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Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.

AbstractBACKGROUND:
Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.
METHODOLOGY/PRINCIPAL FINDINGS:
DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG.
CONCLUSIONS/SIGNIFICANCE:
We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.
AuthorsAndrea Harrer, Roland Lang, Robert Grims, Michaela Braitsch, Thomas Hawranek, Werner Aberer, Lothar Vogel, Walther Schmid, Fatima Ferreira, Martin Himly
JournalPloS one (PLoS One) Vol. 5 Issue 10 Pg. e13707 (Oct 28 2010) ISSN: 1932-6203 [Electronic] United States
PMID21060839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies
  • Diclofenac
  • Immunoglobulin E
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (adverse effects)
  • Antibodies (immunology)
  • Basophils (immunology)
  • Diclofenac (adverse effects)
  • Drug Hypersensitivity (immunology)
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunoglobulin E (immunology)
  • Mice
  • Mice, Inbred BALB C

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