多沙唑嗪及其光学异构体对兔离体心肌和肠肌药理作用的立体选择性
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摘要
目的:观察多沙唑嗪(rac-doxazosin, rac-DOX)及其光学异构体(S-DOX和R-DOX)对兔离体心房肌和心室肌收缩活动的影响,对兔离体回肠和十二指肠收缩活动的影响。
方法:制备兔离体左心房、右心房、右心室肌标本。对于心房标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体。对于右心室标本,非累积给予3、10、30μmol·L~(-1)多沙唑嗪及其光学异构体。观察多沙唑嗪及其光学异构体对心率和心肌收缩力的影响。
制备兔离体回肠、回肠纵肌、回肠环肌标本。对于回肠和回肠纵肌标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体。对于回肠环肌标本,先给予30μmol·L~(-1)的多沙唑嗪及其光学异构体,再给予20μmol·L~(-1)的卡巴胆碱。观察多沙唑嗪及其光学异构体对离体回肠肠肌收缩频率和收缩幅度的影响。
制备兔离体十二指肠标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体,观察多沙唑嗪及其光学异构体对离体十二指肠自发收缩频率和收缩幅度的影响。
结果:
1 S-DOX、R-DOX及rac-DOX对兔离体右心房心率的影响
R-DOX(30μmol·L~(-1)),使23%的实验标本发生停搏,rac-DOX和S-DOX未诱发停搏反应。
S-DOX(30μmol·L~(-1))对兔离体右心房心率无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心房心率, 30μmol·L~(-1)时R-DOX组心率减慢(25.7±10.5)%,rac-DOX组心率减慢(23.6±7.7)%。
2 S-DOX、R-DOX及rac-DOX对兔离体右心房收缩力的影响
S-DOX(3、10、30μmol·L~(-1))对兔离体右心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心房心肌收缩力,30μmol·L~(-1)时R-DOX组心肌收缩力下降了(78.6±8.6)%,rac-DOX组心肌收缩力下降了(56.7±11.7)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
3 S-DOX、R-DOX及rac-DOX对兔离体左心房收缩力的影响
S-DOX(3、10、30μmol·L~(-1))对兔离体左心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔左心房心肌收缩力,30μmol·L~(-1)时,R-DOX和rac-DOX对左心房心肌收缩力的抑制百分率分别为(89.9±4.9)%和(45.4±15.6)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
4 S-DOX、R-DOX及rac-DOX对兔离体右心室肌收缩力的影响
S-DOX(30μmol·L~(-1))显著增强兔离体右心室肌收缩力,30μmol·L~(-1)时右心室肌收缩力增强了(26.7±21.5)%。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心室肌收缩力,30μmol·L~(-1)时,R-DOX和rac-DOX对右心室肌收缩力的抑制百分率分别为(38.1±28.1)%和(29.4±24.4)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
5 S-DOX、R-DOX及rac-DOX对兔离体回肠、回肠纵肌和环肌收缩反应的影响
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对兔离体回肠自发收缩幅度无显著影响。S-DOX仅在30μmol·L~(-1)浓度减慢回肠自发收缩频率。R-DOX和rac-DOX(10、30μmol·L~(-1))显著抑制回肠自发收缩频率,30μmol·L~(-1)时R-DOX和rac-DOX使自发收缩频率分别减慢至7.1cycles·min-1和6.8cycles·min-1。
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对兔离体回肠纵肌自发收缩幅度无显著影响。S-DOX仅在30μmol·L~(-1)浓度减慢自发收缩频率。R-DOX和rac-DOX(10μmol·L~(-1)、30μmol·L~(-1))显著抑制兔离体回肠纵肌的自发收缩频率;30μmol·L~(-1)时R-DOX和rac-DOX使回肠纵肌自发收缩频率分别减慢至9.7cycles·min-1和9.0cycles·min-1。
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对卡巴胆碱所诱发的兔离体回肠环肌收缩频率和收缩幅度均无显著影响。
6 S-DOX、R-DOX及rac-DOX对兔离体十二指肠收缩反应的影响。
S-DOX仅在30μmol·L~(-1)浓度显著抑制兔离体十二指肠自发收缩频率。R-DOX(10、30μmol·L~(-1))、rac-DOX(10、30μmol·L~(-1))显著抑制兔离体十二指肠自发收缩频率,30μmol·L~(-1)时两组标本的收缩频率分别由给药前的17.5cycles·min-1减慢至14.2cycles·min-1以及15.1cycles·min-1减慢至12.5cycles·min-1。
S-DOX、R-DOX和rac-DOX(10、30μmol·L~(-1) )均显著抑制兔离体十二指肠自发收缩幅度;30μmol·L~(-1)时十二指肠的收缩幅度分别被抑制至0.75g、0.71g和0.87g。
结论:
R-DOX抑制右心房心率的作用强于rac-DOX,甚至诱发停搏反应;S-DOX不影响心率。R-DOX对心房肌和心室肌收缩力的抑制作用强于rac-DOX;S-DOX不影响心房肌收缩力,对心室肌具有正性肌力作用。
S-DOX、R-DOX及rac-DOX对兔离体回肠和回肠纵肌的收缩力无影响,对卡巴胆碱所诱发回肠环肌收缩反应亦无明显影响,但显著抑制离体十二指肠收缩力。S-DOX、R-DOX及rac-DOX显著抑制兔离体回肠、回肠纵肌和十二指肠的自发收缩频率,其中S-DOX的抑制作用相对较弱。
Objective: To study the effects of rac-doxazosin (rac-DOX) and its enantiomers (S-doxazosin, S-DOX and R-Doxazosin, R-DOX) on the rabbit isolated atrial and ventricular strips and ileum and duodenal smooth muscle.
Methods: The strips of the rabbit isolated right atrium, left atrium and right ventricle were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively administered into the organ bath containing the rabbit isolated atrial strips, but they were non-cumulatively administered into the organ bath containing the rabbit isolated right ventricular strips. The effects of doxazosin and its enantiomers on contractile force and heart rate were observed.
The rabbit isolated ileum, ileum longitudinal muscle strips and circular muscle strips were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively given into the organ bath containing the rabbit isolated ileum, ileum longitudinal muscle. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively administered into the organ bath containing the rabbit isolated ileum circular muscle, then carbachol at 20μmol·L~(-1) was applied. Effects of doxazosin and its enantiomers on the contractile force, contractile frequency and carbachol-induced responses were observed in the rabbit isolated ileum preparations.
The rabbit isolated duodenal smooth muscle preparations were prepared, and doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively given into the organ bath containing the rabbit isolated duodenum. Effects of doxazosin and its enantiomers on the contractile force and contractile frequency were observed in the rabbit isolated duodenal smooth muscle.
Results:
1 Effects of doxazosin and its enantiomers on the heart rate in the rabbit isolated right atrium
In 23% of the used atrial preparations, the cardiac arrest was induced by R-DOX at 30μmol·L~(-1), but S-DOX and rac-DOX at the same concentration did not induce the same effect. S-DOX at 30μmol·L~(-1) did not affect the heart rate of the rabbit isolated right atrium, R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the heart rate. R-DOX and rac-DOX at 30μmol·L~(-1) decreased the heart rate by 25.7±10.5% and 23.6±7.7%, respectively.
2 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right atrium
S-DOX did not affect the contractile force of the rabbit isolated right atrium. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the contractile force of the rabbit isolated right atrium and both of them at 30μmol·L~(-1) decreased the contractile force by 78.6±8.6% and 56.7±11.7%, respectively. The negative inotropic effect in the right atrium by R-DOX was stronger than that by rac-DOX.
3 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated left atrium
S-DOX did not affect the contractile force of the rabbit isolated left atrium. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the contractile force of the rabbit isolated left atrium and both of them at 30μmol·L~(-1) decreased the contractile force by 89.9±4.9% and 45.4±15.6%, respectively. The negative inotropic effect in the left atrium by R-DOX was stronger than that by rac-DOX.
4 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right ventricular strips
S-DOX at 30μmol·L~(-1) increased the contractile force of the rabbit isolated right ventricular strips, and S-DOX at 30μmol·L~(-1) increased the contractile force by 26.7±21.5%. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration -dependently decreased the contractile force of the rabbit isolated right ventricular strips and both of them at 30μmol·L~(-1) decreased the contractile force by 38.1±28.1% and 29.4±24.4%, respectively. The negative inotropic effect in the ventricular strips by R-DOX was stronger than that by rac-DOX.
5 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated ileum smooth muscle
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the spontaneous contractile force in the rabbit isolated ileum. S-DOX only at 30μmol·L~(-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum, R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frequency from 10.3cycles·min-1 to 7.1cycles·min-1 and from 10.6cycles·min-1 to 6.8cycles·min-1, respectively.
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the spontaneous contractile force in the rabbit isolated ileum longitudinal muscle strips. S-DOX only at 30μmol·L~(-1) decreased the contractile frequency from 12.9cycles·min-1 to 10.1cycles·min-1 in the rabbit isolated ileum longitudinal muscle. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum longitudinal muscle strips, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frequency from 13.9cycles·min-1 to 9.7cycles·min-1 and from 13.0cycles·min-1 to 9.0cycles·min-1, respectively.
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the contractile force and contractile frequency of the contraction induced by carbachol in the rabbit isolated ileum circular muscle strips.
6 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated duodenal smooth muscle
S-DOX only at 30μmol·L~(-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenum. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenal smooth muscle, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frquency from 17.5cycles·min-1 to 14.2cycles·min-1 and from 15.1cycles·min-1 to 12.5cycles·min-1, respectively.
Doxazosin and its enantiomers (10~30μmol·L~(-1)) all decreased the spontaneous contractile force in the rabbit isolated duodenal muscle. S-DOX at 30μmol·L~(-1) decreased the spontaneous contractile force from 3.81g to 0.75g, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the spontaneous contractile force from 4.12g to 0.71g and from 3.96g to 0.87g, respectively.
Conclusion: R-DOX produces a negative chronotropic effect in the rabbit isolated right atrium more potently than rac-DOX, and it even causes cardiac arrest at higher concentration. S-DOX does not affect the heart rate. R-DOX produces a negative inotropic effect in the rabbit isolated atrial and ventricular strips more potently than rac-DOX. On the contrary, S-DOX produces the positive inotropic effect.
Doxazosin and its enantiomers do not affect the spontaneous contractile force in the rabbit isolated ileum and ileum longitudinal muscle, and do not affect the contraction induced by carbachol in the rabbit isolated ileum circular muscle, but decrease the spontaneous contractile force in the rabbit duodenal muscle. Doxazosin and its enantiomers decrease the spontaneous contractile frequency in the rabbit isolated ileum, ileum longitudinal muscle and duodenum muscle, and the inhibitory effect by S-DOX is weaker.
方法:制备兔离体左心房、右心房、右心室肌标本。对于心房标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体。对于右心室标本,非累积给予3、10、30μmol·L~(-1)多沙唑嗪及其光学异构体。观察多沙唑嗪及其光学异构体对心率和心肌收缩力的影响。
制备兔离体回肠、回肠纵肌、回肠环肌标本。对于回肠和回肠纵肌标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体。对于回肠环肌标本,先给予30μmol·L~(-1)的多沙唑嗪及其光学异构体,再给予20μmol·L~(-1)的卡巴胆碱。观察多沙唑嗪及其光学异构体对离体回肠肠肌收缩频率和收缩幅度的影响。
制备兔离体十二指肠标本,累积给予3、10、30μmol·L~(-1)浓度的多沙唑嗪及其光学异构体,观察多沙唑嗪及其光学异构体对离体十二指肠自发收缩频率和收缩幅度的影响。
结果:
1 S-DOX、R-DOX及rac-DOX对兔离体右心房心率的影响
R-DOX(30μmol·L~(-1)),使23%的实验标本发生停搏,rac-DOX和S-DOX未诱发停搏反应。
S-DOX(30μmol·L~(-1))对兔离体右心房心率无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心房心率, 30μmol·L~(-1)时R-DOX组心率减慢(25.7±10.5)%,rac-DOX组心率减慢(23.6±7.7)%。
2 S-DOX、R-DOX及rac-DOX对兔离体右心房收缩力的影响
S-DOX(3、10、30μmol·L~(-1))对兔离体右心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心房心肌收缩力,30μmol·L~(-1)时R-DOX组心肌收缩力下降了(78.6±8.6)%,rac-DOX组心肌收缩力下降了(56.7±11.7)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
3 S-DOX、R-DOX及rac-DOX对兔离体左心房收缩力的影响
S-DOX(3、10、30μmol·L~(-1))对兔离体左心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔左心房心肌收缩力,30μmol·L~(-1)时,R-DOX和rac-DOX对左心房心肌收缩力的抑制百分率分别为(89.9±4.9)%和(45.4±15.6)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
4 S-DOX、R-DOX及rac-DOX对兔离体右心室肌收缩力的影响
S-DOX(30μmol·L~(-1))显著增强兔离体右心室肌收缩力,30μmol·L~(-1)时右心室肌收缩力增强了(26.7±21.5)%。R-DOX和rac-DOX(3、10、30μmol·L~(-1))浓度依赖性地抑制兔右心室肌收缩力,30μmol·L~(-1)时,R-DOX和rac-DOX对右心室肌收缩力的抑制百分率分别为(38.1±28.1)%和(29.4±24.4)%。R-DOX的心肌收缩力抑制作用强于rac-DOX。
5 S-DOX、R-DOX及rac-DOX对兔离体回肠、回肠纵肌和环肌收缩反应的影响
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对兔离体回肠自发收缩幅度无显著影响。S-DOX仅在30μmol·L~(-1)浓度减慢回肠自发收缩频率。R-DOX和rac-DOX(10、30μmol·L~(-1))显著抑制回肠自发收缩频率,30μmol·L~(-1)时R-DOX和rac-DOX使自发收缩频率分别减慢至7.1cycles·min-1和6.8cycles·min-1。
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对兔离体回肠纵肌自发收缩幅度无显著影响。S-DOX仅在30μmol·L~(-1)浓度减慢自发收缩频率。R-DOX和rac-DOX(10μmol·L~(-1)、30μmol·L~(-1))显著抑制兔离体回肠纵肌的自发收缩频率;30μmol·L~(-1)时R-DOX和rac-DOX使回肠纵肌自发收缩频率分别减慢至9.7cycles·min-1和9.0cycles·min-1。
S-DOX、R-DOX和rac-DOX(3、10、30μmol·L~(-1))对卡巴胆碱所诱发的兔离体回肠环肌收缩频率和收缩幅度均无显著影响。
6 S-DOX、R-DOX及rac-DOX对兔离体十二指肠收缩反应的影响。
S-DOX仅在30μmol·L~(-1)浓度显著抑制兔离体十二指肠自发收缩频率。R-DOX(10、30μmol·L~(-1))、rac-DOX(10、30μmol·L~(-1))显著抑制兔离体十二指肠自发收缩频率,30μmol·L~(-1)时两组标本的收缩频率分别由给药前的17.5cycles·min-1减慢至14.2cycles·min-1以及15.1cycles·min-1减慢至12.5cycles·min-1。
S-DOX、R-DOX和rac-DOX(10、30μmol·L~(-1) )均显著抑制兔离体十二指肠自发收缩幅度;30μmol·L~(-1)时十二指肠的收缩幅度分别被抑制至0.75g、0.71g和0.87g。
结论:
R-DOX抑制右心房心率的作用强于rac-DOX,甚至诱发停搏反应;S-DOX不影响心率。R-DOX对心房肌和心室肌收缩力的抑制作用强于rac-DOX;S-DOX不影响心房肌收缩力,对心室肌具有正性肌力作用。
S-DOX、R-DOX及rac-DOX对兔离体回肠和回肠纵肌的收缩力无影响,对卡巴胆碱所诱发回肠环肌收缩反应亦无明显影响,但显著抑制离体十二指肠收缩力。S-DOX、R-DOX及rac-DOX显著抑制兔离体回肠、回肠纵肌和十二指肠的自发收缩频率,其中S-DOX的抑制作用相对较弱。
Objective: To study the effects of rac-doxazosin (rac-DOX) and its enantiomers (S-doxazosin, S-DOX and R-Doxazosin, R-DOX) on the rabbit isolated atrial and ventricular strips and ileum and duodenal smooth muscle.
Methods: The strips of the rabbit isolated right atrium, left atrium and right ventricle were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively administered into the organ bath containing the rabbit isolated atrial strips, but they were non-cumulatively administered into the organ bath containing the rabbit isolated right ventricular strips. The effects of doxazosin and its enantiomers on contractile force and heart rate were observed.
The rabbit isolated ileum, ileum longitudinal muscle strips and circular muscle strips were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively given into the organ bath containing the rabbit isolated ileum, ileum longitudinal muscle. Doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively administered into the organ bath containing the rabbit isolated ileum circular muscle, then carbachol at 20μmol·L~(-1) was applied. Effects of doxazosin and its enantiomers on the contractile force, contractile frequency and carbachol-induced responses were observed in the rabbit isolated ileum preparations.
The rabbit isolated duodenal smooth muscle preparations were prepared, and doxazosin and its enantiomers (3, 10, 30μmol·L~(-1)) were cumulatively given into the organ bath containing the rabbit isolated duodenum. Effects of doxazosin and its enantiomers on the contractile force and contractile frequency were observed in the rabbit isolated duodenal smooth muscle.
Results:
1 Effects of doxazosin and its enantiomers on the heart rate in the rabbit isolated right atrium
In 23% of the used atrial preparations, the cardiac arrest was induced by R-DOX at 30μmol·L~(-1), but S-DOX and rac-DOX at the same concentration did not induce the same effect. S-DOX at 30μmol·L~(-1) did not affect the heart rate of the rabbit isolated right atrium, R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the heart rate. R-DOX and rac-DOX at 30μmol·L~(-1) decreased the heart rate by 25.7±10.5% and 23.6±7.7%, respectively.
2 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right atrium
S-DOX did not affect the contractile force of the rabbit isolated right atrium. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the contractile force of the rabbit isolated right atrium and both of them at 30μmol·L~(-1) decreased the contractile force by 78.6±8.6% and 56.7±11.7%, respectively. The negative inotropic effect in the right atrium by R-DOX was stronger than that by rac-DOX.
3 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated left atrium
S-DOX did not affect the contractile force of the rabbit isolated left atrium. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration-dependently decreased the contractile force of the rabbit isolated left atrium and both of them at 30μmol·L~(-1) decreased the contractile force by 89.9±4.9% and 45.4±15.6%, respectively. The negative inotropic effect in the left atrium by R-DOX was stronger than that by rac-DOX.
4 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right ventricular strips
S-DOX at 30μmol·L~(-1) increased the contractile force of the rabbit isolated right ventricular strips, and S-DOX at 30μmol·L~(-1) increased the contractile force by 26.7±21.5%. R-DOX (3~30μmol·L~(-1)) and rac-DOX (3~30μmol·L~(-1)) concentration -dependently decreased the contractile force of the rabbit isolated right ventricular strips and both of them at 30μmol·L~(-1) decreased the contractile force by 38.1±28.1% and 29.4±24.4%, respectively. The negative inotropic effect in the ventricular strips by R-DOX was stronger than that by rac-DOX.
5 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated ileum smooth muscle
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the spontaneous contractile force in the rabbit isolated ileum. S-DOX only at 30μmol·L~(-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum, R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frequency from 10.3cycles·min-1 to 7.1cycles·min-1 and from 10.6cycles·min-1 to 6.8cycles·min-1, respectively.
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the spontaneous contractile force in the rabbit isolated ileum longitudinal muscle strips. S-DOX only at 30μmol·L~(-1) decreased the contractile frequency from 12.9cycles·min-1 to 10.1cycles·min-1 in the rabbit isolated ileum longitudinal muscle. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum longitudinal muscle strips, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frequency from 13.9cycles·min-1 to 9.7cycles·min-1 and from 13.0cycles·min-1 to 9.0cycles·min-1, respectively.
Doxazosin and its enantiomers (3~30μmol·L~(-1)) did not affect the contractile force and contractile frequency of the contraction induced by carbachol in the rabbit isolated ileum circular muscle strips.
6 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated duodenal smooth muscle
S-DOX only at 30μmol·L~(-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenum. R-DOX (10~30μmol·L~(-1)) and rac-DOX (10~30μmol·L~(-1)) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenal smooth muscle, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the contractile frquency from 17.5cycles·min-1 to 14.2cycles·min-1 and from 15.1cycles·min-1 to 12.5cycles·min-1, respectively.
Doxazosin and its enantiomers (10~30μmol·L~(-1)) all decreased the spontaneous contractile force in the rabbit isolated duodenal muscle. S-DOX at 30μmol·L~(-1) decreased the spontaneous contractile force from 3.81g to 0.75g, and R-DOX and rac-DOX at 30μmol·L~(-1) decreased the spontaneous contractile force from 4.12g to 0.71g and from 3.96g to 0.87g, respectively.
Conclusion: R-DOX produces a negative chronotropic effect in the rabbit isolated right atrium more potently than rac-DOX, and it even causes cardiac arrest at higher concentration. S-DOX does not affect the heart rate. R-DOX produces a negative inotropic effect in the rabbit isolated atrial and ventricular strips more potently than rac-DOX. On the contrary, S-DOX produces the positive inotropic effect.
Doxazosin and its enantiomers do not affect the spontaneous contractile force in the rabbit isolated ileum and ileum longitudinal muscle, and do not affect the contraction induced by carbachol in the rabbit isolated ileum circular muscle, but decrease the spontaneous contractile force in the rabbit duodenal muscle. Doxazosin and its enantiomers decrease the spontaneous contractile frequency in the rabbit isolated ileum, ileum longitudinal muscle and duodenum muscle, and the inhibitory effect by S-DOX is weaker.
引文
1 Wilde MI, Fitton A, Mc Tavish D. Alfuzosin, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in benign prostatic hyperplasia. Drugs, 1993, 4(3)5:410~429
2 Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol, 1976, 48(4):255~263
3 Lefevre-Borg F, O’Connor SE, Schoemaker H, et al. Alfuzosin, a selective alpha1-adrenoceptor antagonist in the lower urinary tract. Br J Pharmacol, 1993, 109(4):1282~1289
4 Khanna OMP, Gonick P. Effects of phenoxybenzamine hydrochloride on canine lower urinury tract. Urology, 1975,6(3):323~330
5 Caine M, Perlberg S, Shapiro A. Phenoxybenzamine for benign prostatic obstruction. Urology, 1981, 17(6):542~546
6 Hedlund H, Andersson KE. Effects of prazosin in patients with benign prostatic obstruction. J Urol, 1983, 130(2):275~278
7 Martorana G, Gilberti C, Damone P, et al. The effects of prazosin in benign prostatic hypertrophy, a placebcontrolled double-blind study. IRCS Med Sci, 1984, 12(2):11~12
8 Kirby RS, Coppinger SWC, Corcoran MO, et al. Prazosin in the treatment of prostatic obstruction: A placebcontrolled study. Br J Urol, 1987, 60(2):136~142
9 Owens PK, Fell AF, Coleman MW, et al. Chiral recognition in liquid chromatography utilizing chargeable cyclodextrins for resolution of doxazosin enantiomers. Chirality, 1997, 9(2):184~190
10 Hatano A, Tang R, Walden PD, et al. The alpha-1 adrenoceptor antagonist properties of the enantiomers of doxazosin in human prostate. Eur J Pharmacol, 1996, 313(1~2):135~143
11 牛长群, 任雷鸣. 3 种新型 α1-受体阻断剂的高效毛细管电用手性分离. 药学学报, 2000, 35(6):451~453
12 牛长群, 任雷鸣. 3 种新型 α1-受体阻断剂的手性流动相HPLC 分离与制备. 药学学报, 2002, 37(6):450~453
13 Niu CQ, Zhao D, Jia XM, et al. α1-Adrenoceptor antagonist profile of doxazosin and its enantiomers inisolated rabbit blood vessels. Chin J Pharmacol Toxical, 2003, 17(5):354~359
14 ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 2000, 283(15):1967~1975
15 Messerli FH. Doxazosin and congestive heart failure. J Am Coll Cardiol, 2001, 38(5):1295~1296
1 Hoogerbrugge N, de Groot E, de Heide LH, et al. Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hyperchole-sterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands. Neth J Med, 2002, 60(9):354~361
2 Pessina AC, Ciccariello L, Perrone F, et al. Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism. Nutr Metab Cardiovasc Dis, 2006, 16(2):137~147
3 华琦. 老年单纯收缩期高血压的特点与防治. 中国心血管病研究杂志, 2006, 4(3):165~168
4 潘启超. 新α1受体阻断剂-多沙唑嗪药理及临床(二). 广州医药, 1999, 30(6):1~3
5 孟祥中. 药源性消化系统疾病. 现代实用医学, 2005, 17(2):71~74
6 史勇. 852 例内科住院患者药品不良反应发生情况的调查与分析. 天津药学, 2004, 16(3):37~39
7 Ren LM, Burnstock G. Prominent sympathetic purinergic vasoconstriction in the rabbit splenic artery: potentiation by 2, 2’-pyridylisatogen tosylate. Br J Pharmacol, 1997, 120(3): 530~536
8Be Wilkenfeld, B Levy. The effects of theophylline, diazoxide and imidazoleon isoproterenol-induced inhibition of the rabbit ileum. J Pharmacol Exp Ther, 1969, 169(1): 61~67
9 K Yamada, M Iizuka. Enhancement of the contraction of the isolated duodenum and Oddi's sphincter of rabbits by alpha adrenergic agents. Nippon Heikatsukin Gakkai Zasshi, 1983, 19(2):115~122
10 牛长群, 赵丁, 贾湘曼, 任雷鸣. 多沙唑嗪及其手性对映体对离体兔血管α1受体的拮抗特性. 中国药理学与毒理学杂志, 2003, 17(5):354~359
11Hu ZW, Shi XY, Hoffman BB. Doxazosin inhibits proliferation and migration of human vascular smooth-muscle cells independent of α1-arenergic receptor antagonism. J Cardiovasc Pharmacol, 1998, 31(6): 833~838
1 Lukacs B, Leple`ge A, Thibault P. Prospectivestudy of men with clinical benign prostatic hyperplasia treated with alfuzosin by general practitioners:1-yearresults. Urology, 1996, 48(5):731~740
2 Lee M. Alfuzosin hydrochloride for the treatment of benign prostatic hyperplasia. Am J Health Syst Pharm, 2003, 60(14):1426~1439
3 Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists inpatients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol, 1999, 36(1):1~13
4 Barendrecht MM, Koopmans RP, de la Rosette J. Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int, 2005, 95(S4):19~28
5 de Mey C. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol, 1998, 34(1):18~28
6 Djavan B, Chapple C, Milani S. State of the art on the efficacy and tolerability of alpha-adrenoreceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology, 2004, 64(6):1081~ 1088
7 Buzelin JM, Fonteyne E, Kontturi M. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). The European Tamsulosin Study Group. Br J Urol, 1997, 80(4):597~605
8 Lukacs B, Blondin P, MacCarthy C. Safetyprofile of 3 months’ therapy with alfuzosin in 13389 patients suffering from benign prostatic hypertrophy. Eur Urol, 1996, 29(1): 29~35
9 de Mey C, Michel MC, McEwen J. A doubleblind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol, 1998, 33(5):481~488
10 Wilde MI, Fitton A, McTavish D. Alfuzosin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in benign prostatic hyperplasia. Drugs, 1993, 45(3):410~429
11 Roehrborn CG, Van Kerrebroeck P, Nordling J. Safety and efficacy of alfuzosin 10mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatichyperplasia: a pooled analysis of three doubleblind placebo- controlled studies. BJU Int, 2003, 92(3):257~261
12 Milani S, Djavan B. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists. BJU Int, 2005, 95(S4): 29~36
13 Hofner K, Claes H, for the European Tamsulosin Study Group. Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol, 1999, 36(4):335~341
14 McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med, 1998, 338(9):557~563
15 Debruyne F, Barkin J, van Erps PV, et al. Efficacy and safety of longterm treatment with the dual 5α-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol, 2004, 46(4):488~494
16 Ekman P. Finasteride in the treatment of benign prostatic hypertrophy: an update. New indications for finasteride therapy. Scand J Urol Nephrol Suppl, 1999, 203(1):15~20
17 Wessells H, Roy J, Bannow J, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia.Urology, 2003, 61(31):579~584
18 Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology, 2002, 60(3):434~441
19 Andriole GL, Kirby R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol, 2003, 44(1):82~88
20 Clark RV, Hermann DJ, Cunningham GR, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J Clin Endocrinol Metab, 2004, 89(5):2179~2184
21 Dull P, Reagan RW, Bahnson RR. Managing benign prostatichy perplasia. Am Fam Physician, 2002, 66(1):77~84
22 ThompsonIM, ChiC, GoodmanP, et al. Comparison of the operating characteristics of PSA for prostate cancer detection for finasteride and placebo in the Prostate Cancer Prevention Trial. J Urol, 2006, 175(1):152
23 Roehrborn CG, Lee M, Meehan A, et al. Effects of finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia. Urology, 2003, 62(5):894~899
24 Clifford GM, Farmer RD. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol, 2000, 38(1):2~19
25 McConnell JD, Roehrborn CG, Bautista OM, et al. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med, 2003, 349(25):2387~2398
26 Barkin J, Guimaraes M, Jacobi G, et al. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapywith the dual 5α-reductase inhibitor dutasteride. Eur Urol, 2003, 44(1):461~466
27 Vela-Navarrete R, Gonzalez-Enguita C, Garcia-Cardoso JV, et al. The impact of medical therapy on surgery for benign prostatic hyperplasia: a study comparing changes in a decade (1992~2002). BJU Int, 2005, 96(7):1045~1048
28 Debruyne FMJ, Djavan B, de la Rosette, et al. Interventional treatment for benign prostatic hyperplasia. In: Chatelain C, Denis L, Foo KT, Khoury S, McConnell J, editors. Benign prostatic hyperplasia. Proceedings of the 5th Consultation on Benign Prostatic Hyperplasia (BPH), 2000, 25~28(Paris):399~422
29 Madersbacher S, Alivizatos G, Nordling J, et al. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol, 2004, 46(5):547~554
30 Elzayat EA, Elhilali MM. Holmium laser enucleation of the prostate (HoLEP): the endourologic alternative to open prostatectomy. Eur Urol, 2006, 49(1):87~91
31 Montorsi F, Naspro R, Salonia A, et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center, prospective, randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol, 2004, 172(pt1):1926~1929
32 Gilling PJ, Cass CB, Malcolm AR, et al. Combination holmium and Nd:YAG laser ablation of the prostate: initial clinical experience. J Endourol, 1995, 9(2):151~153
33 Mebust WK, Holtgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and post-operative complications. A cooperative study of 13 participating institutions evaluating 3885 patients. J Urol, 1989, 141(2):243~247, Reprinted J Urol, 2002, 167(1):5~9
34 Djavan B, Madersbacher S, Klingler C, et al. Urodynamic assessment of patients with acute urinary retention: is treatment failure after prostatectomy predictable? J Urol, 1997, 158(5):1829~1833
35 Reynard JM, Shearer RJ. Failure to void after transurethral resection of the prostate and mode of presentation. Urology, 1999, 53(2):336~339
36Hoffman RM, MacDonald R, Monga M, et al. Transurethral microwave thermotherapy vs transurethral resection for treating benign prostatic hyperplasia: a systematic review. BJU Int, 2004, 94(7):1031~1036
37 Wagrell L, Schelin S, Nordling J, et al. Three-year followup of feedback microwave thermotherapy versus TURP for clinical BPH: a prospective randomized multicenter study. Urology, 2004, 64(4):698~702
38 Taher A. Erectile dysfunction after transurethral resection of the prostate: incidence and risk factors. World J Urol, 2004, 22(6):457~460
39 McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical Practice Guideline number 8. AHCPR Publication No. 94-0582. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, 1994
40 AUA Practice Guidelines Committee. AUA guidelines on management of benign prostatic hyperplasia (2003).Chapter 1. Diagnosis and treatment recommendations. J Urol, 2003, 170(2pt1):530~547
41 Madersbacher S, Marberger M. Is transurethral resection of the prostate still justified? Br J Urol, 1999, 83(2):227~237
2 Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol, 1976, 48(4):255~263
3 Lefevre-Borg F, O’Connor SE, Schoemaker H, et al. Alfuzosin, a selective alpha1-adrenoceptor antagonist in the lower urinary tract. Br J Pharmacol, 1993, 109(4):1282~1289
4 Khanna OMP, Gonick P. Effects of phenoxybenzamine hydrochloride on canine lower urinury tract. Urology, 1975,6(3):323~330
5 Caine M, Perlberg S, Shapiro A. Phenoxybenzamine for benign prostatic obstruction. Urology, 1981, 17(6):542~546
6 Hedlund H, Andersson KE. Effects of prazosin in patients with benign prostatic obstruction. J Urol, 1983, 130(2):275~278
7 Martorana G, Gilberti C, Damone P, et al. The effects of prazosin in benign prostatic hypertrophy, a placebcontrolled double-blind study. IRCS Med Sci, 1984, 12(2):11~12
8 Kirby RS, Coppinger SWC, Corcoran MO, et al. Prazosin in the treatment of prostatic obstruction: A placebcontrolled study. Br J Urol, 1987, 60(2):136~142
9 Owens PK, Fell AF, Coleman MW, et al. Chiral recognition in liquid chromatography utilizing chargeable cyclodextrins for resolution of doxazosin enantiomers. Chirality, 1997, 9(2):184~190
10 Hatano A, Tang R, Walden PD, et al. The alpha-1 adrenoceptor antagonist properties of the enantiomers of doxazosin in human prostate. Eur J Pharmacol, 1996, 313(1~2):135~143
11 牛长群, 任雷鸣. 3 种新型 α1-受体阻断剂的高效毛细管电用手性分离. 药学学报, 2000, 35(6):451~453
12 牛长群, 任雷鸣. 3 种新型 α1-受体阻断剂的手性流动相HPLC 分离与制备. 药学学报, 2002, 37(6):450~453
13 Niu CQ, Zhao D, Jia XM, et al. α1-Adrenoceptor antagonist profile of doxazosin and its enantiomers inisolated rabbit blood vessels. Chin J Pharmacol Toxical, 2003, 17(5):354~359
14 ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 2000, 283(15):1967~1975
15 Messerli FH. Doxazosin and congestive heart failure. J Am Coll Cardiol, 2001, 38(5):1295~1296
1 Hoogerbrugge N, de Groot E, de Heide LH, et al. Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hyperchole-sterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands. Neth J Med, 2002, 60(9):354~361
2 Pessina AC, Ciccariello L, Perrone F, et al. Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism. Nutr Metab Cardiovasc Dis, 2006, 16(2):137~147
3 华琦. 老年单纯收缩期高血压的特点与防治. 中国心血管病研究杂志, 2006, 4(3):165~168
4 潘启超. 新α1受体阻断剂-多沙唑嗪药理及临床(二). 广州医药, 1999, 30(6):1~3
5 孟祥中. 药源性消化系统疾病. 现代实用医学, 2005, 17(2):71~74
6 史勇. 852 例内科住院患者药品不良反应发生情况的调查与分析. 天津药学, 2004, 16(3):37~39
7 Ren LM, Burnstock G. Prominent sympathetic purinergic vasoconstriction in the rabbit splenic artery: potentiation by 2, 2’-pyridylisatogen tosylate. Br J Pharmacol, 1997, 120(3): 530~536
8Be Wilkenfeld, B Levy. The effects of theophylline, diazoxide and imidazoleon isoproterenol-induced inhibition of the rabbit ileum. J Pharmacol Exp Ther, 1969, 169(1): 61~67
9 K Yamada, M Iizuka. Enhancement of the contraction of the isolated duodenum and Oddi's sphincter of rabbits by alpha adrenergic agents. Nippon Heikatsukin Gakkai Zasshi, 1983, 19(2):115~122
10 牛长群, 赵丁, 贾湘曼, 任雷鸣. 多沙唑嗪及其手性对映体对离体兔血管α1受体的拮抗特性. 中国药理学与毒理学杂志, 2003, 17(5):354~359
11Hu ZW, Shi XY, Hoffman BB. Doxazosin inhibits proliferation and migration of human vascular smooth-muscle cells independent of α1-arenergic receptor antagonism. J Cardiovasc Pharmacol, 1998, 31(6): 833~838
1 Lukacs B, Leple`ge A, Thibault P. Prospectivestudy of men with clinical benign prostatic hyperplasia treated with alfuzosin by general practitioners:1-yearresults. Urology, 1996, 48(5):731~740
2 Lee M. Alfuzosin hydrochloride for the treatment of benign prostatic hyperplasia. Am J Health Syst Pharm, 2003, 60(14):1426~1439
3 Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists inpatients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol, 1999, 36(1):1~13
4 Barendrecht MM, Koopmans RP, de la Rosette J. Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int, 2005, 95(S4):19~28
5 de Mey C. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol, 1998, 34(1):18~28
6 Djavan B, Chapple C, Milani S. State of the art on the efficacy and tolerability of alpha-adrenoreceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology, 2004, 64(6):1081~ 1088
7 Buzelin JM, Fonteyne E, Kontturi M. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). The European Tamsulosin Study Group. Br J Urol, 1997, 80(4):597~605
8 Lukacs B, Blondin P, MacCarthy C. Safetyprofile of 3 months’ therapy with alfuzosin in 13389 patients suffering from benign prostatic hypertrophy. Eur Urol, 1996, 29(1): 29~35
9 de Mey C, Michel MC, McEwen J. A doubleblind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol, 1998, 33(5):481~488
10 Wilde MI, Fitton A, McTavish D. Alfuzosin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in benign prostatic hyperplasia. Drugs, 1993, 45(3):410~429
11 Roehrborn CG, Van Kerrebroeck P, Nordling J. Safety and efficacy of alfuzosin 10mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatichyperplasia: a pooled analysis of three doubleblind placebo- controlled studies. BJU Int, 2003, 92(3):257~261
12 Milani S, Djavan B. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists. BJU Int, 2005, 95(S4): 29~36
13 Hofner K, Claes H, for the European Tamsulosin Study Group. Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol, 1999, 36(4):335~341
14 McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med, 1998, 338(9):557~563
15 Debruyne F, Barkin J, van Erps PV, et al. Efficacy and safety of longterm treatment with the dual 5α-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol, 2004, 46(4):488~494
16 Ekman P. Finasteride in the treatment of benign prostatic hypertrophy: an update. New indications for finasteride therapy. Scand J Urol Nephrol Suppl, 1999, 203(1):15~20
17 Wessells H, Roy J, Bannow J, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia.Urology, 2003, 61(31):579~584
18 Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology, 2002, 60(3):434~441
19 Andriole GL, Kirby R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol, 2003, 44(1):82~88
20 Clark RV, Hermann DJ, Cunningham GR, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J Clin Endocrinol Metab, 2004, 89(5):2179~2184
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