A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease
Identifieur interne : 002531 ( Istex/Curation ); 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 [France] ; Joaquim Ferreira [Portugal] ; Laurence Nègre-Pages [France] ; Santiago Perez-Lloret [France] ; Lucette Lacomblez [France] ; Monique Galitzky [France] ; Jean-Christophe Lemarié [France] ; Jean-Christophe Corvol [France] ; Jonathan M. Brotchie [Canada] ; Laura Bossi [France]Source :
- 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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sortKey="Perez Loret, Santiago" sort="Perez Loret, Santiago" uniqKey="Perez Loret S" first="Santiago" last="Perez-Lloret">Santiago Perez-Lloret</name><affiliation wicri:level="1"><mods:affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM CIC9023 and UMR 825, Toulouse</wicri:regionArea></affiliation></author><author><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><affiliation wicri:level="1"><mods:affiliation>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Clinical Pharmacology, Hopital Pitié‐Salpétriêre, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Galitzky, Monique" sort="Galitzky, Monique" uniqKey="Galitzky M" first="Monique" last="Galitzky">Monique Galitzky</name><affiliation wicri:level="1"><mods:affiliation>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Departments of Clinical Pharmacology and Neurosciences, Hospital and University Paul Sabatier of Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>INSERM CIC9023 and UMR 825, Toulouse, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM CIC9023 and UMR 825, Toulouse</wicri:regionArea></affiliation></author><author><name sortKey="Lemarie, Jean Hristophe" sort="Lemarie, Jean Hristophe" uniqKey="Lemarie J" first="Jean-Christophe" last="Lemarié">Jean-Christophe Lemarié</name><affiliation wicri:level="1"><mods:affiliation>Effi‐Stat, Paris, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Effi‐Stat, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><affiliation wicri:level="1"><mods:affiliation>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>APHP, Service de Pharmacologie, Hôpital de la Salpêtrière, Paris F‐75013</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>UMPC, Pharmacologie, Paris 6, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>UMPC, Pharmacologie, Paris 6</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>INSERM, CIC 9503, Paris F‐75013, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM, CIC 9503, Paris F‐75013</wicri:regionArea></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><mods:affiliation>Toronto Western Research Institute, University Health Network, Toronto, ON, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, ON</wicri:regionArea></affiliation></author><author><name sortKey="Bossi, Laura" sort="Bossi, Laura" uniqKey="Bossi L" first="Laura" last="Bossi">Laura Bossi</name><affiliation wicri:level="1"><mods:affiliation>Faust Pharmaceutical, Illkirch Graffenstaden, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Faust Pharmaceutical, Illkirch Graffenstaden</wicri:regionArea></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></record>Pour manipuler ce document sous Unix (Dilib)
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