建立台灣常用中藥方劑與阿司匹靈藥物交互作用快速分析平台

楊玲玲1, 蔡金川2, 陳蕙如1, 吳宗修2
1中國醫藥大學附設醫院中醫藥轉譯研究中心, 2義守大學學士後中醫系
中西藥可否併用?如何並用藥物才會達到安全，有效及低副作用和毒性之系統分析迄目前為止尚並無完整之數據可提供醫療參考。中藥配合現代醫療之輔助療法已深受對疾病治療能提升疾病治癒率、緩和症狀或縮短病程，由此可提高治癒效益、改善病患疾痛及降低醫療成本。因此如何建立完善中西藥併用方法之相關安全資料，減少中醫藥併用毒性或造成血中藥物濃度過量之副作用，方可提升民眾就醫信心，增加癒後良效及維護醫療品質均會有相當的助益並具正向的價值，更開啟臺灣醫療發展新頁。近年來有許多藥物交互作用之報告，急需澄清中藥對人體之毒性印象。重點選擇以慢性疾病常用西藥與中藥併用對人體之影響，利用人類血清運輸蛋白結合能力分析臨床中西藥物併用是否影響血清濃度之改變並建立快速分析平台。本計劃首期選擇對心臟血管慢性病病人常用於預防血栓及消炎止痛阿司匹靈藥物，探討此藥物與常用中藥方劑可能之交互作用及機制，以提供中西藥並用之安全性資訊。故建立快速藥物分析平台是本計畫之首要目標。本研究計畫採用統計分析近三年來義大醫院門診處方簽常用百種之中藥方劑（如：平胃散、香砂六君子湯、加味逍遙散、柴胡桂枝湯、小柴胡湯、五苓散、甘露飲、四物湯、知柏地黃丸、參苓白朮散等，共計100種），將透過健保局醫療資料來分析中西藥併用之頻率，並首期針對僅次於癌症、經常使用之止痛藥，並且心血管慢性病人亦常使用的水楊酸類藥物（Aspirin）為研究對象，進行中藥與人類血清蛋白結合能力之藥物定量分析。Aspirin口服對於人體的吸收，吸收時部份水解為水楊酸 (salicylic acid)。Aspirin 迅速分佈至全身組織及體液，包括胎兒組織，乳汁及中樞神經。水楊酸鹽類與蛋白質之結合率與濃度有密切相關，100汹贡g/ml 時為 90%；400汹贡g/ml 時為76%。血中濃度 > 200 贡g/ml 時就會出現水楊酸中毒的徵兆，如耳鳴；400汹贡g/ml 時會有更嚴重的毒性反應。首先試驗 以特定濃度的血清蛋白於攝氏溫度37度與aspirin及中藥方劑作用1小時，利用10 kDa 的分子篩分離游離態的aspirin，以高效能液相層析儀(HPLC)定性及定量。利用楊教授實驗室已建立多年之分析平台將可快速進行目前市售或常用之中藥方劑與西藥之交互作用分析，本結果提供給臨床用藥參考將可以降低藥物多重及多樣性使用減少對人體在未知下造成的毒性與副作用之產生。依此快速平台的結果中再選擇前十種中藥方劑，進一步測定aspirin與選擇之前十種中藥方劑分別在中西藥併用時之相關藥物進入人體之作用機制，特別是中藥方劑改變藥物對血清吸收影響之機制，將可解析aspirin與中藥方劑併用時在臨床醫療效果上是否產生不良影響?是否有藥物加乘、或相斥作用等反應?本研究結果對中藥方劑在臨床應用上將可預防或降低副作用以及減少藥害之發生。
關鍵字：中藥方劑、水楊酸類藥物、血清蛋白、 藥物定量、快速平台

High-throughput analysis of drug interaction between aspirin and top 100 regular Chinese medicinal prescriptions in Taiwan

Ling-Ling Yang1, Chin-Chuan Tsai2, Hui-Ju Chen1, Tsung-Hsiu Wu2
1Center of Translational Research on Traditional Medicine, China Medical University and Hospital and 2School of Chinese Medicine for post-baccalaureate, I-Shou university
Can we use the western drug and traditional Chinese medicinal prescriptions together? So far, there is not yet complete as of data can provide medical information which is efficient and reliable between western drugs and Chinese medicinal prescriptions. How to arrange the different types of western drugs and concurrent with Chinese medicinal prescriptions? And where can tell us it is is safety, effective and low side effects and toxicity for out body systems? Chinese medicine and modern medical care has been well received adjuvant therapy can improve the treatment of diseases, alleviate symptoms or shorten the disease course, which can improve the healing benefits, reduce pain and patient’s illness medical costs. So, how to establish and improve the methods used in medicine and related safety information, and use of Chinese medicine to reduce toxic drug concentrations in blood or cause side effects overdose. To seek medical treatment only to enhance public confidence, increase efficiency and maintain good prognosis for quality of care they will have considerable help benefits and a positive value, but also open a new page in Taiwans medical development. Recent years, many reports of drug interactions need to clarify the toxicity of traditional Chinese medicine on the body. We choose to focus on the common chronic diseases to see the impact on the human body that combined intake the traditional Chinese medicine and western medicine. To use of human serum albumin binding capacity of transport system, and its change of drug dose would be the observed point to concern the free form drug concentration in the serum, and to establish a rapid analysis platform is our goal. Firstly, selected the program used on patients who with chronic cardiovascular problems, thrombosis, inflammation and pain in “aspirin” medication and discuss this drug used with the commonly Chinese medicinal prescription interactions and possible mechanisms to provide Chinese and western medicine uses of security information. Therefore, to setup a rapid drug analysis platform is the primary aim of this project. This project uses the last three years prior to outpatientprescriptions which top-hundred of Chinese medicinal formulas (such as: Pingwei, Xiangsha Liujunzi soup, flavored Xiaoyaosan, Chaihuguizhi Tang, Xiao Chai Hu Tang, etc. a total of 100 species) together with NHI and medical information to understand and use the frequency with western medicine is our concerned cross-interaction prescriptions. Therefore, we focus on people who got chronic cardiovascular disease in the begining and we realized the salicylic acid (Aspirin) drug used in common. In this study, we evaluated drugs interaction by carried out with human serum albumin (HSA) as our model which is a transfer protein and 90% mainly content of vascular system, drugs have to be bound with it before arrived at destination. So, a first, fast, and reliable analysis mode is setup to analyze the HSA binding capacity. Aspirin is often by oral medication, and it is the rapid and complete absorption after oral administration of about 80-100%, it will be decomposed and hydrolysed into salicylic acid form when it is in the absorption part. It is reported that aspirin could rapidly distributed to body tissue and body fluids, including fetal tissue, breast milk, and central nervous system. The protein binding ratio of salicylic acid salts is regard on the concentration dependent, such as almost 100 m g/mL HSA when 90%, 400 mg/mL HAS when 76%. The salicylic acid poisoning happened when symptoms occur, such as tinnitus, the plasma concentration raised and dose over 200 m g/mL, if the dose goes to 400 m g/mL, there will be more severe toxicity. Initial
關鍵字：Chinese prescription、salicylic acid、serum albumin、binding dose、high-throughput platform