Influence of Chemical Structure on Hypersensitivity Reactions Induced by Antiepileptic Drugs

Abstract

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.

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage

“…Handoko and coworkers have also confirmed that the association for T cellmediated reactions was strongest in cutaneous reactions (13). Although aromatic vs. non-aromatic AED studies have demonstrated that cutaneous hypersensitive reactions can be partly explained by a commonality in chemical structures (13,14), these studies did not consider and failed to explain why clobazam and clonazepam, which are AEDs with aromatic rings, do not show a significant number of hypersensitive reactions as observed in our analysis. The strong association of hypersensitivity reactions with BDDCS class 2 drugs, certain BDDCS class 1 drugs, and our in vitro results suggests that parent or a combination of parent/metabolite interactions is responsible for the drug hypersensitivity event.…”

“…Drug-specific T cells have been identified for lamotrigine and carbamazepine (25,26). Handoko and coworkers have also confirmed that the association for T cellmediated reactions was strongest in cutaneous reactions (13). Although aromatic vs. non-aromatic AED studies have demonstrated that cutaneous hypersensitive reactions can be partly explained by a commonality in chemical structures (13,14), these studies did not consider and failed to explain why clobazam and clonazepam, which are AEDs with aromatic rings, do not show a significant number of hypersensitive reactions as observed in our analysis.…”

“…It has been previously hypothesized that Bidiosyncraticĥ ypersensitive reactions occur with AEDs containing an aromatic ring in their chemical structure that can form an arene-oxide intermediate (13). This chemically reactive product may become immunogenic through interactions with proteins or cellular macromolecules in accordance with the hapten hypothesis (24).…”

“…Recently, however, the results of a routine clinical service policy at a system-wide level in Hong Kong implemented in 2008 was reported to be associated with the prevention of CBZinduced SJS/TEN without reducing the overall burden of AED-induced SJS/TEN in more than 110,000 epilepsy patients (12). Attempts to predict the potential for various AEDs to cause cutaneous hypersensitivity through structureactivity relationships, suggesting that CARs occur with aromatic AEDS, but not with non-aromatic AEDs (13,14), have ignored data for aromatic AEDs exhibiting low CARs incidence such as clobazam and clonazepam. Thus, in spite of the strong genetic associations and some structure-activity success, the initiation of hypersensitivity for AEDs is still not very well characterized.…”

Síndrome de hipersensibilidad a anticomiciales: una entidad para recordar

“…Esta teoría indica que el sistema inmunitario no diferencia simplemente las mol eculas como propias o ajenas, sino que sólo responde ante una mol ecula ajena en caso de que esta se asocie a una señal de alarma (muerte o estr es celular). El daño celular inducido por otros factores, como una cirugía o infecciones virales (especialmente VIH), parece incrementar tambi en el riesgo de presentar una reacción idiosincr asica a f armacos 20,21 . El tratamiento de estos pacientes exige una suspensión precoz del f armaco implicado 22 .…”