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1. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

Author

Ernst Wilhelm, Radue, William, H. Stuart, Peter, A. Calabresi, Christian, Confavreux, Steven, L. Galetta, Richard, A. Rudick, Fred, D. Lublin, Bianca, Weinstock Guttman, Daniel, R. Wynn, Elizabeth, Fisher, Athina, Papadopoulou, Frances, Lynn, Michael, A. Panzara, Alfred, W. Sandrock, For, the SENTINEL Investigators including F. Fazekas, Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Deisenhammer, F., Decoo, D, Lampaert, J., Bartholome, E., Bier, J., Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Finland:, J. Eralinna, Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, Ferriby, D., Debouverie, M., Pittion Vouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach, L., Decavel, P., Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, Guttman, Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher E. Rothenfusser Körber, A. Steinbrecher E. Rothenfusser Körber, Zellner, Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Israel:, O. Abramsky, Karusiss, D., Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, : C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fernandez Fernandez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Switzerland:, L. Kappos, Achtnichts, L., Wilmes, S., Turkey:, R. Karabudak, Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni, G., Lim, E. T., Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss, M., Gupta, V., Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel, A., Babu, A., Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor, P., Humphries, S., Wynn, D., Nagar, C., O'Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Javerbaum, J., Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo, B., Kishner, R., Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan, S., Yerby, M., Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., Ko, M., Gelber, D., Fortin, C., Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir J. Brockington, K. Bashir J. Brockington, Nicholas, A., Slaughter, R., Archer S. Harik, R. Archer S. Harik, Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Chandler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., Tandon, R., Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O'Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair, M., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Relapsing-Remitting, Placebo, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, Central nervous system disease, Pharmacotherapy, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, pathology/therapy, Drug Therapy, Internal medicine, Monoclonal, Medicine, Humans, Immunologic Factors, Humanized, medicine.diagnostic_test, business.industry, Multiple sclerosis, Patient Selection, Interferon beta-1a, Antibodies, Monoclonal, Brain, Magnetic resonance imaging, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Treatment Outcome, Neurology, therapeutic use, Combination, Drug Therapy, Combination, pathology, Female, Neurology (clinical), Adolescent, Adult, Antibodies, Humanized, Antibodies, therapeutic use, Brain, pathology, Drug Therapy, Combination, Female, Humans, Immunologic Factors, therapeutic use, Interferon-beta, therapeutic use, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, pathology/therapy, Patient Selection, Treatment Outcome, business, medicine.drug
Abstract

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

Published
2010

2. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL

Author

Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Affirm, Investigators, Fazekas, SENTINEL Investigators including: F., Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Eisenhammer, F., Decoo J. Lampaert, D. Decoo J. Lampaert, Bartholome J. Bier, E. Bartholome J. Bier, Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittionvouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach P. Decavel, L. Rumbach P. Decavel, Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, A., Guttman, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher, A., Rothenfusser Körber, E., Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky D. Karusiss, O. Abramsky D. Karusiss, Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fern ez Fern ez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, L., Achtnichts, L., Wilmes, S., Karabudak, R., Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni ET Lim, G. Giovannoni E. T. Lim, Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss V. Gupta, M. Reiss V. Gupta, Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel A. Babu, A. Perel A. Babu, Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor S. Humphries, P. Fodor S. Humphries, Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., S. M, El, Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Kaiser, J. Javerbaum, Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo R. Kishner, B. Steingo R. Kishner, Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan M. Yerby, S. Cohan M. Yerby, Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., KoD Gelber C. Fortin, M. K. o. D. Gelber C. Fortin, Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, J., Nicholas, A., Slaughter, R., Archer, R., Harik, S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Ch ler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., R. T, On, Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Ari, D. B, Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair EW Radue, M. S. i. n. c. l. a. i. r. E. W. Radue, de Vera, A., Bacelar, O., Kuster, P., and Kappos, L. .

Subjects
medicine.medical_specialty, Multiple Sclerosis, Enzyme-Linked Immunosorbent Assay, Relapsing-Remitting, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, law.invention, Disability Evaluation, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Antibody Specificity, Internal medicine, Monoclonal, medicine, Secondary Prevention, Humans, Adverse effect, Antibodies, Blocking, Humanized, Antibodies, Monoclonal, Brain, Flow Cytometry, Interferon-beta, Magnetic Resonance Imaging, Placebo Effect, Treatment Outcome, Neuroscience (all), Expanded Disability Status Scale, business.industry, Multiple sclerosis, Incidence (epidemiology), Interferon beta-1a, medicine.disease, Blocking, Multiple sclerosis functional composite, Immunology, Neurology (clinical), business, medicine.drug
Abstract

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression ( p ≤ 0.05), relapse rate ( p = 0.009), and MRI ( p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.

Published
2007

3. Health-related quality of life in multiple sclerosis: Effects of natalizumab

Author

Rudick, R. A., Miller, D., Hass, S., Hutchinson, M, Calabresi, P. A., Confavreux, C., Galetta, S. L., Giovannoni, G., Havrdova, E., Kappos, L., Lublin, F. D., Miller, D. H., O'Connor, P. W., Phillips, J. T., Polman, C. H., Radue, Ew, Stuart, W. H., Wajgt, A., Weinstock Guttman, B., Wynn, D. R., Lynn, F., Panzara, M. A., Affirm, Macdonell, SENTINEL Investigators including: R., Hughes, A., Taylor, I., Lee, Y. C., Ma, H., King, J., Kilpatrick, T., Butzkueven, H., Marriott, M., Pollard, J., Spring, P., Spies, J., Barnett, M., Dehaene, I., Vanopdenbosch, L., D’Hooghe, M., Van Zandijcke, M., Derijck, O., Seeldrayers, P., Jacquy, J., Piette, T., De Cock, C., Medaer, R., Soors, P., Vanroose, E., Vanderhoven, L., Nagels, G., Dubois, B., Deville, M. C., D’Haene, R., Jacques, F., Hallé, D., Gagnon, S., Likavcan, E., Murray, T. J., Bhan, V., Mackelvey, R., Maxner, C. E., Christie, S., Giaccone, R., Guzman, D. A., Melanson, M., Esfahani, F., Gomori, A. J., Nagaria, M. H., Grand’Maison, F., Berger, L., Nasreddine, Z., Duplessis, M., Brunet, D., Jackson, A., Pari, G., O’Connor, P., Gray, T., Hohol, M., Marchetti, P., Lee, L., Murray, B., Sahlas, J., Perry, J., Devonshire, V., Hooge, J., Hashimoto, S., Oger, J., Smyth, P., Rice, G., Kremenchutzky, M., Stourac, P., Kadanka, Z., Benesova, Y., Niedermayerova, I., Meluzinova, E., Marusic, P., M, Bojar, Zarubova, K., Houzvicková, E., Piková, J., Talab, R., Faculty, Hospital Olomouc, Olomouc, B. Muchova, Urbánek, K, Kettnerova, Z., Mares, J., Otruba, P., Zapletalová, O., Hradilek, P., Ddolezil, D. Dolezil, Woznicova, I., Höfer, R., Ambler J. Fiedler, Z. Ambler J. Fiedler, Sucha, J., Matousek, V., Rektor, I., Dufek, M., Mikulik, R., Mastik, J., Tyrlikova, I., General, Teaching Hospital, Prague, E. 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Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Visual analogue scale, Health Status, Population, Pain, Comorbidity, Placebo, Antibodies, law.invention, Natalizumab, Randomized controlled trial, Quality of life, Double-Blind Method, law, Internal medicine, Surveys and Questionnaires, Monoclonal, medicine, Prevalence, Humans, Longitudinal Studies, education, Humanized, education.field_of_study, Expanded Disability Status Scale, Neuroscience (all), business.industry, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Female, Patient Satisfaction, Treatment Outcome, United States, Quality of Life, Multiple sclerosis, medicine.disease, Neurology, Physical therapy, Neurology (clinical), business, medicine.drug
Abstract

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007

Published
2007

4. The incidence and significance of anti-natalizumab antibodies. Results from the AFFIRM and SENTINEL

Author

Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Fazekas, The following investigators participated in the SENTINEL study: F., Enzinger, * C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, * E., Egg, R., Deisenhammer, F., Lampaert, D. Decoo* J., Bier, E. Bartholome* J., Stenager, Denmark: E., Rasmussen, * M., Binzer, M., Ravnborg, M., Soelberg Sørensen, * P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, * E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, * J., Soilu Hänninen, M., Reunanen, M., Remes, * A., Keskinarkaus, I., Moreau, T., Noblet, * M., Rouaud, O., Couvreur, G., Edan, G., Lepage, * E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Gout, O., Deschamps, * R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, * J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittion Vouyouvitch, * S., Lacour, J. C., Pelletier, J., Feuillet, * L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, * K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, * D., Renouil Guy, N., Cesaro, P., Degos, * F., Benisty, S., Decavel, L. Rumbach* P., Confavreux, C., Blanc, * S., Aubertin, P., Riche, G., Brochet, B., Ouallet, * J. C., Anne, O., Menck, S., Grupe, * A., Guttman, E., Lensch, E., Fucik, * E., Heitmann, S., Hartung, H. P., Schröter, * M., Kurz, F. M. W., Heidenreich, F., Trebst, * C., Pul, R., Hohlfeld, R., Krumbholz, * M., Pellkofer, H., Haas, J., Segert, * A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, * K., Hoffmann, V., Zettl, U., Steinhagen, * V., Adler, S., Steinbrecher, A., Rothenfusser Körber, * E., Zellner, R., Baum, K., Günther, * A., Bläsing, H., Stoll, G., Gold, * R., Bayas, * A., Kleinschnitz, C., Limmroth, V., Katsarava, * Z., Kastrup, O., Haller, P., Stoeve, * S., Höbel, D., Oschmann, P., Voigt, * K., Burger, C. V., Karusiss, O. Abramsky* D., Achiron, A., Kishner, * I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, * D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, Paolo, Ranzato, * F., Tiberio, M., Perini, P., Laroni, A., Marrosu, M., Marchi, * E. Cocco P., Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, * A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, G., Pizzorno, * M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, * V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, * M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, * E., Tacken, H., Frequin, S. T. F. M., Siegers, * H. P., Mauser, H. W., Fernandez Fernandez, O., León, * A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, * C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, * L., Moral, E., Martinez, S., Kappos, L., Achtnichts, * L., Wilmes, S., Karabudak, R., Kurne, * A., Erdem, S., Siva, A., Saip, * S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, * F., Topcular, B., Lim, G. Giovannoni* E. T., Lava, N., Murnane, * M., Dentinger, M., Zimmerman, E., Gupta, M. Reiss* V., Scott, T., Brillman, * J., Kunschner, L., Wright, D., Babu, A. Perel* A., Rivera, V., Killian, * J., Hutton, G., Lai, E., Picone, Bernard W. M., Cadivid, * D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, * A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, * P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, * M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, * C., Tyler, R., Horvit, A., Humphries, P. Fodor* S., Wynn, D., Nagar, * C., O’Brien, D., Allen, N., Turel, A., Friedenberg, * S., Carlson, J., Hosey, J., Crayton, H., Richert, * J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, * Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, * C., Rorick, M., Reed, R., Elias, S., Feit, * H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, * K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, * C., Fleck, J., Horak, H., Javerbaum, J., Elmore, * R., Garcia, E., Tasch, E., Gruener, G., Celesia, * G., Chawla, J., Miller, A., Drexler, * E., Keilson, M., Wolintz, R., Drasby, E., Muscat, * P., Belden, J., Sullivan, R., Cohen, J., Stone, * L., Marrie, R. A., Fox, R., Hughes, B., Babikian, * P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, * W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, * G., Martin, J., Kaufman, D., Stuart, W., English, * J. B., Stuart, D. S., Gilbert, R. W., Kaufman, MS M., Putman, . *. S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, * E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, * H., Rizo, M., Kitaj, M., Blevins, Neurolo J., Smith, * T., Mcgee, F., Honeycutt, W., Brown, * M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, * J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, * S., Dorn, D., Groeschel, A., Kishner, B. Steingo* R., Cohen, B., Melen, * O., Simuni, T., Zee, P., Yerby, S. Cohan* M., Hendin, B., Levine, * T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, * R., Ferrell, W., Stefoski, D., Stevens, * S., Katsamakis, G., Topel, J., Ko, M., Fortin, D. Gelber* C., Green, B., Logan, * W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, * A., Sim, G., Mihai, C., Vertino, * M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, * A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, * A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, * J., Nicholas, A., Slaughter, R., Archer, R., Harik, * S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, * G., Olek, M., Demetriou, M., Shin, R., Cala bresi, * P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, * S., Sherbert, R., Herndon, R., Uschmann, * H., Chandler, A., Markowitz, C., Jacobs, * D., Balcer, L., Mitchell, G., Chakra vorty, * S., Heyman, R., Stauber, Z., Goodman, A., Segal, * B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, * M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, * M., Hawker, K., Ulrich, R., Panitch, H., Hamill, * R., Tandon, R., Dulaney, E., Simnad, V., Miller, * J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, * M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, * R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, * B., Hart, D., Moses, H., Sriram, * S., Fang, J., O’Duffy, A., Kita, M., Taylor, * L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, * S., Lefkowitz, D., Kumar, S., and Sinclair, M.

Published
2007

5. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis

Author

Richard, A. Rudick, William, H. Stuart, Peter, A. Calabresi, Christian, Confavreux, Steven, L. Galetta, Ernst Wilhelm, Radue, Fred, D. Lublin, Bianca, Weinstock Guttman, Daniel, R. Wynn, Frances, Lynn, Msc, M. S. c., Michael, A. Panzara, Alfred, W. Sandrock, For, the SENTINEL Investigators including: F. Fazekas, Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Eisenhammer, F., Decoo J. Lampaert, D. Decoo J. Lampaert, Bartholome J. Bier, E. Bartholome J. Bier, Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittionvouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach P. Decavel, L. Rumbach P. Decavel, Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, A., Guttman, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher, A., Rothenfusser Körber, E., Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky D. Karusiss, O. Abramsky D. Karusiss, Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fern ez Fern ez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, L., Achtnichts, L., Wilmes, S., Karabudak, R., Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni ET Lim, G. Giovannoni E. T. Lim, Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss V. Gupta, M. Reiss V. Gupta, Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel A. Babu, A. Perel A. Babu, Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor S. Humphries, P. Fodor S. Humphries, Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., S. M, El, Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Kaiser, J. Javerbaum, Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo R. Kishner, B. Steingo R. Kishner, Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan M. Yerby, S. Cohan M. Yerby, Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., KoD Gelber C. Fortin, M. K. o. D. Gelber C. Fortin, Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, J., Nicholas, A., Slaughter, R., Archer, R., Harik, S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Ch ler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., R. T, On, Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Ari, D. B, Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair EW Radue, M. S. i. n. c. l. a. i. r. E. W. Radue, de Vera, A., Bacelar, O., Kuster, P., and Kappos, L. .

Subjects
Adult, Male, Infusions, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Combination therapy, Integrin alpha4, Peripheral edema, Progressive Multifocal, Relapsing-Remitting, Gastroenterology, Antibodies, Natalizumab, Drug Therapy, Leukoencephalopathy, Internal medicine, Monoclonal, Secondary Prevention, medicine, Humans, Humanized, Proportional Hazards Models, Expanded Disability Status Scale, business.industry, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Brain, Cell Adhesion Molecules, Disease Progression, Drug Therapy, Combination, Female, Infusions, Intravenous, Interferon-beta, JC Virus, Leukoencephalopathy, Progressive Multifocal, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Medicine (all), Progressive multifocal leukoencephalopathy, Multiple sclerosis, Hazard ratio, Interferon beta-1a, General Medicine, medicine.disease, Surgery, Combination, medicine.symptom, Intravenous, business, medicine.drug
Abstract

Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P

Published
2006

6. Phase II pilot study of imatinib mesylate in neurofibromatosis (NF1) patients with plexiform neurofibromas.

Author

Robertson, K. A., primary, Bowers, D. C., additional, Yang, F., additional, Vik, T., additional, Ho, C., additional, Croop, J., additional, Walsh, L. E., additional, Hingtgen, C., additional, Pradhan, K. R., additional, Hutchins, G., additional, Fletcher, J. W., additional, Cohen, M., additional, Edwards-Brown, M., additional, Travers, J. B., additional, Yu, M., additional, Nalepa, G., additional, Denne, S., additional, Ingram, D., additional, and Clapp, W., additional

Published
2011
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11. Stroke code simulation benefits advanced practice providers similar to neurology residents.

Author

Khan M, Baird GL, Price T, Tubergen T, Kaskar O, De Jesus M, Zachariah J, Oostema A, Scurek R, Coleman RR, Sherman W, Hingtgen C, Abdelhak T, Smith B, and Silver B

Abstract

Background: Advanced practice providers (APPs) are important members of stroke teams. Stroke code simulations offer valuable experience in the evaluation and treatment of stroke patients without compromising patient care. We hypothesized that simulation training would increase APP confidence, comfort level, and preparedness in leading a stroke code similar to neurology residents., Methods: This is a prospective quasi-experimental, pretest/posttest study. Nine APPs and 9 neurology residents participated in 3 standardized simulated cases to determine need for IV thrombolysis, thrombectomy, and blood pressure management for intracerebral hemorrhage. Emergency medicine physicians and neurologists were preceptors. APPs and residents completed a survey before and after the simulation. Generalized mixed modeling assuming a binomial distribution was used to evaluate change., Results: On a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree), confidence in leading a stroke code increased from 2.4 to 4.2 ( p < 0.05) among APPs. APPs reported improved comfort level in rapidly assessing a stroke patient for thrombolytics (3.1-4.2; p < 0.05), making the decision to give thrombolytics (2.8 vs 4.2; p < 0.05), and assessing a patient for embolectomy (2.4-4.0; p < 0.05). There was no difference in the improvement observed in all the survey questions as compared to neurology residents., Conclusion: Simulation training is a beneficial part of medical education for APPs and should be considered in addition to traditional didactics and clinical training. Further research is needed to determine whether simulation education of APPs results in improved treatment times and outcomes of acute stroke patients.

Published
2018
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12. N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/- mice.

Author

Duan JH, Hodgdon KE, Hingtgen CM, and Nicol GD

Subjects
Animals, Calcium Channel Blockers pharmacology, Calcium Channels metabolism, Calcium Channels, L-Type metabolism, Capsaicin pharmacology, Cells, Cultured, Ganglia, Spinal drug effects, Ganglia, Spinal physiology, Mice, Inbred C57BL, Mice, Transgenic, Neurofibromin 1 genetics, Patch-Clamp Techniques, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Sensory Receptor Cells drug effects, Sensory System Agents pharmacology, Calcium metabolism, Calcium Channels, N-Type metabolism, Neurofibromin 1 metabolism, Sensory Receptor Cells physiology
Abstract

Major aspects of neuronal function are regulated by Ca(2+) including neurotransmitter release, excitability, developmental plasticity, and gene expression. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited both greater excitability and evoked release of neuropeptides compared to wildtype mice. Furthermore, augmented voltage-dependent sodium currents but not potassium currents contribute to the enhanced excitability. To determine the mechanisms giving rise to the enhanced release of substance P and calcitonin gene-related peptide in the Nf1+/- sensory neurons, the potential differences in the total voltage-dependent calcium current (ICa) as well as the contributions of individual Ca(2+) channel subtypes were assessed. Whole-cell patch-clamp recordings from small-diameter capsaicin-sensitive sensory neurons demonstrated that the average peak ICa densities were not different between the two genotypes. However, by using selective blockers of channel subtypes, the current density of N-type (Cav2.2) ICa was significantly larger in Nf1+/- neurons compared to wildtype neurons. In contrast, there were no significant differences in L-, P/Q- and R-type currents between the two genotypes. Quantitative real-time polymerase chain reaction measurements made from the isolated but intact dorsal root ganglia indicated that N-type (Cav2.2) and P/Q-type (Cav2.1) Ca(2+) channels exhibited the highest mRNA expression levels although there were no significant differences in the levels of mRNA expression between the genotypes. These results suggest that the augmented N-type (Cav2.2) ICa observed in the Nf1+/- sensory neurons does not result from genomic differences but may reflect post-translational or some other non-genomic modifications. Thus, our results demonstrate that sensory neurons from Nf1+/- mice, exhibit increased N-type ICa and likely account for the increased release of substance P and calcitonin gene-related peptide that occurs in Nf1+/- sensory neurons., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Published
2014
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13. Dorsal root ganglia isolated from Nf1+/- mice exhibit increased levels of mRNA expression of voltage-dependent sodium channels.

Author

Hodgdon KE, Hingtgen CM, and Nicol GD

Subjects
Animals, Mice, Mice, Inbred C57BL, Mutation, NAV1.1 Voltage-Gated Sodium Channel, NAV1.3 Voltage-Gated Sodium Channel, NAV1.7 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel, Nerve Tissue Proteins biosynthesis, Nerve Tissue Proteins genetics, Real-Time Polymerase Chain Reaction, Ganglia, Spinal metabolism, Genes, Neurofibromatosis 1, RNA, Messenger biosynthesis, Sodium Channels biosynthesis, Sodium Channels genetics
Abstract

We reported previously that sensory neurons isolated from mice with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited greater excitability and increased sodium current densities compared with wildtype mice. This raises the question as to whether the increased current density resulted from post-translational modifications or increased expression of sodium channels. Quantitative real-time polymerase chain reaction was used to measure expression levels of the nine different voltage-gated sodium channel α subunits and the four associated auxiliary β subunits in the dorsal root ganglia (DRG) obtained from wildtype and Nf1+/- mice. The Relative Expression Software Tool indicated that Nav1.1, Nav1.3, Nav1.7, and Nav1.8 were significantly elevated in DRG isolated from Nf1+/- mice. Expression of Nav1.2, Nav1.5, Nav1.6, and Nav1.9 were not significantly altered. The gene transcript for Nav1.4 was not detected. There were no significant changes in the relative expression levels of β subunits. The Nav1.9 subtype was the most abundant with Nav1.7 and Nav1.8 being the next most abundant subtypes, whereas Nav1.3 was relatively less abundant. For the β subunits, β1 was by far the most abundant subtype. These results demonstrate that the increased expression levels of Nav1.7, Nav1.8, and perhaps Nav1.1 in the Nf1+/- DRG make the largest contribution to the increased sodium current density and thus give rise to the enhanced excitability. Though the mechanisms by which many people with NF1 experience increased pain have not been elucidated, these abnormal painful states may involve elevated expression of specific sodium channel subtypes in small diameter nociceptive sensory neurons., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Published
2012
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14. Ras signaling pathways mediate NGF-induced enhancement of excitability of small-diameter capsaicin-sensitive sensory neurons from wildtype but not Nf1+/- mice.

Author

Duan JH, Wang Y, Duarte D, Vasko MR, Nicol GD, and Hingtgen CM

Subjects
Action Potentials drug effects, Animals, Cell Size, Mice, Mice, Knockout, NFI Transcription Factors genetics, Sensory Receptor Cells cytology, Sensory Receptor Cells drug effects, Signal Transduction drug effects, Species Specificity, Action Potentials physiology, Capsaicin pharmacology, NFI Transcription Factors metabolism, Nerve Growth Factor pharmacology, Sensory Receptor Cells physiology, Signal Transduction physiology, ras Proteins metabolism
Abstract

Nerve growth factor (NGF) activates multiple downstream effectors, including Ras, phosphoinositide-3 kinase, and sphingomyelins. However, pathway mediating the NGF-induced augmentation of sensory neuronal excitability remains largely unknown. We previously reported that small-diameter sensory neurons with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited increased excitability. The protein product of the Nf1 gene is neurofibromin, a guanosine triphosphatase-activating protein (GAP) for p21ras (Ras) that accelerates the conversion of active Ras-GTP to inactive Ras-GDP. Thus, Nf1+/- cells have augmented basal and stimulated Ras activity. To investigate whether NGF-induced increases in excitability of small-diameter sensory neurons are dependent on Ras signaling, an antibody that blocks the activation of Ras, Y13-259, was perfused into the cell. Under these conditions, the enhanced excitability produced by NGF was suppressed in wildtype neurons but the excitability of Nf1+/- neurons was unaltered. In addition, expression of a dominant-negative form of Ras abolished the ability of NGF to increase the excitability of small-diameter sensory neurons. These results demonstrate that NGF enhances excitability of small-diameter sensory neurons in a Ras-dependent manner while the consequences of decreased expression of neurofibromin cannot be restored by blocking Ras signaling; suggesting that Ras-initiated signaling pathways can regulate both transcriptional and posttranslational control of ion channels important in neuronal excitability., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Published
2011
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15. Signaling pathways that mediate nerve growth factor-induced increase in expression and release of calcitonin gene-related peptide from sensory neurons.

Author

Park KA, Fehrenbacher JC, Thompson EL, Duarte DB, Hingtgen CM, and Vasko MR

Subjects
Animals, Calcitonin Gene-Related Peptide biosynthesis, Cells, Cultured, Ganglia, Spinal metabolism, Ganglia, Spinal physiology, Male, Nerve Growth Factor metabolism, Nociceptors physiology, Radioimmunoassay, Rats, Rats, Sprague-Dawley, Sensory Receptor Cells physiology, Signal Transduction genetics, Up-Regulation genetics, Calcitonin Gene-Related Peptide genetics, Calcitonin Gene-Related Peptide metabolism, Nerve Growth Factor physiology, Nociceptors metabolism, Sensory Receptor Cells metabolism, Signal Transduction physiology, Up-Regulation physiology
Abstract

Nerve growth factor (NGF) can augment transmitter release in sensory neurons by acutely sensitizing sensory neurons and by increasing the expression of calcitonin gene-related peptide (CGRP) over time. The current study examined the intracellular signaling pathways that mediate these two temporally distinct effects of NGF to augment CGRP release from sensory neurons. Growing sensory neurons in 30 or 100 ng/mL of NGF for 7 days increases CGRP content and this increase augments the amount of CGRP that is released by high extracellular potassium. Overexpressing a dominant negative Ras, Ras(17N) or treatment with a farnesyltransferase inhibitor attenuates the NGF-induced increase in CGRP content. Conversely, overexpressing a constitutively active Ras augments the NGF-induced increase in content of CGRP. Inhibiting mitogen activated protein kinase (MEK) activity also blocks the ability of NGF to increase CGRP expression. In contrast to the ability of chronic NGF to increase peptide content, acute exposure of sensory neurons to 100 ng/mL NGF augments capsaicin-evoked release of CGRP without affecting the content of CGRP. This sensitizing action of NGF is not affected by inhibiting Ras, MEK, or PI3 kinases. In contrast, the NGF-induced increase in capsaicin-evoked release of CGRP is blocked by the protein kinase C (PKC) inhibitor, BIM and the Src family kinases inhibitor, PP2. These data demonstrate that different signaling pathways mediate the alterations in expression of CGRP by chronic NGF and the acute actions of the neurotrophin to augment capsaicin-evoked release of CGRP in the absence of a change in the content of the peptide., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Published
2010
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16. Glial cell line-derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons.

Author

Schmutzler BS, Roy S, and Hingtgen CM

Subjects
Animals, Cells, Cultured, Glial Cell Line-Derived Neurotrophic Factors pharmacology, In Vitro Techniques, Mice, Mice, Inbred C57BL, Spinal Cord metabolism, Calcitonin Gene-Related Peptide metabolism, Capsaicin pharmacology, Glial Cell Line-Derived Neurotrophic Factors physiology, Sensory Receptor Cells metabolism
Abstract

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are a group of peptides that have been implicated as important factors in inflammation, since they are released in increased amounts during inflammation and induce thermal hyperalgesia upon injection. Mouse isolated sensory neurons in culture and freshly dissociated spinal cord slices were used to examine the enhancement in stimulated-release of the neuropeptide, calcitonin gene-related peptide (CGRP), as a measure of sensitization. Exposure of isolated sensory neurons in culture to GDNF, neurturin, and artemin enhanced the capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide (iCGRP) two- to threefold, but did not increase potassium-stimulated release of iCGRP. A similar profile of sensitization was observed in freshly dissociated spinal cord slices. Persephin, another member of the GFL family thought to be important in development, was unable to induce an enhancement in the release of iCGRP. These results demonstrate that specific GFLs are important mediators affecting sensory neuronal sensitivity, likely through modulation of the capsaicin receptor. The sensitization of sensory neurons during inflammation, and the pain and neurogenic inflammation resulting from this sensitization, may be due in part to the effects of these selected GFLs.

Published
2009
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17. Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene.

Author

Hingtgen CM, Roy SL, and Clapp DW

Subjects
Afferent Pathways drug effects, Animals, Calcitonin Gene-Related Peptide metabolism, Capsaicin pharmacology, Cells, Cultured, Ganglia, Spinal drug effects, Heterozygote, Hyperalgesia genetics, Hyperalgesia metabolism, Hyperalgesia physiopathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Growth Factor pharmacology, Neuralgia genetics, Neuralgia metabolism, Neuralgia physiopathology, Neurofibromatosis 1 metabolism, Neurofibromatosis 1 physiopathology, Neurons, Afferent drug effects, Organ Culture Techniques, Pain Threshold physiology, Posterior Horn Cells drug effects, Presynaptic Terminals metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Substance P metabolism, Synaptic Transmission genetics, Afferent Pathways metabolism, Ganglia, Spinal metabolism, Neurofibromatosis 1 genetics, Neurons, Afferent metabolism, Neuropeptides metabolism, Posterior Horn Cells metabolism
Abstract

Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21(ras). Loss of NF1 results in an increase in activity of the p21(ras) transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21(ras) transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

Published
2006
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18. Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands.

Author

Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, and He JJ

Subjects
Amyloid beta-Protein Precursor metabolism, Animals, Apolipoprotein E4, Apolipoproteins E metabolism, Basal Ganglia pathology, Biological Transport, Brain cytology, Brain pathology, CHO Cells, Cricetinae, Endocytosis, Fetus, Gestational Age, Heparan Sulfate Proteoglycans metabolism, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Macaca, PC12 Cells, Rats, Simian Acquired Immunodeficiency Syndrome pathology, alpha-Macroglobulins metabolism, tat Gene Products, Human Immunodeficiency Virus, AIDS Dementia Complex etiology, Gene Products, tat metabolism, HIV-1, Neurons metabolism, Receptors, Immunologic metabolism
Abstract

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-protein. In a model of macaques infected with a chimeric strain of simian-human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian-human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.

Published
2000
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19. The tragedy of Sergei Prokofiev.

Author

Hingtgen CM

Subjects
Cerebral Hemorrhage history, Famous Persons, History, 20th Century, Humans, Male, Music history
Abstract

Sergei Sergeevich Prokofiev (1891-1953) was one of the great Russian composers. He died, at age 61, of a supposed intracerebral brain hemorrhage. During the 8 years before his death, he suffered from episodic headaches, nausea and dizziness. This article reviews the historical information about Prokofiev's illness leading to a plausible underlying etiology for his death.

Published
1999

20. The painful perils of a pair of pianists: the chronic pain of Clara Schumann and Sergei Rachmaninov.

Author

Hingtgen CM

Subjects
Chronic Disease, Famous Persons, Female, Fibromyalgia history, History, 19th Century, History, 20th Century, Humans, Male, Temporomandibular Joint Disorders history, Trigeminal Neuralgia history, Music history, Somatoform Disorders history
Abstract

Clara Wieck Schumann (1819-1896) and Sergei Vassilievich Rachmaninov (1873-1943) were two of the greatest pianists that ever lived. They had full lives composing and performing music. Each also had more than his or her fair share of hardships. In addition to all the pressures that are part of a performer's life, both Clara Schumann and Sergei Rachmaninov also suffered from chronic pain. This article discusses the pain syndromes that plagued these great musicians and the effect of chronic illness on their music.

Published
1999

21. The treatment of Parkinson's disease: current concepts and rationale.

Author

Hingtgen CM and Siemers E

Subjects
Clinical Trials as Topic, Female, Globus Pallidus surgery, Humans, Male, Prognosis, Thalamus surgery, Treatment Outcome, Antiparkinson Agents administration & dosage, Parkinson Disease drug therapy, Parkinson Disease surgery
Abstract

The recent advances in the treatment of Parkinson's disease have made for significant improvements in the quality of life and mortality rate of those who suffer from this neurodegenerative disease. At the same time, the number of options and the complexity of multi-drug regimens have posed a great challenge for the clinician caring for the patient with Parkinson's disease. Though there are still many questions to be answered in regard to the potential neuroprotective effects of several medications, a few general rational treatment plans can be outlined. In patients requiring treatment in the early stages of the disease, especially with a predominance of tremor, anticholinergics or amantadine should be considered initially. At this point, it would be reasonable to add selegiline for both therapeutic and possible neuroprotective effects. As a patient becomes more affected by the disease and additional therapy is necessary, starting either a dopamine agonist or levodopa would be a rational choice. Continuation of selegiline and, possibly, amantadine for neuroprotective reasons should be contemplated. Titration in levodopa therapy (with controlled-release or standard levodopa) to higher levels should prompt addition of a dopamine receptor agonist if one has not been started previously. Conversely, if a patient is receiving only a dopamine receptor agonist and is becoming progressively disabled, levodopa should be added to the regimen. Fluctuations in motor abilities may be improved further by the use of a COMT inhibitor. Patients with uncontrollable motor fluctuations should be considered for surgery. Undoubtedly, the coming years will bring more treatment options and more evidence on which sequences and combinations of therapies are the most beneficial. Differences in efficacy and adverse effects for each patient must be taken into consideration when outlining and carrying out a treatment plan. By using a rational approach to the treatment of Parkinson's disease, with the above guidelines in mind, the patient should be able to enjoy a good quality of life and level of function for many years.

Published
1998

22. Prostaglandins facilitate peptide release from rat sensory neurons by activating the adenosine 3',5'-cyclic monophosphate transduction cascade.

Author

Hingtgen CM, Waite KJ, and Vasko MR

Subjects
Adenylyl Cyclase Inhibitors, Animals, Calcitonin Gene-Related Peptide metabolism, Cyclic AMP metabolism, Radioimmunoassay, Rats, Rats, Sprague-Dawley, Cyclic AMP physiology, Neurons, Afferent metabolism, Neuropeptides metabolism, Prostaglandins pharmacology, Signal Transduction drug effects
Abstract

Prostaglandins sensitize sensory neurons to activation by mechanical, thermal and chemical stimuli. This sensitization also results in an increase in the stimulus-evoked release of the neuroactive peptides, substance P and calcitonin gene-related peptide from sensory neurons. The cellular transduction cascade underlying the prostaglandin-induced augmentation of peptide release is not known. Therefore, we examined whether the sensitizing action of prostaglandins on peptide release from sensory neurons grown in culture is mediated by the second messenger, adenosine 3', 5' cyclic monophosphate (cAMP). Prostaglandin E2 and carba prostacyclin (a stable analog of prostaglandin I2) significantly increase the content of cAMP-like immunoreactive substance (icAMP) in the sensory neuron cultures at concentrations that also augment the bradykinin- or capsaicin-evoked release of peptides. Furthermore, pretreating sensory neurons with agents that increase intracellular cAMP mimics the sensitizing action of prostaglandins. Exposing cultures to either forskolin (0.1-10 microM), cholera toxin (1.5 micrograms), or 8-bromo-cAMP (100 microM) results in a significant enhancement of the bradykinin- or capsaicin-stimulated release of both substance P-like and calcitonin gene-related peptide-like immunoreactive substances. Pretreating sensory neurons with the adenylyl cyclase inhibitor, 9-tetrahydro-2-furyl adenine (5 mM), abolishes the prostaglandin-induced increases in icAMP content and attenuates the prostaglandin E2 or carba prostacyclin enhancement of the evoked release of calcitonin gene-related peptide-like immunoreactive substance. These results demonstrate that the cAMP transduction cascade mediates the sensitizing actions of prostaglandins on peptide release from sensory neurons.

Published
1995

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