中華民國八十九年七月 第七卷 第三期 1
台中榮總藥訊
VGHTC Drug Bulletin
發行人：邵克勇 總編輯：陳本源 (04)23592539
編 輯：邱正己、鄭鴻基、吳培基、李興深、吳明芬、黃文龍、劉媖媚、劉婉香、鄭珮文 地 址：台中市中港路三段 160 號 藥劑部 毒藥物諮詢中心
網 址：http://www3.vghtc.gov.tw:8082/pharmacy/pharmacy1.htm 電子信箱：phar@vghtc.gov.tw
創刊日期：八十三年一月二十日
超級比一比
比較 Fluoroqunolone 引起的 QT interval 延長 及 torsade de pointes
黎美惠 藥師
所謂 QT interval 是指心室去極化及再極 化的時間。在健康的情況下 QT interval 為小 於或等於 400 msec. 而經過與心跳速率關 係的校正後（QTc）為小於或等於 440 msec 男女間略有差異：當男士大於 450，女士大於 470 則視為 QT interval 延長。（見表一）
表一、CPMP Suggested Ranges for QTc
Intervals (msec)
QTc
aMen Women
Normal < 430 < 450
Borderline 430-450 450-470 Prolonged > 450 > 470
QT interval 的過度延長可能導致心室心 律不整或昏厥或猝死…等等。Torsade de pointes (Tdp) 是一種快速，多形性之心室心 搏過速，係因 QT interval 延長所致。藥品引 發的 QT interval 延長，多與鉀離子通道受阻 有關，但由於藥品引起的頻率相當低。
會造成 QT interval 延長,甚至是 Tdp 的
藥品，依其可能性被劃分成三大類：definite, probable, and proposed association, 詳見 下表二。
依據 adverse event data submitted to US Food and Drug Administration（FDA）
Spontaneous Reporting System (1969 to 1997) 及 the Adverse Events Reporting System （1997 and thereafter）從 1996 年 一月至 2001 年五月的 fluoroquinolone 所做 的 the crude rates of TORSADE DE POINTES 針對五個不同的結果。（見表四）
與 ciprofloxacin 相比，gatifloxacin 和 levofloxacin 的 crude rates of torsade de pointes 是 ciprofloxacin 的 90 和 18 倍之多，
（p less than 0.001, either comparison）, 而 gatifloxacin 則 為 levofloxacin 的 5 倍
（p=0.001）（Frothingham, 2001）.
現將 Fluoroquinolone 對心臟之動物實 驗結果整理如下（表五），供大家參考。
第 三 期
第七卷 第三期 台中榮總藥訊 2
表二、Drugs Associated with QT Interval Prolongation
Drugs by Class Association
a Torsadogenicb FDA LabelingcComments
Gatifloxacin
Probable --- QTGrepafloxacin
Definite --- NA Removed from U.S. marketLevofloxacin
Proposed --- TDP Lower risk than that of similar agents.Moxifloxacin
Probable --- QT Lower risk than that of similar agents.Sparfloxacin
Definite --- NA Removed from U.S. marketFDA = United States Food and Drug Administration;
QT = QT interval prolongation; TDP = torsade de pointes; NA = not applicable;
aAssociations are based on the strength of evidence that supports whether QT prolongation can occur.
This categorization does not delineate an individual patient's risk of QT prolongation.
bTorsadogenic potential is divided into four categories as characterized in a previous publication[9]: high = drugs that are potent blockers of currents prolonging myocardial repolarization;
medium high = drugs that prolong myocardial repolarization at higher doses, or at normal doses with concurrent administration of drugs that inhibit drug metabolism; low = drugs that prolong action potential duration and QT interval at high doses or
concentrations that are clearly above the therapeutic range; and not clear = drugs that block repolarizing ion currents in vitro but that have so far not been shown to prolong repolarization in other in vitro models.
cDescribes whether the FDA-approved product labeling includes mention of QT prolongation, torsade de pointes, or both.
另外，Fluoroquinolone 所致的 TDP 會因 一些個人因素而有差異。以下表三為 FDA 所 歸納出可能因服用或注射 Fluoroquinolone 導 致 TDP 的個人因素。
表三、Characteristics of Patients Developing Torsade de Pointes From the FDA Adverse
Event Reporting System
Characteristics Macrolide Fluoroquinolone
Age, y 61+/-22 72+/-15
Female, % 70 67
Mean baseline QT, msec 432+/-50 434+/-44
Event QT, msec 594+/-80 530+/-151
Fatal outcomes, % (n/N) 9 (14/156) 13 (6/46) Patients receiving concomitant drugs known to prolong QT, % 22 24
中華民國八十九年七月 第七卷 第三期 3 表四、Fluoroquinolone 發生 TDP 之比較：
AGENT NUMBER OF U.S.
CASES REPORTED
CASE RATE (PER 10 MILLION PRESRIPTIONS)
Ciprofloxacin 2 0.3
Gatifloxacin 8 27
Levofloxacin 13 5.4
Moxifloxacin 0 0
Ofloxacin 2 1.4 表五、Summary of Fluoroquinolone QTc Interval Data
Sparfloxacin Grepafloxacin Levofloxacin Trovafloxacin Moxifloxacin
Animal data
Dogs 25-45 mg/kg, QT prolongation occurred
Rabbits 10-30 mg/kg, arrhythmia developed in 1/4 animals
No data No data
Dogs 90 mg/kg resulted in a 25-msec QT interval
prolongation (no arrhythmias)
QTc interval
prolongation in humans
Yes Yes Minimal No p.o. minimal
Mean ± SD QTc interval prolongation in humans
p.o. 10.3 ± 27.6
msec p.o. 8 msec 4.6 msec ± 23
msec No data p.o. 6 ± 26 msec, i.v. 12.1 msec
QTc interval
prolongation outlier values (> 60 msec from baseline or > 500msec overall)
> 500 msec from baseline in 10/880 pts
No data No data Not observed in clinical trials
> 60 msec from baseline in 3/107 pts
Additive QTc
prolongation effects with other
QTc-prolonging agents
Yes No data 4/37 pts No data Yes
Patients at risk for QTc interval prolongation excluded from trials
Yes No No No Yes
參考資料：
MICROMEDEX® Healthcare Series, Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires [1999/08/15]).
第七卷 第三期 台中榮總藥訊 4
超級比一比
院內 Benzodiazepines 製劑之比較
吳玫君藥師
Agent Supply Time to Peak Blood Level (hr)
Half-life (parent
，hr）
Adult Dose
（daily）
Onset/
Duration
Adjust dose in renal failure
FDA Indications
Pregna ncy Catego ry Anxiolytics
Alprazolam
(Xanax®) 0.5mg/Tab 1~2 12~15 0.5~4mg 1~1.5hr/
ND No
*Anxiety(immediate-release only)
*Panic disorder(with or without agoraphobia)
(immediate-release or extended release)
D
Bromazepam
(Lexotan®) 1.5mg/Tab 1~2 8~20 6~30mg ND No *Anxiety ND
Diazepam (Valium®)
2mg,5mg/
Tab 10mg/2ml/
Amp
0.5~2 20~80 4~40mg PO 30'/
ND No
*Acute alcohol withdrawl
*Anxiety
*Cardioversion
*Endoscopic procedure
*Skeletal muscle spasm
*Seizures
D
Fludiazepam
(Erispan®) 0.25mg/Tab 1 23 0.75mg ND No Not approved by FDA
*Anxiety ND
Lorazepam (Ativan®)
0.5mg,1mg/
Tab
2ml/ml/Amp 1~6 10~16 2~6mg 20'~30'/
8hr No *Anxiety
*Preanesthetic
*Status epilepticus D Oxazepam
(Serax®) 15mg/Tab 2~3 5~20 30~120mg 2~3hr/
12~24hr No *Alcohol withdrawl
*Anxiety D
Oxazolam
(Serenal®) 10mg/cap rat:30'-
rat:60' 30-60mg 30'/ Not approved by FDA
*Anxiety
*Preanesthetic D
Hypnotics Estazolam
(Eurodin®) 2mg/Tab 2 10~24 1~2mg 20'/
10~24hr No *Insomnia X
Flunitrazepam
(Rohypnol®) 1mg/Tab
2mg/Amp 1~2 16~35 1~2mg 20'~30'/
8hr ND
Not approved by FDA
*Anesthesia adjunct
*Anesthesia induction
*Insomnia
*Local anesthesia supplementation
*Premedication
*Status epilepticus
D
Clonazepam
(Rivotril®) 0.5mg,2mg/
Tab 1~4 30~40 1.5~20mg 20'~40'/
6~8hr No *Panic disorder
*Seizure disorders D 參考資料：
MICROMEDEX® Healthcare Series, Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires [1999/08/15]).
