title: Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring.
abstract: OBJECTIVE
  Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can explain symptoms of hypersensitivity.
  
  
  METHODS
  Between January 1985 and January 2007, all adverse drug reactions (ADRs) reported to the Netherlands Pharmacovigilance Centre Lareb related to AEDs as suspected drugs were included in this study. ADRs were analysed using a case/non-case design. Cases were defined as those patients with ADRs involving symptoms of hypersensitivity. Non-cases were patients with all other ADR reports. Symptoms of hypersensitivity were classified according to the Gell and Coombs classification (type I-IV) and the organ involved (e.g. cutaneous, hepatic). AEDs were classified as aromatic anticonvulsant if their chemical structure contained at least one aromatic ring. All other AEDs were classified as non-aromatic. We assessed the strength of the association between aromatic AEDs versus non-aromatic AEDs and reported hypersensitivity reactions with logistic regression analysis and expressed these as reporting odds ratios (RORs).
  
  
  RESULTS
  In total, 303 cases of hypersensitivity associated with the use of AEDs were reported. Aromatic AEDs were suspected in 64.4% of these reports versus 41.3% (574/1389) of the non-hypersensitivity reports. A significant ROR of 2.15 (95% CI 1.63, 2.82) was found for aromatic AEDs and all hypersensitivity reactions. Aromatic AEDs were significantly associated with immunoglobin E-mediated type I hypersensitivity reactions (ROR 2.15; 95% CI 1.23, 3.78) and T-cell-mediated type IV reactions (ROR 6.06; 95% CI 3.41, 10.75). Type II and III reactions did not show an association. Cutaneous symptoms represented 39.9% of the hypersensitivity-related ADRs. Aromatic AEDs were significantly associated with cutaneous hypersensitivity reactions (ROR 5.81; 95% CI 3.38, 9.99).
  
  
  CONCLUSIONS
  This study confirms that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains apparent 'idiosyncratic' hypersensitivity reactions. Symptoms of hypersensitivity were reported twice as frequently with aromatic AEDs than with non-aromatic AEDs. Strong associations for aromatic AEDs versus non-aromatic AEDs were found for T-cell-mediated (type IV) reactions, as well as for cutaneous reactions.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Kim B
authors.initials: KB
authors.lastname: Handoko
authors.forename: Eugène P
authors.initials: EP
authors.lastname: van Puijenbroek
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Bijl
authors.forename: Walter A J J
authors.initials: WA
authors.lastname: Hermens
authors.forename: Jeannette E F
authors.initials: JE
authors.lastname: Zwart-van Rijkom
authors.forename: Yechiel A
authors.initials: YA
authors.lastname: Hekster
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
mesh_terms: D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects* / Q000737:chemistry; D004342:Drug Hypersensitivity / Q000209:etiology*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D007073:Immunoglobulin E