title: Biological safety assessment of docosahexaenoic acid supplementation in a randomized clinical trial for X-linked retinitis pigmentosa.
abstract: BACKGROUND
  In a 4-year placebo-controlled trial to elevate blood docosahexaenoic acid levels in patients with X-linked retinitis pigmentosa (XLRP), the goal was to assess the potential benefit of docosahexaenoic acid supplementation in altering disease progression. However, docosahexaenoic acid (22:6omega3) is a highly unsaturated fatty acid and considered a target molecule for free-radical oxidative damage. Thus, nutritional provision of docosahexaenoic acid might lead to an increase in antioxidant stress. Additional concerns, such as decreased platelet aggregation, increased bleeding time, and alterations in lipoprotein cholesterol levels, have been reported in supplementation studies with long-chain polyunsaturates.
  
  
  OBJECTIVE
  To assess the biological safety of long-term docosahexaenoic acid supplementation.
  
  
  METHODS
  Forty-four male patients (mean age, 16 years) enrolled in a randomized, double-masked, clinical trial and received docosahexaenoic acid, 400 mg/d, or placebo. Blood samples were collected every 6 months. Biological safety analysis included fatty acids, vitamin A and E concentrations, antioxidant capacity, platelet aggregation, alanine aminotransferase activity, and lipoprotein cholesterol and triglyceride profiles.
  
  
  RESULTS
  Mean plasma docosahexaenoic acid levels were elevated 2.5-fold by supplementation compared with baseline. Patients receiving placebo capsules exhibited no change (P =.35) in plasma docosahexaenoic acid content. All adverse events reported were minor and equivalently distributed between groups. Plasma vitamin A concentrations remained unchanged during the trial. Mean plasma vitamin E concentrations were correlated with age (P =.005), such that as patients with XLRP matured, plasma vitamin E concentrations increased to approach normal values. There was a trend (P =.10) toward lower mean vitamin E concentrations in the docosahexaenoic acid-supplemented group after 4 years. Docosahexaenoic acid supplementation did not compromise plasma antioxidant capacity, platelet aggregation, liver function enzyme activity, or plasma lipoprotein lipid content in patients with XLRP.
  
  
  CONCLUSIONS
  Long-term docosahexaenoic acid supplementation to patients with XLRP was associated with no identifiable safety risks in this 4-year clinical trial.
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX 75231, USA. dwheaton@retinafoundation.org
authors.forename: Dianna H
authors.initials: DH
authors.lastname: Wheaton
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Hoffman
authors.forename: Kirsten G
authors.initials: KG
authors.lastname: Locke
authors.forename: Reginald B
authors.initials: RB
authors.lastname: Watkins
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
mesh_terms: D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000975:Antioxidants / Q000378:metabolism; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D019587:Dietary Supplements; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000097:blood; D004311:Double-Blind Method; D005227:Fatty Acids / Q000097:blood; D040181:Genetic Diseases, X-Linked / Q000097:blood / Q000503:physiopathology*; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008297:Male; D010974:Platelet Aggregation; D012174:Retinitis Pigmentosa / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D012449:Safety; D014280:Triglycerides / Q000097:blood; D014801:Vitamin A / Q000097:blood; D014810:Vitamin E / Q000097:blood
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D008074:Lipoproteins; D014280:Triglycerides; C030104:lipoprotein cholesterol; D014801:Vitamin A; D014810:Vitamin E; D004281:Docosahexaenoic Acids; D002784:Cholesterol; D000410:Alanine Transaminase