, Kirschner, J, Gangfuss, A, Henrich, M, Kolbel, H, Schara, U, Sponemann, N, Temme, E, Seeger, J, Hirsch, A, Denecke, J, Johannsen, J, Neu, A, Osinski, D, Rugner, S, Schussler, S, Trollmann, R, Kaindl, A, Schneider, Jb, Stoltenburg, C, Weiss, C, Schreiber, G, Hahn, A, Grzybowski, M, Pavlidou, E, Pavlou, E, Dobner, S, Liptai, Z, Dor, T, Brogna, C, Catteruccia, M, D’Amico, A, Pane, E, Bello, L, Pegoraro, E, Semplicini, C, Albamonte, E, Baranello, G, Comi, G, Govoni, A, Lerario, A, Magri, F, Masson, R, Mauri, E, Sansone, V, Brusa, C, Mongini, T, Ricci, F, Vacchetti, M, Bruno, C, Paniucci, C, Pedemonte, M, Giannotta, M, Pini, A, Messina, S, Sframeli, M, Vita, Gl, Vita, G, Ruggiero, L, Santoro, L, Craiu, D, Motoescu, C, Sandu, C, Teleanu, R, Vasile, D, Hughes, I, Childs, A-M, Alhaswani, Z, Roper, H, Parasuraman, D, Degoede, C, Gowda, V, Manzur, A, Munot, P, Sarkokzy, A, Charlesworth, C, Lemon, J, Turner, L, Spinty, S, Dubrovsky, A, Kornberg, A, Ryan, M, Webster, R, Biggar, Wd, Mcadam, Lc, Mah, Jh, Kolski, H, Vishwanathan, V, Chidambaranathan, S, Nevo, Y, Gorni, K, Carlo, J, Abresch, Rt, Joyce, Nc, Cnaan, A, Leshner, R, Tesi-Rocha, C, Thangarajh, M, Duong, T, Clemens, Pr, Abdel-Hamid, H, Connolly, Am, Pestronk, A, Teasley, J, Harper, A, Bertorini, Te, Kuntz, N, Driscoll, S, Day, Jw, Karachunski, P, and Lotze, T.

Subjects
safety, medicine.medical_specialty, nonsense mutation Duchenne muscular dystrophy, Duchenne muscular dystrophy, Neurosurgery, STRIDE, effectiveness, Duchenne Muscular Dystrophy, Pediatrics, Dystrophin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Child Development, STRIDE Registry, International database, Internal medicine, medicine, Humans, In patient, Registries, Child, 030304 developmental biology, Pediatric, 0303 health sciences, Brain Diseases, Oxadiazoles, business.industry, Health Policy, Disease progression, Infant, ataluren, medicine.disease, Ataluren, Muscular Dystrophy, Duchenne, Treatment Outcome, chemistry, Neurology, Muscle Disorders, Codon, Nonsense, Neuromuscular, Propensity score matching, dystrophin, Nervous System Diseases, business, 030217 neurology & neurosurgery, Natural history study, Research Article
Abstract

Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.

Published
2020

3. Randomized, double-blind, cross-over phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references

Author

Velinova, M., primary, Bellon, A., additional, Nakov, R., additional, Schussler, S., additional, Schier-Mumzhiu, S., additional, Schelcher, C., additional, Koch, S.D., additional, Skerjanec, A., additional, Wang, J., additional, Krendyukov, A., additional, and Otto, G.P., additional

Published
2019
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5. Oxidative Stress and Cardiovascular Risk in Type 1 Diabetes Mellitus: Insights From the DCCT/EDIC Study

Author

Tang, W.H. Wilson, primary, McGee, Paula, additional, Lachin, John M., additional, Li, Daniel Y., additional, Hoogwerf, Byron, additional, Hazen, Stanley L., additional, Nathan, D.M., additional, Zinman, B., additional, Crofford, O., additional, Genuth, S., additional, Brown‐Friday, J., additional, Crandall, J., additional, Engel, H., additional, Engel, S., additional, Martinez, H., additional, Phillips, M., additional, Reid, M., additional, Shamoon, H., additional, Sheindlin, J., additional, Gubitosi‐Klug, R., additional, Mayer, L., additional, Pendegast, S., additional, Zegarra, H., additional, Miller, D., additional, Singerman, L., additional, Smith‐Brewer, S., additional, Novak, M., additional, Quin, J., additional, Genuth, Saul, additional, Palmert, M., additional, Brown, E., additional, McConnell, J., additional, Pugsley, P., additional, Crawford, P., additional, Dahms, W., additional, Gregory, N.S., additional, Lackaye, M.E., additional, Kiss, S., additional, Chan, R., additional, Orlin, A., additional, Rubin, M., additional, Brillon, D., additional, Reppucci, V., additional, Lee, T., additional, Heinemann, M., additional, Chang, S., additional, Levy, B., additional, Jovanovic, L., additional, Richardson, M., additional, Bosco, B., additional, Dwoskin, A., additional, Hanna, R., additional, Barron, S., additional, Campbell, R., additional, Bhan, A., additional, Kruger, D., additional, Jones, J.K., additional, Edwards, P.A., additional, Carey, J.D., additional, Angus, E., additional, Thomas, A., additional, Galprin, A., additional, McLellan, M., additional, Whitehouse, F., additional, Bergenstal, R., additional, Johnson, M., additional, Gunyou, K., additional, Thomas, L., additional, Laechelt, J., additional, Hollander, P., additional, Spencer, M., additional, Kendall, D., additional, Cuddihy, R., additional, Callahan, P., additional, List, S., additional, Gott, J., additional, Rude, N., additional, Olson, B., additional, Franz, M., additional, Castle, G., additional, Birk, R., additional, Nelson, J., additional, Freking, D., additional, Gill, L., additional, Mestrezat, W., additional, Etzwiler, D., additional, Morgan, K., additional, Aiello, L.P., additional, Golden, E., additional, Arrigg, P., additional, Asuquo, V., additional, Beaser, R., additional, Bestourous, L., additional, Cavallerano, J., additional, Cavicchi, R., additional, Ganda, O., additional, Hamdy, O., additional, Kirby, R., additional, Murtha, T., additional, Schlossman, D, additional, Shah, S., additional, Sharuk, G., additional, Silva, P., additional, Silver, P., additional, Stockman, M., additional, Sun, J., additional, Weimann, E., additional, Wolpert, H., additional, Aiello, L.M., additional, Jacobson, A., additional, Rand, L., additional, Rosenzwieg, J., additional, Larkin, M.E., additional, Christofi, M., additional, Folino, K., additional, Godine, J., additional, Lou, P., additional, Stevens, C., additional, Anderson, E., additional, Bode, H., additional, Brink, S., additional, Cornish, C., additional, Cros, D., additional, Delahanty, L., additional, eManbey, ., additional, Haggan, C., additional, Lynch, J., additional, McKitrick, C., additional, Norman, D., additional, Moore, D., additional, Ong, M., additional, Taylor, C., additional, Zimbler, D., additional, Crowell, S., additional, Fritz, S., additional, Hansen, K., additional, Gauthier‐Kelly, C., additional, Service, F.J., additional, Ziegler, G., additional, Barkmeier, A., additional, Schmidt, L., additional, French, B., additional, Woodwick, R., additional, Rizza, R., additional, Schwenk, W.F., additional, Haymond, M., additional, Pach, J., additional, Mortenson, J., additional, Zimmerman, B., additional, Lucas, A., additional, Colligan, R., additional, Luttrell, L., additional, Lopes‐Virella, M., additional, Caulder, S., additional, Pittman, C., additional, Patel, N., additional, Lee, K., additional, Nutaitis, M., additional, Fernandes, J., additional, Hermayer, K., additional, Kwon, S., additional, Blevins, A, additional, Parker, J., additional, Colwell, J., additional, Lee, D., additional, Soule, J., additional, Lindsey, P., additional, Bracey, M., additional, Farr, A., additional, Elsing, S., additional, Thompson, T., additional, Selby, J., additional, Lyons, T., additional, Yacoub‐Wasef, S., additional, Szpiech, M., additional, Wood, D., additional, Mayfield, R., additional, Molitch, M., additional, Adelman, D., additional, Colson, S., additional, Jampol, L., additional, Lyon, A., additional, Gill, M., additional, Strugula, Z., additional, Kaminski, L., additional, Mirza, R., additional, Simjanoski, E., additional, Ryan, D., additional, Johnson, C., additional, Wallia, A., additional, Ajroud‐Driss, S., additional, Astelford, P., additional, Leloudes, N., additional, Degillio, A., additional, Schaefer, B., additional, Mudaliar, S., additional, Lorenzi, G, additional, Goldbaum, M., additional, Jones, K., additional, Prince, M., additional, Swenson, M., additional, Grant, I., additional, Reed, R., additional, Lyon, R., additional, Kolterman, O., additional, Giotta, M., additional, Clark, T., additional, Friedenberg, G., additional, Sivitz, W.I., additional, Vittetoe, B., additional, Kramer, J., additional, Bayless, M., additional, Zeitler, R., additional, Schrott, H., additional, Olson, N., additional, Snetselaar, L., additional, Hoffman, R., additional, MacIndoe, J., additional, Weingeist, T., additional, Fountain, C., additional, Miller, R., additional, Johnsonbaugh, S., additional, Patronas, M., additional, Carney, M., additional, Mendley, S., additional, Salemi, P., additional, Liss, R., additional, Hebdon, M., additional, Counts, D., additional, Donner, T., additional, Gordon, J., additional, Hemady, R., additional, Kowarski, A., additional, Ostrowski, D., additional, Steidl, S., additional, Jones, B., additional, Herman, W.H., additional, Martin, C.L., additional, Pop‐Busui, R., additional, Greene, D.A., additional, Stevens, M.J., additional, Burkhart, N., additional, Sandford, T., additional, Floyd, J., additional, Bantle, J., additional, Flaherty, N., additional, Terry, J., additional, Koozekanani, D., additional, Montezuma, S., additional, Wimmergren, N., additional, Rogness, B., additional, Mech, M., additional, Strand, T., additional, Olson, J., additional, McKenzie, L., additional, Kwong, C., additional, Goetz, F., additional, Warhol, R., additional, Hainsworth, D., additional, Goldstein, D., additional, Hitt, S., additional, Giangiacomo, J., additional, Schade, D.S, additional, Canady, J.L., additional, Burge, M.R., additional, Das, A., additional, Avery, R.B., additional, Ketai, L.H., additional, Chapin, J.E., additional, Schluter, M.L., additional, Rich, J., additional, Johannes, C., additional, Hornbeck, D., additional, Schutta, M., additional, Bourne, P.A., additional, Brucker, A., additional, Braunstein, S., additional, Schwartz, S., additional, Maschak‐Carey, B.J., additional, Baker, L., additional, Orchard, T., additional, Cimino, L., additional, Songer, T., additional, Doft, B., additional, Olson, S., additional, Becker, D., additional, Rubinstein, D., additional, Bergren, R.L., additional, Fruit, J., additional, Hyre, R., additional, Palmer, C., additional, Silvers, N., additional, Lobes, L., additional, Rath, P. Paczan, additional, Conrad, P.W., additional, Yalamanchi, S., additional, Wesche, J., additional, Bratkowksi, M., additional, Arslanian, S., additional, Rinkoff, J., additional, Warnicki, J., additional, Curtin, D., additional, Steinberg, D., additional, Vagstad, G., additional, Harris, R., additional, Steranchak, L., additional, Arch, J., additional, Kelly, K., additional, Ostrosaka, P., additional, Guiliani, M., additional, Good, M., additional, Williams, T., additional, Olsen, K., additional, Campbell, A., additional, Shipe, C., additional, Conwit, R., additional, Finegold, D., additional, Zaucha, M., additional, Drash, A., additional, Morrison, A., additional, Malone, J.I., additional, Bernal, M.L., additional, Pavan, P.R., additional, Grove, N., additional, Tanaka, E.A., additional, McMillan, D., additional, Vaccaro‐Kish, J., additional, Babbione, L., additional, Solc, H., additional, DeClue, T.J., additional, Dagogo‐Jack, S., additional, Wigley, C., additional, Ricks, H., additional, Kitabchi, A., additional, Chaum, E., additional, Murphy, M.B., additional, Moser, S., additional, Meyer, D., additional, Iannacone, A., additional, Yoser, S., additional, Bryer‐Ash, M., additional, Schussler, S., additional, Lambeth, H., additional, Raskin, P., additional, Strowig, S., additional, Basco, M., additional, Cercone, S., additional, Barnie, A., additional, Devenyi, R., additional, Mandelcorn, M., additional, Brent, M., additional, Rogers, S., additional, Gordon, A., additional, Bakshi, N., additional, Perkins, B., additional, Tuason, L., additional, Perdikaris, F., additional, Ehrlich, R., additional, Daneman, D., additional, Perlman, K., additional, Ferguson, S, additional, Palmer, J., additional, Fahlstrom, R., additional, de Boer, I.H., additional, Kinyoun, J., additional, Van Ottingham, L., additional, Catton, S., additional, Ginsberg, J., additional, McDonald, C., additional, Harth, J., additional, Driscoll, M., additional, Sheidow, T., additional, Mahon, J., additional, Canny, C., additional, Nicolle, D., additional, Colby, P., additional, Dupre, J., additional, Hramiak, I., additional, Rodger, N.W., additional, Jenner, M., additional, Smith, T., additional, Brown, W., additional, May, M., additional, Lipps Hagan, J., additional, Agarwal, A., additional, Adkins, T., additional, Lorenz, R., additional, Feman, S., additional, Survant, L., additional, White, N.H., additional, Levandoski, L., additional, Grand, G., additional, Thomas, M., additional, Joseph, D., additional, Blinder, K., additional, Shah, G., additional, Burgess, D., additional, Boniuk, I., additional, Santiago, J., additional, Tamborlane, W., additional, Gatcomb, P., additional, Stoessel, K., additional, Ramos, P., additional, Fong, K., additional, Ossorio, P., additional, Ahern, J., additional, Meadema‐Mayer, L., additional, Beck, C., additional, Farrell, K., additional, Quin, J, additional, Gaston, P., additional, Trail, R., additional, Lachin, J., additional, Backlund, J., additional, Bebu, I., additional, Braffett, B., additional, Diminick, L., additional, Gao, X., additional, Hsu, W., additional, Klumpp, K., additional, Pan, H., additional, Trapani, V., additional, Cleary, P., additional, McGee, P., additional, Sun, W., additional, Villavicencio, S., additional, Anderson, K., additional, Dews, L., additional, Younes, Naji, additional, Rutledge, B., additional, Chan, K., additional, Rosenberg, D., additional, Petty, B., additional, Determan, A., additional, Kenny, D., additional, Williams, C., additional, Cowie, C., additional, Siebert, C., additional, Steffes, M., additional, Arends, V., additional, Bucksa, J., additional, Nowicki, M., additional, Chavers, B., additional, O'Leary, D., additional, Polak, J., additional, Harrington, A., additional, Funk, L., additional, Crow, R, additional, Gloeb, B., additional, Thomas, S., additional, O'Donnell, C., additional, Soliman, E.Z., additional, Zhang, Z.M., additional, Li, Y., additional, Campbell, C., additional, Keasler, L., additional, Hensley, S., additional, Hu, J., additional, Barr, M., additional, Taylor, T., additional, Prineas, R., additional, Feldman, E.L., additional, Albers, J.W., additional, Low, P., additional, Sommer, C., additional, Nickander, K., additional, Speigelberg, T., additional, Pfiefer, M., additional, Schumer, M., additional, Moran, M., additional, Farquhar, J., additional, Ryan, C., additional, Sandstrom, D., additional, Geckle, M., additional, Cupelli, E., additional, Thoma, F., additional, Burzuk, B., additional, Woodfill, T., additional, Danis, R., additional, Blodi, B., additional, Lawrence, D., additional, Wabers, H., additional, Gangaputra, S., additional, Neill, S., additional, Burger, M., additional, Dingledine, J., additional, Gama, V., additional, Sussman, R., additional, Davis, M., additional, Hubbard, L., additional, Budoff, M., additional, Darabian, S., additional, Rezaeian, P., additional, Wong, N., additional, Fox, M., additional, Oudiz, R., additional, Kim, L, additional, Detrano, R., additional, Cruickshanks, K., additional, Dalton, D., additional, Bainbridge, K., additional, Lima, J., additional, Bluemke, D., additional, Turkbey, E., additional, der Geest, ., additional, Liu, C., additional, Malayeri, A., additional, Jain, A., additional, Miao, C., additional, Chahal, H., additional, Jarboe, R., additional, Monnier, V., additional, Sell, D., additional, Strauch, C., additional, Hazen, S., additional, Pratt, A., additional, Tang, W., additional, Brunzell, J., additional, Purnell, J., additional, Natarajan, R., additional, Miao, F., additional, Zhang, L., additional, Chen, Z., additional, Paterson, A., additional, Boright, A., additional, Bull, S., additional, Sun, L., additional, Scherer, S., additional, Lyons, T.J., additional, Jenkins, A., additional, Klein, R., additional, Virella, G., additional, Jaffa, A., additional, Carter, R., additional, Stoner, J., additional, Garvey, W.T., additional, Lackland, D., additional, Brabham, M., additional, McGee, D., additional, Zheng, D., additional, Mayfield, R.K., additional, Maynard, J., additional, Wessells, H., additional, Sarma, A, additional, Dunn, R., additional, Holt, S., additional, Hotaling, J., additional, Kim, C., additional, Clemens, Q., additional, Brown, J., additional, and McVary, K., additional

Published
2018
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10. Nursing home research: the first International Association of Gerontology and Geriatrics (IAGG) research conference

Author

Rolland, Y., Resnick, B., Katz, P.R., Little, M.O., Ouslander, J.G., Bonner, A., Geary, C.R., Schumacher, K.L., Thompson, S., Martin, F.C., Wilbers, J., Zuniga, F., Ausserhofer, D., Schwendimann, R., Schussler, S., Dassen, T., Lohrmann, C., Levy, C., Whitfield, E., Souto Barreto, P. de, Etherton-Beer, C., Dilles, T., Azermai, M., Bourgeois, J., Orrell, M., Grossberg, G.T., Kergoat, H., Thomas, D.R., Visschedijk, J., Taylor, S.J., Team, O.S., Handajani, Y.S., Widjaja, N.T., Turana, Y., Rantz, M.J., Skubic, M., Morley, J.E., Rolland, Y., Resnick, B., Katz, P.R., Little, M.O., Ouslander, J.G., Bonner, A., Geary, C.R., Schumacher, K.L., Thompson, S., Martin, F.C., Wilbers, J., Zuniga, F., Ausserhofer, D., Schwendimann, R., Schussler, S., Dassen, T., Lohrmann, C., Levy, C., Whitfield, E., Souto Barreto, P. de, Etherton-Beer, C., Dilles, T., Azermai, M., Bourgeois, J., Orrell, M., Grossberg, G.T., Kergoat, H., Thomas, D.R., Visschedijk, J., Taylor, S.J., Team, O.S., Handajani, Y.S., Widjaja, N.T., Turana, Y., Rantz, M.J., Skubic, M., and Morley, J.E.

Abstract

Item does not contain fulltext, The International Association of Gerontology and Geriatrics held its first conference on nursing home research in St Louis, MO, in November 2013. This article provides a summary of the presentations.

Published
2014

14. Isolation of Biologically Active Fractions from Wood Hemicellulose Extracts

Author

Miller, B. L., Fahey, G. C., and Schussler, S. L.

Abstract

Chick bioassays were used to evaluate the phenolic, carbohydrate, and phenolic-carbohydrate complexes present in wood hemicellulose extracts (WHE). Eighty percent ethanol extractions of WHE induced the precipitation of high molecular weight phenolic-hemicellulose components (Fraction 1) leaving an alcohol supernatant containing residual phenolics and lower molecular weight sugars. Alkali treatment of the supernatant resulted in the precipitation of the sugars with some contamination from phenolic moieties (Fraction 2). The remaining material (Fraction 3) contained mostly low molecular weight phenolic material, but some carbohydrate was also present. Spectrophotometry, thin layer chromatography and dialysis according to molecular weight were used to identify the chemical properties of the WHE fractions. Eight-day-old male chicks of the Hubbard strain were fed a practical corn-soybean meal basal diet supplemented with each of the three fractions isolated from both Laurel and Ukiah WHE. All fractions were neutralized and concentrated before addition to the chick diets. A total of 30 animals per treatment were used in two separate trials. Growth rate (GR), feed consumption (FC) and gain to feed ratios (G/F) were the parameters measured. Fraction 1 isolated from Laurel WHE improved G/F on day 6, whereas the same fraction isolated from its Ukiah counterpart, significantly improved GR on days 3, 6 and 9 of the experiment. An improvement in G/F was also noted on day 3. The addition of Laurel Fraction 2 depressed G/F on days 9 and 12 with no effect on GR or FC. Ukiah Fraction 2 improved GR on days 3 and 6 and depressed G/F on day 12. Fraction 3 isolated from Laurel WHE improved GR on day 3 and 6 and G/F on day 3, while the same fraction isolated from Ukiah WHE significantly improved GR on days 3, 6 and 9 and G/F on day 3. This fractionation procedure appears to be acceptable for isolating the short-term growth-promoting moieties of WHE. The data indicate that WHE contains growth promoting substances that are evidently different from those moieties that cause increases in FC.

Published
1979
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16. Memory Effects above T<INF>g</INF> in Poled Guest/Host Polymers

Author

Schussler, S., Albrecht, U., Richert, R., and Bassler, H.

Abstract

We present systematic experiments of electric field poling and relaxation of 4-(dimethylamino)-4‘-nitrostilbene doped at 1 wt % in poly(isobutyl methacrylate) in a sandwich configuration of ITO electrodes using the second harmonic generation technique. A novel ultraslow relaxation mode at temperatures far above the glass transition temperature Tg has been identified qualitatively with a special repoling technique. Isothermal alignment and relaxation of the chromophore orientations show significant differences in their mean rates and in their sensitivity to variations of the field strength and the presence of small amounts of plasticizer molecules. A tentative qualitative model is proposed in which the necessity for considering nonlinear responses is postulated.

Published
1996

17. Development of a platform method for rapid detection and characterization of domain-specific post-translational modifications in bispecific antibodies.

Author

Liu S, Nguyen JB, Zhao Y, Schussler S, Kim S, Qiu H, Li N, Rosconi MP, and Pyles EA

Subjects
Immunoglobulin Fab Fragments immunology, Immunoglobulin Fab Fragments chemistry, Humans, Immunoglobulin G immunology, Immunoglobulin Fc Fragments chemistry, Antibodies, Bispecific immunology, Protein Processing, Post-Translational, Isoelectric Focusing methods
Abstract

Charge heterogeneity is inherent to all therapeutic antibodies and arises from post-translational modifications (PTMs) and/or protein degradation events that may occur during manufacturing. Among therapeutic antibodies, the bispecific antibody (bsAb) containing two unique Fab arms directed against two different targets presents an additional layer of complexity to the charge profile. In the context of a bsAb, a single domain-specific PTM within one of the Fab domains may be sufficient to compromise target binding and could potentially impact the stability, safety, potency, and efficacy of the drug product. Therefore, characterization and routine monitoring of domain-specific modifications is critical to ensure the quality of therapeutic bispecific antibody products. We developed a Digestion-assisted imaged Capillary isoElectric focusing (DiCE) method to detect and quantitate domain-specific charge variants of therapeutic bispecific antibodies (bsAbs). The method involves enzymatic digestion using immunoglobulin G (IgG)-degrading enzyme of S. pyogenes (IdeS) to generate F(ab) 2 and Fc fragments, followed by imaged capillary isoelectric focusing (icIEF) under reduced, denaturing conditions to separate the light chains (LCs) from the Fd domains. Our results suggest that DiCE is a highly sensitive method that is capable of quantitating domain-specific PTMs of a bsAb. In one case study, DiCE was used to quantitate unprocessed C-terminal lysine and site-specific glycation of Lys 98 in the complementarity-determining region (CDR) of a bsAb that could not be accurately quantitated using conventional, platform-based charge variant analysis, such as intact icIEF. Quantitation of these PTMs by DiCE was comparable to results from peptide mapping, demonstrating that DiCE is a valuable orthogonal method for ensuring product quality. This method may also have potential applications for characterizing fusion proteins, antibody-drug conjugates, and co-formulated antibody cocktails., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer Nguyen, Sophia Liu, Michael Rosconi, and Erica Pyles have patent #16/882,453 pending to US. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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18. GP2017-HCF, a high concentration formulation, demonstrates similar pharmacokinetics, immunogenicity and safety to GP2017, an approved adalimumab biosimilar.

Author

von Richter O, O'Reilly T, Guerrieri D, Fan J, Fey C, Schussler S, Furlan F, and Lemke L

Abstract

Background: GP2017 is an adalimumab biosimilar. The objective of this study is to compare the pharmacokinetics (PK) of GP2017 in its approved formulation and GP2017-high concentration formulation (HCF) in a randomized, double-blind, two-arm PK bridging study., Research Design and Methods: Healthy male subjects received a single 40 mg subcutaneous injection of either GP2017-HCF (n = 162) or GP2017 (n = 168). PK, safety, and immunogenicity were assessed over 72 days post-injection., Results: The 90% confidence intervals [CIs] of geometric mean ratios between GP2017-HCF and GP2017 for C max , AUC 0-inf , AUC 0-360 and AUC 0-last were within the pre-defined margin of 0.80 to 1.25; thus, PK comparability between GP2017-HCF and GP2017 was demonstrated. Subgroup analysis of PK comparability by anti-drug antibody (ADA) subpopulation showed that the 90% CIs of geometric mean ratios between GP2017-HCF and GP2017 for C max , AUC 0-inf , AUC 0-360 and AUC 0-last were within the margin of 0.80 to 1.25 in ADA-positive and ADA-negative subjects. The proportions of subjects with positive ADA responses and with neutralizing antibodies were comparable between the GP2017-HCF and GP2017 groups. GP2017-HCF and GP2017 were well tolerated, and there were no reports of deaths or other serious adverse events., Conclusion: Results show PK comparability between GP2017-HCF and GP2017 and comparable safety and tolerability.

Published
2023
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19. A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.

Author

Bellon A, Wang J, Skerjanec A, Velinova M, Dickerson D, Sabet A, Ngo L, O'Reilly T, Tomek C, Schussler S, Schier-Mumzhiu S, Gattu S, Koch SD, Schelcher C, Dobreva M, Boldea A, Nakov R, and Otto GP

Subjects
Adult, Cross-Over Studies, Double-Blind Method, Filgrastim, Healthy Volunteers, Humans, Polyethylene Glycols adverse effects, Biosimilar Pharmaceuticals adverse effects
Abstract

Aims: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics., Methods: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults., Results: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar., Conclusions: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2020
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20. Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study.

Author

Piazza G, Mani V, Goldhaber SZ, Grosso MA, Mercuri M, Lanz HJ, Schussler S, Hsu C, Chinigo A, Ritchie B, Nadar V, Cannon K, Pullman J, Concha M, Schul M, and Fayad ZA

Subjects
Administration, Intravenous, Administration, Oral, Adult, Aged, Anticoagulants adverse effects, Drug Therapy, Combination, Factor Xa Inhibitors adverse effects, Feasibility Studies, Female, Heparin adverse effects, Humans, International Normalized Ratio, Male, Middle Aged, Predictive Value of Tests, Pyridines adverse effects, Thiazoles adverse effects, Time Factors, Treatment Outcome, United States, Warfarin adverse effects, Anticoagulants administration & dosage, Blood Coagulation drug effects, Factor Xa Inhibitors administration & dosage, Heparin administration & dosage, Magnetic Resonance Angiography, Phlebography methods, Pyridines administration & dosage, Thiazoles administration & dosage, Venous Thrombosis diagnostic imaging, Venous Thrombosis drug therapy, Warfarin administration & dosage
Abstract

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266., (© The Author(s) 2016.)

Published
2016
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21. Age-dependence of relative change in circulating epinephrine and norepinephrine concentrations during tilt-induced vasovagal syncope.

Author

Benditt DG, Detloff BL, Adkisson WO, Lu F, Sakaguchi S, Schussler S, Austin E, and Chen LY

Subjects
Adult, Age Factors, Female, Humans, Linear Models, Male, Middle Aged, Prospective Studies, Statistics, Nonparametric, Tilt-Table Test, Epinephrine blood, Norepinephrine blood, Syncope, Vasovagal physiopathology
Abstract

Background: Although vasovagal syncope (VVS) is preceded by a surge of circulating catecholamines (epinephrine [Epi] and norepinephrine [NE]) of adrenal/renal and synaptic origin, prevention of VVS with β-adrenergic blockade has been ineffective except in "older" VVS patients., Objective: We hypothesized that age-related differences of β-blocker effect may be due in part to differences in the relative magnitudes of Epi and NE release during an evolving faint, specifically, greater Epi/NE ratio in younger fainters compared to older patients. To assess this hypothesis, we measured changes in Epi/NE ratios in younger (<40 years) vs older (≥40 years) patients during head-up tilt-table test-induced VVS., Methods: The study comprised 29 patients (12 patients ≥40 years [mean 56 ± 10.7 years] and 17 patients <40 years mean 25 ± 5.7 years]) with recurrent suspected VVS in whom 70° head-up tilt testing reproduced symptoms. Arterial Epi and NE concentrations were measured at baseline (supine), 2 minutes of head-up tilt, and syncope., Results: Baseline Epi and NE concentrations and the Epi/NE ratio did not differ in younger and older groups (Epi: 90 ± 65 pg/mL vs 70 ± 32 pg/mL; NE: 226 ± 122 pg/mL vs 244 ± 183 pg/mL). However, Epi/NE ratio increased to a greater extent in younger fainters during head-up tilt and tended to be greater in younger patients at both 2 minutes (<40: 1.02 ± 1.29 vs ≥40: 0.40 ± 0.27, P = .11) and at symptoms (<40: 2.6 ± 1.26 vs ≥40: 1.6 ± 0.71, P = .03). At symptoms, Epi/NE ratio ≥2.5 was observed in 9 of 17 younger patients vs 1 of 12 older patients (P = .02)., Conclusion: Epi/NE ratios tend to be greater in younger fainters, a finding that may account in part for the observation that β-blocker therapy is less effective in reducing VVS susceptibility in younger individuals., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2012
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22. In person versus computer screening for intimate partner violence among pregnant patients.

Author

Chang JC, Dado D, Schussler S, Hawker L, Holland CL, Burke JG, and Cluss PA

Subjects
Adult, Communication, Female, Follow-Up Studies, Humans, Interpersonal Relations, Interviews as Topic, Male, Middle Aged, Physician-Patient Relations, Pregnancy, Prenatal Care, Sexual Partners, Socioeconomic Factors, Spouse Abuse statistics & numerical data, Stress, Psychological, Surveys and Questionnaires, Tape Recording, Young Adult, Computers, Mass Screening methods, Pregnancy Complications psychology, Self Disclosure, Spouse Abuse diagnosis, Spouse Abuse psychology
Abstract

Objective: To compare in person versus computerized screening for intimate partner violence (IPV) in a hospital-based prenatal clinic and explore women's assessment of the screening methods., Methods: We compared patient IPV disclosures on a computerized questionnaire to audio-taped first obstetric visits with an obstetric care provider and performed semi-structured interviews with patient participants who reported experiencing IPV., Results: Two-hundred and fifty patient participants and 52 provider participants were in the study. Ninety-one (36%) patients disclosed IPV either via computer or in person. Of those who disclosed IPV, 60 (66%) disclosed via both methods, but 31 (34%) disclosed IPV via only one of the two methods. Twenty-three women returned for interviews. They recommended using both types together. While computerized screening was felt to be non-judgmental and more anonymous, in person screening allowed for tailored questioning and more emotional connection with the provider., Conclusion: Computerized screening allowed disclosure without fear of immediate judgment. In person screening allows more flexibility in wording of questions regarding IPV and opportunity for interpersonal rapport., Practice Implications: Both computerized or self-completed screening and in person screening is recommended. Providers should address IPV using non-judgmental, descriptive language, include assessments for psychological IPV, and repeat screening in person, even if no patient disclosure occurs via computer., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Published
2012
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