米诺环素与远程缺血预处理联合治疗的2×2析因设计：在小鼠血栓栓塞性中风模型的临床前试验中的疗效
A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model.
作者信息
Hoda Md Nasrul, Fagan Susan C, Khan Mohammad B, Vaibhav Kumar, Chaudhary Aizaz, Wang Phillip, Dhandapani Krishnan M, Waller Jennifer L, Hess David C
机构信息
Department of Neurology, Georgia Regents University, Augusta, GA 30912, USA ; Department of Medical Laboratory, Imaging and Radiologic Sciences, Georgia Regents University, Augusta, GA 30912, USA ; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, USA ; Charlie Norwood VA Medical Centre, Augusta, USA.
Department of Neurology, Georgia Regents University, Augusta, GA 30912, USA ; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, USA ; Charlie Norwood VA Medical Centre, Augusta, USA.
出版信息
Exp Transl Stroke Med. 2014 Oct 9;6:10. doi: 10.1186/2040-7378-6-10. eCollection 2014.
BACKGROUND
After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/ or the use of mechanical reperfusion devices in the hospital.
METHODS
We performed a 2 × 2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded.
RESULTS
RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P < 0.001). MINO and RIPerC treatment were effective alone at reducing infarct size (p < 0.0001) and improving short-term functional outcomes (p < 0.001) in the tPA and non-tPA treated animals. The combination treatment of MINO and RIPerC significantly reduced the infarct size greater than either intervention alone (p < 0.05). There were trends in favor of improving functional outcomes after combination treatment of MINO and RIPerC; however combination treatment group was not significantly different than the individual treatments of MINO and RIPerC. There was no "statistical" interaction between minocycline and RIPerC treatments indicating that the effects of RIPerC and MINO were additive and not synergistic on the outcome measures.
CONCLUSION
In the future, combining these two safe and low cost interventions in the ambulance has the potential to "freeze" the penumbra and improve outcomes in stroke patients. This pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial.
背景
在众多急性缺血性中风药物和治疗方法均告失败后，需要创新方法来开发新的治疗手段。一种有前景的策略是在院前环境中，在静脉注射组织纤溶酶原激活剂（IV-tPA）之前和/或在医院使用机械再灌注设备之前，测试药物组合。
方法
我们进行了一项2×2析因设计的临床前试验，在小鼠血栓栓塞性中风模型中测试米诺环素（MINO）、远程缺血预处理（RIPerC）及其联合治疗，不使用IV-tPA或在中风后4小时用IV-tPA治疗。通过激光散斑对比成像（LSCI）测量脑血流量（CBF），在中风后48小时进行行为学评估，如神经功能缺损评分（NDS）和胶带去除试验，并测量梗死灶大小。实验组内的小鼠被随机分配接受不同治疗，所有结果测量均采用盲法。
结果
通过LSCI测量，RIPerC在使用和未使用tPA治疗的小鼠中均显著改善了CBF（P < 0.001）。在使用tPA和未使用tPA治疗的动物中，MINO和RIPerC单独治疗在减少梗死灶大小（p < 0.0001）和改善短期功能结局（p < 0.001）方面均有效。MINO和RIPerC联合治疗显著降低梗死灶大小，比单独任何一种干预措施都更有效（p < 0.05）。MINO和RIPerC联合治疗后在改善功能结局方面有趋势；然而联合治疗组与MINO和RIPerC单独治疗组无显著差异。米诺环素和RIPerC治疗之间没有“统计学”相互作用，表明RIPerC和MINO对结局指标的影响是相加的而非协同的。
结论
未来，在救护车上将这两种安全且低成本的干预措施结合起来，有可能“冻结”半暗带并改善中风患者的预后。这种临床前2×2设计可以很容易地转化为院前临床试验。
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