title: A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.
abstract: Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. wintrone@mail.nih.gov
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Introne
authors.forename: Monique B
authors.initials: MB
authors.lastname: Perry
authors.forename: James
authors.initials: J
authors.lastname: Troendle
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsilou
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kayser
authors.forename: Pim
authors.initials: P
authors.lastname: Suwannarat
authors.forename: Kevin E
authors.initials: KE
authors.lastname: O'Brien
authors.forename: Joy
authors.initials: J
authors.lastname: Bryant
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moylan
authors.forename: Isa
authors.initials: I
authors.lastname: Bernardini
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors*; D000328:Adult; D000474:Alkaptonuria / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003512:Cyclohexanones / Q000627:therapeutic use*; D006713:Homogentisic Acid / Q000097:blood / Q000652:urine; D006801:Humans; D008875:Middle Aged; D009579:Nitrobenzoates / Q000627:therapeutic use*; D011446:Prospective Studies; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003512:Cyclohexanones; D009579:Nitrobenzoates; D014443:Tyrosine; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone; D006713:Homogentisic Acid