Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients
Identifieur interne : 000152 ( Pmc/Corpus ); précédent : 000151; suivant : 000153Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients
Auteurs : Eiichiro Nagata ; Mieko Ogino ; Kounosuke Iwamoto ; Yasuhisa Kitagawa ; Yasuo Iwasaki ; Fumihito Yoshii ; Joh-E. IkedaSource :
- PLoS ONE [ 1932-6203 ] ; 2016.
Abstract
Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.
A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.
The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing.
Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.
BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.
UMIN Clinical Trials
Url:
DOI: 10.1371/journal.pone.0149509
PubMed: 26910108
PubMed Central: 4765990
Links to Exploration step
PMC:4765990Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients</title><author><name sortKey="Nagata, Eiichiro" sort="Nagata, Eiichiro" uniqKey="Nagata E" first="Eiichiro" last="Nagata">Eiichiro Nagata</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Neurology, Tokai University School of Medicine, Isehara, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ogino, Mieko" sort="Ogino, Mieko" uniqKey="Ogino M" first="Mieko" last="Ogino">Mieko Ogino</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iwamoto, Kounosuke" sort="Iwamoto, Kounosuke" uniqKey="Iwamoto K" first="Kounosuke" last="Iwamoto">Kounosuke Iwamoto</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kitagawa, Yasuhisa" sort="Kitagawa, Yasuhisa" uniqKey="Kitagawa Y" first="Yasuhisa" last="Kitagawa">Yasuhisa Kitagawa</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Neurology, Tokai University Hachioji Hospital, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iwasaki, Yasuo" sort="Iwasaki, Yasuo" uniqKey="Iwasaki Y" first="Yasuo" last="Iwasaki">Yasuo Iwasaki</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yoshii, Fumihito" sort="Yoshii, Fumihito" uniqKey="Yoshii F" first="Fumihito" last="Yoshii">Fumihito Yoshii</name><affiliation><nlm:aff id="aff005"><addr-line>Department of Neurology, Tokai University Oiso Hospital, Kanagawa, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ikeda, Joh E" sort="Ikeda, Joh E" uniqKey="Ikeda J" first="Joh-E." last="Ikeda">Joh-E. Ikeda</name><affiliation><nlm:aff id="aff006"><addr-line>Molecular Neurology, Faculty of Medicine, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Department of Pediatrics, Faculty of Medicine, University of Ottawa, ARC/Children’s Hospital of Eastern Ontario, Ottawa, Canada</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26910108</idno><idno type="pmc">4765990</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765990</idno><idno type="RBID">PMC:4765990</idno><idno type="doi">10.1371/journal.pone.0149509</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000152</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000152</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients</title><author><name sortKey="Nagata, Eiichiro" sort="Nagata, Eiichiro" uniqKey="Nagata E" first="Eiichiro" last="Nagata">Eiichiro Nagata</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Neurology, Tokai University School of Medicine, Isehara, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ogino, Mieko" sort="Ogino, Mieko" uniqKey="Ogino M" first="Mieko" last="Ogino">Mieko Ogino</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iwamoto, Kounosuke" sort="Iwamoto, Kounosuke" uniqKey="Iwamoto K" first="Kounosuke" last="Iwamoto">Kounosuke Iwamoto</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kitagawa, Yasuhisa" sort="Kitagawa, Yasuhisa" uniqKey="Kitagawa Y" first="Yasuhisa" last="Kitagawa">Yasuhisa Kitagawa</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Neurology, Tokai University Hachioji Hospital, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iwasaki, Yasuo" sort="Iwasaki, Yasuo" uniqKey="Iwasaki Y" first="Yasuo" last="Iwasaki">Yasuo Iwasaki</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yoshii, Fumihito" sort="Yoshii, Fumihito" uniqKey="Yoshii F" first="Fumihito" last="Yoshii">Fumihito Yoshii</name><affiliation><nlm:aff id="aff005"><addr-line>Department of Neurology, Tokai University Oiso Hospital, Kanagawa, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ikeda, Joh E" sort="Ikeda, Joh E" uniqKey="Ikeda J" first="Joh-E." last="Ikeda">Joh-E. Ikeda</name><affiliation><nlm:aff id="aff006"><addr-line>Molecular Neurology, Faculty of Medicine, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Department of Pediatrics, Faculty of Medicine, University of Ottawa, ARC/Children’s Hospital of Eastern Ontario, Ottawa, Canada</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Objective</title><p>Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.</p></sec><sec id="sec002"><title>Design</title><p>A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.</p></sec><sec id="sec003"><title>Methods</title><p>The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1<sup>st</sup> endpoint) and upon completion or discontinuation of the study (2<sup>nd</sup> endpoint) of the dosing.</p></sec><sec id="sec004"><title>Results</title><p>Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1<sup>st</sup> and 2<sup>nd</sup> endpoint analysis. In the 1<sup>st</sup> endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2<sup>nd</sup> endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.</p></sec><sec id="sec005"><title>Conclusions</title><p>BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.</p></sec><sec id="sec006"><title>Trial Registration</title><p>UMIN Clinical Trials <ext-link ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E">UMIN000008527</ext-link></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rowland, Lp" uniqKey="Rowland L">LP Rowland</name></author><author><name sortKey="Shneider, Na" uniqKey="Shneider N">NA Shneider</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sreedharan, J" uniqKey="Sreedharan J">J Sreedharan</name></author><author><name sortKey="Brown, Rh" uniqKey="Brown R">RH Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barber, Sc" uniqKey="Barber S">SC Barber</name></author><author><name sortKey="Mead, Rj" uniqKey="Mead R">RJ Mead</name></author><author><name sortKey="Shaw, Pj" uniqKey="Shaw P">PJ Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boillee, S" uniqKey="Boillee S">S Boillee</name></author><author><name sortKey="Vande Velde, C" uniqKey="Vande Velde C">C Vande Velde</name></author><author><name sortKey="Cleveland, Dw" uniqKey="Cleveland D">DW Cleveland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pasinelli, P" uniqKey="Pasinelli P">P Pasinelli</name></author><author><name sortKey="Brown, Rh" uniqKey="Brown R">RH Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barber, Sc" uniqKey="Barber S">SC Barber</name></author><author><name sortKey="Shaw, Pj" uniqKey="Shaw P">PJ Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rao, Sd" uniqKey="Rao S">SD Rao</name></author><author><name sortKey="Yin, Hz" uniqKey="Yin H">HZ Yin</name></author><author><name sortKey="Weiss, Jh" uniqKey="Weiss J">JH Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Hao, W" uniqKey="Hao W">W Hao</name></author><author><name sortKey="Dawson, A" uniqKey="Dawson A">A Dawson</name></author><author><name sortKey="Liu, S" uniqKey="Liu S">S Liu</name></author><author><name sortKey="Fassbender, K" uniqKey="Fassbender K">K Fassbender</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okada, Y" uniqKey="Okada Y">Y Okada</name></author><author><name sortKey="Sakai, H" uniqKey="Sakai H">H Sakai</name></author><author><name sortKey="Kohiki, E" uniqKey="Kohiki E">E Kohiki</name></author><author><name sortKey="Suga, E" uniqKey="Suga E">E Suga</name></author><author><name sortKey="Yanagisawa, Y" uniqKey="Yanagisawa Y">Y Yanagisawa</name></author><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roy, N" uniqKey="Roy N">N Roy</name></author><author><name sortKey="Mahadevan, Ms" uniqKey="Mahadevan M">MS Mahadevan</name></author><author><name sortKey="Mclean, M" uniqKey="Mclean M">M Mclean</name></author><author><name sortKey="Shutler, G" uniqKey="Shutler G">G Shutler</name></author><author><name sortKey="Yaraghi, Z" uniqKey="Yaraghi Z">Z Yaraghi</name></author><author><name sortKey="Farahani, R" uniqKey="Farahani R">R Farahani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liston, P" uniqKey="Liston P">P Liston</name></author><author><name sortKey="Roy, N" uniqKey="Roy N">N Roy</name></author><author><name sortKey="Tamai, K" uniqKey="Tamai K">K Tamai</name></author><author><name sortKey="Lefebvre, C" uniqKey="Lefebvre C">C Lefebvre</name></author><author><name sortKey="Baird, S" uniqKey="Baird S">S Baird</name></author><author><name sortKey="Cherton Horvat, G" uniqKey="Cherton Horvat G">G Cherton-Horvat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author><author><name sortKey="Okada, Y" uniqKey="Okada Y">Y Okada</name></author><author><name sortKey="Kanno, T" uniqKey="Kanno T">T Kanno</name></author><author><name sortKey="Otomo, A" uniqKey="Otomo A">A Otomo</name></author><author><name sortKey="Yanagisawa, Y" uniqKey="Yanagisawa Y">Y Yanagisawa</name></author><author><name sortKey="Shouguchi Miyata, J" uniqKey="Shouguchi Miyata J">J Shouguchi-Miyata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author><author><name sortKey="Kanno, T" uniqKey="Kanno T">T Kanno</name></author><author><name sortKey="Yanagisawa, Y" uniqKey="Yanagisawa Y">Y Yanagisawa</name></author><author><name sortKey="Yasutake, K" uniqKey="Yasutake K">K Yasutake</name></author><author><name sortKey="Inoue, S" uniqKey="Inoue S">S Inoue</name></author><author><name sortKey="Hirayama, N" uniqKey="Hirayama N">N Hirayama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lim, Jh" uniqKey="Lim J">JH Lim</name></author><author><name sortKey="Kim, Km" uniqKey="Kim K">KM Kim</name></author><author><name sortKey="Kim, Sw" uniqKey="Kim S">SW Kim</name></author><author><name sortKey="Hwang, O" uniqKey="Hwang O">O Hwang</name></author><author><name sortKey="Choi, Hj" uniqKey="Choi H">HJ Choi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ludolph, Ac" uniqKey="Ludolph A">AC Ludolph</name></author><author><name sortKey="Bendotti, C" uniqKey="Bendotti C">C Bendotti</name></author><author><name sortKey="Blaugrund, E" uniqKey="Blaugrund E">E Blaugrund</name></author><author><name sortKey="Chio, A" uniqKey="Chio A">A Chio</name></author><author><name sortKey="Greensmith, L" uniqKey="Greensmith L">L Greensmith</name></author><author><name sortKey="Loeffler, Jp" uniqKey="Loeffler J">JP Loeffler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bensimon, G" uniqKey="Bensimon G">G Bensimon</name></author><author><name sortKey="Lacomblez, L" uniqKey="Lacomblez L">L Lacomblez</name></author><author><name sortKey="Meininger, V" uniqKey="Meininger V">V Meininger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miller, Rg" uniqKey="Miller R">RG Miller</name></author><author><name sortKey="Mitchell, Jd" uniqKey="Mitchell J">JD Mitchell</name></author><author><name sortKey="Lyon, M" uniqKey="Lyon M">M Lyon</name></author><author><name sortKey="Moore, Dh" uniqKey="Moore D">DH Moore</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mitsumoto, H" uniqKey="Mitsumoto H">H Mitsumoto</name></author><author><name sortKey="Brookd, Br" uniqKey="Brookd B">BR Brookd</name></author><author><name sortKey="Silani, V" uniqKey="Silani V">V Silani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brooks, Br" uniqKey="Brooks B">BR Brooks</name></author><author><name sortKey="Miller, Rg" uniqKey="Miller R">RG Miller</name></author><author><name sortKey="Swash, M" uniqKey="Swash M">M Swash</name></author><author><name sortKey="Munsat, Tl" uniqKey="Munsat T">TL Munsat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Benatar, M" uniqKey="Benatar M">M Benatar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Turner, Bj" uniqKey="Turner B">BJ Turner</name></author><author><name sortKey="Talbot, K" uniqKey="Talbot K">K Talbot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cudkowicz, M" uniqKey="Cudkowicz M">M Cudkowicz</name></author><author><name sortKey="Bozik, Me" uniqKey="Bozik M">ME Bozik</name></author><author><name sortKey="Ingersoll, Ew" uniqKey="Ingersoll E">EW Ingersoll</name></author><author><name sortKey="Miller, R" uniqKey="Miller R">R Miller</name></author><author><name sortKey="Mitsumoto, H" uniqKey="Mitsumoto H">H Mitsumoto</name></author><author><name sortKey="Shefner, J" uniqKey="Shefner J">J Shefner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cudkowicz, Me" uniqKey="Cudkowicz M">ME Cudkowicz</name></author><author><name sortKey="Van Den Berg, Lh" uniqKey="Van Den Berg L">LH van den Berg</name></author><author><name sortKey="Shefner, Jm" uniqKey="Shefner J">JM Shefner</name></author><author><name sortKey="Mitsumoto, H" uniqKey="Mitsumoto H">H Mitsumoto</name></author><author><name sortKey="Mora, Js" uniqKey="Mora J">JS Mora</name></author><author><name sortKey="Ludolph, A" uniqKey="Ludolph A">A Ludolph</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kondo, T" uniqKey="Kondo T">T Kondo</name></author><author><name sortKey="Ito, T" uniqKey="Ito T">T Ito</name></author><author><name sortKey="Sugita, Y" uniqKey="Sugita Y">Y Sugita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ogawa, N" uniqKey="Ogawa N">N Ogawa</name></author><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author><author><name sortKey="Asanuma, M" uniqKey="Asanuma M">M Asanuma</name></author><author><name sortKey="Kawai, M" uniqKey="Kawai M">M Kawai</name></author><author><name sortKey="Masumizu, T" uniqKey="Masumizu T">T Masumizu</name></author><author><name sortKey="Kohno, M" uniqKey="Kohno M">M Kohno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshikawa, T" uniqKey="Yoshikawa T">T Yoshikawa</name></author><author><name sortKey="Minamiyama, Y" uniqKey="Minamiyama Y">Y Minamiyama</name></author><author><name sortKey="Naito, Y" uniqKey="Naito Y">Y Naito</name></author><author><name sortKey="Kondo, M" uniqKey="Kondo M">M Kondo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author><author><name sortKey="Kanno, T" uniqKey="Kanno T">T Kanno</name></author><author><name sortKey="Yanagisawa, Y" uniqKey="Yanagisawa Y">Y Yanagisawa</name></author><author><name sortKey="Yasutake, K" uniqKey="Yasutake K">K Yasutake</name></author><author><name sortKey="Hadano, S" uniqKey="Hadano S">S Hadano</name></author><author><name sortKey="Yoshii, F" uniqKey="Yoshii F">F Yoshii</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Gt" uniqKey="Liu G">GT Liu</name></author><author><name sortKey="Hwang, Cs" uniqKey="Hwang C">CS Hwang</name></author><author><name sortKey="Hsieh, Ch" uniqKey="Hsieh C">CH Hsieh</name></author><author><name sortKey="Lu, Ch" uniqKey="Lu C">CH Lu</name></author><author><name sortKey="Chang, Sly" uniqKey="Chang S">SLY Chang</name></author><author><name sortKey="Huang, Cf" uniqKey="Huang C">CF Huang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26910108</article-id><article-id pub-id-type="pmc">4765990</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0149509</article-id><article-id pub-id-type="publisher-id">PONE-D-15-29010</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Neurology</subject><subj-group><subject>Neurodegenerative Diseases</subject><subj-group><subject>Motor Neuron Diseases</subject><subj-group><subject>Amyotrophic Lateral Sclerosis</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Chemical Compounds</subject><subj-group><subject>Organic Compounds</subject><subj-group><subject>Amines</subject><subj-group><subject>Catecholamines</subject><subj-group><subject>Dopamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Organic Chemistry</subject><subj-group><subject>Organic Compounds</subject><subj-group><subject>Amines</subject><subj-group><subject>Catecholamines</subject><subj-group><subject>Dopamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Neurochemistry</subject><subj-group><subject>Neurotransmitters</subject><subj-group><subject>Biogenic Amines</subject><subj-group><subject>Catecholamines</subject><subj-group><subject>Dopamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Neuroscience</subject><subj-group><subject>Neurochemistry</subject><subj-group><subject>Neurotransmitters</subject><subj-group><subject>Biogenic Amines</subject><subj-group><subject>Catecholamines</subject><subj-group><subject>Dopamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Hormones</subject><subj-group><subject>Catecholamines</subject><subj-group><subject>Dopamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Physiological Processes</subject><subj-group><subject>Eating</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Physiological Processes</subject><subj-group><subject>Eating</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmaceutics</subject><subj-group><subject>Drug Therapy</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Research Design</subject><subj-group><subject>Clinical Research Design</subject><subj-group><subject>Adverse Events</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Oxidative Stress</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Gastroenterology and Hepatology</subject><subj-group><subject>Gastrointestinal Infections</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Signs and Symptoms</subject><subj-group><subject>Nausea</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients</article-title><alt-title alt-title-type="running-head">Safety and Efficacy of Bromocriptine in Japanese ALS</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nagata</surname><given-names>Eiichiro</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ogino</surname><given-names>Mieko</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Iwamoto</surname><given-names>Kounosuke</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kitagawa</surname><given-names>Yasuhisa</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Iwasaki</surname><given-names>Yasuo</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yoshii</surname><given-names>Fumihito</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ikeda</surname><given-names>Joh-E.</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author"><collab>ALS Consortium Investigators</collab><xref ref-type="author-notes" rid="fn001"><sup>¶</sup></xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Neurology, Tokai University School of Medicine, Isehara, Japan</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Neurology, Tokai University Hachioji Hospital, Tokyo, Japan</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Department of Neurology, Tokai University Oiso Hospital, Kanagawa, Japan</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Molecular Neurology, Faculty of Medicine, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Pediatrics, Faculty of Medicine, University of Ottawa, ARC/Children’s Hospital of Eastern Ontario, Ottawa, Canada</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Wang</surname><given-names>Yun</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>National Health Research Institutes, TAIWAN</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: JEI. Performed the experiments: EN MO KI YK YI FY. Analyzed the data: EN FY JEI. Contributed reagents/materials/analysis tools: EN MO KI YK YI FY JEI. Wrote the paper: EN FY JEI.</p></fn><fn fn-type="other" id="fn001"><p>¶ Membership of the ALS Consortium Investigators is listed in the Acknowledgments.</p></fn><corresp id="cor001">* E-mail: <email>joh-e@mgcheo.med.uottawa.ca</email></corresp></author-notes><pub-date pub-type="epub"><day>24</day><month>2</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>11</volume><issue>2</issue><elocation-id>e0149509</elocation-id><history><date date-type="received"><day>9</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>1</day><month>2</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 Nagata et al</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Nagata et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0149509.pdf"></self-uri><abstract><sec id="sec001"><title>Objective</title><p>Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.</p></sec><sec id="sec002"><title>Design</title><p>A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.</p></sec><sec id="sec003"><title>Methods</title><p>The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1<sup>st</sup> endpoint) and upon completion or discontinuation of the study (2<sup>nd</sup> endpoint) of the dosing.</p></sec><sec id="sec004"><title>Results</title><p>Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1<sup>st</sup> and 2<sup>nd</sup> endpoint analysis. In the 1<sup>st</sup> endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2<sup>nd</sup> endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.</p></sec><sec id="sec005"><title>Conclusions</title><p>BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.</p></sec><sec id="sec006"><title>Trial Registration</title><p>UMIN Clinical Trials <ext-link ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E">UMIN000008527</ext-link></p></sec></abstract><funding-group><funding-statement>This work was supported by Ministry of Health, Labor and Welfare, Japan (H20-ClinicalResearch-G-014).</funding-statement></funding-group><counts><fig-count count="10"></fig-count><table-count count="2"></table-count><page-count count="16"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>Data are available from UMIN website (<ext-link ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E">https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E</ext-link>).</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>Data are available from UMIN website (<ext-link ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E">https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E</ext-link>).</p></notes></front><body><sec sec-type="intro" id="sec007"><title>Introduction</title><p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that preferentially targets motor neurons controlling muscle movement and is usually fatal. Approximatley 90% of ALS cases occur sporadically in the absence of a clear family history, the remainder have a clear genetic background and are diagnosed as familial ALS [<xref rid="pone.0149509.ref001" ref-type="bibr">1</xref>,<xref rid="pone.0149509.ref002" ref-type="bibr">2</xref>]. While the precise etiology or etiologies of ALS remains unknown, a complex interplay of many pathogenic factors, including oxidative stress, excitotoxicity, mitochondrial dysfunction, disruption of neurofilament network, neural inflammation, non-cell autonomous damage and protein aggregations such as mutant SOD1, TDP-43, and FUS proteins, have been suggested as possible potential factors [<xref rid="pone.0149509.ref003" ref-type="bibr">3</xref>–<xref rid="pone.0149509.ref006" ref-type="bibr">6</xref>]. Notably, an elevation of reactive oxygen species (ROS) possibly reflecting mitochondrial dysfunction [<xref rid="pone.0149509.ref003" ref-type="bibr">3</xref>,<xref rid="pone.0149509.ref006" ref-type="bibr">6</xref>], the reduction of glutamate uptake in motor neurons, and induction of oxidation in neighboring astrocytes [<xref rid="pone.0149509.ref007" ref-type="bibr">7</xref>] point to roles for oxidative stress and inflammatory response in ALS [<xref rid="pone.0149509.ref008" ref-type="bibr">8</xref>]. We believe that oxidative stress therefore represents a credible target for the development of novel therapeutic agents for ALS. We have previously developed the neuronal apoptosis inhibitory protein (NAIP)-ELISA-based drug screening system [<xref rid="pone.0149509.ref009" ref-type="bibr">9</xref>]. NAIP is a founding member of anti-apoptosis IAP family [<xref rid="pone.0149509.ref010" ref-type="bibr">10</xref>] and selectively suppresses oxidative stress-induced cell death. Both upregulation and exogenous over expression of NAIP protects neuronal cells against oxidative stress in vivo and in vitro [<xref rid="pone.0149509.ref011" ref-type="bibr">11</xref>–<xref rid="pone.0149509.ref013" ref-type="bibr">13</xref>]. Using this system, we have identified several compounds that transiently upregulate NAIP, including bromocriptine methylate (BRC) [<xref rid="pone.0149509.ref009" ref-type="bibr">9</xref>,<xref rid="pone.0149509.ref013" ref-type="bibr">13</xref>]. BRC confered protection against oxidative stress-induced cell death [<xref rid="pone.0149509.ref014" ref-type="bibr">14</xref>,<xref rid="pone.0149509.ref015" ref-type="bibr">15</xref>]. Currently the only Food and Drug Administration (FDA)-approved drug for the treatment of ALS, the anti-glutamatergic Riluzole, confers only a modest therapeutic efficacy [<xref rid="pone.0149509.ref016" ref-type="bibr">16</xref>,<xref rid="pone.0149509.ref017" ref-type="bibr">17</xref>]. Therefore, there is a clear unmet need for effective ALS therapeutic interventions [<xref rid="pone.0149509.ref018" ref-type="bibr">18</xref>]. The present study is designed to evaluate both the efficacy of BRC in the presence of Riluzole on motor function and quality of life (QOL) as well as safety in Japanese patients with solitary ALS.</p></sec><sec sec-type="materials|methods" id="sec008"><title>Materials and Methods</title><sec id="sec009"><title>Participants and study design</title><p>A double blind, Riluzole add-on placebo controlled BRC safety and efficacy trial in Japanese ALS patients was designed. The study protocol (08R-103) was approved by the Institutional Review Board for Clinical Research, Tokai University, followed the tenets of the Declaration of Helsinki and is registered at UMIN (UMIN000008527). The approved protocol for this trial and supporting CONSORT checklist are available as supporting information; see <xref ref-type="supplementary-material" rid="pone.0149509.s002">S1 Protocol</xref> and <xref ref-type="supplementary-material" rid="pone.0149509.s001">S1 CONSORT Checklist</xref>. All participants provided written informed consent. This is a Phase 2a clinical trial to evaluate the safety and the efficacy of BRC. We determined 50 ALS patients who lived around Tokyo metropolitan area suburbs in Japan.</p><p>48 ALS patients were recruited from 3 university hospitals and 4 general hospitals in Japan between January 1<sup>st</sup>, 2009 and March 31<sup>th</sup>, 2012. We enrolled patients with a diagnosis of possible, laboratory-supported probable, probable, or definite ALS in accordance with the revised El Escorial Modified Airlie House Diagnostic criteria [<xref rid="pone.0149509.ref019" ref-type="bibr">19</xref>]. ALS was diagnosed in all study entrants within 3 years of the inception of our study. The forced vital capacity (FVC) of patients was more than 70%. The ages of patients were between 20 and 75 at the time of taking informed consent. The changes in ALSFRS-R scores of patients were between -1 and -4 during the pretreatment 12-week observation period. All study entrants were treated with 100mg of Riluszole (50mg a twice daily) during the course of this study. 10 participants were disqualified during 12 weeks observation period (<xref ref-type="fig" rid="pone.0149509.g001">Fig 1</xref>). The final number of participants was 38 (BRC group: n = 31, control (placebo group: n = 7)). 10 participants were withdrawn during the course of study. Eight participants withdrew from the BRC group following adverse events such as nausea, constipation, there was one death in the placebo group, and one participant in the BRC group left the study of his own accord. In the placebo group, one participant died secondary to ALS progression. In the full analysis set (FAS) to efficacy assessment, 2 patients were disqualified (BRC n = 2, placebo n = 0). In one patient, his secrecy obligation was not defended. In other patient, we could not get the validity at all about this medicine. In per protocol set (PPS) to efficacy assessment, there were no unqualified patients. No significant differences between BRC and placebo groups was detected for the baseline characteristics including age, gender, body weight, BMI, ALS duration, family history, ALSFRS-R score, and vital capacity (<xref ref-type="table" rid="pone.0149509.t001">Table 1</xref>).</p><fig id="pone.0149509.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g001</object-id><label>Fig 1</label><caption><title>Trial profile.</title><p>BRC: bromocriptine methylate.</p></caption><graphic xlink:href="pone.0149509.g001"></graphic></fig><table-wrap id="pone.0149509.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.t001</object-id><label>Table 1</label><caption><title>Summary of demographic and baseline characteristics for randomized groups in BRC and placebo.</title></caption><alternatives><graphic id="pone.0149509.t001g" xlink:href="pone.0149509.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">BRC (n = 29)</th><th align="left" rowspan="1" colspan="1">Placebo (n = 7)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age/ years</td><td align="left" rowspan="1" colspan="1">59.7(±9.0)</td><td align="left" rowspan="1" colspan="1">58.7(±10.1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Male</td><td align="left" rowspan="1" colspan="1">21(72.4%)</td><td align="left" rowspan="1" colspan="1">6(85.7%)</td></tr><tr><td align="left" rowspan="1" colspan="1">Female</td><td align="left" rowspan="1" colspan="1">8(27.6%)</td><td align="left" rowspan="1" colspan="1">1(14.3%)</td></tr><tr><td align="left" rowspan="1" colspan="1">Body weight/ Kg</td><td align="left" rowspan="1" colspan="1">58.08(±9.47)</td><td align="left" rowspan="1" colspan="1">58.97(±7.53)</td></tr><tr><td align="left" rowspan="1" colspan="1">Body-mass index/ kg/m2</td><td align="left" rowspan="1" colspan="1">21.9</td><td align="left" rowspan="1" colspan="1">21.6</td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of symptoms/ years</td><td align="left" rowspan="1" colspan="1">1.45(±0.69)</td><td align="left" rowspan="1" colspan="1">1.60(±0.77)</td></tr><tr><td align="left" rowspan="1" colspan="1">Family history of amyotrophic lateral sclerosis</td><td align="center" rowspan="1" colspan="1">NA</td><td align="center" rowspan="1" colspan="1">NA</td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline ALSFRS-R score</td><td align="left" rowspan="1" colspan="1">40.0(±5.0)</td><td align="left" rowspan="1" colspan="1">39.9(±5.6)</td></tr><tr><td align="left" rowspan="1" colspan="1">Mean vital capacity at baseline</td><td align="left" rowspan="1" colspan="1">105.03(±20.30)</td><td align="left" rowspan="1" colspan="1">92.19(±14.89)</td></tr><tr><td align="left" rowspan="1" colspan="1">ALS severity/ patients</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">I</td><td align="left" rowspan="1" colspan="1">8(27.6%)</td><td align="left" rowspan="1" colspan="1">1(14.3%)</td></tr><tr><td align="left" rowspan="1" colspan="1">II</td><td align="left" rowspan="1" colspan="1">11(37.9%)</td><td align="left" rowspan="1" colspan="1">3(42.9%)</td></tr><tr><td align="left" rowspan="1" colspan="1">III</td><td align="left" rowspan="1" colspan="1">10(34.5%)</td><td align="left" rowspan="1" colspan="1">3(42.9%)</td></tr><tr><td align="left" rowspan="1" colspan="1">unknown</td><td align="left" rowspan="1" colspan="1">0(0.0%)</td><td align="left" rowspan="1" colspan="1">0(0.0%)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>We classified clinical manners of ALS severity of five grades established by Japanese Ministry of Health, labor and Welfare as follows.</p></fn><fn id="t001fn002"><p>ALS severity</p></fn><fn id="t001fn003"><p>I: Housekeeping and working are possible in general.</p></fn><fn id="t001fn004"><p>II: Although housekeeping and working are impossible, daily life becomes independent in general.</p></fn><fn id="t001fn005"><p>III: Meal, excretion, and any one or more movements, but daily life takes care.</p></fn><fn id="t001fn006"><p>IV: Breathing difficulty, sputum excretion difficulty, or swallowing difficulty.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec010"><title>Randomisation and masking</title><p>This investigator initiated study was designed as a Riluzole add-on, randomized, double-blind, placebo-controlled trial. Efficacy and safety were evaluated through analysis of change in each variable measured at the beginning of the observation period and at the commencement and the end of the treatment with BRC/ Riluzole/ lactose (BRC arm) and Riluzole/ lactose (placebo arm). The participants were blinded and we randomly allocated them in a 4: 1 ratio to receive each drugs using a computer-generated random allocation sequence.</p></sec><sec id="sec011" sec-type="materials|methods"><title>Procedures</title><p>For patients who had been dosed Riluzole 4 weeks prior or on time of the observation period, the 12-week treatment with 100mg Riluzole alone (50mg twice daily) during the observation period was performed and followed by the either BRC or placebo treatments. The initial dose of 1.25 mg BRC per day was increased to 15 mg/day at 2-week intervals over 12-weeks (<xref ref-type="fig" rid="pone.0149509.g002">Fig 2</xref>). The dosing period from 58 to 90 week ended in a 4 week stepwise dose reduction followed by a one month observational period following the completion of dosing. When a dose-related adverse effect was observed rendering the, for example, 10mg/day difficult to maintain, a reduced dose of 7.5 mg/day was used as the maintenance dose. One patient took 10mg/day of BRC as the maintenance dose for his nausea.</p><fig id="pone.0149509.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g002</object-id><label>Fig 2</label><caption><title>Flow chart of the clinical study (drug treatment method): BRC stepwise dosing schedule.</title><p>There was no significant difference on each heading between BRC and Placebo groups.</p></caption><graphic xlink:href="pone.0149509.g002"></graphic></fig><p>Statistical analyses of ALSFRS-R, %FVC, modified Norris scale (limb and bulbar), ALSAQ-40, manual muscle testing (MMT), pinch strength and grip strength were performed.</p></sec><sec id="sec012"><title>Outcomes</title><p>The BRC and placebo identities were revealed once the dosing was completed and we evaluated efficacy by two statistical analyses. The 1<sup>st</sup> endpoint analysis compared baseline scores at the end of the observation period to those upon completion of stepwise dosing of 14 weeks (<xref ref-type="fig" rid="pone.0149509.g002">Fig 2</xref>). The 2<sup>nd</sup> endpoint analysis compared the baseline score at the observation period endpoint to that at the time of study completion (<xref ref-type="fig" rid="pone.0149509.g002">Fig 2</xref>).</p></sec><sec id="sec013"><title>Primary efficacy analysis I (ANCOVA)</title><p>Efficacy was estimated by a comparison of BRC and placebo groups mean scores at 1<sup>st</sup> and 2<sup>nd</sup> endpoints. Analysis of covariance (ANCOVA) was applied (p<0.05).</p></sec><sec id="sec014"><title>Primary efficacy analysis II</title><p>The primary efficacy analysis II was a comparison of the mean of time-course score changes in BRC and placebo groups.</p><p>Efficacy and marginal significance were derived from a p-value of either primary efficacy analysis I (ANCOVA) or primary efficacy analysis II. Marginal significance was defined as a P-value within two-tailed test at 80% confidence level. Moreover, the time-course of the values of summary statistics, mean changes from baseline, and the slope of changes were also used in the analysis.</p></sec><sec id="sec015"><title>Laboratory data</title><p>WBC count with fractionation, liver, and renal function tests as well as blood sugar were measured at regular intervals; electrocardiograms, echocardiograms, chest X-ray and vital signs were also taken.</p></sec><sec id="sec016"><title>Statistical analysis</title><p>The study was sufficiently powered to independently assess a potential benefit of BRC compared with placebo for ALSFRS-R total scores and survival. Failure analyses undertaken for ALSFRS-R used the change from baseline to 1<sup>st</sup> and 2<sup>nd</sup> endpoints with the last observation carried forward (LOCF) for subjects who discontinued in Part I and Part II. We believe that the LOCF method was appropriate for exploratory analyses because of the very small number of drop-outs and the absence of study entrant deaths. The statistical analysis of this study was conducted by CMIC (CRO/CMO company, Statistical Analysis Division, Tokyo, Japan).</p></sec></sec><sec sec-type="results" id="sec017"><title>Results</title><sec id="sec018"><title>Primary efficacy analysis I (ANCOVA)</title><p>Efficacy was analyzed by a comparison of the mean changes calculated at 1<sup>st</sup> and 2<sup>nd</sup> endpoints between BRC and placebo groups. Observed differences with P values less than 0.2 at the 1st endpoint included ALSAQ40-communication (P = 0.012, <xref ref-type="fig" rid="pone.0149509.g003">Fig 3(A))</xref>, ALSAQ40 eating & drinking (P = 0.022, <xref ref-type="fig" rid="pone.0149509.g004">Fig 4(A))</xref>, ALSFRS-R total score (P = 0.176, <xref ref-type="fig" rid="pone.0149509.g005">Fig 5(A))</xref>, and grip strength (right hand)(P = 0.198, <xref ref-type="fig" rid="pone.0149509.g006">Fig 6(A))</xref>. At the 2<sup>nd</sup> endpoint analysis, significant differences were observed for Limb Norris Scale (P = 0.183, <xref ref-type="fig" rid="pone.0149509.g007">Fig 7(B))</xref>, ALSAQ40-communication (P = 0.119, <xref ref-type="fig" rid="pone.0149509.g003">Fig 3(B))</xref>, ALSAQ40 eating & drinking (P = 0.136, <xref ref-type="fig" rid="pone.0149509.g004">Fig 4(B))</xref>, and degree of neck flexion (P = 0.154, <xref ref-type="fig" rid="pone.0149509.g008">Fig 8(B))</xref>.</p><fig id="pone.0149509.g003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g003</object-id><label>Fig 3</label><caption><title>The results of primary efficacy analysis I on Limb Norris Scale total score.</title><p>In 1<sup>st</sup> endpoint analysis, the group of BRC treatment tended to be recovered compared to the group of placebo treatment. Moreover, in 2<sup>nd</sup> endpoint analysis, the group of BRC was significantly recovered in Limb Norris Scale total score compared to the group of placebo (p < 0.2).</p></caption><graphic xlink:href="pone.0149509.g003"></graphic></fig><fig id="pone.0149509.g004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g004</object-id><label>Fig 4</label><caption><title>The results of primary efficacy analysis I on ALSAQ40 communication.</title><p>In both 1<sup>st</sup> endpoint and 2<sup>nd</sup> endpoint analyses, the groups of BRC treatment were significantly recovered in ALSAQ40 communication compared to the groups of placebo (p < 0.2).</p></caption><graphic xlink:href="pone.0149509.g004"></graphic></fig><fig id="pone.0149509.g005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g005</object-id><label>Fig 5</label><caption><title>The results of primary efficacy analysis I on ALSAQ40 eating and drinking.</title><p>In both 1<sup>st</sup> endpoint and 2<sup>nd</sup> endpoint analyses, the groups of NDDPX08 treatment were significantly recovered in ALSAQ40 eating and drinking compared to the groups of placebo (p < 0.2).</p></caption><graphic xlink:href="pone.0149509.g005"></graphic></fig><fig id="pone.0149509.g006" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g006</object-id><label>Fig 6</label><caption><title>The results of primary efficacy analysis I on ALSFR-S.</title><p>In 1<sup>st</sup> endpoint analysis, the group of BRC treatment was significantly recovered compared to the group of placebo treatment (p < 0.2). Moreover, in 2<sup>nd</sup> endpoint analysis, the group of BRC tended to be recovered in ALSFR-S total score compared to the group of placebo.</p></caption><graphic xlink:href="pone.0149509.g006"></graphic></fig><fig id="pone.0149509.g007" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g007</object-id><label>Fig 7</label><caption><title>The results of primary efficacy analysis I on Grip strength (right side).</title><p>In 1<sup>st</sup> endpoint analysis, the group of BRC treatment was significantly recovered compared to the group of placebo treatment (p < 0.2). Moreover, in 2<sup>nd</sup> endpoint analysis, the group of BRC tended to be recovered compared to the group of placebo.</p></caption><graphic xlink:href="pone.0149509.g007"></graphic></fig><fig id="pone.0149509.g008" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g008</object-id><label>Fig 8</label><caption><title>The results of primary efficacy analysis I on neck forward-bent/ anteflexion.</title><p>In 1<sup>st</sup> endpoint analysis, the group of BRC treatment tended to be recovered compared to the group of placebo treatment. Moreover, in 2<sup>nd</sup> endpoint analysis, the group of BRC was significantly recovered compared to the group of placebo (p < 0.2).</p></caption><graphic xlink:href="pone.0149509.g008"></graphic></fig><p>Primary efficacy analysis II for the comparison of the mean of time-course score changes in BRC and placebo. P values of less than 0.2 were observed for the following items; Limb Norris Scale, ALSAQ40-communication, ALSAQ40 eating & drinking, and grip strength (right hand). Moreover, the abolition rate of lower limb function in ALS treated with BRC was less than that for non-treated ALS patients (<xref ref-type="fig" rid="pone.0149509.g009">Fig 9</xref>).</p><fig id="pone.0149509.g009" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g009</object-id><label>Fig 9</label><caption><title>Alterations of differential white blood counts in ALS patients with or without BRC.</title><p>Placebo treated ALS patients revealed significant increase of eosinophil. On the other hand, BRC treated ALS patients showed no increase of it (A). However, the number of the other blood cells stayed constant during the disease progression in both placebo and BRC treated group (B, C, D, E). LOCF: last observation carried forward. *P<0.05 BRC group vs Placebo group.</p></caption><graphic xlink:href="pone.0149509.g009"></graphic></fig><p>The above ALS scores indicated ALS severity was improved in BRC group compared to Placebo group.</p><p>On the other hand, almost patients were diagnosed with “definite” according to ALS diagnosis criteria. Moreover, there was no significant correlation between the efficacy for BRC and ALS progression.</p></sec><sec id="sec019"><title>Safety (<xref ref-type="table" rid="pone.0149509.t002">Table 2</xref>)</title><table-wrap id="pone.0149509.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.t002</object-id><label>Table 2</label><caption><title>Summary of safety assessment.</title></caption><alternatives><graphic id="pone.0149509.t002g" xlink:href="pone.0149509.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Adverse events</th><th align="left" rowspan="1" colspan="1">BRC (n = 31)</th><th align="left" rowspan="1" colspan="1">Placebo (n = 7)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Infection and infestations</td><td align="left" rowspan="1" colspan="1">19 (61.3%)</td><td align="left" rowspan="1" colspan="1">3 (42.9%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> (nasopharyngitis)</td><td align="left" rowspan="1" colspan="1">(11 (35.5%))</td><td align="left" rowspan="1" colspan="1">(1 (14.3%))</td></tr><tr><td align="left" rowspan="1" colspan="1">Gastrointestinal disorders</td><td align="left" rowspan="1" colspan="1">14 (45.2%)</td><td align="left" rowspan="1" colspan="1">4 (57.1%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> (constipation)</td><td align="left" rowspan="1" colspan="1">(5 (16.1%))</td><td align="left" rowspan="1" colspan="1">(2 (28.6%))</td></tr><tr><td align="left" rowspan="1" colspan="1"> (nausea)</td><td align="left" rowspan="1" colspan="1">(5 (16.1%))</td><td align="left" rowspan="1" colspan="1">(2 (28.6%))</td></tr><tr><td align="left" rowspan="1" colspan="1">Skin and subcutaneous tissue disorders</td><td align="left" rowspan="1" colspan="1">12 (38.7%)</td><td align="left" rowspan="1" colspan="1">1 (14.3%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> (eczema)</td><td align="left" rowspan="1" colspan="1">(4 (12.9%))</td><td align="left" rowspan="1" colspan="1">(0 (0%))</td></tr><tr><td align="left" rowspan="1" colspan="1">Adverse drug events</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Gastrointestinal disorders</td><td align="left" rowspan="1" colspan="1">6 (19.4%)</td><td align="left" rowspan="1" colspan="1">3 (42.9%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> (nausea)</td><td align="left" rowspan="1" colspan="1">3 (9.7%)</td><td align="left" rowspan="1" colspan="1">2 (28.6%)</td></tr><tr><td align="left" rowspan="1" colspan="1">Serious adverse events</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Respiratory, thoracic and mediastinal</td><td align="left" rowspan="1" colspan="1">3 (9.7%)</td><td align="left" rowspan="1" colspan="1">0 (0%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> (aspiration pneumonias)</td><td align="left" rowspan="1" colspan="1">(2 (6.5%))</td><td align="left" rowspan="1" colspan="1">(0 (0%))</td></tr><tr><td align="left" rowspan="1" colspan="1">Serious adverse drug events</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Gastrointestinal disorder (ischemic colitis)</td><td align="left" rowspan="1" colspan="1">1 (3.2%)</td><td align="left" rowspan="1" colspan="1">0 (0%)</td></tr></tbody></table></alternatives></table-wrap><list list-type="order"><list-item><p>Adverse events</p><p>The sole significant differences between the treatment groups were for comparatively minor issues including 19 infections, 14 gastrointestinal disorders, 12 skin and subcutaneous tissue disorders, 11 cases of nasopharyngitis, 5 individuals with constipations, 5 with nausea, and 4 with eczema in BRC group.</p></list-item><list-item><p>Adverse drug reactions</p><p>There was no significant difference in incidence between the treatment groups expect for 6 gastrointestinal disorders and 3 nauseas in BRC group.</p></list-item><list-item><p>Serious adverse events</p><p>There was no significant difference in serious adverse event incidence between the treatment groups. Three respiratory, thoracic and mediastinal disorders and 2 aspiration pneumonias according to the worse of ALS symptoms in both the treatment groups.</p></list-item><list-item><p>Serious adverse drug reactions</p><p>There was no significant difference in serious adverse drug reactions incidence between the treatment groups; there was one case of gastrointestinal disorder and ischemic colitis.</p></list-item></list></sec><sec id="sec020"><title>Laboratory data</title><p>All laboratory data were within normal range with the exception of the increasing eosinophils exclusively seen in placebo treated ALS patients (<xref ref-type="fig" rid="pone.0149509.g010">Fig 10</xref>).</p><fig id="pone.0149509.g010" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0149509.g010</object-id><label>Fig 10</label><caption><title>Case abolition rate of lower limb function.</title><p>BRC signifiantly suppressed abolition rate of lower limb function in ALS compared to placebo.</p></caption><graphic xlink:href="pone.0149509.g010"></graphic></fig></sec></sec><sec sec-type="conclusions" id="sec021"><title>Discussion</title><p>There are a limited number of therapeutic strategies that effectively relieve symptoms and improve the quality of life for ALS patients. Preclinical animal studies are an essential step on the path novel and effective therapeutic agents for the ALS. However, the outcomes of drug efficacy tests using animal models vary due to different methodological conditions such as the differences in giving pre-symptomatic versus post-symptomatic administration of agent [<xref rid="pone.0149509.ref020" ref-type="bibr">20</xref>]. In this regard, standard operating procedures for the preclinical animal study for ALS/MND has recently been published and strongly recommends the exclusive post-onset administration of candidate agents to approximate the clinical reality [<xref rid="pone.0149509.ref021" ref-type="bibr">21</xref>]. Previous studies have shown that dexpramipexole, a dopamine D2 receptor agonists used for Parkinson disease therapy might have the efficacy as an ALS treatment. Dexpramipexole is thought to enhance mitochondrial function and leads to increased survival and retention of motor function in <italic>in vivo</italic> models of ALS. Subsequently, EMPOWER, a phase 3 trial has shown that dexpramipexole although generally well tolerated did not differ from placebo in any prespecified efficacy endpoint measurement [<xref rid="pone.0149509.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0149509.ref023" ref-type="bibr">23</xref>]. BRC is a unique member of the class of dopamine D2 receptor agonists with <italic>in vitro</italic> antioxidant properties [<xref rid="pone.0149509.ref024" ref-type="bibr">24</xref>–<xref rid="pone.0149509.ref026" ref-type="bibr">26</xref>]. Our previous studies have also shown that BRC upregulates NAIP and protects neuronal cells against oxidative insults independent of D2 receptor function as outlined below as well as delayings disease progression of ALS mouse. Interestingly, dopamine receptor antagonists (SCH23390: D1 dopamine receptor antagonist, Sulpiride: D2&D3 dopamine receptor antagonist, Raclopride: D2 dopamine receptor antagonist) did not affect BRC dependent anti-oxidative stress activity [<xref rid="pone.0149509.ref027" ref-type="bibr">27</xref>]. Interestingly, the alleviation of motor neuronal dysfunction in ALS mice by a post-onset administration of BRC was unchangeable by the presence or absence of Riluzole [<xref rid="pone.0149509.ref027" ref-type="bibr">27</xref>]. Furthermore, the results of this study imply that BRC in the presence of Riluzole is safe and well tolerated. Although this study had a comparative low number of ALS patients for an effectiveness evaluation, our results showed the BRC group showed trend toward efficacy suggesting it could be an effective treatment for ALS. In both primary efficacy analyses I and II, the patients treated with BRC had greater residual functions of the upper and lower limbs as reflected in the ALSAQ40-communication, ALSAQ40-eating & drinking, and Grip strength scores when compared to placebos (Figs <xref ref-type="fig" rid="pone.0149509.g004">4</xref> and <xref ref-type="fig" rid="pone.0149509.g005">5</xref>). Moreover, total ALSFRS-R scores and neck flexion test also tended to stability (<xref ref-type="fig" rid="pone.0149509.g006">Fig 6</xref>). The patients with early stage ALS showed the greatest effect on clinical scores. ALS is a complex neuromuscular degenerative disease, with an as yet undelineated and likely therapeutically refractory molecular pathology; the expectation of a panacea must be viewed as low. In this regard BRC protects cells against oxidative stress, which may underlie neuronal dysfunction (and/or degeneration) and manifestation of ALS but might not indeed is unlikely to account for all aspects of pathogenesis. It is conceivable for example that BRC sustains motoneuronal function at least in part through suppression of oxidative stress. BRC sustained both ALSFRS-R and grip strength until the 1<sup>st</sup> endpoint but not the 2<sup>nd</sup>. On the other hand, BRC treated cases revealed some preservation of the Limb Norris and degree of neck flextion with 15mg/day dosing at the 2<sup>nd</sup> endpoint. In addition placebo treated cases showed progressive deterioration of lower limb muscle function which BRC slowed (<xref ref-type="fig" rid="pone.0149509.g010">Fig 10</xref>). In addition to these encouraging functional effects, the progressive eosinophilia in the placebo but not BRC group was noteworth (<xref ref-type="fig" rid="pone.0149509.g009">Fig 9</xref>). This is first report of the cumulative increase of eosinophil but not other blood cells including basophil, neutrophil, and lymphocyte with ALS disease progression. Although the role of eosinophils in ALS is not clear, an upregulation of eosinophil-derived neurotoxin (END) from ALS patients but not Alzheimer or Parkinson diseases patients has been reported [<xref rid="pone.0149509.ref028" ref-type="bibr">28</xref>]. This may be attributable to neuronal inflammation via induction of oxidative stress. Whether eosinophil can be used as a biomarker for ALS, will emerge from closer analysis of the relationship between the eosinophil including END and ALS progression. In conclusion, the efficacy and safety of BRC should be further explored by further investigation of phase 2b/3 clinical trial.</p></sec><sec sec-type="supplementary-material" id="sec022"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0149509.s001"><label>S1 CONSORT Checklist</label><caption><p>(DOC)</p></caption><media xlink:href="pone.0149509.s001.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0149509.s002"><label>S1 Protocol</label><caption><title>IRB protocol approved for the trial.</title><p>(PDF)</p></caption><media xlink:href="pone.0149509.s002.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank Prof. Alex MacKenzie (Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada) for fruitful discussion and encouragement in the preparation of this manuscript. This work was supported by Grant-of- Aid from Japanese Ministry of Health, Labor and welfare.</p><sec id="sec023"><title>ALS consortium investigators</title><list list-type="order"><list-item><p>Study director: Joh-E Ikeda, Molecular Neurology-CMIC, Faculty of Medicine, Kitasato University, Department of Molecular Life Science, Faculty of Medicine, Tokai University, Kanagawa, Japan, ARC/Children’s Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada</p></list-item><list-item><p>Researchers: Shigeharu Takagi, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Fumihito Yoshii, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Shunya Takizawa, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Eiichiro Nagata, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Tomohide Ohnuki, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Yasuhisa Kitagawa, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Yasuo Iwasaki, Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan; Yasunosuke Iwamoto, Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan; Mieko Ogino, Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan</p></list-item><list-item><p>Study contributors: Wako Takahashi, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Yuko Ohnuki, Department of Neurology, Tokai University School of Medicine, Isehara, Japan; Kyuichiro Onoue, General Institute of Medicine, Tokai University, Isehara, Japan</p></list-item><list-item><p>ALS treatment plan evaluation committee: <italic>Chairman</italic>: Ichiro Kanazawa, Chief Medical officer, Grand Steward’s Secretariat, Imperial Household Agency, Professor, International University of Health and Welfare Graduate School, Tochigi, Japan. <italic>Members</italic>: Shigeki Kuzuhara, Director, National Center of Neurology and Psychiatry, Tokyo, Japan; Yasuo Itoyama, Professor, Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Hajime Sobue, Professor, Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan</p></list-item></list></sec></ack><ref-list><title>References</title><ref id="pone.0149509.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Rowland</surname><given-names>LP</given-names></name>, <name><surname>Shneider</surname><given-names>NA</given-names></name>. <article-title>Amyotrophic lateral sclerosis</article-title>. <source><italic>N Engl J Med</italic></source>. <year>2001</year>; <volume>344</volume>: <fpage>1688</fpage>–<lpage>1700</lpage>. <pub-id pub-id-type="pmid">11386269</pub-id></mixed-citation></ref><ref id="pone.0149509.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Sreedharan</surname><given-names>J</given-names></name>, <name><surname>Brown</surname><given-names>RH</given-names><suffix>Jr</suffix></name>. <article-title>Amyotrophic lateral sclerosis: problems and prospects</article-title>. <source><italic>Ann Neurol</italic></source>. <year>2013</year>; <volume>74</volume>: <fpage>309</fpage>–<lpage>316</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/ana.24012">10.1002/ana.24012</ext-link></comment><pub-id pub-id-type="pmid">24038380</pub-id></mixed-citation></ref><ref id="pone.0149509.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>Barber</surname><given-names>SC</given-names></name>, <name><surname>Mead</surname><given-names>RJ</given-names></name>, <name><surname>Shaw</surname><given-names>PJ</given-names></name>. <article-title>Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target</article-title>. <source><italic>Biochem Biophys Acta</italic></source>. <year>2006</year>; <volume>1762</volume>: <fpage>1051</fpage>–<lpage>1067</lpage>. <pub-id pub-id-type="pmid">16713195</pub-id></mixed-citation></ref><ref id="pone.0149509.ref004"><label>4</label><mixed-citation publication-type="journal"><name><surname>Boillee</surname><given-names>S</given-names></name>, <name><surname>Vande Velde</surname><given-names>C</given-names></name>, <name><surname>Cleveland</surname><given-names>DW</given-names></name>. <article-title>ALS: a disease of motor neurons and their nonneuronal neighbors</article-title>. <source><italic>Neuron</italic></source>. <year>2006</year>; <volume>52</volume>: <fpage>39</fpage>–<lpage>59</lpage>. <pub-id pub-id-type="pmid">17015226</pub-id></mixed-citation></ref><ref id="pone.0149509.ref005"><label>5</label><mixed-citation publication-type="journal"><name><surname>Pasinelli</surname><given-names>P</given-names></name>, <name><surname>Brown</surname><given-names>RH</given-names></name>. <article-title>Molecular biology of amyotrophic lateral sclerosis from genetics</article-title>. <source><italic>Nat Rev Neurosci</italic></source>. <year>2006</year>; <volume>7</volume>: <fpage>710</fpage>–<lpage>723</lpage>. <pub-id pub-id-type="pmid">16924260</pub-id></mixed-citation></ref><ref id="pone.0149509.ref006"><label>6</label><mixed-citation publication-type="journal"><name><surname>Barber</surname><given-names>SC</given-names></name>, <name><surname>Shaw</surname><given-names>PJ</given-names></name>. <article-title>Oxidative stress in ALS: key role in motor neuron injury and therapeutic target</article-title>. <source><italic>Free Radic Biol Med</italic></source>. <year>2010</year>; <volume>48</volume>: <fpage>629</fpage>–<lpage>641</lpage>., 2010. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.freeradbiomed.2009.11.018">10.1016/j.freeradbiomed.2009.11.018</ext-link></comment><pub-id pub-id-type="pmid">19969067</pub-id></mixed-citation></ref><ref id="pone.0149509.ref007"><label>7</label><mixed-citation publication-type="journal"><name><surname>Rao</surname><given-names>SD</given-names></name>, <name><surname>Yin</surname><given-names>HZ</given-names></name>, <name><surname>Weiss</surname><given-names>JH</given-names></name>. <article-title>Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons</article-title>. <source><italic>J Neurosci</italic></source>. <year>2003</year>; <volume>23</volume>: <fpage>2627</fpage>–<lpage>2633</lpage>. <pub-id pub-id-type="pmid">12684448</pub-id></mixed-citation></ref><ref id="pone.0149509.ref008"><label>8</label><mixed-citation publication-type="journal"><name><surname>Liu</surname><given-names>Y</given-names></name>, <name><surname>Hao</surname><given-names>W</given-names></name>, <name><surname>Dawson</surname><given-names>A</given-names></name>, <name><surname>Liu</surname><given-names>S</given-names></name>, <name><surname>Fassbender</surname><given-names>K</given-names></name>. <article-title>Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2</article-title>. <source><italic>J Biol Chem</italic></source>. <year>2009</year>; <volume>284</volume>: <fpage>3691</fpage>–<lpage>3699</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1074/jbc.M804446200">10.1074/jbc.M804446200</ext-link></comment><pub-id pub-id-type="pmid">19091752</pub-id></mixed-citation></ref><ref id="pone.0149509.ref009"><label>9</label><mixed-citation publication-type="journal"><name><surname>Okada</surname><given-names>Y</given-names></name>, <name><surname>Sakai</surname><given-names>H</given-names></name>, <name><surname>Kohiki</surname><given-names>E</given-names></name>, <name><surname>Suga</surname><given-names>E</given-names></name>, <name><surname>Yanagisawa</surname><given-names>Y</given-names></name>, <name><surname>Tanaka</surname><given-names>K</given-names></name>, <etal>et al</etal><article-title>A dopamine D4 recptor antagonist attenuates ischemia-induced neuronal cell damage via upregulaton of neuronal of neuronal apoptosis inhibitory protein</article-title>. <source><italic>J Cereb Blood Flow</italic></source>. <year>2005</year>; <volume>25</volume>: <fpage>794</fpage>–<lpage>806</lpage>.</mixed-citation></ref><ref id="pone.0149509.ref010"><label>10</label><mixed-citation publication-type="journal"><name><surname>Roy</surname><given-names>N</given-names></name>, <name><surname>Mahadevan</surname><given-names>MS</given-names></name>, <name><surname>Mclean</surname><given-names>M</given-names></name>, <name><surname>Shutler</surname><given-names>G</given-names></name>, <name><surname>Yaraghi</surname><given-names>Z</given-names></name>, <name><surname>Farahani</surname><given-names>R</given-names></name>, <etal>et al</etal><article-title>The gene for apoptosis inhibitory protein is partially deleted in individuals with spinal muscle atrophy</article-title>. <source><italic>Cell</italic></source>. <year>1995</year>; <volume>80</volume>: <fpage>167</fpage>–<lpage>178</lpage>. <pub-id pub-id-type="pmid">7813013</pub-id></mixed-citation></ref><ref id="pone.0149509.ref011"><label>11</label><mixed-citation publication-type="journal"><name><surname>Liston</surname><given-names>P</given-names></name>, <name><surname>Roy</surname><given-names>N</given-names></name>, <name><surname>Tamai</surname><given-names>K</given-names></name>, <name><surname>Lefebvre</surname><given-names>C</given-names></name>, <name><surname>Baird</surname><given-names>S</given-names></name>, <name><surname>Cherton-Horvat</surname><given-names>G</given-names></name>, <etal>et al</etal><article-title>Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes</article-title>. <source><italic>Nature</italic></source>. <year>1996</year>; <volume>379</volume>: <fpage>349</fpage>–<lpage>353</lpage>. <pub-id pub-id-type="pmid">8552191</pub-id></mixed-citation></ref><ref id="pone.0149509.ref012"><label>12</label><mixed-citation publication-type="journal"><name><surname>Tanaka</surname><given-names>K</given-names></name>, <name><surname>Okada</surname><given-names>Y</given-names></name>, <name><surname>Kanno</surname><given-names>T</given-names></name>, <name><surname>Otomo</surname><given-names>A</given-names></name>, <name><surname>Yanagisawa</surname><given-names>Y</given-names></name>, <name><surname>Shouguchi-Miyata</surname><given-names>J</given-names></name>, <etal>et al</etal><article-title>A dopamine receptor antagonist L-745870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice</article-title>. <source><italic>Exp Neurol</italic></source>. <year>2008</year>; <volume>211</volume>: <fpage>378</fpage>–<lpage>386</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.expneurol.2008.02.004">10.1016/j.expneurol.2008.02.004</ext-link></comment><pub-id pub-id-type="pmid">18423451</pub-id></mixed-citation></ref><ref id="pone.0149509.ref013"><label>13</label><mixed-citation publication-type="journal"><name><surname>Tanaka</surname><given-names>K</given-names></name>, <name><surname>Kanno</surname><given-names>T</given-names></name>, <name><surname>Yanagisawa</surname><given-names>Y</given-names></name>, <name><surname>Yasutake</surname><given-names>K</given-names></name>, <name><surname>Inoue</surname><given-names>S</given-names></name>, <name><surname>Hirayama</surname><given-names>N</given-names></name>, <etal>et al</etal><article-title>A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model</article-title>. <source><italic>PLOS ONE</italic></source>. <year>2014</year>; <volume>9</volume>: <fpage>e87728</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1371/journal.pone.0087728">10.1371/journal.pone.0087728</ext-link></comment><pub-id pub-id-type="pmid">24498180</pub-id></mixed-citation></ref><ref id="pone.0149509.ref014"><label>14</label><mixed-citation publication-type="journal"><name><surname>Lim</surname><given-names>JH</given-names></name>, <name><surname>Kim</surname><given-names>KM</given-names></name>, <name><surname>Kim</surname><given-names>SW</given-names></name>, <name><surname>Hwang</surname><given-names>O</given-names></name>, <name><surname>Choi</surname><given-names>HJ</given-names></name>. <article-title>Bromocriptine activates NQo1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage</article-title>. <source><italic>Pharmacol Res</italic></source>. <year>2008</year>; <volume>57</volume>: <fpage>325</fpage>–<lpage>331</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.phrs.2008.03.004">10.1016/j.phrs.2008.03.004</ext-link></comment><pub-id pub-id-type="pmid">18455424</pub-id></mixed-citation></ref><ref id="pone.0149509.ref015"><label>15</label><mixed-citation publication-type="journal"><name><surname>Ludolph</surname><given-names>AC</given-names></name>, <name><surname>Bendotti</surname><given-names>C</given-names></name>, <name><surname>Blaugrund</surname><given-names>E</given-names></name>, <name><surname>Chio</surname><given-names>A</given-names></name>, <name><surname>Greensmith</surname><given-names>L</given-names></name>, <name><surname>Loeffler</surname><given-names>JP</given-names></name>, <etal>et al</etal><article-title>Guidline for preclinical animal research in ALS/MND: a consensus meeting</article-title>. <source><italic>Amyotroph Lateral Scler</italic></source>. <year>2010</year>; <volume>11</volume>: <fpage>38</fpage>–<lpage>45</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3109/17482960903545334">10.3109/17482960903545334</ext-link></comment><pub-id pub-id-type="pmid">20184514</pub-id></mixed-citation></ref><ref id="pone.0149509.ref016"><label>16</label><mixed-citation publication-type="journal"><name><surname>Bensimon</surname><given-names>G</given-names></name>, <name><surname>Lacomblez</surname><given-names>L</given-names></name>, <name><surname>Meininger</surname><given-names>V</given-names></name>. <article-title>A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole study group</article-title>. <source><italic>N Engl J Med</italic></source>. <year>1994</year>; <volume>330</volume>: <fpage>585</fpage>–<lpage>591</lpage>. <pub-id pub-id-type="pmid">8302340</pub-id></mixed-citation></ref><ref id="pone.0149509.ref017"><label>17</label><mixed-citation publication-type="journal"><name><surname>Miller</surname><given-names>RG</given-names></name>, <name><surname>Mitchell</surname><given-names>JD</given-names></name>, <name><surname>Lyon</surname><given-names>M</given-names></name>, <name><surname>Moore</surname><given-names>DH</given-names></name>. <article-title>Riluzole for amyotrophic latral sclerosis (ALS)/motor neuron disease (MND)</article-title>. <source>Cochrane Database Syst Rev</source>. CD001447, <year>2007</year>.</mixed-citation></ref><ref id="pone.0149509.ref018"><label>18</label><mixed-citation publication-type="journal"><name><surname>Mitsumoto</surname><given-names>H</given-names></name>, <name><surname>Brookd</surname><given-names>BR</given-names></name>, <name><surname>Silani</surname><given-names>V</given-names></name>. <article-title>Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?</article-title><source><italic>Lancet Neurol</italic></source>. <year>2014</year>; <volume>13</volume>: <fpage>1127</fpage>–<lpage>1138</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/S1474-4422(14)70129-2">10.1016/S1474-4422(14)70129-2</ext-link></comment><pub-id pub-id-type="pmid">25316019</pub-id></mixed-citation></ref><ref id="pone.0149509.ref019"><label>19</label><mixed-citation publication-type="journal"><name><surname>Brooks</surname><given-names>BR</given-names></name>, <name><surname>Miller</surname><given-names>RG</given-names></name>, <name><surname>Swash</surname><given-names>M</given-names></name>, <name><surname>Munsat</surname><given-names>TL</given-names></name>. <article-title>El Escorial revised: revised criteria for the diagnosis of amyotrophic lateral sclerosis</article-title>. <source><italic>Amyotroph Lateral Scler Other Motor Neuron Disord</italic></source>. <year>2000</year>; <volume>11</volume>: <fpage>497</fpage>–<lpage>501</lpage>.</mixed-citation></ref><ref id="pone.0149509.ref020"><label>20</label><mixed-citation publication-type="journal"><name><surname>Benatar</surname><given-names>M</given-names></name>. <article-title>Lost in translation: treatment trials in the SOD1 mouse and in human ALS</article-title>. <source><italic>Neurobiol Dis</italic></source>. <year>2007</year>; <volume>26</volume>: <fpage>1</fpage>–<lpage>13</lpage>. <pub-id pub-id-type="pmid">17300945</pub-id></mixed-citation></ref><ref id="pone.0149509.ref021"><label>21</label><mixed-citation publication-type="journal"><name><surname>Turner</surname><given-names>BJ</given-names></name>, <name><surname>Talbot</surname><given-names>K</given-names></name>. <article-title>Transgenics, toxicity and therapeutics in rodent models of disease progression in inherited amyotrophic lateral sclerosis</article-title>. <source><italic>Nat Neurosci</italic></source>. <year>2008</year>; <volume>11</volume>: <fpage>251</fpage>–<lpage>253</lpage>.<pub-id pub-id-type="pmid">18246065</pub-id></mixed-citation></ref><ref id="pone.0149509.ref022"><label>22</label><mixed-citation publication-type="journal"><name><surname>Cudkowicz</surname><given-names>M</given-names></name>, <name><surname>Bozik</surname><given-names>ME</given-names></name>, <name><surname>Ingersoll</surname><given-names>EW</given-names></name>, <name><surname>Miller</surname><given-names>R</given-names></name>, <name><surname>Mitsumoto</surname><given-names>H</given-names></name>, <name><surname>Shefner</surname><given-names>J</given-names></name>, <etal>et al</etal><article-title>The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis</article-title>. <source><italic>Lancet Neurol</italic></source>. <year>2011</year>; <volume>17</volume>: <fpage>1652</fpage>–<lpage>1657</lpage>.</mixed-citation></ref><ref id="pone.0149509.ref023"><label>23</label><mixed-citation publication-type="journal"><name><surname>Cudkowicz</surname><given-names>ME</given-names></name>, <name><surname>van den Berg</surname><given-names>LH</given-names></name>, <name><surname>Shefner</surname><given-names>JM</given-names></name>, <name><surname>Mitsumoto</surname><given-names>H</given-names></name>, <name><surname>Mora</surname><given-names>JS</given-names></name>, <name><surname>Ludolph</surname><given-names>A</given-names></name>, <etal>et al</etal><article-title>Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomized, double-blind, phase 3 trial</article-title>. <source><italic>Lancet Neurol</italic></source>. <year>2013</year>; <volume>12</volume>: <fpage>1059</fpage>–<lpage>1067</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/S1474-4422(13)70221-7">10.1016/S1474-4422(13)70221-7</ext-link></comment><pub-id pub-id-type="pmid">24067398</pub-id></mixed-citation></ref><ref id="pone.0149509.ref024"><label>24</label><mixed-citation publication-type="journal"><name><surname>Kondo</surname><given-names>T</given-names></name>, <name><surname>Ito</surname><given-names>T</given-names></name>, <name><surname>Sugita</surname><given-names>Y</given-names></name>. <article-title>Bromocriptine scavenges methamphetamine-induced hydroxyl radicals and attenuates dopamine depletion in mouse striatum</article-title>. <source><italic>Ann N Y Acad Sci</italic></source>. <year>1994</year>; <volume>738</volume>: <fpage>222</fpage>–<lpage>229</lpage>. <pub-id pub-id-type="pmid">7832431</pub-id></mixed-citation></ref><ref id="pone.0149509.ref025"><label>25</label><mixed-citation publication-type="journal"><name><surname>Ogawa</surname><given-names>N</given-names></name>, <name><surname>Tanaka</surname><given-names>K</given-names></name>, <name><surname>Asanuma</surname><given-names>M</given-names></name>, <name><surname>Kawai</surname><given-names>M</given-names></name>, <name><surname>Masumizu</surname><given-names>T</given-names></name>, <name><surname>Kohno</surname><given-names>M</given-names></name>, <etal>et al</etal><article-title>Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro</article-title>. <source><italic>Brain Res</italic></source>. <year>1994</year>; <volume>657</volume>: <fpage>207</fpage>–<lpage>213</lpage>. <pub-id pub-id-type="pmid">7820619</pub-id></mixed-citation></ref><ref id="pone.0149509.ref026"><label>26</label><mixed-citation publication-type="journal"><name><surname>Yoshikawa</surname><given-names>T</given-names></name>, <name><surname>Minamiyama</surname><given-names>Y</given-names></name>, <name><surname>Naito</surname><given-names>Y</given-names></name>, <name><surname>Kondo</surname><given-names>M</given-names></name>. <article-title>Antioxidant properties of bromocriptine, a dopamine agonist</article-title>. <source><italic>J Neurochem</italic></source>. <year>1994</year>; <volume>62</volume>: <fpage>1034</fpage>–<lpage>1038</lpage>. <pub-id pub-id-type="pmid">8113789</pub-id></mixed-citation></ref><ref id="pone.0149509.ref027"><label>27</label><mixed-citation publication-type="journal"><name><surname>Tanaka</surname><given-names>K</given-names></name>, <name><surname>Kanno</surname><given-names>T</given-names></name>, <name><surname>Yanagisawa</surname><given-names>Y</given-names></name>, <name><surname>Yasutake</surname><given-names>K</given-names></name>, <name><surname>Hadano</surname><given-names>S</given-names></name>, <name><surname>Yoshii</surname><given-names>F</given-names></name>, <etal>et al</etal><article-title>Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis</article-title>. <source><italic>Exp Neurol</italic></source>. <year>2011</year>; <volume>232</volume>: <fpage>21</fpage>–<lpage>52</lpage>.</mixed-citation></ref><ref id="pone.0149509.ref028"><label>28</label><mixed-citation publication-type="journal"><name><surname>Liu</surname><given-names>GT</given-names></name>, <name><surname>Hwang</surname><given-names>CS</given-names></name>, <name><surname>Hsieh</surname><given-names>CH</given-names></name>, <name><surname>Lu</surname><given-names>CH</given-names></name>, <name><surname>Chang</surname><given-names>SLY</given-names></name>, <name><surname>Huang</surname><given-names>CF</given-names></name>, <etal>et al</etal><article-title>Eosinophil-derived neurotoxin is elevated in patients with amyotrophic lateral sclerosis</article-title>. <source><italic>Mediators Inflamm</italic></source>. <year>2013</year>; <volume>2013</volume>: <fpage>1</fpage>–<lpage>7</lpage>.</mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000152 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000152 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Canada
|area= ParkinsonCanadaV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:4765990
|texte= Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:26910108" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonCanadaV1
| This area was generated with Dilib version V0.6.29. |  |