title: Association of drug-serum protein adducts and anti-drug antibodies in dogs with sulphonamide hypersensitivity: a naturally occurring model of idiosyncratic drug toxicity.
abstract: BACKGROUND
  Sulphonamide antimicrobials, such as sulphamethoxazole (SMX), provide effective infection prophylaxis in immunocompromised patients, but can lead to drug hypersensitivity (HS) reactions. These reactions also occur in dogs, with a similar time course and clinical presentation as seen in humans.
  
  
  OBJECTIVE
  Drug-serum adducts and anti-drug antibodies have been identified in sulphonamide HS humans. The aim of this study was to determine whether similar markers were present in dogs with sulphonamide HS.
  
  
  METHODS
  Thirty-four privately owned sulphonamide HS dogs, 10 sulphonamide-'tolerant' dogs, 18 sulphonamide-naïve dogs, and four dogs experimentally dosed with SMX and the oxidative metabolite SMX-nitroso, were tested for drug-serum adducts by immunoblotting, and anti-drug antibodies by ELISA.
  
  
  RESULTS
  Sulphonamide-serum adducts were found in 10/20 HS dogs tested (50%), but in no tolerant dogs. Anti-sulphonamide IgG antibodies were detected in 17/34 HS dogs (50%), but in only one tolerant dog; antibody absorbance values were significantly higher in HS dogs. There was a significant association between the presence of sulphonamide-serum adducts and anti-sulphonamide antibodies (P = 0.009). Anti-drug antibodies were also found in dogs experimentally dosed with SMX-nitroso followed by SMX, but not in a dog dosed with drug vehicle, followed by SMX.
  
  
  CONCLUSIONS
  Similar humoral markers are present in dogs and humans with sulphonamide HS, supporting the use of dogs as a naturally occurring model for this syndrome in humans. These data suggest the potential use of drug-serum adducts and anti-drug antibodies as markers for sulphonamide HS. Preliminary data indicate that anti-sulphonamide antibodies may be triggered by the SMX-nitroso metabolite, not by the parent drug, in dogs.
authors.affiliation: Department of Medical Sciences, University of Wisconsin-Madison, Madison, WI 53706-1102, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Lavergne
authors.forename: R S
authors.initials: RS
authors.lastname: Danhof
authors.forename: E M
authors.initials: EM
authors.lastname: Volkman
authors.forename: L A
authors.initials: LA
authors.lastname: Trepanier
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000276:immunology / Q000633:toxicity*; D000918:Antibody Specificity; D001798:Blood Proteins / Q000378:metabolism*; D003429:Cross Reactions; D004195:Disease Models, Animal; D004285:Dogs; D004342:Drug Hypersensitivity / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D011485:Protein Binding; D013420:Sulfamethoxazole / Q000276:immunology; D013449:Sulfonamides / Q000097:blood / Q000276:immunology / Q000633:toxicity*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D001798:Blood Proteins; D007074:Immunoglobulin G; D013449:Sulfonamides; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013420:Sulfamethoxazole