CN102089035A - 抗血小板治疗中血小板抑制的维持 - Google Patents
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Abstract
描述了一种治疗或预防之前接收过至少一种噻吩并吡啶类药物治疗的主体的疾病或不适的方法。所述方法包括给予主体有效量的至少一种可逆的、短效P2Y12抑制剂。所描述的方法可以用于诊断患有稳定型或不稳定型心绞痛、动脉缺血事件、动脉硬化、急性冠状动脉综合症也就是STEMI或N-STEMI症状的主体。所述的方法还可以用于之前接受了支架,例如裸金属支架或药物涂层支架的患者,以治疗或预防支架血栓。所述方法可以用于入侵性操作,例如冠状动脉搭桥术、经皮冠状动脉介入治疗或其它常规的入侵性操作,的之前、期间、和/或之后。
Description
发明领域
本发明涉及血小板抑制领域,并且特别涉及抑制血小板聚集的方法,以及在之前经过噻吩并吡啶类药物(thienopyridines)治疗的患者中的相对活性。
发明背景
抗血小板治疗已经显示出减少了临床缺血事件并改善了急性冠状动脉综合症(ACS)患者的预后。目前,批准的抗血小板产品包括阿司匹林和噻吩并吡啶类药物,例如氯吡格雷和噻氯匹定。最广泛使用的噻吩并吡啶类药物是氯吡格雷,也就是
医师通常给被诊断为急性冠状动脉综合症(ACS)的患者或表现出ACS相关症状的患者在处方中开出双重抗血小板治疗作为首选疗法,其包括阿司匹林和一种噻吩并吡啶类药物,例如氯吡格雷。在进一步的检查期间,这些患者可以继续该治疗或者接受其它治疗,例如冠状动脉搭桥术(CABG)和PCI。与这个做法一致的是,目前ACC/AHA指南推荐在患者被诊断为ACS后立即开始氯吡格雷和阿司匹林的双重抗血小板治疗。同样地,接受裸金属支架或药物涂层支架的患者也长期使用阿司匹林和以防止缺血事件。
对于许多患者,这个双重抗血小板治疗提供了巨大的临床益处,并使缺血事件,例如心脏病和中风的风险最小化。然而,对于特定的患者,这个治疗方法也存在问题。使用噻吩并吡啶类药物的副作用包括严重中性粒细胞减少症、血栓性血小板减少性紫癜和出血频率的增加。此外,还观察到接受双重抗血小板治疗的患者在进行手术和其它入侵性治疗时经历了更多的输血需求和更高频率的出血并发症。这对通常接受手术,例如CABG和PCI、以及其它入侵性治疗,例如植入裸金属支架(BMS)或药物涂层支架(DES)的ACS患者来尤其是这样。
由于这些利害关系,对于许多以进行手术或其它入侵性治疗作为后续治疗的患者来说,继续阿司匹林和氯吡格雷的双重抗血小板治疗是不合适的。目前ACC/AHA和STS指南推荐在所有非紧急心脏外科手术之前停用氯吡格雷和阿司匹林,以减小手术中出血的风险。
使问题进一步复杂的是,阿司匹林和噻吩并吡啶类药物都是不可逆的(irreversible)、长效的血小板拮抗剂。只有在产生新的血小板时才能撤销对血小板功能的抑制,因此,即使在不继续使用阿司匹林和噻吩并吡啶类药物后,它们的效果也要持续数天才能完全消失。因此,通常要求患者在停止双重抗血小板治疗并等待五至七天后才能进行任何手术或入侵性操作。
结果,医师常常面临困难的抉择,是在手术前停止氯吡格雷和阿司匹林并在手术前的无保护期冒着潜在的缺血事件的风险,还是推迟手术直到不再需要氯吡格雷以后。
发明概述
本发明涉及在惯用的噻吩并吡啶类药物治疗不能使用或不再有效的情况下,抑制血小板活性,例如聚集的方法。例如,本发明描述了一种对于之前使用噻吩并吡啶类药物、阿司匹林或这两者治疗的人在需要时治疗或防止缺血的方法。
特别地,本发明描述了一种治疗或预防缺血的方法,包含对需要这种治疗的主体施用有效量的至少一种可逆的、短效的P2Y12抑制剂,其中所述主体在之前接受过至少一种噻吩并吡啶类药物、阿司匹林或两者的治疗。在一个优选的具体实施方式中,所述方法在入侵性操作,例如外科手术的之前、期间和/或之后对主体施用。本发明进一步描述了一种当需要的主体在停用阿司匹林或至少一种噻吩并吡啶类药物、或这两者时,向其施用有效量的至少一种可逆的、短效的P2Y12抑制剂以抑制血小板活性,例如血小板聚集的方法。
可逆的、短效的P2Y12抑制剂的实例包括但不限于坎格雷洛(cangrelor)、替卡格雷(ticagrelor)和PRT060128。另外的化合物也可以使用美国专利No.5,721,219中描述的方法,或本领域技术人员已知的方法获得。噻吩并吡啶类药物的实例包括但不限于氯吡格雷、噻氯匹定、普拉格雷、以及那些具有相同性质的其它化合物。
在治疗方法中,当预定停止抗血小板治疗是适当的时,例如在入侵性操作期间,可以在入侵性操作前几天开始施用可逆的、短效的P2Y12抑制剂,并在治疗前数小时停用。一个特别的实例是可以在入侵性操作前7天开始施用可逆的、短效的P2Y12抑制剂,并在治疗前1小时停用。需要注意的是,所述方法或持续施予可逆的、短效的P2Y12抑制剂的时间通常与使用哪种可逆的、短效的P2Y12抑制剂非常相关。
描述的方法可以用于诊断有稳定型或不稳定型心绞痛、动脉缺血事件、动脉硬化、急性冠状动脉综合症、包括STEMI或N-STEMI症状的主体。所描述的方法还可以用于之前接受了支架,例如裸金属支架或药物涂层支架的患者,以治疗或预防支架血栓。
所描述的方法可以用于入侵性操作之前、期间、和/或之后的主体,例如冠状动脉搭桥术、骨科手术、泌尿外科手术、经皮冠状动脉介入治疗、其它常规的入侵性操作,例如动脉内膜切除术、肾透析、心肺转流、内镜手术或任意可能潜地引起额外的流血或出血的医学的、外科的、或牙科的操作。
附图简述
考虑到以下对本发明具体实施方式以及与之协力的附图的详细描述将促进对本发明的理解,其中相似的附图标记表示相似的部件,并且其中:
附图.1是ADP-诱导的血小板聚集的抑制百分数和对出血时间的影响的图形;和
附图.2是实施本发明的时间流程图。
详述和优选实施例
需要理解的是,本发明的附图和详述使得清楚理解本发明的相关要素的理解简单化了,为了清楚起见,排除了许多其它在典型的抗血小板治疗中发现的要素。本领域技术人员将认识到其它的要素和/或步骤在实施本发明时是合理的和/或必需的。然而,由于这些要素和步骤在本领域是已知的,并且由于它们并没有促进对本发明的更好的理解,在此没有提供对这些要素和步骤的讨论。在此的讨论集中在那些对本领域技术人员已知的要素和步骤的变化和改进上。进一步地,在此确定和描述的具体实施方式仅是示例性的,并不意在排除或限制它们在本发明中的种类。
本申请提供了一种至少部分抑制之前给予过噻吩并吡啶类药物的主体的血小板活性的方法,其通过停用噻吩并吡啶类药物并施予可逆的、短效的血小板抑制剂以维持血小板抑制。所述方法可以在入侵性操作之前、期间、和/或之后使用。血小板活性的实例包括血小板聚集。所述入侵行操作的实例包括冠状动脉搭桥术、骨科手术、泌尿外科手术、经皮冠状动脉介入治疗、其它常规的入侵性操作,例如动脉内膜切除术、肾透析、心肺转流、内镜手术或任意可能潜地引起患者额外的流血或出血的医学的、外科的、或牙科的操作。血小板抑制可以维持在可接受的和目标的水平,并且具有停用后快速的血小板功能恢复,以使患者可以进行入侵性操作而不增加出血并发症的风险。
所述方法可以用于治疗或预防疾病或不适。例如,所述方法可以用诊断有稳定型或不稳定型心绞痛、动脉缺血事件、动脉硬化、急性冠状动脉综合症、也就是STEMI或N-STEMI症状的主体。所述方法还可以用于之前接受了支架,例如裸金属支架或药物涂层支架的患者,以治疗或预防支架血栓。虽然本发明通常目标为用于人主体,所述方法可以用于任何活体动物。
本发明进一步包含一种在停用噻吩并吡啶类药物后具有快速可逆的、维持适当的P2Y12抑制的方法。例如,具有内置药物洗脱支架的患者一般继续使用阿司匹林和氯吡格雷以预防支架血栓。如果这些患者需要进行外科手术,停用氯吡格雷会增加缺血事件或支架血栓的风险。进一步地,使用阿司匹林和噻吩并吡啶类药物维持不可逆的血小板抑制会导致不可接受的术中出血的风险。正如之前所提到的,由于血小板活性的“反弹”效应,停用氯吡格雷可能会在短期内增加缺血事件的发生率(Ho et al JAMA299(5):532-9(2008);erratum JAMA 299(20):2390(2208))。通过可逆的、短效血小板抑制剂在停用氯吡格雷期间提供有效的血小板抑制,可以预防患者的缺血,并且预防手术中的出血。
如之前所解释,氯吡格雷和阿司匹林的双重抗血小板治疗可以减少临床缺血事件,并且可以进一步改善ACS患者的预后。对于实施血管重建术的ACS患者,CABG之前的氯吡格雷的P2Y12抑制预防了手术患者的缺血事件。
可逆的、短效P2Y12抑制剂相对于与其相对的噻吩并吡啶类药物具有多项好处。例如,噻吩并吡啶类药物,例如氯吡格雷、噻氯匹定和普拉格雷是需要转化为活性代谢物的前药。与此形成对比的是,可逆的、短效P2Y12抑制剂不需要任何代谢转换就可以直接作用于P2Y12受体。它们相对于噻吩并吡啶类药物通常具有相对短的半衰期。例如,坎格雷洛的血浆半衰期小于10分钟,并且能在停药后短时间里恢复血小板功能。通过减少对通过代谢获得活性的化合物的需要,并且具有相对短的半衰期,可逆的、短效P2Y12抑制剂是相对“可逆”的,这意味着与噻吩并吡啶类药物相比,全部的血小板功能可以相当迅速地恢复。
正如在此讨论的,许多情况下噻吩并吡啶类药物治疗不能用于控制主体的血小板活性。例如,急症患者大多数服用了镇静剂、进行多重静脉给药,具有弱的肠胃吸收,并且通常有插管。在这样的情况下,口服治疗(噻吩并吡啶类药物给药的首选方式)是不可行的,并且由于患者不能吞咽口服试剂可能带来潜在的危险。
另外,急症处理要求根据患者的情况灵活处理,并且危险会频繁变化。静脉内的血小板抑制剂可以不需要吸收和代谢(与口服疗法需要吸收和潜在的肝代谢将前药转化为活性化合物不同)而立即在短时间里达到迅速起效的效果,并且可逆的药效在对急症患者的处理中是非常重要的。
在此使用的术语“可逆的、短效P2Y12抑制剂”是指抑制受体P2Y12活性的化合物,其与那些噻吩并吡啶类药物相比具有迅速的起效时间,相对短的代谢率。起效快的、可逆的P2Y12抑制剂的实例包括但不限于,坎格雷洛、替卡格雷和PRT060128。需要注意的是,本发明并不限制于这些实例。具有相似功能的其它化合物也可以用于本发明。
一个特别优选的可逆的、短效的P2Y12抑制剂的实例为坎格雷洛。坎格雷洛是一种有效的、直接的并且可逆的血小板P2Y12受体拮抗剂。坎格雷洛与P2Y12受体的结合抑制了血小板的活性,也包括全部或部分通过该受体引发的聚集。坎格雷洛可以完全由合成原料获得,并且是P2Y12受体的天然拮抗剂三磷酸腺苷(ATP)的类似物。坎格雷洛表现出立即起效(t1/2~5-6min),并且可以以丸药和/或输液的方式给药。它并不要求胃肠道吸收或肝脏代谢以获得其活性所必须的治疗量的血药浓度。由于坎格雷洛在血小板上的药效是可逆的,它因此能够在停止输液后的短时间内动态平衡。同样的,它用于需要灵活处理的急症是很理想的,例如,急症室程序,用于ICU以及操作前设置和术前和术后的恢复期,当血小板抑制对患者的治疗是重要构成时。对坎格雷洛及其相关化合物的描述可以在美国专利No.5,721,219(Ingall等)中找到,其全部内容通过引用结合于此。
然而本发明的另一方面是在停用噻吩并吡啶类药物、阿司匹林或这两者之后给予一种可逆的、短效P2Y12抑制剂以维持抗血小板水平在至少与通过噻吩并吡啶类药物、阿司匹林或这两者获得的平均预期水平相同的水平上的方法。如前所述,抑制剂的使用可以发生在对主体的入侵性操作之前、期间和/或之后。
在此使用涉及的血小板的功能或活性包括所有由血小板P2Y12受体带来的功能和活性,包括血小板聚集。
可逆的、短效P2Y12抑制剂,例如坎格雷洛、替卡格雷和PRT060128可以通过本领域技术人员已知的任何方法或递送系统给药。给药的实施可以为例如静脉内注射、口服、植入、黏膜、经皮、肌肉注射、鞘内和皮下注射给药。根据一个优选的具体实施方式,可逆的、短效P2Y12抑制剂可以通过静脉内注射或口服给药。可以预期的是,在依照本发明的入侵性操作期间,例如手术,当患者处于昏睡状态或其它任何口服给予血小板抑制剂被禁止的情形下,所述可逆的、短效P2Y12抑制剂可以通过静脉内注射给药。
根据本发明的一个具体实施方式,在给药和在手术前中止治疗的情况下,这样的应用使患者能够进行手术或其它入侵性操作,而没有围手术期的额外出血。例如,如在此所描述的,在停用氯吡格雷之后和手术开始之前,坎格雷洛的输入可以维持血小板抑制在大约高于或等于60%的水平。
对于确定如何给予可逆的、短效P2Y12抑制剂或是给予的可逆的、短效P2Y12抑制剂的量,可以用本领域技术人员已知的方法分析可逆的、短效P2Y12抑制剂的药动学特征。
例如,坎格雷洛的药动学基本上显示为线性的,并且其可以在静脉输注给药后少于5分钟内获得恒定不变的血药浓度。
通过ADP介导的血小板聚集的抑制的间接体内模型评价坎格雷洛的剂量反应关系。在从10ng/kg/min至4000ng/kg/min范围的输注中从观察到了剂量相关的抑制。间接体内模型中ADP介导的血小板聚集的抑制百分率的量效曲线在男性和女性健康志愿者、不稳定性心绞痛以及接受其它附加的阿司匹林、肝素和硝酸甘油治疗的患者之间是相似的。坎格雷洛在间接体内模型中产生了强效的ADP介导的血小板聚集的抑制,其IC50为7.72+/-1.95ng/mL。正如在附图1中可以看到的,在约0.5ug/kg/min以及更高时达到了超过80%的抑制。抑制是迅速可逆的,并且血小板聚集反应在停止输注后1小时内恢复到基线。输注剂量为约0.5ug/kg/min的坎格雷洛可以在输注时在目标患者上维持足够的抗血小板活性。
经测定,持续的和完全的抑制可以通过输注坎格雷洛来维持,而在输注停止后大约1格小时全面恢复血小板功能。在坎格雷洛输注中止时施予氯吡格雷可能达到预期的血小板抑制,其可以通过P-选择素表达、电阻抗和透光率血小板聚集检测法进行检测。
在本发明的每个具体实施方式中,对主体施用的可逆的、短效P2Y12抑制剂的量可以由主治医师来决定。然而,一般来说,可以给主体施用在约0.1至约3.0μg/kg/min之间的剂量。可以给主体施用0.25、0.5、0.75、1.0、1.25、1.5、1.75、2.0、2.25、2.5、2.75和3.0μg/kg/min的特定剂量。
可以对主体施用的可逆的、短效P2Y12抑制剂的总量在每24小时约0.01和1000mg之间,典型的为每24小时约0.5、0.75、1.0、1.25、1.5、1.75、2.0和2.5mg。
本领域技术人员将理解对主体施用的可逆的、短效P2Y12抑制剂的精确剂量与需要的血小板活性抑制的程度非常相关。例如,对会引起出血的在入侵性操作期间的主体施用的可逆的、短效P2Y12抑制剂的剂量可能大大小于对没有进行该操作的主体施用的剂量。可以对在入侵性操作期间的主体施用0.025、0.05、0.075、0.10、0.125、0.15、0.175、0.20、0.225、0.25、0.275和0.30、0.325、0.35、0.375、0.40、0.425、0.45、0.475、0.50、0.525、0.55、0.575、0.60、0.625、0.65、0.675、0.70、0.725、0.75、0.775、0.80、0.825、0.85、0.875、0.90、0.925、0.95、0.975和1.0μg/kg/min的特定剂量。
可以将所述可逆的、短效P2Y12抑制剂连续地静脉内输注给药,或以不连续的剂量给药,例如在每24小时内给予1至48个之间的,或更多的剂量。
可逆的、短效P2Y12抑制剂的剂量可以随着时间变化,在开始施用时为较低的剂量,接着在一段继续的时间里施用增加的剂量,任选在完全停止施用可逆的、短效P2Y12抑制剂前施用减小的剂量。这样的剂量安排可以用于在噻吩并吡啶类药物和/或阿司匹林治疗停用后开始使用可逆的、短效P2Y12抑制剂时。这样的剂量安排可以保证血小板活性抑制水平的一致性。
可以将所述可逆的、短效P2Y12抑制剂以包含一种可逆的、短效P2Y12抑制剂和一种或多种药学上可接受的载体或稀释剂的药学上可接受的制剂的形式施予主体。所述载体或稀释剂是本领域技术人员所已知的。
不意在限制,附图2提供了本发明中描述的方法如何用于需要其的主体的简要概述。需要理解的是,本发明的所述方法并不限制于附图2所描述的步骤。
如附图2所示,试用期210可以用于决定达到高于预期水平的血小板聚集抑制,例如大约60%的血小板抑制水平,需要的剂量。直到外科手术前大约5天的手术前期220可以用于给予可逆的、短效P2Y12抑制剂。从停用可逆的、短效P2Y12抑制剂持续到外科手术结束可以按需要使用手术期间230。
在试用期210,可以决定达到高于预期水平的血小板聚集抑制,例如大约60%的血小板抑制水平,需要的可逆的、短效P2Y12抑制剂的剂量。例如,静脉内输注可逆的、短效P2Y12抑制剂可以给予患者的典型的在从0.1至3.0μg/kg/min的范围内的剂量,并且更特别的为0.5μg/kg/min、0.75μg/kg/min、1.0μg/kg/min、1.5μg/kg/min和2.0μg/kg/min的剂量,直至测得的血小板抑制高于预期的水平。也可以根据需要达到的血小板抑制水平按需使用更小或更大的剂量。在另一种形式下,可逆的、短效P2Y12抑制剂可以按从0.1mg至1000mg的日剂量给予,其可以为分次剂量的形式,例如每天6次。可逆的、短效P2Y12抑制剂的剂量也可以事前确定,以减少多剂量给药以达到预期的血小板抑制水平的需要。在所有情况下都需要测定血小板抑制,需要获得基线值以精确地确定什么时候达到了可接受的水平。
在手术前期间220,可逆的、短效P2Y12抑制剂的施用可以从决定停用氯吡格雷或其它的噻吩并吡啶类药物的那天起,并且可以持续整个手术前期间220。例如,患者可以接受至少约48小时的可逆的、短效P2Y12抑制剂的输注,并且至多大约7天的输注。在一个具体实施方式中,患者可以从停用氯吡格雷5天后进行CABG。在另一个具体实施方式中,可逆的、短效P2Y12抑制剂施用的停止可以为从手术前大约1小时至入侵性操作例如手术前大约3小时。所述可逆的、短效P2Y12抑制剂的剂量可以在治疗期间保持连续或可以为间歇性的。治疗可以随后在预定手术的麻醉前1小时中止。
也是在手术前期间220,可以进行与本发明相关的任意数量的程序和/或测试,例如血红蛋白、红细胞积压、白细胞、和血小板计数检测;血肌酐检测;血小板活性抑制测量;以及合并用药、不良事件、严重不良事件和其它多项临床终点的评估。另外,例如CK和CK-MB以及VerifyNowP2Y12分析的程序可以在手术前24小时进行。
在手术期间230,可逆的、短效P2Y12抑制剂的施用可以在为手术实施麻醉前至少1小时至大约3小时停止。本领域技术人员可以理解在手术期间采用护理治疗的基本标准。合并用药的收集和不良事件、严重不良事件以及临床终点的评估也可以根据需要在这个阶段中进行。
血小板功能的评价可以通过使用Accumetrics VerifyNowTM P2Y12(Accumetrics,San Diego,CA)分析来评价。VerifyNowTM P2Y12分析是一种为了评价血小板活性抑制水平,特别是针对使用噻吩并吡啶类药物的患者的救护地点检测法。需要理解的是,如本领域技术人员所理解的,任何检测血小板活性抑制水平的分析系统都可以使用。用于VerifyNowTM P2Y12分析的血液样品可以收集到含有3.2%的柠檬酸盐的Greiner Bio-OneVacuette部分填充血液收集管(2ml填充体积)中,或通过其它合适的方法。
VerifyNowTM P2Y12分析是一种基于试剂盒的(cartridge-based)快速血小板功能分析,其使用二磷酸腺苷(ADP)激活血小板活性,但也使用前列腺素E1抑制了ADP介导的P2Y1介导的细胞内钙水平的增加,以增加P2Y12受体抑制测试的特异性。该检测试剂盒含有人纤维蛋白原包衣珠子、血小板激动剂、缓冲剂和防腐剂的冻干制剂。纤维蛋白原包衣的微粒用于连接可用的血小板受体。当活化的血小板暴露于蛋白原包衣的微粒中时,发生与可用的血小板受体数量成比例的聚集。将全血柠檬酸混合物加入到试剂盒中,并且记录血小板和包衣珠子之间的聚集。VerifyNowTMP2Y12设备是一种比浊法光学检测系统,其检测了血小板引发的聚集带来的透光率的增加。检测结果用P2Y12反应单位(PRU)[Malinin等,2006]来表示。VerifyNowTMP2Y12检测可以于在此描述的任何时间点使用,以分析血小板活性的抑制水平。
根据本发明的另一方面,附加的药物可以被允许合并用药。作为非限制性的例子,例如阿司匹林、ε氨基己酸、氨甲环酸、和肝素的化合物可以用于合并用药。
实施例
实施例1
在第一个实施例中,坎格雷洛可以通过静脉内输注给药,并且可以以步进方式给予患者组预先确定的剂量(0.5μg/kg/min、0.75μg/kg/min、1.0μg/kg/min and 1.5μg/kg/min),直到通过VerifyNowTM P2Y12测量的血小板抑制达到了大于约60%的水平或达到了2.0μg/kg/min的剂量。
可以给第一组患者施予达到约0.5μg/kg/min的输注。如果通过VerifyNowTM P2Y12测量的血小板抑制小于约60%,可以对第二组的5个患者静脉内输注施予约0.75μg/kg/min的坎格雷洛。如果通过VerifyNowTMP2Y12测量的血小板抑制小于约60%,可以对第三组的5个患者静脉内输注施予约1.0μg/kg/min的坎格雷洛。如果通过VerifyNowTMP2Y12测量的血小板抑制小于约60%,可以对余下的组静脉内输注施予约2.0μg/kg/分钟的坎格雷洛。在确定了达到通过VerifyNowTM P2Y12测量的血小板抑制大于约60%的坎格雷洛的有效剂量之后,可以施予单个剂量的坎格雷洛。
接下来,可以将患者随机分为两组,给予坎格雷洛或接受标准护理。在第一组中,患者只接受标准护理,其中在确定需要手术后停用氯吡格雷,并输注施予安慰剂。在第二组中,在确定需要手术后停用氯吡格雷,除标准护理外,可以开始输注施予之前确定的达到VerifyNowTM P2Y12测量的血小板抑制大于约60%的有效量的坎格雷洛。所述输注(坎格雷洛或相应的安慰剂)可以在整个手术之前的时期持续施予。与ACC/AHA和STS指南一致,患者可以在停用氯吡格雷后等待大约5天然后进行手术。可以在手术前约1至3小时停止静脉内输注坎格雷洛。
实施例2
在另一个实施例中,与本发明的一个具体实施方式一致,在主体被施予入侵性操作期间施予至少一种可逆的、短效P2Y12抑制剂。在这种情况下,由于主体不能通过口服进行治疗,可以预期抑制剂将会通过静脉内施予。
实施例3a
在另一个实施例中,与本发明的另一个具体实施方式一致,至少一种可逆的、短效P2Y12抑制剂的施予发生在对主体进行入侵性操作之后,如果主体不能接受口服治疗,例如主体是昏迷的,手术后抑制剂的施予也可以是静脉内的。
实施例3b
在手术后早期应用坎格雷洛的研究
目前,在患者进行PCI术后通过植入支架维持抗血小板治疗的标准护理是基于美国心脏病协会/美国心脏协会(ACC/AHA)指南(Fleisher LA等,ACC/AHA 2007 guidelines on perioperative cardiovascular evaluationand care for noncardiac surgery:a report of the ACC/AHA Task Forceon Practice Guidelines.Circulation.2007 Oct 23;116(17):e418-99)的推荐,其建议早期使用双重抗血小板治疗,并根据支架的种类在PCI术后6至12个月继续使用阿司匹林和氯吡格雷维持治疗,以防止术后支架血栓。阿司匹林和氯吡格雷都是不可逆的血小板拮抗剂,因此ACC/AHA指南推荐在非紧急手术操作前停用氯吡格雷以使出血的风险最小化。
然而,当植入支架的患者需要手术操作,早期停用氯吡格雷将增加缺血事件以及由血小板活性“反弹”效应引发的支架血栓的风险(Berger etal.,Circulation.2002Oct 22;106(17):2284-7;Ho et al.JAMA.2008Feb 6;299(5):532-9)。相反地,使用阿司匹林和氯吡格雷维持不可逆的血小板抑制将导致不可接受的术中出血风险(Fox et al.,Circulation.2004;110;1202-1208;Shim et al.,J Thorac Cardiovasc Surg.2007Jul;134(1):59-64;Pickard et al.,Pharmacotherapy.2008Mar;28(3):376-92.Review)。
由于手术部位出血的风险,当手术操作可能与术后出血的高风险联合时,外科医生更愿意避免在术后早期使用抗凝血剂,特别是不可逆的口服治疗,这将不能达到预期的血小板抑制水平,并且血小板功能将快速恢复。
已知外科干涉会引发血小板活化和聚集,因此,如果患者不继续抗血小板治疗,手术后期间支架血栓的风险将增加。
多项研究已经证明,抗凝血治疗的早期使用可能减小静脉血栓的风险(Segers A.J Thromb Haemost.2008Aug;6(8):1313-8;Turpie et al.,Lancet.2009 May 1),然而,对于植入了支架的患者需要外科手术操作时减少动脉支架血栓,没有得到一致认同的或标准的抗血小板治疗方法。
典型地,外科手术操作的结束要达到完全地止血,然而,手术位置出血的风险在术后的第一个小时里依然很高。在手术后即早期期间开始抗血小板治疗可能进一步增加这种风险。相反地,鉴于手术操作引发的血小板活化和聚集,继续维持抗血小板治疗的延迟将大大增加支架血栓的风险。因此,使用可以滴定到需要的血小板抑制水平的、并且具有超短的血小板功能恢复时间的可逆的抗血小板试剂进行早期治疗对预防这类患者的支架血栓是有好处的。此外,由于其在出血的情况下停用后,血小板功能可以完全恢复,这类试剂将是安全的。
坎格雷洛是一种强效的、可逆的和特异性的P2Y12受体拮抗剂,其能够克服现有使用阿司匹林和氯吡格雷的双重抗血小板疗法的局限,这是由于其快速的起效和失效、以及其能够在数分钟内达到恒定的血药浓度、并且滴定以调节血小板抑制的水平,还有最重要的,其以<5分钟的清除半衰期快速代谢,使血小板功能能够在60分钟内完全恢复。因此,坎格雷洛可以是一种理想的抗血小板试剂,在植入了支架又需要外科手术操作患者的手术后早期控制血小板抑制。
手术后早期坎格雷洛输注的最佳的血小板抑制剂量和方案以及向口服抗血小板疗法的转换是可以确定的。
患者群体可以为那些在PCI术后植入了支架并且需要大型外科手术(CABG、肠胃吻合术(GI anastomoses)、肺切除术、前列腺切除术、整形外科手术等)的ACS患者,N=40个主体(每组10个主体共4组)。坎格雷洛输注将在手术完成后1-2小时后由外科医生判断开始。主体随机分到下列组中:
组1:坎格雷洛0.5μg/kg/min剂量输注24小时,输注停止后转换为300mg负荷剂量的口服氯吡格雷抗血小板治疗,以及之后75mg的每日维持剂量
组2:坎格雷洛0.5μg/kg/min剂量输注24小时,输注停止后转换为600mg负荷剂量的口服氯吡格雷的血小板治疗,以及之后75mg的每日维持剂量
组3:坎格雷洛1μg/kg/min剂量输注24小时,输注停止后转换为300mg负荷剂量的口服氯吡格雷抗血小板治疗,以及之后75mg的每日维持剂量
组4:坎格雷洛1μg/kg/min剂量输注24小时,输注停止后转换为600mg负荷剂量的口服氯吡格雷抗血小板治疗,以及之后75mg的每日维持剂量
主要终点可以为:(1)手术操作后48小时期间发生的急性支架血栓,和(2)手术操作后48小时期间发生的严重出血和轻度出血。
评估方法为:(1)使用VerifyNow-P2Y12测试血小板聚集,(2)血流动力学测量,(3)验血,(4)临床观察轻度毛细血管出血迹象(瘀斑、血肿),(5)需要检测潜在的出血并发症(积血)时,使用CT、MRI、US进行颅内、腹膜和胸腔影像学诊断。
本领域技术人员将会认识到,在不偏离本发明的精神或范围的情况下,本发明的许多的改进和变化是可以实现的。因此,意图是包括了本发明的改进和变化的本发明包含在所附权利要求及其等效物的范围内。
在此涉及的所有的文献、出版物、专利、图书、指南、文章、论文、摘要、海报以及其它材料特别地在此全部引用合并到本文。
Claims (35)
1.一种治疗或预防之前接受过至少一种噻吩并吡啶类药物治疗的主体的疾病或不适的方法,包括在所述入侵性操作之前施予主体有效量的至少一种可逆的、短效P2Y12抑制剂。
2.权利要求1所述的方法,其中入侵性操作为冠状动脉搭桥术。
3.权利要求1所述的方法,其中入侵性操作为经皮冠状动脉介入治疗。
4.权利要求1所述的方法,其中至少一种可逆的、短效P2Y12抑制剂为坎格雷洛。
5.权利要求1所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予发生在入侵性操作前5天内。
6.一种治疗或预防之前接受过至少一种噻吩并吡啶类药物治疗的主体的疾病或不适的方法,包括在所述入侵性操作之前施予主体有效量的至少一种可逆的、短效P2Y12抑制剂以至少部分地抑制主体的血小板活性。
7.权利要求6所述的方法,其中所述主体先前安装了支架。
8.权利要求6所述的方法,其中至少一种可逆的、短效P2Y12抑制剂为坎格雷洛。
9.权利要求7所述的方法,其中支架为裸金属支架。
10.权利要求7所述的方法,其中支架为药物涂层支架。
11.一种至少部分地抑制主体血小板活性的方法,包括步骤:
施予有效量的至少一种噻吩并吡啶类药物;和
在停止施用至少一种噻吩并吡啶类药物后施予有效量的至少一种可逆的、短效P2Y12抑制剂。
12.权利要求11所述的方法,其中至少一种噻吩并吡啶类药物为不可逆的。
13.权利要求11所述的方法,其中至少一种噻吩并吡啶类药物为氯吡格雷。
14.权利要求11所述的方法,其中至少一种可逆的、短效P2Y12抑制剂为坎格雷洛。
15.权利要求14所述的方法,其中静脉内输注的坎格雷洛的有效量为0.5至2.0μg/kg/min之间。
16.权利要求11所述的方法,其中血小板抑制大于约60%。
17.权利要求11所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予发生在对主体进行入侵性操作前5天内。
18.权利要求11所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予发生在对主体进行入侵性操作期间。
19.权利要求11所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予发生在对主体进行入侵性操作之后。
20.一种至少部分地抑制之前接受过至少一种噻吩并吡啶类药物治疗的主体的血小板活性的方法,包括对主体施予有效量的至少一种可逆的、短效P2Y12抑制剂。
21.权利要求20所述的方法,其中至少一种噻吩并吡啶类药物为氯吡格雷。
22.权利要求20所述的方法,其中至少一种可逆的、短效P2Y12抑制剂为坎格雷洛。
23.权利要求20所述的方法,其中坎格雷洛的施予在对主体进行入侵性操作之前5天开始。
24.权利要求23所述的方法,其中在入侵性操作前1至24小时停止坎格雷洛的施予。
25.一种抑制主体血小板活性的方法,包括:
(a)对需要治疗的主体施予治疗有效量的至少一种噻吩并吡啶类药物;
(b)停止至少一种噻吩并吡啶类药物的施予;和
(c)对主体施予治疗有效量的至少一种可逆的、短效P2Y12抑制剂,抑制主体的血小板活性。
26.权利要求25所述的方法,其中至少一种噻吩并吡啶类药物的抑制活性为不可逆的。
27.权利要求25所述的方法,其中至少一种噻吩并吡啶类药物为氯吡格雷。
28.权利要求25所述的方法,其中至少一种可逆的、短效P2Y12抑制剂为坎格雷洛。
30.权利要求25所述的方法,其中静脉内输注的坎格雷洛的治疗有效量为约0.5至2.0μg/kg/min之间。
31.权利要求25所述的方法,其中血小板活性的抑制为抑制大于约60%的血小板聚集。
32.权利要求25所述的方法,其中至少一种噻吩并吡啶类药物的施用的停止发生在对主体进行入侵性操作之前至少5天。
33.权利要求32所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予开始在入性操作之前。
34.权利要求32所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予开始在对主体进行入侵性操作期间。
35.权利要求32所述的方法,其中至少一种可逆的、短效P2Y12抑制剂的施予开始在对主体进行入侵性操作之后。
36.权利要求25所述的方法,其中血小板活性是血小板聚集。
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CA2724470A1 (en) | 2009-11-19 |
CA2724470C (en) | 2018-01-02 |
BRPI0912693B8 (pt) | 2021-05-25 |
SI2276541T1 (sl) | 2017-02-28 |
ES2601524T3 (es) | 2017-02-15 |
PL2276541T3 (pl) | 2017-08-31 |
WO2009140407A1 (en) | 2009-11-19 |
JP2014077005A (ja) | 2014-05-01 |
HRP20161443T1 (hr) | 2016-12-30 |
PT2276541T (pt) | 2016-11-10 |
US20170049798A1 (en) | 2017-02-23 |
EP2276541B1 (en) | 2016-08-03 |
US8871736B2 (en) | 2014-10-28 |
LT2276541T (lt) | 2016-12-12 |
EP2276541A4 (en) | 2012-05-09 |
BRPI0912693A2 (pt) | 2019-01-15 |
HUE031704T2 (hu) | 2017-07-28 |
DK2276541T3 (en) | 2016-11-28 |
JP2011520899A (ja) | 2011-07-21 |
BRPI0912693B1 (pt) | 2021-05-11 |
JP5792059B2 (ja) | 2015-10-07 |
CY1118653T1 (el) | 2017-07-12 |
US10022391B2 (en) | 2018-07-17 |
AU2009246396A1 (en) | 2009-11-19 |
US20110288043A1 (en) | 2011-11-24 |
AU2009246396B2 (en) | 2015-07-09 |
EP2276541A1 (en) | 2011-01-26 |
WO2009140092A1 (en) | 2009-11-19 |
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