傳統中草藥安全監測與相關實證研究

Abstract

藥物安全一直是健康領域的重要議題，但傳統的被動式通報系統存在著許多問題，對於具有不同治療理論與實務的中草藥而言，更需發展多途徑的安全監測方法。本論文旨在架構一套主動安全監測系統及利用資料庫分析來評估中草藥使用的安全性；前者除進行二項實證研究以針對不同研究藥物、適應症來測試該系統的可行性外，也以主動、有系統的分析評估中藥不良反應 (事件)，並進而探討其可能機轉；後者則分別分析台灣中醫師在2004年開立中草藥的處方型態及1997-2004年間開立疑似含馬兜鈴酸之中草藥產品（SAA CHP）的處方型態。 研究一：由台北市立中醫醫院、台北市立陽明醫院、林口長庚中醫分院及中國醫藥大學之中醫門診收集更年期有潮熱盜汗症候，但未有重大肝、腎、內分泌等重大疾病的患者。受試者接受本研究藥物 (中藥複方) 治療三個月，每日服藥3次，每次4公克，期間並接受追蹤觀察及實驗室檢查以評估藥物安全性。 研究期間共有134位合格個案服用研究藥物，收集到203件不良反應事件，發生10件以上的不良反應事件 (風險) 依序為咳嗽 (2.57/103人-日)，喉嚨痛（2.47/103人-日），流鼻水 （1.88/103人-日），腹痛（1.78/103人-日），腹脹（1.68/103人-日）及腹瀉（1.58/103人-日）與身體發癢（1.58/103人-日），除了一件嚴重不良事件－因血小板大量降低而全身皮膚發生紫斑外，所有不良反應事件皆輕微至中度不適，並不影響日常生活功能。其中共有5件被判定為『可能的』藥物不良反應，分別為2件腹瀉及噁心，腹痛與腹脹各1件。 研究二：除臨床觀察研究外，本研究也與食品藥物檢驗局合作同時針對研究藥物進行定量及定性分析。在主動安全監測試驗方面，由台大公共衛生學院成立監測中心，在台北市立聯合醫院陽明院區中醫科門診及中醫院區成立主動安全監測系統，以追蹤、監測退化性關節炎患者使用研究藥物前後的變化。凡進入試驗的合格受試者須先經過藥物擴清期 (0-2週)，並接受用藥前的臨床評估，之後接受為期4週的獨活寄生湯治療 (每日服藥2次，每次2.5公克)。在安全性的評估上，本研究主動觀察受試者在研究期間所出現的不良反應。 經分析後發現本研究藥物雖含有細辛，卻未被檢測出含馬兜鈴酸成分 (樣品在濃縮至25倍時可微量檢出)。研究期間共有71位合格個案服用研究藥物，共收集287件不良反應事件，最常見的不良反應事件 (風險) 依序為皮膚紅疹 (14.5/103人-日)，腹脹 （12.9/103人-日），咳嗽 （12.4/103人-日），嗜睡 （11.9/103人-日），抽筋 （10.3/103人-日）及腹瀉 （10.3/103人-日），其中共有4件被判定為『可能的』藥物不良反應，分別膚色素改變，臉潮紅、腹瀉、心跳加快各1件。但是經過四週服用後，主動偵測未發現到腎臟病變。 研究三：本研究分析台灣全民健保資料庫2004年20萬歸人檔，除了以描述分析方式呈現該年度國人接受中草藥處方的概況外，也使用「採礦」法 (data-mining)中的「市場購物籃分析」 (market basket analysis) 探討單方及複方中草藥品中的「相關法則」 (association rule)。20萬承保人中共有166,929人看過一次門診，有46,938位病人曾接受一次以上的中藥處方。曾接受過中藥處方的病人年齡集中於35-59歲，且平均年齡略高於不曾接受過中藥處方的病人﹔女性病人較男性病人更傾向使用中草藥﹔曾接受過中藥處方的病人在該年度中看過較多次的門診、有較少的住院日數、但花費較多的醫療費用。該年度共有22,013張中草藥處方，有94.3%是由基層診所開立。所含1,073,030筆中草藥紀錄中，處方頻次最高的單方及複方分別是「延胡索」及「加味逍遙散」。絕大部分中草藥的開立模式為：每日三次，不超過7日﹔「急性鼻咽炎」是最常出現的處方診斷，為其開立的單方及複方以「桔梗」及「銀翹散」最多﹔有99.5%的中草藥處方都是由2種以上的中草藥組成。而「乳香」及「沒藥」，「夜交藤」及「酸棗仁湯」與「芍藥甘草湯」及「疏經活血湯」是最常被同時開立的單單方，單複方及複複方組合。除了証實台灣中醫師有按古方開「藥對」之外，也發現ニ種以上常開複方結合成之「複方對」，是古書所沒有的﹔其藥效與安全性待未來更多驗證。 研究四：本研究分析台灣全民健保1997-2003年的20萬歸人檔資料，以了解七年間國人使用可疑含馬兜鈴酸中草藥製劑 (SAA CHP) 的概況。結果發現：研究期間共有526,867筆SAA CHP處方資料，其中涉及1,218張藥證。共有78,644位病人至少被處方一次SAA CHP，其中以女性及/或中年病人居多，暴露群中有超過85% 病人使用不超過60毫克累積劑量的疑似含馬兜鈴酸草藥（SAA herb），但卻有約7% 的暴露病人曾被開處方超過100毫克累積劑量的細辛、木通及馬兜鈴。呼吸及肌肉骨骼系統的疾病是SAA CHP處方中最常見的診斷，最常被開立的SAACHP是「疏經活血湯」、「川芎茶調散」及「龍膽瀉肝湯」，其分別含有防己、細辛及木通等SAA herb。 上述研究除可收集與計算單一中草藥產品可能發生的不良反應與藥物不良反應風險外，也可經由了解中草藥產品的處方型態等方式而逐步建立中藥安全資料庫；主動安全監測系統及資料庫分析方法或可彌補既有藥物安全監測系統的不足，而有效建構中草藥使用的安全環境。

Despite the absence of safety data, the worldwide use of Chinese herbal products (CHPs) is on the increase; the rising number of reports of herb-related toxic events therefore indicates an urgent need to establish safety profiles for such products. In this thesis, we tried to establish an active safety surveillance system and take use of databases analysis to supplement the current pharmacovigilance function on traditional Chinese medicine. We also conducted four empirical studies to test the feasibilities of these two approaches. Study 1: This is a multi-center and prospective observational study. We recruited 134 women with climacteric symptoms. During 12-week study period, the subjects made 9 visits, took TMN-1 three times a day, and received routine hematologic tests, biochemical tests, and tests for gynecologically relevant hormones at baseline and after 4 and 12 weeks of beginning medication. At every visit, the subjects were asked by questionnaire about any adverse events. All adverse events were examined through a process of causality assessment by a research team. In total, we recorded 203 adverse events, in order of decreasing incidences-- cough, pharyngitis, rhinitis, abdominal pain, abdominal fullness, diarrhea, and pruritus with incidence rates of 2.57, 2.47, 1.88, 1.78, 1.68, 1.58 and 1.58 per 103 person-days, respectively. Most adverse events were tolerable. Five of the adverse events were judged to be “probable” adverse drug reactions: 2 events of diarrhea and 1 event each of nausea, abdominal pain, and abdominal fullness. Study 2: In this study, we conducted a qualitative/quantitative investigation on Dwu-Hwo-Jih-Sheng-Tang (DHJST) along with a prospective observational study. During the study period, we actively monitor adverse events (AE) and adverse drug reactions (ADR) amongst patients who took 2.5 grams of DHJST twice a day for four weeks. A list of AEs and complete blood counts, liver and kidney function tests were measured at the scheduled visits. Although containing Xi xin, DHJST did not contain detectable aristolochic acid under thin-layer chromatography analysis and gas chromatography coupled with mass spectrometry. A total of 71 eligible subjects were included in the clinical study. 287 AEs were reported, all of which seemed tolerable. The incidence rates (per 103 person-days) for the most often reported AEs were: rashes (14.5), abdominal fullness (12.9), coughs (12.4), somnolence (11.9), muscle cramps (10.3) and diarrhea (10.3). The probable ADRs included single events of change in skin color, flush, tachycardia and diarrhea. There were no significant changes in liver or kidney functions. Both studies demonstrate the effectiveness using active safety surveillance to document safety of traditional Chinese medicines. This surveillance system could probably be useful to document the safety of other alternative or complementary medicines. Study 3: We carried out a cross-sectional analysis on a cohort of 200,000 patients, based on 2004 data from the National Health Insurance (NHI) reimbursement database. Data mining techniques were applied to explore CHP co-prescription patterns. A total of 46,938 patients had been prescribed CHPs on at least one occasion in 2004. Patients using CHPs were generally female and middle-aged, made more outpatient visits, had fewer hospitalizations and consumed more medical resources than non-users of CHPs. A total of 1,073,030 CHPs were contained within 220,123 prescriptions, for which acute nasopharyngitis was the most common indication. Yan hu suo and Jia Wei Xiao Yao San were the most frequently prescribed single herb (SH) and herbal formula (HF), respectively. The results of the data mining showed that the best predictions were provided by co-prescriptions of ‘Mo yao and Ru xiang’, ‘Ye jiao teng and Suan Zao Ren Tan’ and ‘Dang Gui Nian Tong Tang and Shu Jing Huo Xue Tang’ in the groups of SH-SH, SH-HF and HF-HF, respectively. Such combination prescriptions of more than two herbal formulas warrant future studies to secure their efficacy and safety. Study 4: A longitudinal analysis was carried out on a randomly sampled cohort of 200,000 patients using 1997-2003 data obtained from the Taiwan NHI reimbursement database. During the seven-year study period, a total of 78,644 patients had been prescribed with SAA (suspected aristolochic acid containing) CHPs on at least one occasion, the majority of whom were females and/or middle-aged. A total of 526,867 prescriptions were issued containing 1,218 licensed SAA CHP items. Over 85 per cent of SAA-exposed patients took less than 60gms of SAA herbs; however, about seven per cent were exposed to a cumulative dose in excess of 100gms of Xi xin, Mu tong or Ma dou ling. Diseases of the respiratory and musculoskeletal system were the most common indications for the SAA CHP prescriptions. The most frequently prescribed SAA CHPs were Shu jing huo xie tang, Chuan qiong cha diao san, and Long dan xie gan tang, respectively containing Fang ji, Xi xin, and Mu tong. In study 3, it provides national-level CHP prescription profiles and utilization rates, and documents, for the first time, HF-HF combination prescriptions in Chinese medicine practices in Taiwan. To further target the CHPs of concern, the study 4 showed that about one-third of people in Taiwan have, at some time, been prescribed with SAA CHPs, and although the cumulated dosages may not be large. It is therefore concluded that future studies are indicated to safeguard CHP usage.