Project Details
Abstract
Drug induced delayed-type hypersensitivity reactions, involving in the activation of T
cells, include variable clinical manifestations, ranging from mild skin rash, maculopapular
exathem (MPE), fixed drug eruption (FDE), with increasing severity to and acute generalized
exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms
(DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The
notorious drugs associated with delayed drug hypersensitivity include 3 major categories:
anticonvulsants (e.g phenytoin, carbamazepine, lamotrigine), antibiotics (e.g.
amino-penicillins, vancomycin, sulfamethoxazole, cephalosporins, anti-tuberculosis), and
NSAIDs. Severe drug induced hypersensitivity reactions, such as SJS, TEN and DRESS may
lead to complex complications with high morbidity and mortality.
In Taiwan, SJS/TEN cause more than 50% annual compensation funds from the Drug
Relief Foundation. As a high proportion of patients in Taiwan frequently expose to multiple
drugs and are at higher risk to develop drug hypersensitivity with undesirable outcome and
high costs, the identification of risk factors as well as the genetic susceptibility of individuals
who are at risk for severe ADRs is an urgent issue.
Pharmacogenetics is the tailoring of drug treatment according to individual genotype, which
has been widely proclaimed as a first step toward personalized medicine. If the genetic
susceptibility of individuals to drug hypersensitivity is known, a simple genetic test could be
performed before the prescribing and therefore avoid the patient morbidity and mortality
caused by adverse drug reactions. Although HLA may link to some drugs induced
delayed-type hypersensitivity reactions (e.g. HLA-B*1502 to carbamazepine
induced-SJS/TEN and HLA-B*5801 to allopurinol induced SJS/TEN and DRESS), there are
still many culprit drugs without findings of their genetic association. It has also been
proposed that abnormal drug metabolism (pharmacometabolism) can also result in serious and
unexpected adverse events, the pharmacometabolic study in discovery of defects in drug
metabolic enzymes or abnormal pharmacokinetics of drugs/metabolites elimination in severe
drug induced hypersensitivity is still lacking.
In this 3-year project, we will investigate the pharmacogenomics and pharmacometabolism
(drug metabolism) of drug induced delayed-type hypersensitivity reactions in 3 years:
Specific aims:
(1)To establish a biomaterial repository of patients with drug induced delayed-type
hypersensitivity reactions and drug tolerant controls.
(2). To identify the genetic susceptibility in immune molecules and drug metabolism
pathways of delayed-type drug induced hypersensitivity
(3) To investigate the specific drug-HLA interaction or binding affinity to further verify
potential role of a specific HLA molecule linking to a specific drug-induced hypersensitivity
reactions.
(4). To investigate pharmacokinetics and plasma drug/metabolite levels of patients with drug
induced delayed-type hypersensitivity and its correlation with clinical severity or prognosis
We anticipate that this project will further our understanding of variable drug hypersensitivity,
translate the genetic determinants to clinical tests, and provide a better approach to predict
individual drug handling. In a broader view, this project will reduce the incidence and prevent
delayed-type drug hypersensitivity, and drive the optimum drug selection for therapy.
Project IDs
Project ID:PC10202-0693
External Project ID:NSC101-2628-B182-001-MY3
External Project ID:NSC101-2628-B182-001-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/13 → 31/07/14 |
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