Abstract
BackgroundHypersensitivity 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 FindingsDF, 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/SignificanceWe 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.
Highlights
Diclofenac (DF) is one of the most popular drugs world-wide belonging to the family of nonsteroidal antiinflammatory drugs (NSAIDs)
Two pathomechanisms are currently thought to be involved in NSAIDs hypersensitivity reactions: (i) multiple NSAIDs hypersensitivity has been considered as pharmacokinetic disorders due to non-selective coinhibition of cyclooxygenase (COX)-1 leading to shifts in the prostaglandin and leukotriene levels [2,3]; (ii) in contrast, for selective NSAID hypersensitivities including DF, an involvement of the immune system is still being postulated [4]
In order to exactly define the patterns of reactivity of patients towards DF and other NSAIDs 41 patients underwent OPTs with various NSAIDs, but not with DF, seven patients were challenged with DF, and for eleven patients definition of clinical reactivity was based on history alone
Summary
Diclofenac (DF) is one of the most popular drugs world-wide belonging to the family of nonsteroidal antiinflammatory drugs (NSAIDs). More serious are drug hypersensitivity reactions (DHRs) to DF, which clinically manifest as Type-I-like allergic reactions with sudden and unpredictable occurrence and can progress into anaphylactic shock. The ability of Phase I metabolites to form immunogenic protein conjugates has been shown in animal studies [11,12] and in cases of DF-induced immune hemolytic anemia [13]. Protein conjugates of Phase II metabolites have not been described, it is possible that reactive intermediates of DF might haptenize to proteins in an alternative orientation. Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
