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2. FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes

Author

de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., Beekman, J. M., de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., and Beekman, J. M.

Abstract

Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. One-sentence summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Published
2023
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3. FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes

Author

Longziekten onderzoek 2, Child Health, Arts Assistenten Longziekten, Beleid & Communicatie, CTI, Translational Neuroscience, Revalidatiegeneeskunde Onderwijs, Longziekten patientenzorg, Afdeling Hartcatheterisatie, Epi Kanker Team A, Longziekten, Speerpunt Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., Beekman, J. M., Longziekten onderzoek 2, Child Health, Arts Assistenten Longziekten, Beleid & Communicatie, CTI, Translational Neuroscience, Revalidatiegeneeskunde Onderwijs, Longziekten patientenzorg, Afdeling Hartcatheterisatie, Epi Kanker Team A, Longziekten, Speerpunt Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., and Beekman, J. M.

Published
2023

4. Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Author

de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., Beekman, J. M., de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., and Beekman, J. M.

Abstract

Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

Published
2022

5. Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Author

Longziekten onderzoek 2, CTI, Longziekten patientenzorg, Speerpunt Child Health, Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., Beekman, J. M., Longziekten onderzoek 2, CTI, Longziekten patientenzorg, Speerpunt Child Health, Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., and Beekman, J. M.

Published
2022

6. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M.S. Kolmert, J. Andersson, L.I. Östling, J. Knowles, R.G. Gómez, C. Ericsson, M. Thörngren, J.-O. Khoonsari, P.E. Dahlén, B. Kupczyk, M. de Meulder, B. Auffray, C. Bakke, P.S. Beghe, B. Bel, E.H. Caruso, M. Chanez, P. Chawes, B. Fowler, S.J. Gaga, M. Geiser, T. Gjomarkaj, M. Horváth, I. Howarth, P.H. Johnston, S.L. Joos, G. Krug, N. Montuschi, P. Musial, J. Niżankowska-Mogilnicka, E. Olsson, H.K. Papi, A. Rabe, K.F. Sandström, T. Shaw, D.E. Siafakas, N.M. Uhlén, M. Riley, J.H. Bates, S. Middelveld, R.J.M. Wheelock, C.E. Chung, K.F. Adcock, I.M. Sterk, P.J. Djukanovic, R. Nilsson, P. Dahlén, S.-E. James, A. Ahmed, H. Balgoma, D. Bansal, A.T. Baribaud, F. Bigler, J. Billing, B. Bisgaard, H. Boedigheimer, M.J. Bønnelykke, K. Brandsma, J. Brinkman, P. Bucchioni, E. Burg, D. Bush, A. Chaiboonchoe, A. Checa, T. Compton, C.H. Corfield, J. Cunoosamy, D. D’Amico, A. Emma, R. Erpenbeck, V.J. Erzen, D. Fichtner, K. Fitch, N. Fleming, L.J. Formaggio, E. Frey, U. Gahlemann, M. Goss, V. Guo, Y.-K. Hashimoto, S. Haughney, J. Hedlin, G. Hekking, P.-P.W. Higenbottam, T. Hohlfeld, J.M. Holweg, C.T.J. Knox, A.J. Konradsen, J. Lazarinis, N. Lefaudeux, D. Li, T. Loza, M.J. Lutter, R. Manta, A. Masefield, S. Matthews, J.G. Mazein, A. Meiser, A. Miralpeix, M. Mores, N. Murray, C.S. Myles, D. Naz, S. Nordlund, B. Pahus, L. Pandis, I. Pavlidis, S. Postle, A. Powel, P. Rao, N. Reinke, S. Roberts, A. Roberts, G. Rowe, A. Schofield, J.P.R. Seibold, W. Selby, A. Sigmund, R. Singer, F. Sjödin, M. Skipp, P.J. Sousa, A.R. Sun, K. Thornton, B. Uddin, M. van Aalderen, W.M. van Geest, M. Vestbo, J. Vissing, N.H. Wagener, A.H. Wagers, S.S. Weiszhart, Z. Wheelock, C.E. Wheelock, Å. Wilson, S.J. Yasinska, V. Brusselle, G.G. Campbell, D.A. Contoli, M. Damm, K. de Rudder, I. Delin, I. Devautour, C. Duplaga, M. Eduards, M. Ek, A. Ekström, T. Figiel, E. Gaber, F. Gauw, S. Gawlewicz-Mroczka, A. Gerding, D. Haque, S. Hewitt, L. Hiemstra, P.S. Holgate, S.T. Holloway, J. Kania, A. Kanniess, F. Karlsson, Ö. Kips, J.C. Kumlin, M. Lantz, A.-S. Lazarinis, N. Magnussen, H. Mallia, P. Martling, I. Meziane, L. Oikonomidou, E. Olsson, M. Pace, E. Papadopouli, E. Papadopoulos, N. Plataki, M. Profita, M. Reinius, L.E. Richter, K. Robinson, D.S. Romagnoli, M. Samara, K. Schelfhout, V. Skedinger, M. Stamataki, E. ten Brinke, A. Vachier, I. Wallén-Nielsen, E. van Veen, I. Weersink, E. Wilson, S.J. Yasinska, V. Zervas, E. Ziolkowska-Graca, B. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group BIOAIR (Longitudinal Assessment of Clinical Course Biomarkers in Severe Chronic Airway Disease) Consortium

Abstract

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved.

Published
2022

7. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M. S., Kolmert, J., Andersson, L. I., Ostling, J., Knowles, R. G., Gomez, C., Ericsson, M., Thorngren, J. -O., Khoonsari, P. E., Dahlen, B., Kupczyk, M., de Meulder, B., Auffray, C., Bakke, P. S., Beghe, Bianca, Bel, E. H., Caruso, M., Chanez, P., Chawes, B., Fowler, S. J., Gaga, M., Geiser, T., Gjomarkaj, M., Horvath, I., Howarth, P. H., Johnston, S. L., Joos, G., Krug, N., Montuschi, P., Musial, J., Nizankowska-Mogilnicka, E., Olsson, H. K., Papi, A., Rabe, K. F., Sandstrom, T., Shaw, D. E., Siafakas, N. M., Uhlen, M., Riley, J. H., Bates, S., Middelveld, R. J. M., Wheelock, C. E., Chung, K. F., Adcock, I. M., Sterk, P. J., Djukanovic, R., Nilsson, P., Dahlen, S. -E., James, A., Ahmed, H., Balgoma, D., Bansal, A. T., Baribaud, F., Bigler, J., Billing, B., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Chaiboonchoe, A., Checa, T., Compton, C. H., Corfield, J., Cunoosamy, D., D'Amico, A., Emma, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Frey, U., Gahlemann, M., Goss, V., Guo, Y. -K., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. -P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C. T. J., Knox, A. J., Konradsen, J., Lazarinis, N., Lefaudeux, D., Li, T., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Miralpeix, M., Mores, N., Murray, C. S., Myles, D., Naz, S., Nordlund, B., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Rao, N., Reinke, S., Roberts, A., Roberts, G., Rowe, A., Schofield, J. P. R., Seibold, W., Selby, A., Sigmund, R., Singer, F., Sjodin, M., Skipp, P. J., Sousa, A. R., Sun, K., Thornton, B., Uddin, M., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, A., Wilson, S. J., Yasinska, V., Brusselle, G. G., Campbell, D. A., Contoli, M., Damm, K., de Rudder, I., Delin, I., Devautour, C., Duplaga, M., Eduards, M., Ek, A., Ekstrom, T., Figiel, E., Gaber, F., Gauw, S., Gawlewicz-Mroczka, A., Gerding, D., Haque, S., Hewitt, L., Hiemstra, P. S., Holgate, S. T., Holloway, J., Kania, A., Kanniess, F., Karlsson, O., Kips, J. C., Kumlin, M., Lantz, A. -S., Magnussen, H., Mallia, P., Martling, I., Meziane, L., Oikonomidou, E., Olsson, M., Pace, E., Papadopouli, E., Papadopoulos, N., Plataki, M., Profita, M., Reinius, L. E., Richter, K., Robinson, D. S., Romagnoli, M., Samara, K., Schelfhout, V., Skedinger, M., Stamataki, E., ten Brinke, A., Vachier, I., Wallen-Nielsen, E., van Veen, I., Weersink, E., Zervas, E., and Ziolkowska-Graca, B.

Subjects
Blood Proteins, Humans, Inflammation, Proteomics, Severity of Illness Index, Steroids, Asthma, Quality of Life
Published
2022

8. 665: Forskolin-induced intestinal organoid swelling predicts long-term cystic fibrosis disease progression

Author

Muilwijk, D., primary, de Poel, E., additional, van Mourik, P., additional, Suen, S., additional, Vonk, A., additional, Brunsveld, J., additional, Kruisselbrink, E., additional, Oppelaar, H., additional, Hagemeijer, M., additional, Berkers, G., additional, de Winter-de Groot, K., additional, Michel, S., additional, Jans, S., additional, van Panhuis, H., additional, van der Eerden, M., additional, van der Meer, R., additional, Roukema, J., additional, Dompeling, E., additional, Weersink, E., additional, Koppelman, G., additional, Vries, R., additional, Zomer-van Ommen, D., additional, Eijkemans, R., additional, van der Ent, C., additional, and Beekman, J., additional

Published
2021
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9. Characteristics and treatment regimens across ERS SHARP severe asthma registries

Author

van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., Ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-van der Zee, A. H., Nucera, Eleonora, Nucera E (ORCID:0000-0002-0565-7680), van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., Ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-van der Zee, A. H., Nucera, Eleonora, and Nucera E (ORCID:0000-0002-0565-7680)

Abstract

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Published
2020

10. Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma

Author

Onderzoek Longziekten, MS MDL 1, Longziekten, Infection & Immunity, de Nijs, S B, Krop, E J M, Portengen, L, Rijssenbeek-Nouwens, L H, de Vries, D, Weersink, E J M, Heijerman, H G M, Heederik, D J J, Lammers, J W J, Onderzoek Longziekten, MS MDL 1, Longziekten, Infection & Immunity, de Nijs, S B, Krop, E J M, Portengen, L, Rijssenbeek-Nouwens, L H, de Vries, D, Weersink, E J M, Heijerman, H G M, Heederik, D J J, and Lammers, J W J

Published
2020

12. Inhaled fluticasone

Author

WEERSINK, E J M, MEIJER, R J, KERSTJENS, H A M, and POSTMA, D S

Published
2000

16. Frequent exacerbators - a distinct phenotype of severe asthma

Author

Kupczyk, M. ten Brinke, A. Sterk, P.J. Bel, E.H. Papi, A. Chanez, P. Nizankowska-Mogilnicka, E. Gjomarkaj, M. Gaga, M. Brusselle, G. Dahlén, B. Dahlén, S.-E. Weersink, E. Papadopoulos, N. Oikonomidou, E. Zervas, E. Contoli, M. Pauwels, R.A. Joos, G.F. de Rudder, I. Schelfhout, V. Richter, K. Gerding, D. Magnussen, H. Siafakas, N.M. Tzortzaki, E. Samara, K. Plataki, M. Papadopouli, E. Szczeklik, A. Ziolkowska-Graca, B. Kania, A. Gawlewicz-Mroczka, A. Duplaga, M. Figiel, E. Rabe, K.F. Hiemstra, P.S. Gauw, S. van Veen, I. Kips, J.C. Johnston, S.L. Mallia, P. Campbell, D.A. Robinson, D.S. Kanniess, F. Fabbri, L.M. Romagnoli, M. Vachier, I. Devautour, C. Meziane, L. Vignola, A.M. Pace, E. Profita, M. Holgate, S.T. Howarth, P.H. Wilson, S.J. Hewitt, L. Holoway, J.

Abstract

Background: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. Objective: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. Methods: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. Results: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 μg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1/FVC ratio (-0.07 vs. -0.01 ΔFEV1/FVC, frequent vs. non-frequent, respectively, P 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). Conclusion and Clinical Relevance: We were able to distinguish and characterize a subphenotype of asthma subjects - frequent exacerbators - who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice. © 2013 John Wiley & Sons Ltd.

Published
2014

19. Detection of exacerbations in asthma based on electronic diary data : results from the 1-year prospective BIOAIR study

Author

Kupczyk, M., Haque, S., Sterk, P. J., Nizankowska-Mogilnicka, E., Papi, A., Bel, E. H., Chanez, P., Dahlen, B., Gaga, M., Gjomarkaj, M., Howarth, P. H., Johnston, S. L., Joos, G. F., Kanniess, F., Tzortzaki, E., James, A., Middelveld, R. J. M., Dahlen, S.-E., Weersink, E., Papadopoulos, N., Oikonomidou, E., Zervas, E., Contoli, M., Pauwels, R. A., Brusselle, G., de Rudder, I., Schelfhout, V., Richter, K., Gerding, D., Magnussen, H., Siafakas, N. M., Samara, K., Plataki, M., Papadopouli, E., Szczeklik, A., Ziolkowska-Graca, B., Kania, A., Gawlewicz-Mroczka, A., Duplaga, M., Figiel, E., Rabe, K. F., Hiemstra, P. S., Gauw, S., van Veen, I., Kips, J. C., Mallia, P., Campbell, D. A., Robinson, D. S., Fabbri, L. M., Romagnoli, M., Vachier, I., Devautour, C., Meziane, L., Maurizio Vignola, A., Pace, E., Profita, M., Holgate, S. T., Wilson, S. J., Hewitt, L., Holoway, J., Damm, K., Delin, I., Eduards, M., Ek, A., Ekstrom, T., Gulich, A., Johansson, L. E., Karlsson, O., Kumlin, M., Martling, I., Skedinger, M., Amsterdam institute for Infection and Immunity, and Pulmonology

Subjects
2. Zero hunger, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Exacerbation, business.industry, medicine.disease, Electronic diary, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Asthma Control Questionnaire, medicine, Sputum, Medical history, 030212 general & internal medicine, medicine.symptom, business, Body mass index, Lung function, Asthma
Abstract

Background Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. Methods In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. Results Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index >25 and low quality of life (St George9s Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p Conclusions Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.

Published
2013

20. Inhaled fluticasone

Author

POLOSA, R., WEERSINK, E, MEIJER, R, KERSTJENS, H, and POSTMA, D

Subjects
Pulmonary and Respiratory Medicine, Letters to the Editor
Published
2000

21. A case-control study of the relation between plasma selenium and asthma in European populations : a GAL2EN project

Author

Burney, P., Potts, J., Makowska, J., Kowalski, M., Phillips, J., Gnatiuc, L., Shaheen, S., Joos, G., Van Cauwenberge, P., van Zele, T., Verbruggen, K., van Durme, Y., Derudder, I., Wohrl, S., Godnic-Cvar, J., Salameh, B., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Renz, H., Al-Fakhri, N., Kosche, B., Hildenberg, A., Papadopoulos, N. G., Xepapadaki, P., Zannikos, K., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Bresciani, M., Gramiccioni, C., Fokkens, W., Weersink, E. J. M., Carlsen, K-H., Bakkeheim, E., Loureiro, C., Villanueva, C. M., Sanjuas, C., Zock, J-P., Lundback, B., Janson, Christer, Burney, P., Potts, J., Makowska, J., Kowalski, M., Phillips, J., Gnatiuc, L., Shaheen, S., Joos, G., Van Cauwenberge, P., van Zele, T., Verbruggen, K., van Durme, Y., Derudder, I., Wohrl, S., Godnic-Cvar, J., Salameh, B., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Renz, H., Al-Fakhri, N., Kosche, B., Hildenberg, A., Papadopoulos, N. G., Xepapadaki, P., Zannikos, K., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Bresciani, M., Gramiccioni, C., Fokkens, W., Weersink, E. J. M., Carlsen, K-H., Bakkeheim, E., Loureiro, C., Villanueva, C. M., Sanjuas, C., Zock, J-P., Lundback, B., and Janson, Christer

Abstract

BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

Published
2008
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22. The relation between paracetamol use and asthma : a GA2LEN European case-control study

Author

Shaheen, S., Potts, J., Gnatiuc, L., Makowska, J., Kowalski, M. L., Joos, G., van Zele, T., van Durme, Y., De Rudder, I., Wöhrl, S., Godnic-Cvar, J., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Fokkens, W., Weersink, E. J. M., Loureiro, C., Todo-Bom, A., Villanueva, C. M., Sanjuas, C., Zock, J-P., Janson, Christer, Burney, P., Shaheen, S., Potts, J., Gnatiuc, L., Makowska, J., Kowalski, M. L., Joos, G., van Zele, T., van Durme, Y., De Rudder, I., Wöhrl, S., Godnic-Cvar, J., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Fokkens, W., Weersink, E. J. M., Loureiro, C., Todo-Bom, A., Villanueva, C. M., Sanjuas, C., Zock, J-P., Janson, Christer, and Burney, P.

Abstract

Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.

Published
2008
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24. The relation between paracetamol use and asthma: a GA2LEN European case-control study

Author

Shaheen, S., primary, Potts, J., additional, Gnatiuc, L., additional, Makowska, J., additional, Kowalski, M. L., additional, Joos, G., additional, van Zele, T., additional, van Durme, Y., additional, De Rudder, I., additional, Wohrl, S., additional, Godnic-Cvar, J., additional, Skadhauge, L., additional, Thomsen, G., additional, Zuberbier, T., additional, Bergmann, K. C., additional, Heinzerling, L., additional, Gjomarkaj, M., additional, Bruno, A., additional, Pace, E., additional, Bonini, S., additional, Fokkens, W., additional, Weersink, E. J. M., additional, Loureiro, C., additional, Todo-Bom, A., additional, Villanueva, C. M., additional, Sanjuas, C., additional, Zock, J-P., additional, Janson, C., additional, and Burney, P., additional

Published
2008
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26. Detection of Airway Colonization by Aspergillus fumigatusby Use of Electronic Nose Technology in Patients with Cystic Fibrosis

Author

de Heer, K., Kok, M. G. M., Fens, N., Weersink, E. J. M., Zwinderman, A. H., van der Schee, M. P. C., Visser, C. E., van Oers, M. H. J., and Sterk, P. J.

Abstract

ABSTRACTCurrently, there is no noninvasive test that can reliably diagnose early invasive pulmonary aspergillosis (IA). An electronic nose (eNose) can discriminate various lung diseases through an analysis of exhaled volatile organic compounds. We recently published a proof-of-principle study showing that patients with prolonged chemotherapy-induced neutropenia and IA have a distinct exhaled breath profile (or breathprint) that can be discriminated with an eNose. An eNose is cheap and noninvasive, and it yields results within minutes. We determined whether Aspergillus fumigatuscolonization may also be detected with an eNose in cystic fibrosis (CF) patients. Exhaled breath samples of 27 CF patients were analyzed with a Cyranose 320. Culture of sputum samples defined the A. fumigatuscolonization status. eNose data were classified using canonical discriminant analysis after principal component reduction. Our primary outcome was cross-validated accuracy, defined as the percentage of correctly classified subjects using the leave-one-out method. The Pvalue was calculated by the generation of 100,000 random alternative classifications. Nine of the 27 subjects were colonized by A. fumigatus. In total, 3 subjects were misclassified, resulting in a cross-validated accuracy of the Cyranose detecting IA of 89% (P= 0.004; sensitivity, 78%; specificity, 94%). Receiver operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.89. The results indicate that A. fumigatuscolonization leads to a distinctive breathprint in CF patients. The present proof-of-concept data merit external validation and monitoring studies.

Published
2015
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30. Characteristics and treatment regimens across ERS SHARP severe asthma registries

Author

van Bragt, JJMH, Adcock, IM, Bel, EHD, Braunstahl, GJ, ten Brinke, A, Busby, J, Canonica, GW, Cao, H, Chung, KF, Csoma, Z, Dahlen, B, Davin, E, Hansen, S, Heffler, E, Horvath, I, Korn, S, Kots, M, Kuna, P, Kwon, N, Louis, R, Plaza, V, Porsbjerg, C, Ramos-Barbon, D, Richards, LB, Skrgat, S, Sont, JK, Vijverberg, SJH, Weersink, EJM, Yasinska, V, Wagers, SS, Djukanovic, R, Maitland-van der Zee, AH, Abenhardt, B, Adler, J, Alfonso, R, Ali, R, Alkameh, S, Sanchez, CA, Alvares, L, Anderson, G, Assing, K, Ayre, S, Becker, J, Bergmann, K, Bieksiene, K, Bjerring, N, Blasi, F, Bloemen, P, Blum, H, Boing, S, Bonavia, M, Bossios, A, Bourdin, A, Brons, A, Brusselle, G, Buis, J, Caiaffa, M, Calabrese, C, Camiciottoli, G, Caruso, C, Martinez, MC, Centanni, S, Serrano, CC, Corsico, A, Cosmi, L, Costantino, M, Costello, R, Crimi, N, Dahlen, S, D'Amato, M, Davies, D, Piqueras, FDGC, Decarlo, G, Deimling, A, Del Giacco, S, Campos, RD, Djandji, M, Doberer, D, Dupont, L, Dyett, K, Edelbaher, N, Edelmann, M, Ehmann, R, Ekberg-Jansson, A, Farsi, A, Favero, E, Feimer, J, Fletcher, M, Foschino, B, Frankemolle, B, Gaga, M, Gappa, M, de Pedro, JG, Rivero, JG, Gasplmayr, M, Gebhardt, R, Geldmacher, H, Geltner, C, Gerstlauer, M, Gibson, T, Giuseppe, G, Gogoll, C, Grimm-Sachs, V, Grisle, I, Grun, B, Grunewaldt, A, Guarnieri, G, Blanco, JG, Hamelmann, E, Hamerlijnck, D, Hammers-Reinhard, A, Hanon, S, Harzheim, D, Heaney, L, Hellmich, S, Herden, M, Hering, T, Herth, F, Hilberg, O, Howarth, P, Hubatsch, M, Humbert, M, Husemann, K, Idzko, M, Jackson, D, Jandl, M, Jaumont, X, Joos, G, Jost, M, Juch, M, Kabesch, M, Kaiser-Labusch, P, Kardos, P, Kassner, F, Keeley, T, Kerr, W, Kirschner, J, Klimek, L, Koca, M, Koczulla, R, Koerner-Rettberg, C, Kopac, P, Kronsbein, J, Lipinska, IK, Langer, M, Langeveld, B, Lantz, A, Lazarinis, N, Lazic, Z, Lehtimaki, L, Leuppi, J, Lombardi, C, Lommatzsch, M, Lopez-Vina, A, Luca, R, Ludviksdottir, D, Luttecke-Hecht, C, Macchia, L, Magni, T, Rivera, CM, Mastoridis, P, Mazza, F, Menzella, F, Menzies-Gow, A, Michils, A, Mihaltan, F, Milanese, M, Milger-Kneidinger, K, Molinska, J, Montagna, I, Montuschi, P, Mulleneisen, N, Esquerre, MM, Nanzer-Kelly, A, Nenasheva, N, Neurohr, C, Nucera, E, Otker, J, Oud, K, Paggiaro, P, Parente, R, Parkinson, J, Passalacqua, G, Patberg, N, Patella, V, Patino, O, Paulsson, T, Peche, R, Pelaia, G, Peress, E, de Llano, LP, Pfeffer, P, Pfister, P, Pilette, C, Sierra, CP, Pini, L, Powitz, F, Ranger, T, Rasmussen, L, Rasmussen, K, Rezelj, M, Ricciardi, L, Ricciardolo, F, Ridolo, E, Rijssenbeek-Nouwens, L, Rolla, G, Ribate, DR, Rudiger, S, Safioti, G, Sandstrom, T, Santus, P, Sauer, R, Schauerte, G, Schipmann, R, Schleich, F, Schmid, J, Schmidt, F, Schmidt, O, Schmitz, M, Schrag, T, Schroer, S, Schultz, K, Schulz, C, Scichilone, N, Sedlak, V, Selb, J, Senna, G, Sergejeva, S, Pariente, JS, Sichau, M, Simona, D, Singer, A, Skowasch, D, Smeenk, F, Smith, S, Solidoro, P, Spadaro, G, Spanevello, A, Stefansdottir, M, Steinmetz, K, Steiss, J, Stephan, M, Stieglitz, S, Suhling, H, Taube, C, Yavuz, ST, Tudoric, N, Ulrik, C, van de Ven, M, van den Elshout, F, Van Dyke, M, Van Nederveen-Bendien, S, van Veen, I, Vandenplas, O, Velthove, K, Vianello, A, Vogelberg, C, Wallen-Nielsen, E, Weersink, EJ, Wisskirchen, T, Yacoub, M, Yancey, S, Zappa, M, Zielen, S, Zimmermann, C, Zimmermann, R, Graduate School, AII - Inflammatory diseases, APH - Personalized Medicine, Pulmonology, Paediatric Pulmonology, van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-Van der Zee, A. H., Abenhardt, B., Adler, J., Alfonso, R., Ali, R., Alkameh, S., Almonacid Sanchez, C., Alvares, L., Anderson, G., Assing, K., Ayre, S., Becker, J., Bergmann, K., Bieksiene, K., Bjerring, N., Blasi, F., Bloemen, P., Blum, H., Boing, S., Bonavia, M., Bossios, A., Bourdin, A., Brons, A., Brusselle, G., Buis, J., Caiaffa, M., Calabrese, C., Camiciottoli, G., Caruso, C., Castilla Martinez, M., Centanni, S., Cisneros Serrano, C., Corsico, A., Cosmi, L., Costantino, M., Costello, R., Crimi, N., Dahlen, S., D'Amato, M., Davies, D., de Borja Garcia-Cosio Piqueras, F., Decarlo, G., Deimling, A., Del Giacco, S., Diaz Campos, R., Djandji, M., Doberer, D., Dupont, L., Dyett, K., Edelbaher, N., Edelmann, M., Ehmann, R., Ekberg-Jansson, A., Farsi, A., Favero, E., Feimer, J., Fletcher, M., Foschino, B., Frankemolle, B., Gaga, M., Gappa, M., Garcia de Pedro, J., Garcia Rivero, J., Gasplmayr, M., Gebhardt, R., Geldmacher, H., Geltner, C., Gerstlauer, M., Gibson, T., Giuseppe, G., Gogoll, C., Grimm-Sachs, V., Grisle, I., Grun, B., Grunewaldt, A., Guarnieri, G., Gullon Blanco, J., Hamelmann, E., Hamerlijnck, D., Hammers-Reinhard, A., Hanon, S., Harzheim, D., Heaney, L., Hellmich, S., Herden, M., Hering, T., Herth, F., Hilberg, O., Howarth, P., Hubatsch, M., Humbert, M., Husemann, K., Idzko, M., Jackson, D., Jandl, M., Jaumont, X., Joos, G., Jost, M., Juch, M., Kabesch, M., Kaiser-Labusch, P., Kardos, P., Kassner, F., Keeley, T., Kerr, W., Kirschner, J., Klimek, L., Koca, M., Koczulla, R., Koerner-Rettberg, C., Kopac, P., Kronsbein, J., Kuprys Lipinska, I., Langer, M., Langeveld, B., Lantz, A., Lazarinis, N., Lazic, Z., Lehtimaki, L., Leuppi, J., Lombardi, C., Lommatzsch, M., Lopez-Vina, A., Luca, R., Ludviksdottir, D., Luttecke-Hecht, C., Macchia, L., Magni, T., Martinez Rivera, C., Mastoridis, P., Mazza, F., Menzella, F., Menzies-Gow, A., Michils, A., Mihalthan, F., Milanese, M., Milger-Kneidinger, K., Molinska, J., Montagna, I., Montuschi, P., Mulleneisen, N., Munoz Esquerre, M., Nanzer-Kelly, A., Nenasheva, N., Neurohr, C., Nucera, E., Otker, J., Oud, K., Paggiaro, P., Parente, R., Parkinson, J., Passalacqua, G., Patberg, N., Patella, V., Patino, O., Paulsson, T., Peche, R., Pelaia, G., Peress, E., Perez de Llano, L., Pfeffer, P., Pfister, P., Pilette, C., Pinedo Sierra, C., Pini, L., Powitz, F., Ranger, T., Rasmussen, L., Rasmussen, K., Rezelj, M., Ricciardi, L., Ricciardolo, F., Ridolo, E., Rijssenbeek-Nouwens, L., Rolla, G., Romero Ribate, D., Rudiger, S., Safioti, G., Sandstrom, T., Santus, P., Sauer, R., Schauerte, G., Schipmann, R., Schleich, F., Schmid, J., Schmidt, F., Schmidt, O., Schmitz, M., Schrag, T., Schroer, S., Schultz, K., Schulz, C., Scichilone, N., Sedlak, V., Selb, J., Senna, G., Sergejeva, S., Serrano Pariente, J., Sichau, M., Simona, D., Singer, A., Skowasch, D., Smeenk, F., Smith, S., Solidoro, P., Spadaro, G., Spanevello, A., Stefansdottir, M., Steinmetz, K., Steiss, J., Stephan, M., Stieglitz, S., Suhling, H., Taube, C., Tolga Yavuz, S., Tudoric, N., Ulrik, C., van de Ven, M., van den Elshout, F., van Dyke, M., van Nederveen-Bendien, S., van Veen, I., Vandenplas, O., Velthove, K., Vianello, A., Vogelberg, C., Wallen-Nielsen, E., Wisskirchen, T., Yacoub, M., Yancey, S., Zappa, M., Zielen, S., Zimmermann, C., Zimmermann, R., UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - (MGD) Service de pneumologie, van Bragt J.J.M.H., Adcock I.M., Bel E.H.D., Braunstahl G.-J., ten Brinke A., Busby J., Canonica G.W., Cao H., Chung K.F., Csoma Z., Dahlen B., Davin E., Hansen S., Heffler E., Horvath I., Korn S., Kots M., Kuna P., Kwon N., Louis R., Plaza V., Porsbjerg C., Ramos-Barbon D., Richards L.B., Skrgat S., Sont J.K., Vijverberg S.J.H., Weersink E.J.M., Yasinska V., Wagers S.S., Djukanovic R., Maitland-Van der Zee A.H., Abenhardt B., Adler J., Alfonso R., Ali R., Alkameh S., Almonacid Sanchez C., Alvares L., Anderson G., Assing K., Ayre S., Becker J., Bergmann K., Bieksiene K., Bjerring N., Blasi F., Bloemen P., Blum H., Boing S., Bonavia M., Bossios A., Bourdin A., Brons A., Brusselle G., Buis J., Caiaffa M., Calabrese C., Camiciottoli G., Caruso C., Castilla Martinez M., Centanni S., Cisneros Serrano C., Corsico A., Cosmi L., Costantino M., Costello R., Crimi N., Dahlen S., D'Amato M., Davies D., de Borja Garcia-Cosio Piqueras F., Decarlo G., Deimling A., Del Giacco S., Diaz Campos R., Djandji M., Doberer D., Dupont L., Dyett K., Edelbaher N., Edelmann M., Ehmann R., Ekberg-Jansson A., Farsi A., Favero E., Feimer J., Fletcher M., Foschino B., Frankemolle B., Gaga M., Gappa M., Garcia de Pedro J., Garcia Rivero J., Gasplmayr M., Gebhardt R., Geldmacher H., Geltner C., Gerstlauer M., Gibson T., Giuseppe G., Gogoll C., Grimm-Sachs V., Grisle I., Grun B., Grunewaldt A., Guarnieri G., Gullon Blanco J., Hamelmann E., Hamerlijnck D., Hammers-Reinhard A., Hanon S., Harzheim D., Heaney L., Hellmich S., Herden M., Hering T., Herth F., Hilberg O., Howarth P., Hubatsch M., Humbert M., Husemann K., Idzko M., Jackson D., Jandl M., Jaumont X., Joos G., Jost M., Juch M., Kabesch M., Kaiser-Labusch P., Kardos P., Kassner F., Keeley T., Kerr W., Kirschner J., Klimek L., Koca M., Koczulla R., Koerner-Rettberg C., Kopac P., Kronsbein J., Kuprys Lipinska I., Langer M., Langeveld B., Lantz A., Lazarinis N., Lazic Z., Lehtimaki L., Leuppi J., Lombardi C., Lommatzsch M., Lopez-Vina A., Luca R., Ludviksdottir D., Luttecke-Hecht C., Macchia L., Magni T., Martinez Rivera C., Mastoridis P., Mazza F., Menzella F., Menzies-Gow A., Michils A., Mihalthan F., Milanese M., Milger-Kneidinger K., Molinska J., Montagna I., Montuschi P., Mulleneisen N., Munoz Esquerre M., Nanzer-Kelly A., Nenasheva N., Neurohr C., Nucera E., Otker J., Oud K., Paggiaro P., Parente R., Parkinson J., Passalacqua G., Patberg N., Patella V., Patino O., Paulsson T., Peche R., Pelaia G., Peress E., Perez de Llano L., Pfeffer P., Pfister P., Pilette C., Pinedo Sierra C., Pini L., Powitz F., Ranger T., Rasmussen L., Rasmussen K., Rezelj M., Ricciardi L., Ricciardolo F., Ridolo E., Rijssenbeek-Nouwens L., Rolla G., Romero Ribate D., Rudiger S., Safioti G., Sandstrom T., Santus P., Sauer R., Schauerte G., Schipmann R., Schleich F., Schmid J., Schmidt F., Schmidt O., Schmitz M., Schrag T., Schroer S., Schultz K., Schulz C., Scichilone N., Sedlak V., Selb J., Senna G., Sergejeva S., Serrano Pariente J., Sichau M., Simona D., Singer A., Skowasch D., Smeenk F., Smith S., Solidoro P., Spadaro G., Spanevello A., Stefansdottir M., Steinmetz K., Steiss J., Stephan M., Stieglitz S., Suhling H., Taube C., Tolga Yavuz S., Tudoric N., Ulrik C., van de Ven M., van den Elshout F., van Dyke M., van Nederveen-Bendien S., van Veen I., Vandenplas O., Velthove K., Vianello A., Vogelberg C., Wallen-Nielsen E., Wisskirchen T., Yacoub M., Yancey S., Zappa M., Zielen S., Zimmermann C., Zimmermann R., Amsterdam UMC, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands., Medical Centre Leeuwarden, Queen's University [Belfast] (QUB), Humanitas University [Milan] (Hunimed), Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, Korányi National Institute of Pulmonology (OKPI), Karolinska University Hospital [Stockholm], The European Lung Foundation (ELF), Bispebjerg and Frederiksberg Hospitals, Humanitas Clinical and Research Center [Rozzano, Milan, Italy], University Medical Center of the Johannes Gutenberg-University Mainz, Chiesi Farmaceutici, Medical University of Łódź (MUL), GlaxoSmithKline, Brentford, Middlesex, Centre Hospitalier Universitaire de Liège (CHU-Liège), Hospital de la Santa Creu i Sant Pau, Copenhagen University Hospital, Respiratory and Allergic Diseases [Golnik, Slovenia], University Clinic of Respiratory and Allergic Diseases Golnik, Leiden University Medical Center (LUMC), Biosci Consulting, University Hospital Southampton NHS Foundation Trust, SHARP Clinical Research, Hôpital Arnaud de Villeneuve [CHRU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Severe asthma, Pediatrics, MESH: Registries, MESH: Asthma, Cross-sectional study, Respiratory System, Medizin, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, MESH: Belgium, Belgium, Medicine research, Anti-Asthmatic Agents, Registries, 030212 general & internal medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, 10. No inequality, 11 Medical and Health Sciences, Netherlands, 2. Zero hunger, education.field_of_study, SHARP CRC, MESH: Administration, Inhalation, MESH: Anti-Asthmatic Agents, 3. Good health, Europe, Italy, MESH: Poland, MESH: Sweden, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, MESH: Hungary, Population, Investigació mèdica, Settore MED/10 - Malattie Dell'Apparato Respiratorio, 03 medical and health sciences, MESH: Cross-Sectional Studies, Administration, Inhalation, MESH: Spain, medicine, Humans, education, Asma, Retrospective Studies, Asthma, Sweden, Hungary, MESH: Humans, business.industry, Settore MED/09 - MEDICINA INTERNA, MESH: Italy, MESH: Retrospective Studies, Retrospective cohort study, Original Articles, asthma, medicine.disease, Clinical trial, Cross-Sectional Studies, Clinical research, 030228 respiratory system, Spain, MESH: Netherlands, MESH: Europe, Poland, business, Body mass index, Mepolizumab
Abstract

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Published
2019
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31. Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids.

Author

de Poel E, Spelier S, Suen SWF, Kruisselbrink E, Graeber SY, Mall MA, Weersink EJM, van der Eerden MM, Koppelman GH, van der Ent CK, and Beekman JM

Subjects
Benzodioxoles therapeutic use, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Humans, Mutation, Nonsense Mediated mRNA Decay, Organoids, Codon, Nonsense, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Cystic Fibrosis metabolism
Abstract

Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation., Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs., Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome., Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function., Competing Interests: Declaration of Competing Interest J.M.B. and C.K.v.d.E. are inventors on patent(s) related to the FIS-assay and received financial royalties from 2017 onward. J.M.B report receiving research grant(s) and consultancy fees from various industries, including Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos outside the submitted work. C.K.v.d.E report receiving research grant(s) grant(s) from Vertex Pharmaceuticals (money to institution) outside the submitted work. G.H.K. reports research grants from Vertex Pharmaceuticals, GSK, TEVA, Ubbo Emmius Foundation, European Union, Lung Foundation Netherlands (Money to institution), outside the submitted work. M.A.M. reports research grants and patient recruitment fees for clinical trials from Vertex, for which his institution Charité-Universitätsmedizine Berlin received payment; fees for consulting and advisory board participation from Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Sathera, Sterna Biologicals, and Vertex outside the submitted work. S.Y.G. reports fees for advisory board participation from Chiesi outside the submitted work. All other authors have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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32. Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.

Author

de Nijs SB, Krop EJM, Portengen L, Rijssenbeek-Nouwens LH, de Vries D, Weersink EJM, Heijerman HGM, Heederik DJJ, and Lammers JWJ

Subjects
Adolescent, Adult, Aged, Asthma physiopathology, Disease Progression, Female, Follow-Up Studies, Forced Expiratory Volume, Humans, Linear Models, Male, Middle Aged, Netherlands, Quality of Life, Severity of Illness Index, Switzerland, Time Factors, Treatment Outcome, Young Adult, Altitude, Asthma rehabilitation, Exercise Therapy methods, Lung physiopathology
Abstract

Background: Beneficial effects of pulmonary rehabilitation at high-altitude (HAPR) in patients with severe refractory asthma have been reported earlier, but evidence for the effectiveness is limited., Aim: To investigate the effectiveness of high-altitude pulmonary rehabilitation to comparable treatment at sea-level (LAPR) on patient outcome parameters., Methods: Adults with severe refractory asthma living in The Netherlands were included. Treatment consisted of a 12-week personalized multidisciplinary rehabilitation program either at high-altitude (Davos Switzerland) (n = 93) or in a tertiary lung center at sea-level in The Netherlands (n = 45). At baseline, after treatment, and during 12 months follow-up asthma related quality of life (AQLQ), asthma control (ACQ), pulmonary function and OCS-dose were assessed. Patients could not be randomized resulting in different asthma populations. Groups were compared using linear regression analysis (ANCOVA) adjusted for baseline values, in addition to age, atopy, smoking history, BMI and gender., Results: After treatment, and at 12 months follow-up, improved AQLQ(0.92,p < 0.001 and 0.82,p = 0.001, respectively), ACQ(-0.87,p < 0.001 and -0.69,p = 0.008, respectively) and lower maintenance OCS dose (Unadjusted linear regression analysis-5.29 mg, p = 0.003 and Crude Odds Ratio-1.67, p = 0.003, respectively) were observed in the HAPR-group compared to the LAPR group. Patients receiving HAPR also had less asthma exacerbations (≥1 exacerbation: 20% vs 60%,p < 0.001) and showed improvement in lung function (%predFEV 1 3.4%,p = 0.014) compared to the LAPR group, but at 12 months no differences between groups were observed., Conclusion: HAPR resulted in a larger improvement in patient outcome parameters compared to LAPR, on the long run the improvement in patient reported symptoms and lower maintenance OCS-dose persists. Underlying factors that explain this observed effect need to be investigated., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2020
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33. Predictors of benefit from high-altitude climate therapy in adults with severe asthma.

Author

Hashimoto S, Rijssenbeek-Nouwens LH, Fieten KB, Weersink EJ, and Bel EH

Subjects
Adrenal Cortex Hormones administration & dosage, Adult, Age Factors, Asthma drug therapy, Body Mass Index, Female, Forced Expiratory Volume, Humans, Leukocyte Count, Male, Middle Aged, Prospective Studies, Quality of Life, Severity of Illness Index, Altitude, Asthma physiopathology, Asthma therapy, Climatotherapy, Eosinophils
Abstract

Background: High-altitude climate therapy has been shown to benefit patients with severe asthma but it is not known which patients benefit most from this treatment. In the current study we aimed to identify clinical, functional and inflammatory predictors of favourable outcome of high-altitude climate therapy., Methods: This is a secondary analysis of a prospective cohort including 136 adult patients with a diagnosis of severe refractory asthma, referred to the Dutch Asthma Centre in Davos (1600 metres above sea level), Switzerland. They had assessments of medication usage, asthma-related quality of life (Asthma-related Quality of Life Questionnaire, AQLQ), asthma control, body mass index (BMI), sino-nasal symptoms, fatigue, lung function (forced expiratory volume in one second, FEV1), exercise tolerance, allergy and inflammation (fraction of exhaled nitric oxide, blood eosinophils) at entry and after 12 weeks of treatment. Five clinically relevant outcomes were considered: AQLQ, oral corticosteroid dose, FEV1, body mass index and blood eosinophils. Independent predictors of beneficial outcome were identified by multiple linear regression analysis., Results: Lower blood eosinophil counts (p < 0.01), younger age (p = 0.02) and poorer asthma control (p < 0.01) were independently associated with greater reduction in the dose of oral corticosteroids. Lower fatigue score at baseline (p = 0.01) was associated with greater weight loss (reduction in BMI). Higher levels of total IgE at baseline (p < 0.01), and higher doses of inhaled corticosteroids (p = 0.03) were associated with greater decreases in blood eosinophils. There were no predictors for improvement in AQLQ or FEV1., Conclusions: The beneficial effect of high-altitude climate therapy in adults with severe asthma can be predicted by patient characteristics, such as age, blood eosinophils and degree of asthma control before admission.

Published
2018

34. Health-related quality of life and functional status in end-stage COPD: a longitudinal study.

Author

Habraken JM, van der Wal WM, Ter Riet G, Weersink EJ, Toben F, and Bindels PJ

Subjects
Activities of Daily Living psychology, Aged, Dyspnea physiopathology, Dyspnea psychology, Female, Humans, Longitudinal Studies, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive mortality, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Disease, Chronic Obstructive rehabilitation, Respiratory Function Tests, Severity of Illness Index, Lung physiopathology, Pulmonary Disease, Chronic Obstructive psychology, Quality of Life
Abstract

Since there is still a dearth of information about the end stage of chronic obstructive pulmonary disease (COPD), the main aim of this study was to examine the development of health-related quality of life (HRQoL) and functional status over time in COPD patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV. 82 Dutch COPD patients completed the St George's Respiratory Questionnaire (SGRQ) for HRQoL and the Groningen Activities for Daily Living Restriction Scale (GARS) for functional status every 3 months during the year following enrolment. Survival was followed up to 5 yrs after enrolment. Data were analysed by stratifying the study population into severity subgroups according to the lowest, intermediate and highest tertile of SGRQ and GARS at baseline. Outcome measures were change in SGRQ and GARS scores over time and survival time. In the majority of patients, scores on the SGRQ and GARS declined gradually over time. In the subgroup of 32 patients that died within 2 yrs of enrolment, these scores also declined gradually, without steep deteriorations. In patients with end-stage COPD, HRQoL and functional status deteriorated gradually over time, indicating that clinicians did not gain much additional support for differentiating the end stage of COPD by considering HRQoL and functional status using the SGRQ and GARS.

Published
2011
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35. T-Cell repertoire in the blood and lungs of atopic asthmatics before and after ragweed challenge.

Author

Yurovsky VV, Weersink EJ, Meltzer SS, Moore WC, Postma DS, Bleecker ER, and White B

Subjects
Adult, Allergens immunology, Animals, Asthma blood, Bronchoalveolar Lavage Fluid immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cats, Female, Humans, Hypersensitivity, Immediate blood, Male, Mites immunology, Pollen immunology, Sequence Analysis, DNA, Asthma immunology, Hypersensitivity, Immediate immunology, Lung immunology, Receptors, Antigen, T-Cell, alpha-beta genetics, T-Lymphocytes immunology
Abstract

T cells play a pivotal role in initiating and orchestrating allergic responses in asthma. The goal of this work was to learn whether ragweed challenge in the lungs alters the T-cell repertoire expressed in the blood and lungs of atopic asthmatics. Analyses of cell numbers, differentials, and T-cell subsets in bronchoalveolar lavage (BAL) fluids showed that ragweed challenge was associated with preferential recruitment of CD4+ T cells into the lungs. A reverse transcriptase-polymerase chain reaction (RT-PCR) was used to amplify T-cell receptor (TCR) gene transcripts from unfractionated, CD4+, and CD8+ T cells in blood and BAL fluids. As judged by RT-PCR, the usage of TCR Valpha and Vbeta gene families in BAL fluids was similar to that in blood. Ragweed challenge did not change the levels of expression of these V gene families. The clonality of T cells was estimated by analyzing the diversity of TCR V-(D)-J junctional region nucleotide lengths associated with each Valpha and Vbeta gene family, using sequencing gel electrophoresis. Most V gene families in blood and BAL fluids were associated with multiple junctional region lengths before and after ragweed challenge, indicating polyclonal expression. Some V gene families were expressed in an oligoclonal manner in unfractionated, CD4+, and CD8+ T cells in BAL fluids before ragweed challenge, as indicated by a few predominant junctional region lengths. The majority of these V gene families became polyclonal after challenge, compatible with polyclonal T-cell influx during inflammation immediately after ragweed challenge. However, some V gene families became oligoclonal or developed a new oligoclonal pattern of junctional region lengths in BAL T cells after ragweed challenge. Surprisingly, this occurred in both CD4+ and CD8+ T cells. In one of these instances, DNA sequencing of Vbeta21 junctional regions in CD8+ T cells confirmed a change from polyclonal to oligoclonal expression after ragweed challenge. These findings show that ragweed challenge is associated with polyclonal influx and oligoclonal activation of both CD4+ and CD8+ T cells in the lungs.

Published
1998
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36. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics.

Author

Weersink EJ, van Zomeren EH, Koëter GH, and Postma DS

Subjects
Administration, Inhalation, Adult, Airway Obstruction etiology, Airway Obstruction physiopathology, Albuterol administration & dosage, Albuterol analogs & derivatives, Albuterol therapeutic use, Androstadienes administration & dosage, Androstadienes therapeutic use, Anti-Asthmatic Agents administration & dosage, Anti-Asthmatic Agents therapeutic use, Asthma complications, Asthma drug therapy, Bronchodilator Agents administration & dosage, Bronchodilator Agents therapeutic use, Cognition drug effects, Double-Blind Method, Drug Therapy, Combination, Female, Fluticasone, Humans, Male, Peak Expiratory Flow Rate drug effects, Psychometrics, Salmeterol Xinafoate, Treatment Outcome, Airway Obstruction drug therapy, Asthma physiopathology, Circadian Rhythm physiology, Cognition physiology
Abstract

It has been shown that asthmatics have nocturnal symptoms associated with impaired cognitive performance. We explored more carefully different therapeutic approaches on this performance in relation to lung function in 46 atopics with mild to moderate asthma and with a circadian variation in peak expiratory flow (PEF) > or = 15%. In a double-blind, parallel study they inhaled salmeterol 50 microg or fluticasone 250 microg or a combination of both twice daily for 6 wk. The psychometric tests used informed about focused attention, mental flexibility, concentration, and attention. The results of the psychometric tests were compared with those in healthy control subjects. The PASAT score and the finishing time of the color-word chart subtest were significantly lower in these asthmatics than in the control subjects. Circadian PEF variation was the only independent factor significantly associated with impaired cognitive performance before the treatment period. The three treatment groups were equally effective in reducing circadian PEF variation below 10% and in improving FEV1 and bronchial hyperresponsiveness to methacholine (MCh) both day and night. After 6 wk of therapy, the daytime cognitive performance was improved to levels comparable to those of the healthy control subjects no matter which drug was inhaled. We conclude that a high level of circadian PEF variation (> or = 20%) has been associated with lower daytime cognitive performance in asthmatics. Reduction of circadian PEF variation to below 10% is an important goal of treatment in asthmatics.

Published
1997
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37. The angiotensin converting enzyme inhibitor perindopril improves survival after experimental myocardial infarction in pigs.

Author

Tobé TJ, de Langen CD, Weersink EG, van Wijngaarden J, Bel KJ, de Graeff PA, van Gilst WH, and Wesseling H

Subjects
Animals, Blood Pressure drug effects, Cardiac Output drug effects, Double-Blind Method, Electric Stimulation, Electrocardiography drug effects, Heart Rate drug effects, Indoles administration & dosage, Male, Myocardial Infarction physiopathology, Myocardial Reperfusion, Perindopril, Random Allocation, Swine, Tachycardia drug therapy, Angiotensin-Converting Enzyme Inhibitors pharmacology, Heart physiopathology, Hemodynamics drug effects, Indoles pharmacology, Myocardial Infarction drug therapy
Abstract

In this randomized, blinded study the effect of the angiotensin converting enzyme inhibitor perindopril on electrical stability after myocardial infarction in pigs was compared to placebo. The left anterior descending artery was occluded for 45 min. Perindoprilat (0.06 mg/kg, n = 12) or saline (n = 12) was injected 15 min before reperfusion. Treatment was continued till day 13 with perindopril (12 mg, once daily) or placebo. At day 14 an electrophysiologic study was performed. The release of creatine phosphokinase did not differ significantly. During the subsequent days, seven of 12 placebo-treated pigs died (six within 24 h), whereas two of the 12 perindopril-treated pigs died (one within 24 h; p less than 0.04). Sustained ventricular tachycardia was inducible in one of five placebo-treated pigs versus three of 10 perindopril-treated survivors (NS). Late potentials had developed in one placebo-treated pig but not in pigs that received perindopril. Characteristics of infarct border zone heterogeneity (percentages of a reference electrode in viable myocardium) such as a dispersion of current thresholds (127 +/- 96 vs. 238 +/- 463% in perindopril-treated pigs, NS) and refractoriness (9.8 +/- 8.4 vs. 11.9 +/- 6.0% in perindopril-treated pigs, NS) were comparable. This treatment with perindopril significantly improved survival while electrical stability was comparable between survivors. The latter indicates that a comparable electrical stability 2 weeks after myocardial infarction is obtained in perindopril-treated pigs at a significantly higher survival rate.

Published
1992

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