Sodium phenylbutyrate in Huntington's disease: a dose-finding study.
Identifieur interne : 001D95 ( Ncbi/Checkpoint ); précédent : 001D94; suivant : 001D96Sodium phenylbutyrate in Huntington's disease: a dose-finding study.
Auteurs : Penelope Hogarth [États-Unis] ; Luca Lovrecic ; Dimitri KraincSource :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2007.
English descriptors
- KwdEn :
- Adult, Aged, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Gene Expression (drug effects), Genetic Markers (genetics), Histone Deacetylase Inhibitors, Humans, Huntington Disease (drug therapy), Huntington Disease (genetics), Lymphocytes (metabolism), Male, Middle Aged, Phenylbutyrates (administration & dosage), Phenylbutyrates (toxicity), Polymerase Chain Reaction, RNA, Messenger (genetics), Sodium (administration & dosage), Sodium (toxicity).
- MESH :
- chemical , administration & dosage : Phenylbutyrates, Sodium.
- chemical , genetics : Genetic Markers, RNA, Messenger.
- drug effects : Gene Expression.
- drug therapy : Huntington Disease.
- genetics : Huntington Disease.
- metabolism : Lymphocytes.
- chemical , toxicity : Phenylbutyrates, Sodium.
- Adult, Aged, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Histone Deacetylase Inhibitors, Humans, Male, Middle Aged, Polymerase Chain Reaction.
Abstract
Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD.
DOI: 10.1002/mds.21632
PubMed: 17702032
Affiliations:
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Neurology, Oregon Health & Science University, Portland, Oregon 97239-3098, USA. hogarthp@ohsu.edu</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, Oregon 97239-3098</wicri:regionArea><orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName><placeName><settlement type="city">Portland</settlement><region type="state">Oregon</region></placeName></affiliation></author><author><name sortKey="Lovrecic, Luca" sort="Lovrecic, Luca" uniqKey="Lovrecic L" first="Luca" last="Lovrecic">Luca Lovrecic</name></author><author><name sortKey="Krainc, Dimitri" sort="Krainc, Dimitri" uniqKey="Krainc D" first="Dimitri" last="Krainc">Dimitri Krainc</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="ISSN">0885-3185</idno><imprint><date when="2007" 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xml:lang="en"><term>Phenylbutyrates</term><term>Sodium</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Genetic Markers</term><term>RNA, Messenger</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Gene Expression</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lymphocytes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Phenylbutyrates</term><term>Sodium</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Dose-Response Relationship, Drug</term><term>Drug Administration Schedule</term><term>Female</term><term>Histone Deacetylase Inhibitors</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Oregon</li></region><settlement><li>Portland</li></settlement><orgName><li>Université des sciences et de la médecine de l'Oregon</li></orgName></list><tree><noCountry><name sortKey="Krainc, Dimitri" sort="Krainc, Dimitri" uniqKey="Krainc D" first="Dimitri" last="Krainc">Dimitri Krainc</name><name sortKey="Lovrecic, Luca" sort="Lovrecic, Luca" uniqKey="Lovrecic L" first="Luca" last="Lovrecic">Luca Lovrecic</name></noCountry><country name="États-Unis"><region name="Oregon"><name sortKey="Hogarth, Penelope" sort="Hogarth, Penelope" uniqKey="Hogarth P" first="Penelope" last="Hogarth">Penelope Hogarth</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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