| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 98 === Adverse drug reactions (ADR) are harmful, unintended reactions to drugs during treatment. Severe cutaneous adverse reactions (SCAR) include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic syndrome (DRESS). These reactions are rare, but highly life-threatening. In clinical, many aromatic antiepileptic drugs (AEDs) have been reported to cause SCAR, for example, carbamazepine (CBZ), phenytion (PHT), and lamotrigine (LTG). Lamotrigine, an anticonvulsant drug, has been used to treat many types of seizures, however, higher ADR frequency than the non-aromatic AEDs restricts its application.
In this study, the gene polymorphism in gene encoding drug metabolism enzymes or the immune system were examined for the association with LTG-induced ADRs. Lamotrigine has been reported to be majorly metabolized by subtypes of UGT (UDP-glucuronosyltransferase), including UGT1A3, UGT1A4 and UGT2B7 in human. To investigate whether gene polymorphisms affect metabolism of LTG, DNA samples from the peripheral blood mononuclear cells (PBMC) of LTG-ADR patients were collected and screened for single nucleotide polymorphism (SNP) in the enzyme gene promoters and exons sequences. Several SNPs were identified from genes of UGT1A3/4 and UGT2B7, and some of them could change the amino acids in the enzymes and thus might change enzyme activity. However, these SNPs showed no statistical association with LTG-ADRs when comparing with tolerant controls.
Furthermore, the LTG serum level of these LTG-ADR patients who were enrolled at an active stage of ADRs was analyzed by LC-MS (Liquid Chromatography-Mass Spectrometry) to figure out the relationship between ADR and LTG serum level. Increased LTG serum levels were identified from half of LTG ADR patients, especially a patient who took both LTG and valproic acid (VPA) before ADRs and developed SCAR with hepatitis. While UGT1A4*3 carriers expressed lower LTG serum level.
In addition, the genotype of human leukocyte antigen (HLA) of LTG-ADR patients was also analyzed and compared to the phenotype frequency of tolerant control subjects and Taiwanese general population. The data revealed that the frequency of HLA-A*3303, HLA-A*0207 and HLA-B*1502 are higher in LTG-SJS patients, and HLA-DRB1*0101 in DRESS/MPE patients. Furthermore, HLA-B*4001 showed protective effects in LTG-ADR patients. These observations indicated the different HLA alleles contribute to the susceptibility to different phenotypes of LTG-ADR. A larger sample size and biological assays are required to validate these findings.
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