臺灣博碩士論文加值系統

1.Trazodone之生體相等性研究
Trazodone是一個triazolopyridine的抗憂鬱藥物，和一般的三環抗憂鬱藥物或其他類的抗憂鬱藥的結構迥異，而作用的機制也較為特殊；Trazodone有拮抗血清素（serotonin）的作用，但在治療憂鬱症方面的機制目前尚無定論。
本實驗旨在比較兩種主成分為Trazodone之製劑：Mesyrel（標準藥品）與1.Torlex (試驗藥品)單劑量口服投藥之血中trazodone濃度變化。計有十六名男性健康受試者參與，進行兩種製劑之交叉試驗以評估此兩種製劑是否具有身體相等性。其中一名受試者因嚴重的頭昏而意願停止參加試驗，故共有十五名完成全程試驗。
受試者在試驗前一晚九點起禁食至隔天早晨，在服用單劑量50mg藥物後，定時抽取血液檢品。各血漿檢品經前處理後trazodone濃度採用高效能液相層析儀（HPLC）來檢測，此檢品的前處理方式（包含檢品安定性）及分析方法均經確效驗證，具有一定的可信度。
人體試驗所得血中濃度結果，經電腦軟體-Winnonlin運算得到藥動學參數：AUC、Cmax、Tmax…等，先以統計的ANOVA變異數分析得兩製劑並無顯著差異（p>0.05），並利用兩組單邊的假設（two one-sided t-test）去檢定Torlex（試驗藥品）藥動參數均值是否落在Mesyrel（標準藥品）80-125％的範圍內，來證明兩藥具有生體相等性。
2.Meropenem之藥動性質探討
Meropenem是一個種新開發的carbapenem類抗生素。和imipenem十分相似，兩者在體內具高度活性能廣泛的對抗細菌，以及能有效的治療各式輕度到重度感染。Meropenem幾乎能作用於所有的厭氧菌及好氧菌，特別是用在三種最常見的細菌性腦膜炎中：腦膜炎球菌，肺炎鏈球菌，流行感冒嗜血桿菌。
Meropenem及Imipenem兩者都能廣泛的分佈在組織及體液內，例如：脊髓液中；但imipenem的使用受限於常誘發癲癇的副作用。而meropenem使用的範圍及效果和imipenem相似，但並不會有上述的副作用。本實驗在探討感染細菌性腦膜炎的病患，在單劑量輸注meropenem後，藥物分佈在血中及脊髓液中的情況。
本實驗包含28名男性及女性的細菌性腦膜炎患者。Meropenem以單劑量靜脈輸注30分鐘的方式投與。在給藥2小時後抽取病患的血液及脊髓液，再以高效能液相層析法分析檢品。
雖然藥物在腦部和脊髓液的含量較少，但meropenem在脊髓液的濃度也達一般文獻中對此病原菌的最小抑菌濃度。藥物在血中及脊髓液中的濃度比值是界於1-29％間，與一些文獻上的研究相符。本實驗的目的旨在研究本國人感染腦膜炎時，投與meropenem藥物的血中濃度及脊髓液濃度的關係。

1.1.Bioequivalence Studies on Trazodone
Trazodone is a triazolopyridine derivative with antidepressant activity that is chemically unrelated to other currently available antidepressants. Its pharmacological properties differ from those of most other antidepressants. Trazodone exhibits antiserotonin activity, but its mechanism of action in depressive illness in humans is not clear.
Comparative plasma levels of trazodone after oral dosing of two formulations, Mesyrel and Torlex, were investigated. A randomized two-way crossover study with 16 healthy male volunteers was carried out. Owing to the strong drowsiness occurred in one subject, only 15 subjects completed the study.
A 50mg single dose was administrated to each subject after overnight fasting. Blood samples were collected and analyzed by high performance liquid chromatography (HPLC). The methods for sample refrigeration, pretreatment and analysis were validated before study.
The pharmacokinetic parameters includeing AUC, Cmax, Tmax were determined by WinNonlin noncompartmental analysis. Following ANOVA and 90% CI evaluations, there was no statistically significant defferences between the two formulations. The results showed that Torlex and Mesyrel were bioequivalent.
2.Pharmacokinetic Studies on Meropenem
Meropenem is a novel carbapenem antibiotics, similar to imipenem, with high activity in vitro against a broad spectrum of bacteria, effective therapy for a variety of experimental infections and moderate to severe infection in humans. It is active against almost all clinically significant aerobes and anaerobes, particularly the three most common causes of community-acquired bacterial meningitis, Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae.
Meropenem and imipenem are both widely distributed in body tissues and fluids, including cerebrospinal fluid. The wider clinical use of imipenem for the treatment of meningitis has been limited by high incidence of seizures. The use of meropenem appears the similar bacteriological and clinical efficacy to imipenem and there is no significant propensity to cause seizures. This study is undertaken to determine the concentrations of meropenem in the cerebrospinal fluid (CSF) and plasma of patients with inflamed meningitis following a single iv dose.
Patients eligible for inclusion in this study were 28 males and females with bacterial meningitis who were already receiving antibiotics treatment. A single iv dose of meropenem was administrated as a 30-min infusion. CSF and Blood samples were obtained from each patient at 2 hours after the infusion. Meropenem concentrations in CSF and plasma were analyzed by reversed phase high-performance liquid chromatography (HPLC).
Very small amount of drug was found in the brain and CSF, however, the meropenem concentration in CSF was in excess of the reported MIC90 for most of the pathogens associated with this disease. The CSF / Plasma drug concentration ratio was between 1-29%, which is similar to some research.

¨目次¨
目次………………………………………………………………………..…..VII
圖目錄 ………………………………………………………….. ………….…XI
表目錄……………………………………………………………………….. XIII
第一部份、 Trazodone 之生體相等性研究
中文摘要……………………………………………………………………….iii
英文摘要..……………………………..………………………………………...v
壹、 緒論
一、 Trazodone之醫療用途2
1. 關於情緒失調2
2. 憂鬱症的用藥4
3. Trazodone的藥理作用機轉6
4. Trazodone在臨床的運用8
二、 Trazodone藥動學性質11
三、 Trazodone之物理化學性質12
貳、 實驗目的14
參、 材料與方法
一、 藥品與試劑17
二、 儀器與設備18
三、 電腦系統與軟體20
四、 藥品溶液的製備21
五、 實驗方法22
1. 實驗設計:22
2. 志願受試者的選擇22
3. 人體試驗23
4. 分析方法的確效26
六、 數據分析及統計方法30
肆、結果
一、高效能液相層析之分析方法確效35
二、安定性47
三、Trazodone同批內及異批內之精密度與準確度49
四、 耐變性53
五、 試驗進行中之確效作業54
六、 人體試驗的結果56
伍、 討論
一、 Trazodone之定量分析83
1. 專一性89
2. 準確度89
3. 精密度89
4. 檢測限度90
5. 定量限度90
6. 線性91
7. 範園91
8. 耐變性91
二、Trazodone藥物動力學特性93
1. Onset and Duration93
2. 藥物的吸收93
3. 分佈94
4. 排除96
三、 統計結果的分析
1. 概論100
2. 統計分析-變異數的分析（ANOVA）104
3. 檢定假設 （Hypothesis Testing）………………………………..107
4. 信賴區間（Confidence Interval）……………………………...…110
六、 結論……………………………………………….……………………114
參考文獻……………………………………………………………..………115
第二部份、 Meropenem 之藥物動力學探討
中文摘要………………………………...………………………………………ix
英文摘要……………………………………………...…………………………xi
壹、緒論
一、Meropenem 之概論121
1. Meropenem 之發展過程121
2. Meropenem 之藥理作用122
3. Meropenem 在臨床上的用途125
二、Meropenem 藥動學性質130
三、Meropenem的物理化學性質132
貳、實驗目的135
參、材料與方法
一、藥品試劑137
二、儀器設備138
三、電腦系統與軟體140
四、藥品溶液的製備141
五、實驗方法143
1. 實驗設計：143
2. 志願受試者的選擇143
3. 人體試驗146
4. 分析方法的確效……………………………………………...…149
肆、結果
一、高層液相層析圖譜153
二、Meropenem同日內及異日內之確效..158
三、人體試驗的結果163
伍、討論
一、 Meropenem 之分析方法171
二、 Meropenem 之藥物動力學性質172
三、 本研究數據分析與文獻比較184
六、 結論187
參考文獻…………………………………………………………………….188
¨圖目錄¨
第一部份、 Trazodone 之生體相等性研究
圖一、Trazodone水溶液在UV光下之全光譜……………….………….36
圖二-a、Trazodone水溶液之層析圖譜（0.01ug/ml）…………………….37
圖二-b、Trazodone空白血漿之層析圖譜………………………………….37
圖二-c、含Trazodone在血漿中之層析圖譜………………………………38
圖三、表示Trazodone專一性的圖譜….……….…………………….43-46
圖四、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex 之
a、 血中濃度變化曲線圖；b、血中濃度變化之半對數曲線圖…60
圖五-I、編號1之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲圖…..61
圖五-II、編號2之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲圖…62
圖五-III、編號3之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖..………………………………………………………………....63
圖五-IV、編號4之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖..…………………………………………………………………64
圖五-V、編號5之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖..…………………………………………………………………65
圖五-VI、編號6之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖…..………………………………………………………………66
圖五-VII、編號7之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖..…………………………………………………………………67
圖五-VIII、編號8之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖…..………………………………………………………………68
圖五-IX、編號9之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖..…………………………………………………………………69
圖五-X、編號10之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖………………………………………………………..…………70
圖五-XI、編號11之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖………………………………………………………………..…71
圖五-XII、編號12之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖…………………………………………………………………..72
圖五-XIII、編號13之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖………………………………………………....………………..73
圖五-XIV、編號14之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖……..………………………………………………………..…..74
圖五-XV、編號15之受試者經口服對照處方Mesyrel及試驗處方Torlex
之a、血中濃度變化曲線圖；b、血中濃度變化之半對數曲線
圖…..………………………………………………………………75
圖六、層析峰之示意圖……………..……….…………………………...85
圖七、均值相當，但變方不當的示意圖..……………………………..104
圖八、均值和變方均相當的示意圖……………………………………104
圖九、在Tmax附近取樣不足的情形………..….……………………….107
第二部份、 Meropenem 之藥物動力學探討
圖一、血中濃度和時間圖曲線下面積（AUC）和投藥劑量之關係圖..130
圖二、骨架結構式。 a. Penem. b. Carpabenem…….………….……..134
圖三、Meropenem藥品水溶液在UV光下的吸收圖譜………………153
圖四-a、經前處理後空白血漿之分析圖譜………………………………154
圖四-b、服用meropenem的血漿經前處理之分析圖譜…..……………..154
圖五-a、經前處理後空白血漿之分析圖譜………………………………155
圖五-b、服用meropenem的血漿經前處理之分析圖譜….…………...…155
圖六、Meropenem在血液中及脊髓液中之藥物濃度關係圖…..……..167
圖七、Meropenem在脊髓液中濃度與白血球之關係圖………………169
圖八-a、Meropenem之體清除率與creatinine清除率之關係圖……..….181
圖八-b、Meropenem之腎清除率與creatinine清除率之關係圖……..…182
圖九、比較meropenem以及其他藥物所造成的副作用………………183
圖十、給予感染腦膜炎病患meropenem 不同的劑量下，其脊髓液中
藥物的濃度情形………………..……………………………..…185
圖十一、藥物在脊髓液中濃度與發炎程度之關係圖……………………186
圖十二、藥物血中濃度和脊髓液濃度對時間的關係圖…………………186
¨表目錄¨
第一部份、 Trazodone 之生體相等性研究
表一、憂鬱症的分類………………………………………………………2
表二、憂鬱症之亞型………………………………………………………3
表三、Trazodone 之作用機制…………………………………………….5
表四、其他抗憂鬱藥物常見的副作用……………………………………7
表五、抗憂鬱藥物服用過量的情況………………………………………8
表六、Trazodone 之副作用…………………………………………..….10
表七、一些常見抗鬱劑的作用機制…………………………….…….…13
表八、病患之投藥設計表…………………………………….………….23
表九、Trazodone系統適合度因子之評估……………………………….38
表十、血漿中Trazodone濃度的檢量線………………….…..……….…39
表十一、Trazodone檢量線的準確度…………………………………….…40
表十二、準確度與精密度………………………….……………………….41
表十三、Trazodone之靈敏度……………………………………………….42
表十四、Trazodone 在人體血漿中回收率………………………………...42
表十五、Trazodone 在生物流體中安定性的評估……………...…………48
表十六a、同批內之準確度與精密度…………………………..……………51
表十六b、異批間之精密度與準確度…….…………………….………..…..52
表十七、耐變性試驗……………………………...…………..…………….53
表十八、實驗進行中之準確度…………………………………….……….55
表十九-a、十五名受試者口服對照處方Mesyrel 50mg後，於各抽血點
之血中濃度分析值 ………...………..………………..………….58
表十九-b、十五名受試者口服試驗處方Torlex 50mg後，於各抽血點之
血中濃度分析值………….…………..……………………...……59
表二十-a、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之AUC0-∞表………….…………………………………..…..…76
表二十-b、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之AUCpartial表….…………………………………….………….77
表二十-c、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之Cmax表….……………………………………..………………78
表二十-d、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之Tmax表………………………..………………..………..…….79
表二十-e、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之T1/2表…………………………………………………………80
表二十一、對照處方Mesyrel及試驗處方Torlex 後之藥動參數統計
結果………………………………………………………….…….81
表二十二、十五名受試者經口服對照處方Mesyrel及試驗處方Torlex
後之變方分析表（ANOVA Table）…………………….…………81
表二十三、ICH及USP中對分析方法之確效特性之比較…………………….88
表二十四、Trazodone在人體器官內之分佈………………………………….95
表二十五、Trazodone和代謝物m-CPP與肝臟酵素的關係…………………97
第二部份、 Meropenem 之藥物動力學探討
表一、meropenem 及imipenem, biapenem, cephaloridine 對
β-lactamases之安定性………………………….…...……..…...122
表二、各種penicillin-binding proteins (PBPs)所負責的功能……….…123
表三-a、meropenem和其他抗生素在臨床上對革蘭式陽性菌
之抗菌活性比較表………………………………………………124
表三-b、meropenem和其他抗生素在臨床上對革蘭式陰性菌
之抗菌活性比較表………………………………….………...…124
表三-c、meropenem和其他抗生素在臨床上對厭氧菌
之抗菌活性………….……………………..……………..……...125
表四、在各種感染時，正常成人及嬰幼兒血管內注射
meropenem之劑量……………………………..………………..126
表五、比較meropenem在臨床試驗的結果……..………………...127-128
表六、根據creatinine clearence 調整meropenem之劑量…..……….129
表七、受試病患資料…..…………………………………….….…144-146
表八、為血漿中meropenem濃度的檢量線………………………..….156
表九、為脊髓液中meropenem濃度的檢量線…..………………….…157
表十-a、Meropenem血漿檢品之分析同日內精密度…………………....159
表十-b、Meropenem血漿檢品之分析異日間精密度…..………………..159
表十-c、Meropenem血漿檢品之分析同日內準確度……………………160
表十-d、Meropenem血漿檢品之分析異日間準確度……………………160
表十一-a、Meropenem脊髓液檢品之分析同日內精密度………..………..161
表十一-b、Meropenem脊髓液檢品之分析異日間精密度…………………161
表十一-c、Meropenem脊髓液檢品之分析同日內準確度…..….………….162
表十一-d、Meropenem脊髓液檢品之分析異日間準確度…..……………..162
表十二、受試者在給藥後的血中濃度……………………………………164
表十三、受試者在給藥後,在CSF中的濃度………………………….…..165
表十四、受試者在給藥後, 藥物在脊髓液中及血漿中濃度之比值………………......166
表十五、受試者給藥前後紅血球及白血球之變化……………………....168
表十六、投與不同劑量之meropenem其平均藥動學參數……..……....173
表十七、為meorpenem穿透皮膚水泡之情形…………………..………174
表十八、為meorpenem穿透各個體內組織之情形……………………..175
表十九、投與500 mg/kg meropenem（靜脈輸注30分）於年輕人及老
年人其藥動參數之情形…………...……..……………………...179
表二十、投與10，20，40 mg/kg meropenem（靜脈輸注30分）於
小孩其藥動參數之情形………………………….……………...179
表二十一、投與meropenem於腎功能不全之病人之藥物動力學參數..…181
表二十二、比較meropenem以及其他藥物對感染腦膜炎之病患所造成
癲癇副作用……………………..……………………………..…183

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