A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease
Identifieur interne : 002531 ( Istex/Corpus ); précédent : 002530; suivant : 002532A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease
Auteurs : Olivier Rascol ; Joaquim Ferreira ; Laurence Nègre-Pages ; Santiago Perez-Lloret ; Lucette Lacomblez ; Monique Galitzky ; Jean-Christophe Lemarié ; Jean-Christophe Corvol ; Jonathan M. Brotchie ; Laura BossiSource :
- Fundamental & Clinical Pharmacology [ 0767-3981 ] ; 2012-08.
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Abstract
To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.
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DOI: 10.1111/j.1472-8206.2011.00951.x
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Brotchie</name><affiliation><mods:affiliation>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</mods:affiliation></affiliation></author><author><name sortKey="Bossi, Laura" sort="Bossi, Laura" uniqKey="Bossi L" first="Laura" last="Bossi">Laura Bossi</name><affiliation><mods:affiliation>Faust Pharmaceutical, Illkirch Graffenstaden, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Fundamental & Clinical Pharmacology</title><idno type="ISSN">0767-3981</idno><idno type="eISSN">1472-8206</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2012-08">2012-08</date><biblScope unit="volume">26</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="557">557</biblScope><biblScope unit="page" to="564">564</biblScope></imprint><idno type="ISSN">0767-3981</idno></series><idno type="istex">4CECFC3291A09995B8913637D0B2BDB70DE0BD07</idno><idno type="DOI">10.1111/j.1472-8206.2011.00951.x</idno><idno type="ArticleID">FCP951</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0767-3981</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson’s disease</term><term>dyskinesia</term><term>glutamate</term><term>naftazone</term><term>n‐of‐1 trial</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Olivier Rascol</name><affiliations><json:string>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</json:string><json:string>INSERM CIC9023 and UMR 825, Toulouse, France</json:string><json:string>E-mail: rascol@cict.fr</json:string></affiliations></json:item><json:item><name>Joaquim Ferreira</name><affiliations><json:string>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</json:string></affiliations></json:item><json:item><name>Laurence Nègre‐Pages</name><affiliations><json:string>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</json:string><json:string>INSERM CIC9023 and UMR 825, Toulouse, France</json:string><json:string>LN‐Pharma, Neurosciences & Neuro‐epidemiology research unit, Toulouse, France</json:string></affiliations></json:item><json:item><name>Santiago Perez‐Lloret</name><affiliations><json:string>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</json:string><json:string>INSERM CIC9023 and UMR 825, Toulouse, France</json:string></affiliations></json:item><json:item><name>Lucette Lacomblez</name><affiliations><json:string>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris, France</json:string></affiliations></json:item><json:item><name>Monique Galitzky</name><affiliations><json:string>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</json:string><json:string>INSERM CIC9023 and UMR 825, Toulouse, France</json:string></affiliations></json:item><json:item><name>Jean‐Christophe Lemarié</name><affiliations><json:string>Effi‐Stat, Paris, France</json:string></affiliations></json:item><json:item><name>Jean‐Christophe Corvol</name><affiliations><json:string>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013, France</json:string><json:string>UMPC, Pharmacologie, Paris 6, France</json:string><json:string>INSERM, CIC 9503, Paris F‐75013, France</json:string></affiliations></json:item><json:item><name>Jonathan M. Brotchie</name><affiliations><json:string>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</json:string></affiliations></json:item><json:item><name>Laura Bossi</name><affiliations><json:string>Faust Pharmaceutical, Illkirch Graffenstaden, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>dyskinesia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>glutamate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>naftazone</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>n‐of‐1 trial</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson’s disease</value></json:item></subject><articleId><json:string>FCP951</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). 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type="first">Joaquim</forename><surname>Ferreira</surname></persName><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation></author><author xml:id="author-3"><persName><forename type="first">Laurence</forename><surname>Nègre‐Pages</surname></persName><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation><affiliation>LN‐Pharma, Neurosciences & Neuro‐epidemiology research unit, Toulouse, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Santiago</forename><surname>Perez‐Lloret</surname></persName><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">Lucette</forename><surname>Lacomblez</surname></persName><affiliation>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Monique</forename><surname>Galitzky</surname></persName><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation></author><author xml:id="author-7"><persName><forename type="first">Jean‐Christophe</forename><surname>Lemarié</surname></persName><affiliation>Effi‐Stat, Paris, France</affiliation></author><author xml:id="author-8"><persName><forename type="first">Jean‐Christophe</forename><surname>Corvol</surname></persName><affiliation>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013, France</affiliation><affiliation>UMPC, Pharmacologie, Paris 6, France</affiliation><affiliation>INSERM, CIC 9503, Paris F‐75013, France</affiliation></author><author xml:id="author-9"><persName><forename type="first">Jonathan M.</forename><surname>Brotchie</surname></persName><affiliation>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</affiliation></author><author xml:id="author-10"><persName><forename type="first">Laura</forename><surname>Bossi</surname></persName><affiliation>Faust Pharmaceutical, Illkirch Graffenstaden, France</affiliation></author></analytic><monogr><title level="j">Fundamental & Clinical Pharmacology</title><idno type="pISSN">0767-3981</idno><idno type="eISSN">1472-8206</idno><idno type="DOI">10.1111/(ISSN)1472-8206</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2012-08"></date><biblScope unit="volume">26</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="557">557</biblScope><biblScope unit="page" to="564">564</biblScope></imprint></monogr><idno type="istex">4CECFC3291A09995B8913637D0B2BDB70DE0BD07</idno><idno type="DOI">10.1111/j.1472-8206.2011.00951.x</idno><idno type="ArticleID">FCP951</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>dyskinesia</term></item><item><term>glutamate</term></item><item><term>naftazone</term></item><item><term>n‐of‐1 trial</term></item><item><term>Parkinson’s disease</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>ORIGINAL ARTICLE</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/4CECFC3291A09995B8913637D0B2BDB70DE0BD07/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1472-8206</doi><issn type="print">0767-3981</issn><issn type="electronic">1472-8206</issn><idGroup><id type="product" value="FCP"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="FUNDAMENTAL CLINICAL PHARMACOLOGY">Fundamental & Clinical Pharmacology</title></titleGroup></publicationMeta><publicationMeta level="part" position="08104"><doi origin="wiley">10.1111/fcp.2012.26.issue-4</doi><numberingGroup><numbering type="journalVolume" number="26">26</numbering><numbering type="journalIssue" number="4">4</numbering></numberingGroup><coverDate startDate="2012-08">August 2012</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="13" status="forIssue"><doi origin="wiley">10.1111/j.1472-8206.2011.00951.x</doi><idGroup><id type="unit" value="FCP951"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="tocHeading1">ORIGINAL ARTICLES</title><title type="tocHeading2">CLINICAL PHARMACOLOGY</title><title type="articleCategory">ORIGINAL ARTICLE</title></titleGroup><copyright>© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique</copyright><eventGroup><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:3.1.5.1 mode:FullText" date="2012-07-05"></event><event type="publishedOnlineEarlyUnpaginated" date="2011-05-18"></event><event type="firstOnline" date="2011-05-18"></event><event type="publishedOnlineFinalForm" date="2012-07-05"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-12"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.3.4 mode:FullText" date="2015-02-25"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="557">557</numbering><numbering type="pageLast" number="564">564</numbering></numberingGroup><correspondenceTo> Correspondence and reprints:
<email>rascol@cict.fr</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:FCP.FCP951.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 23 November 2010; revised 23 February 2011; accepted 6 April 2011</unparsedEditorialHistory><countGroup><count type="figureTotal" number="2"></count><count type="tableTotal" number="2"></count></countGroup><titleGroup><title type="main">A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease</title><title type="shortAuthors">O. Rascol <i>et al.</i></title><title type="short"><i>Multiple cross‐over (n‐of‐1) study of naftazone in Parkinson’s disease</i></title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1 #a2" corresponding="yes"><personName><givenNames>Olivier</givenNames><familyName>Rascol</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a3"><personName><givenNames>Joaquim</givenNames><familyName>Ferreira</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1 #a2 #a4"><personName><givenNames>Laurence</givenNames><familyName>Nègre‐Pages</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1 #a2"><personName><givenNames>Santiago</givenNames><familyName>Perez‐Lloret</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a5"><personName><givenNames>Lucette</givenNames><familyName>Lacomblez</familyName></personName></creator><creator creatorRole="author" xml:id="cr6" affiliationRef="#a1 #a2"><personName><givenNames>Monique</givenNames><familyName>Galitzky</familyName></personName></creator><creator creatorRole="author" xml:id="cr7" affiliationRef="#a6"><personName><givenNames>Jean‐Christophe</givenNames><familyName>Lemarié</familyName></personName></creator><creator creatorRole="author" xml:id="cr8" affiliationRef="#a7 #a8 #a9"><personName><givenNames>Jean‐Christophe</givenNames><familyName>Corvol</familyName></personName></creator><creator creatorRole="author" xml:id="cr9" affiliationRef="#a10"><personName><givenNames>Jonathan M.</givenNames><familyName>Brotchie</familyName></personName></creator><creator creatorRole="author" xml:id="cr10" affiliationRef="#a11"><personName><givenNames>Laura</givenNames><familyName>Bossi</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="FR"><unparsedAffiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="FR"><unparsedAffiliation>INSERM CIC9023 and UMR 825, Toulouse, France</unparsedAffiliation></affiliation><affiliation xml:id="a3" countryCode="PT"><unparsedAffiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</unparsedAffiliation></affiliation><affiliation xml:id="a4" countryCode="FR"><unparsedAffiliation>LN‐Pharma, Neurosciences & Neuro‐epidemiology research unit, Toulouse, France</unparsedAffiliation></affiliation><affiliation xml:id="a5" countryCode="FR"><unparsedAffiliation>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris, France</unparsedAffiliation></affiliation><affiliation xml:id="a6" countryCode="FR"><unparsedAffiliation>Effi‐Stat, Paris, France</unparsedAffiliation></affiliation><affiliation xml:id="a7" countryCode="FR"><unparsedAffiliation>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013, France</unparsedAffiliation></affiliation><affiliation xml:id="a8" countryCode="FR"><unparsedAffiliation>UMPC, Pharmacologie, Paris 6, France</unparsedAffiliation></affiliation><affiliation xml:id="a9" countryCode="FR"><unparsedAffiliation>INSERM, CIC 9503, Paris F‐75013, France</unparsedAffiliation></affiliation><affiliation xml:id="a10" countryCode="CA"><unparsedAffiliation>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</unparsedAffiliation></affiliation><affiliation xml:id="a11" countryCode="FR"><unparsedAffiliation>Faust Pharmaceutical, Illkirch Graffenstaden, France</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">dyskinesia</keyword><keyword xml:id="k2">glutamate</keyword><keyword xml:id="k3">naftazone</keyword><keyword xml:id="k4">n‐of‐1 trial</keyword><keyword xml:id="k5">Parkinson’s disease</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects <sc>anova</sc>. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, <i>P</i> = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], <i>P</i> = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], <i>P</i> = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Multiple cross‐over (n‐of‐1) study of naftazone in Parkinson’s disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease</title></titleInfo><name type="personal"><namePart type="given">Olivier</namePart><namePart type="family">Rascol</namePart><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation><affiliation>E-mail: rascol@cict.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joaquim</namePart><namePart type="family">Ferreira</namePart><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurence</namePart><namePart type="family">Nègre‐Pages</namePart><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation><affiliation>LN‐Pharma, Neurosciences & Neuro‐epidemiology research unit, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Santiago</namePart><namePart type="family">Perez‐Lloret</namePart><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lucette</namePart><namePart type="family">Lacomblez</namePart><affiliation>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Monique</namePart><namePart type="family">Galitzky</namePart><affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</affiliation><affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐Christophe</namePart><namePart type="family">Lemarié</namePart><affiliation>Effi‐Stat, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐Christophe</namePart><namePart type="family">Corvol</namePart><affiliation>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013, France</affiliation><affiliation>UMPC, Pharmacologie, Paris 6, France</affiliation><affiliation>INSERM, CIC 9503, Paris F‐75013, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonathan M.</namePart><namePart type="family">Brotchie</namePart><affiliation>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laura</namePart><namePart type="family">Bossi</namePart><affiliation>Faust Pharmaceutical, Illkirch Graffenstaden, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2012-08</dateIssued><edition>Received 23 November 2010; revised 23 February 2011; accepted 6 April 2011</edition><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">2</extent><extent unit="tables">2</extent></physicalDescription><abstract lang="en">To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.</abstract><subject lang="en"><genre>keywords</genre><topic>dyskinesia</topic><topic>glutamate</topic><topic>naftazone</topic><topic>n‐of‐1 trial</topic><topic>Parkinson’s disease</topic></subject><relatedItem type="host"><titleInfo><title>Fundamental & Clinical Pharmacology</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>ORIGINAL ARTICLE</topic></subject><identifier type="ISSN">0767-3981</identifier><identifier type="eISSN">1472-8206</identifier><identifier type="DOI">10.1111/(ISSN)1472-8206</identifier><identifier type="PublisherID">FCP</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>26</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>557</start><end>564</end><total>8</total></extent></part></relatedItem><identifier type="istex">4CECFC3291A09995B8913637D0B2BDB70DE0BD07</identifier><identifier type="DOI">10.1111/j.1472-8206.2011.00951.x</identifier><identifier type="ArticleID">FCP951</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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