title: Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis.
abstract: BACKGROUND
  A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis.
  
  
  METHODS
  Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 months).
  
  
  RESULTS
  Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment.
  
  
  CONCLUSIONS
  Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine , Matsumoto , Japan .
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sekijima
authors.forename: Kana
authors.initials: K
authors.lastname: Tojo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morita
authors.forename: Jun
authors.initials: J
authors.lastname: Koyama
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D028226:Amyloidosis, Familial / Q000188:drug therapy* / Q000378:metabolism*; D004061:Diflunisal / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011228:Prealbumin / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D011228:Prealbumin; D004061:Diflunisal
keywords: Amyloid; clinical trial; diflunisal; familial amyloid polyneuropathy; hereditary ATTR amyloidosis; transthyretin