The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: A randomized crossover clinical trial
Identifieur interne : 000017 ( France/Analysis ); précédent : 000016; suivant : 000018The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: A randomized crossover clinical trial
Auteurs : Jean-Christophe Corvol [France] ; Cécilia Bonnet [France] ; Fanny Charbonnier-Beaupel [France] ; Anne-Marie Bonnet [France] ; Marie-Hélène Fiévet ; Agnès Bellanger ; Emmanuel Roze [France] ; Gayané Meliksetyan [France] ; Mouna Ben Djebara [France] ; Andreas Hartmann [France] ; Lucette Lacomblez [France] ; Cédric Vrignaud [France] ; Noël Zahr [France] ; Yves Agid [France] ; Jean Costentin [France] ; Jean-Sébastien Hulot [France] ; Marie Vidailhet [France]Source :
- Annals of Neurology [ 0364-5134 ] ; 2011-01.
Abstract
Objective: In Parkinson disease (PD), the selective C‐O‐methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL), or low (Met/Met, COMTLL). The objective of this study was to determine the response to entacapone in COMTHH and COMTLL PD patients. Methods: Thirty‐three PD patients, homozygous for the COMT alleles COMTHH (n = 17) and COMTLL (n = 16), were randomized in a double‐blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. Results: The gain in the best ON time was higher in COMTHH than in COMTLL patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMTHH than in COMTLL patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMTHH than in COMTLL patients (−0.54 ± 0.07 vs −0.31 ± 0.06 pmol/min/mg protein, p = 0.02). Interpretation: The COMTHH genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. ANN NEUROL 2011;;69:111–118.
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DOI: 10.1002/ana.22155
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Investigation Center (CIC‐9503), Pitié‐Salpêtrière Hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC‐9503), Pitié‐Salpêtrière Hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), UMRS_975 unit, CRICM (Research Center of the Brain and Spine Insitute), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Department of Pharmacology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>UPMC (Pierre and Marie Curie university), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), UMRS_678 unit, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Vrignaud, Cedric" sort="Vrignaud, Cedric" uniqKey="Vrignaud C" first="Cédric" last="Vrignaud">Cédric Vrignaud</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Department of Pharmacology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Zahr, Noel" sort="Zahr, Noel" uniqKey="Zahr N" first="Noël" last="Zahr">Noël Zahr</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Department of Pharmacology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC‐9503), Pitié‐Salpêtrière Hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName><orgName type="hospital" n="4">Hôpital de la Salpêtrière</orgName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName><orgName type="hospital" n="4">Hôpital de la Salpêtrière</orgName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>UPMC (Pierre and Marie Curie university), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName><orgName type="hospital" n="4">Hôpital de la Salpêtrière</orgName></affiliation></author><author><name sortKey="Costentin, Jean" sort="Costentin, Jean" uniqKey="Costentin J" first="Jean" last="Costentin">Jean Costentin</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Neuropharmacology Laboratory, University of Rouen, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Hulot, Jean Ebastien" sort="Hulot, Jean Ebastien" uniqKey="Hulot J" first="Jean-Sébastien" last="Hulot">Jean-Sébastien Hulot</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Department of Pharmacology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>UPMC (Pierre and Marie Curie university), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC‐9503), Pitié‐Salpêtrière Hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié‐Salpêtrière hospital, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>UPMC (Pierre and Marie Curie university), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM (French National Institute of Medical Research and Health), UMRS_975 unit, CRICM (Research Center of the Brain and Spine Insitute), Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-01">2011-01</date><biblScope unit="volume">69</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="111">111</biblScope><biblScope unit="page" to="118">118</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">B5DD2B27B16748C39AFFC4F06B24BA888850268E</idno><idno type="DOI">10.1002/ana.22155</idno><idno type="ArticleID">ANA22155</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: In Parkinson disease (PD), the selective C‐O‐methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL), or low (Met/Met, COMTLL). The objective of this study was to determine the response to entacapone in COMTHH and COMTLL PD patients. Methods: Thirty‐three PD patients, homozygous for the COMT alleles COMTHH (n = 17) and COMTLL (n = 16), were randomized in a double‐blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. Results: The gain in the best ON time was higher in COMTHH than in COMTLL patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMTHH than in COMTLL patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMTHH than in COMTLL patients (−0.54 ± 0.07 vs −0.31 ± 0.06 pmol/min/mg protein, p = 0.02). Interpretation: The COMTHH genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. ANN NEUROL 2011;;69:111–118.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li><li>Rouen</li></settlement><orgName><li>Hôpital de la Salpêtrière</li><li>Université Pierre-et-Marie-Curie</li></orgName></list><tree><noCountry><name sortKey="Bellanger, Agnes" sort="Bellanger, Agnes" uniqKey="Bellanger A" first="Agnès" last="Bellanger">Agnès Bellanger</name><name sortKey="Fievet, Marie Elene" sort="Fievet, Marie Elene" uniqKey="Fievet M" first="Marie-Hélène" last="Fiévet">Marie-Hélène Fiévet</name></noCountry><country name="France"><noRegion><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name></noRegion><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><name sortKey="Ben Djebara, Mouna" sort="Ben Djebara, Mouna" uniqKey="Ben Djebara M" first="Mouna" last="Ben Djebara">Mouna Ben Djebara</name><name sortKey="Bonnet, Anne Arie" sort="Bonnet, Anne Arie" uniqKey="Bonnet A" first="Anne-Marie" last="Bonnet">Anne-Marie Bonnet</name><name sortKey="Bonnet, Cecilia" sort="Bonnet, Cecilia" uniqKey="Bonnet C" first="Cécilia" last="Bonnet">Cécilia Bonnet</name><name sortKey="Charbonnier Eaupel, Fanny" sort="Charbonnier Eaupel, Fanny" uniqKey="Charbonnier Eaupel F" first="Fanny" last="Charbonnier-Beaupel">Fanny Charbonnier-Beaupel</name><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Costentin, Jean" sort="Costentin, Jean" uniqKey="Costentin J" first="Jean" last="Costentin">Jean Costentin</name><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name><name sortKey="Hulot, Jean Ebastien" sort="Hulot, Jean Ebastien" uniqKey="Hulot J" first="Jean-Sébastien" last="Hulot">Jean-Sébastien Hulot</name><name sortKey="Hulot, Jean Ebastien" sort="Hulot, Jean Ebastien" uniqKey="Hulot J" first="Jean-Sébastien" last="Hulot">Jean-Sébastien Hulot</name><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><name sortKey="Meliksetyan, Gayane" sort="Meliksetyan, Gayane" uniqKey="Meliksetyan G" first="Gayané" last="Meliksetyan">Gayané Meliksetyan</name><name sortKey="Roze, Emmanuel" sort="Roze, Emmanuel" uniqKey="Roze E" first="Emmanuel" last="Roze">Emmanuel Roze</name><name sortKey="Roze, Emmanuel" sort="Roze, Emmanuel" uniqKey="Roze E" first="Emmanuel" last="Roze">Emmanuel Roze</name><name sortKey="Roze, Emmanuel" sort="Roze, Emmanuel" uniqKey="Roze E" first="Emmanuel" last="Roze">Emmanuel Roze</name><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><name sortKey="Vrignaud, Cedric" sort="Vrignaud, Cedric" uniqKey="Vrignaud C" first="Cédric" last="Vrignaud">Cédric Vrignaud</name><name sortKey="Zahr, Noel" sort="Zahr, Noel" uniqKey="Zahr N" first="Noël" last="Zahr">Noël Zahr</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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