- 學位論文
藥物不良反應與基因標記的探討
Investigation of genomic biomarkers and adverse drug reactions
摘要
本研究統計，全國藥物不良反應通報中心（National Reporting System of Adverse Drug Reaction in Taiwan），自民國88年至99年為止，已累積了55,268件不良反應通報案件，最近5年總共有41,791通報案件，每年平均增加1,367件不良反應通報案件，每年平均成長 24 %，大約是美國的2倍。藥害救濟總給付件數520件。至99年2月止，整理出藥物不良反應前五項原因共計474件，其中第一名是皮膚皮下組織疾病（skin and subcutaneous tissue disorders）349件；藥害救濟給付案之前五名藥品269案例中，與基因標記有關案例達 208案例，前三名分別為：allopurinol-74件、carbamazepine-71件、phenytoin-63件。 本研究是對於發生嚴重不良反應之藥物，服用藥物前可以檢驗是否帶有過敏基因之措施加以探討，結論如下： 1.依91年臺灣門診使用的carbamazepine處方，只有1/3 是使用於核准適應症的範圍，其餘2/3 皆為非核准適應症外其它用途（off label use），只有約38%的carbamazepine處方用於核准適應症。 2. 目前健保局針對服用後最容易發生史帝文生氏-強生症候群與毒性表皮溶解症之嚴重不良反應之carbamazepine藥物，服用藥前可檢驗是否帶有HLA-B1*1502過敏基因，每人可以申報1次，健保給付點數為3285點 (1點約1元)。但該項基因檢測僅能將造成嚴重過敏的機率從10萬分之6，降到和白種人一樣的10萬分之2，並無法防止carbamazepine造成嚴重皮膚過敏症狀，只能防止90% carbamazepine造成嚴重皮膚過敏症狀，因為還有10%史蒂文強生症候群患不帶此基因，依舊發生嚴重過敏。 3. 從研究報告得知，使用allopurinol引起史帝文生氏-強生症候群與毒性表皮溶解症之嚴重皮膚反應，與HLA-B*5801基因有統計學上明顯相關性。但也有許多帶有HLA-B*5801基因的病患以allopurinol治療時，並未發生史帝文生氏-強生症候群與毒性表皮溶解症的副作用，而未帶有HLA-B*5801基因的病患，無論人種，仍可能發生史帝文生氏-強生症候群與毒性表皮溶解症的副作用。 4. 如果服用藥物前要檢驗是否帶有過敏基因，希望發展運用基因晶片等現代DNA技術，可以方便地檢測藥物不良反應基因位點的變異等位基因，並依此劃分病人的基因型，以降低檢測藥物不良反應基因費用，期待能像篩檢新生兒先天性疾病或像盤尼西林過敏反應（penicillin allergy）者注射盤尼西林前，所做的皮膚測試（penicillin skin test），一樣普及與便宜。
並列摘要
According to this study the total number of adverse cases received by the National Reporting System of Adverse Drug Reaction in Taiwan has reached 55,268 from 1999 to 2010. There were 41,791 cases reported in the recent 5 years, corresponding to an increase of 1,367 adverse cases per annum, equivalent to an average annual growth of 24% -- twice that of the United States. There were 520 cases of drug related damage compensations. Till February 2010, the total number of drug related damages caused by the first five factors amounts to 474, of which skin and subcutaneous tissue disorders was number one, with 349 cases. Among the 269 cases caused by the first five drugs for the drug related compensations, there were 208 cases related to gene labeling, the first three being: allopurinol, 74 cases; carbamazepine, 71 cases; and phenytoin, 63 cases. This study discusses the means to determine the presence of allergy genes before taking those drugs with severe adverse reactions. It is concluded that: 1. Among all the carbamazepine prescriptions ordered by Taiwan clinics during 2002 , a little over 1/3 (38%) here for indicated symptoms, the rest 2/3 were for non-indicated symptoms (off-label use). 2. Under the current policy, for patients with severe adverse reactions toward carbamazepine with indications of Stevens-Johnson Syndrome and toxic epidermal necrolysis, the Bureau of National Health Insurance allows one application per patient to identify whether he/she is a carrier of the HLA-B1*1502 allergy gene prior to administration of the drug, for which the Bureau will be responsible for 3285 points (about 1NT per point). However, by performing the gene screening one can only reduce the occurrence probability of severe allergy from 0.006% down to 0.002% that is similar to the rate for Caucasian males, but one cannot keep the severe skin allergies, caused by carbamazepine, from happening. It is only 90% effective. The rest 10% of the Stevens-Johnson Syndrome patients will suffer from severe allergies even though they do not carry this gene. 3. From the research report, the SJS/TEN severe skin reactions caused by using allopurinol are statistically correlated to the HLA-B*5801 gene. Nevertheless, many patients, who carry HLA-B*5801 gene, when treated with allopurinol did not get SJS/TEN side effects, but for patients without HLA-B*5801 gene, no matter what ethnic group they belong, SJS/TEN side effect is still a possibility. 4. If it is necessary to conduct the allergy screening test before administering the medicine, it is desirable to develop modern DNA techniques such as implanting gene chips, so that the active gene location for adverse reactions can be easily detected. By doing so, the patients may also be categorized according to their gene type in order to reduce the cost for such screening tests. It is hoped that this can be done as widely and economically as those skin tests used for screening penicillin allergy or other congenital disease screenings for the neonates.