Hypersensitivity to Aromatic Anticonvulsants: In Vivo and In Vitro Cross-Reactivity Studies

Abstract

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs

“…33,[59][60][61][62][63][64] In the present work, we observed cross-reactivity between LTG and CBZ. The phenomenon may be explained by the ability of T-cells to recognize the major histocompatibility complex (MHC) of a drug-MHC complex.…”

Pharmacogenetics of cutaneous adverse drug reactions

“…Clinical cross-reactivity among aromatic amine anticonvulsants is observed with high frequency. 26,27 Small case studies in Thailand (four cases phenytoin induced) and Hong Kong (single cases of phenytoin and lamotrigine induced) showed the presence of HLA-B*1502 in all SJS patients. 11,12 In a current case-control association study in a Taiwanese population, the association between HLA-B*1502 and phenytoin-, lamotrigine-and oxcarbazepine-induced SJS ⁄ TEN was observed in 30.8% of 26 patients (P = 4.1 · 10…”

High Procalcitonin in a Patient with Drug Hypersensitivity Syndrome

“…(8,9). Mild to moderate increases of the PCT level may occur in viral infections and various chronic inflammatory diseases (arthritis, vasculitis) (8,10 (12), and the test was positive.…”

“…CBZ is primarily metabolized via cytochrome P450 (CYP 3A3/4) to reactive epoxides -arene oxides responsible for direct cytotoxicity (2). Arene oxides are detoxified mainly by epoxide hydrolase and by conjugation with glutathione (4).…”

“…Arene oxides are detoxified mainly by epoxide hydrolase and by conjugation with glutathione (4). Valproate inhibits epoxide hydrolase, while paracetamol, by depleting hepatic glutathione, increases CBZ toxicity (2,4). Taken together, the additional use of valproate and paracetamol could have contributed to the severe clinical presentation in our patient.…”