Sodium phenylbutyrate in Huntington's disease: a dose-finding study.
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.
Hogarth
Penelope
P
Department of Neurology, Oregon Health & Science University, Portland, Oregon 97239-3098, USA. hogarthp@ohsu.edu
Lovrecic
Luca
L
Krainc
Dimitri
D
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005819:Genetic Markers / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010654:Phenylbutyrates / Q000008:administration & dosage* / Q000633:toxicity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012964:Sodium / Q000008:administration & dosage / Q000633:toxicity
D005819:Genetic Markers; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D012333:RNA, Messenger; D012964:Sodium