联合应用雷洛昔芬和雌激素对去势大鼠血栓前状态的影响
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摘要
目的:雷洛昔芬是第二代雌激素受体调节剂,在骨骼方面起到雌激素样作用,在子宫和乳腺起到抗雌激素作用,广泛用于预防和治疗绝经后骨质疏松症。由于雷洛昔芬加重血管舒缩症状,导致用药依从性差。雌激素治疗可以有效预防低雌激素导致的骨质丢失,是预防绝经后骨质疏松症的常用药物。雌激素有效缓解更年期症状,但对子宫和乳腺有刺激作用。雷洛昔芬与雌激素在骨骼上具有相似的保护作用,在不良反应方面又相互抵消,因此人们设想能否将雷洛昔芬与雌激素联合起来使用,以达到最佳的雌激素受体激动剂和拮抗剂的效应。对去势大鼠的研究证实,雷洛昔芬和雌激素联合应用不减弱对骨骼的保护作用,对子宫、乳腺、主动脉无损害。但两药合用对于血栓前状态的影响如何,是否影响血栓形成还不清楚。本研究通过建立绝经大鼠模型,将雷洛昔芬与不同剂量的结合雌激素配伍,观察两药合用对血栓前状态的影响,探索两药合用的安全性。
方法:选择9-10月龄中年雌性SD大鼠,行双侧卵巢切除术造成绝经模型。术后1周开始药物干预,共10周。采集血标本,检测血浆FIB水平、ATⅢ活性、PAI-1水平、D-D水平、vWF抗原水平、血浆NO浓度以及PGI2和TXB2水平。
结果:绝经导致血浆FIB、PAI-1水平升高,血浆ATⅢ活性增加,但不改变血浆D-D水平;绝经导致血浆NO水平显著下降,vWF抗原水平升高,而血浆PGI2和TXA2的水平同步升高。
凝血和抗凝血方面,RLX组的血浆FIB水平显著高于绝经后对照组,CEE组的血浆FIB水平高于绝经前基线组,但与绝经后对照组持平;RLX组的血浆ATⅢ活性显著高于绝经前水平,与绝经后对照组持平,CEE组则接近绝经前水平。两药合用,血浆FIB水平与RLX组相似;ATⅢ活性介于RLX组和CEE组之间,也就是说,在凝血和抗凝血方面,雌激素没有进一步增加RLX的致血栓风险。
纤溶和抗纤溶方面,RLX组的PAI-1水平在绝经的基础上进一步升高,CEE组的血浆PAI-1水平也明显升高;两药合用,血浆PAI-1水平进一步上升,具有协同作用,使血栓风险增加。然而,重要的排除指标血浆D-D水平在各组之间无显著差异。
在血管内皮功能方面,RLX与CEE作用相反。RLX增加去势大鼠的血浆vWF抗原水平,对血浆NO水平没有显著影响;而CEE组的血浆vWF水平明显下降,NO水平显著增高。两药合用,血浆vWF水平和NO水平介于两者之间,RLX+高量CEE组的保护效应尤其明显,接近绝经前基线组。说明CEE对血管内皮具有显著的保护作用,并在一定程度上抵消了RLX的不利效应。
在血管舒缩功能方面,绝经后血浆PGI2和TXA2的水平同步升高,RLX及CEE治疗后PGI2和TXA2的水平同步降低,因此总的效果不变;两药合用的效果与单用RLX或单用CEE相似,在血管舒缩方面没有施加额外的影响。
结论:在血栓形成的不同环节,雷洛昔芬发挥了不同的效应,可能导致血栓风险增加。雌激素与雷洛昔芬合用后,在不同的环节发挥了或协同或保护的作用,总体评价,没有进一步增加血栓形成的风险。
Objective:Raloxifene,a selective estrogen receptor modulator(SERM) of the second generation,presents an estrogen-like action on bone and an anti-estrogen effect on uterus and breast,which makes it be widely used in prevention and treatment of osteoporosis of postmenopausal women.However,poor compliance is observed since it worsens the vasomotor symptoms in the users.Estrogens,effective in prevention and treatment of bone loss caused by low estrogen level,present a satisfactory effect on eliminate the climacteric symptoms but stimulate uterus and breast.Considering that both agents presenting similar protective effects on bone while counteracting effects on each others' side effects,we hypothesized that combined administration might probably achieve maximal clinical outcomes.Our previous study has demonstrated that the combination did not reduce the protective effect on ovariectomized rats and presented no harmful action on their uteri,breasts and aorta.Yet the combined effect on thrombosis and embolism is still not known,and because of that,we designed this study using ovariectomized rats trying to obtain safety parameters for further application.
Methods:Postmenopausal model was prepared using female SD rats of 9-10 months that were ovariectomized.After one week of rehabiliation,ten weeks of treatment was given.Blood samples were collected for detection of plasma concentration of the following:FIB,ATⅢactivity,PAI-1,D-D,vWF,NO,PGI2 and TXB2.
Results:After menopause,the plasma concentration of FIB and PAI-1 and the ATⅢactivity was elevated.No change was observed in D-D concentration.NO concentration declined dramatically and the vWF antigen increased,the PGI2 and TXA2 concentration increased simultaneously.
Regarding coagulation and anticoagulation,the FIB in RLX group was apparently higher than that of postmenopausal control,and the plasma FIB of CEE group was higher than that of premenopausal baseline but almost equal to that of the premenopausal control.The ATⅢactivity of RLX group was obviously higher than that of premenopausal state and paralleled to that of postmenopausal state,while the ATⅢactivity of CEE group was nearing that of premenopausal state.In the combined administration group,the FIB level was similar to that of RLX group,and the ATⅢactivity was between those of RLX group and CEE group,indicating that estrogen would not increase the present thromboembolism risks caused by RLX.
As far as fibrinolysis and anti-fibrinolysis is concerned,the PAI-1 level increased on the basis of high level after menopause and the PAI-1 in CEE also presented a dramatic raise.After combined administration,the plasma PAI-1 increased more,suggesting a synergetic effect with a higher risk of thrombosis.But the pivot exclusive index,plasma D-D level was not different between the groups.
Regarding the endothelial function,RLX was opposite to CEE.RLX increased the vWF antigen level and did not affect the NO level very much,while the CEE dramatically decreased vWF antigen level and increased NO level.Combined administration showed a medial effect on vWF and NO,but the RLX plus high dose CEE group presented more protective effect that was similar to that of premenopausal state. This indicates that CEE has protective effect on endothelium and counteracts the adverse effect of RLX in some extent.
For those vasomotor parameters,menopause induced simultaneous increase in plasma PGI2 and TXA2,while either RLX or CEE decreased them.Combined administration did not show a stronger effect than either drug,which means no addition effect was exerted by combination of RLX and CEE.
Conclusion:In the different aspects of thrombosis,RLX presented different effects and may increase the risk.Estrogen and RLX are synergetic or protective in these different aspects.In general,the risk of thrombosis is not further increased by combined administration.
方法:选择9-10月龄中年雌性SD大鼠,行双侧卵巢切除术造成绝经模型。术后1周开始药物干预,共10周。采集血标本,检测血浆FIB水平、ATⅢ活性、PAI-1水平、D-D水平、vWF抗原水平、血浆NO浓度以及PGI2和TXB2水平。
结果:绝经导致血浆FIB、PAI-1水平升高,血浆ATⅢ活性增加,但不改变血浆D-D水平;绝经导致血浆NO水平显著下降,vWF抗原水平升高,而血浆PGI2和TXA2的水平同步升高。
凝血和抗凝血方面,RLX组的血浆FIB水平显著高于绝经后对照组,CEE组的血浆FIB水平高于绝经前基线组,但与绝经后对照组持平;RLX组的血浆ATⅢ活性显著高于绝经前水平,与绝经后对照组持平,CEE组则接近绝经前水平。两药合用,血浆FIB水平与RLX组相似;ATⅢ活性介于RLX组和CEE组之间,也就是说,在凝血和抗凝血方面,雌激素没有进一步增加RLX的致血栓风险。
纤溶和抗纤溶方面,RLX组的PAI-1水平在绝经的基础上进一步升高,CEE组的血浆PAI-1水平也明显升高;两药合用,血浆PAI-1水平进一步上升,具有协同作用,使血栓风险增加。然而,重要的排除指标血浆D-D水平在各组之间无显著差异。
在血管内皮功能方面,RLX与CEE作用相反。RLX增加去势大鼠的血浆vWF抗原水平,对血浆NO水平没有显著影响;而CEE组的血浆vWF水平明显下降,NO水平显著增高。两药合用,血浆vWF水平和NO水平介于两者之间,RLX+高量CEE组的保护效应尤其明显,接近绝经前基线组。说明CEE对血管内皮具有显著的保护作用,并在一定程度上抵消了RLX的不利效应。
在血管舒缩功能方面,绝经后血浆PGI2和TXA2的水平同步升高,RLX及CEE治疗后PGI2和TXA2的水平同步降低,因此总的效果不变;两药合用的效果与单用RLX或单用CEE相似,在血管舒缩方面没有施加额外的影响。
结论:在血栓形成的不同环节,雷洛昔芬发挥了不同的效应,可能导致血栓风险增加。雌激素与雷洛昔芬合用后,在不同的环节发挥了或协同或保护的作用,总体评价,没有进一步增加血栓形成的风险。
Objective:Raloxifene,a selective estrogen receptor modulator(SERM) of the second generation,presents an estrogen-like action on bone and an anti-estrogen effect on uterus and breast,which makes it be widely used in prevention and treatment of osteoporosis of postmenopausal women.However,poor compliance is observed since it worsens the vasomotor symptoms in the users.Estrogens,effective in prevention and treatment of bone loss caused by low estrogen level,present a satisfactory effect on eliminate the climacteric symptoms but stimulate uterus and breast.Considering that both agents presenting similar protective effects on bone while counteracting effects on each others' side effects,we hypothesized that combined administration might probably achieve maximal clinical outcomes.Our previous study has demonstrated that the combination did not reduce the protective effect on ovariectomized rats and presented no harmful action on their uteri,breasts and aorta.Yet the combined effect on thrombosis and embolism is still not known,and because of that,we designed this study using ovariectomized rats trying to obtain safety parameters for further application.
Methods:Postmenopausal model was prepared using female SD rats of 9-10 months that were ovariectomized.After one week of rehabiliation,ten weeks of treatment was given.Blood samples were collected for detection of plasma concentration of the following:FIB,ATⅢactivity,PAI-1,D-D,vWF,NO,PGI2 and TXB2.
Results:After menopause,the plasma concentration of FIB and PAI-1 and the ATⅢactivity was elevated.No change was observed in D-D concentration.NO concentration declined dramatically and the vWF antigen increased,the PGI2 and TXA2 concentration increased simultaneously.
Regarding coagulation and anticoagulation,the FIB in RLX group was apparently higher than that of postmenopausal control,and the plasma FIB of CEE group was higher than that of premenopausal baseline but almost equal to that of the premenopausal control.The ATⅢactivity of RLX group was obviously higher than that of premenopausal state and paralleled to that of postmenopausal state,while the ATⅢactivity of CEE group was nearing that of premenopausal state.In the combined administration group,the FIB level was similar to that of RLX group,and the ATⅢactivity was between those of RLX group and CEE group,indicating that estrogen would not increase the present thromboembolism risks caused by RLX.
As far as fibrinolysis and anti-fibrinolysis is concerned,the PAI-1 level increased on the basis of high level after menopause and the PAI-1 in CEE also presented a dramatic raise.After combined administration,the plasma PAI-1 increased more,suggesting a synergetic effect with a higher risk of thrombosis.But the pivot exclusive index,plasma D-D level was not different between the groups.
Regarding the endothelial function,RLX was opposite to CEE.RLX increased the vWF antigen level and did not affect the NO level very much,while the CEE dramatically decreased vWF antigen level and increased NO level.Combined administration showed a medial effect on vWF and NO,but the RLX plus high dose CEE group presented more protective effect that was similar to that of premenopausal state. This indicates that CEE has protective effect on endothelium and counteracts the adverse effect of RLX in some extent.
For those vasomotor parameters,menopause induced simultaneous increase in plasma PGI2 and TXA2,while either RLX or CEE decreased them.Combined administration did not show a stronger effect than either drug,which means no addition effect was exerted by combination of RLX and CEE.
Conclusion:In the different aspects of thrombosis,RLX presented different effects and may increase the risk.Estrogen and RLX are synergetic or protective in these different aspects.In general,the risk of thrombosis is not further increased by combined administration.
引文
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