Gross Garrett J, Lockwood Samuel F
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Mol Cell Biochem. 2005 Apr;272(1-2):221-7. doi: 10.1007/s11010-005-7555-2.
Previous results from our laboratory have shown that a novel carotenoid derivative (disodium disuccinate astaxanthin; Cardax) produced dose-related reductions in myocardial infarct size (IS) in Sprague-Dawley rats when it was administered at any of three doses (25, 50 and 75 mg/kg, iv) on four consecutive days, followed by the acute infarct size study on day 5. Maximum salvage occurred at the highest dose (75 mg/kg) tested, and was shown as a 56% reduction in IS. In the present follow-up study, we used a more relevant large animal model, the dog, and looked at the effect of administering Cardax iv either acutely 2 h prior to occlusion (N = 8) or for 4 days at 50 mg/kg iv as previously done in the rat model (N = 6). The results were compared to a saline vehicle-treated group (N = 10). In all groups, dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion and 3 h of reperfusion. IS was determined using a triphenyltetrazolium chloride (TTZ) histochemical stain and was expressed as a percent of the area at risk (IS/AAR). IS/AAR was 20.9 +/- 1.6 % (mean +/- S.E.M.) in controls and was reduced to 11.0 +/- 1.7% (47.3% salvage; p < 0.01) in dogs treated only once iv at 2 h prior to occlusion, and 6.6 +/- 2.8% (68.4% salvage; p < 0.001) in dogs treated for 4 days. In the chronic treatment group, two of the three dogs with plasma concentrations of non-esterified astaxanthin above 1 microM had 0% IS/AAR (100% cardioprotection). These results suggest that Cardax has marked cardioprotective properties in both rodents and canines. Thus, Cardax may be a novel and powerful new means to prevent myocardial injury and/or necrosis associated with elective and/or urgent cardiac surgical interventions such as coronary angioplasty and stenting, as well as coronary artery bypass surgery (CABG).
我们实验室之前的研究结果表明，一种新型类胡萝卜素衍生物（虾青素二琥珀酸二钠；Cardax）在连续四天以三种剂量（25、50和75毫克/千克，静脉注射）中的任何一种给药后，对Sprague-Dawley大鼠的心肌梗死面积（IS）产生了剂量相关的减小作用，随后在第5天进行急性梗死面积研究。在所测试的最高剂量（75毫克/千克）下出现了最大的挽救效果，表现为梗死面积减小了56%。在本后续研究中，我们使用了更相关的大型动物模型——狗，并观察了在闭塞前2小时急性静脉注射Cardax（N = 8）或如之前在大鼠模型中那样以50毫克/千克静脉注射4天（N = 6）的效果。将结果与生理盐水处理组（N = 10）进行比较。在所有组中，狗都接受了60分钟的左前降支（LAD）冠状动脉闭塞和3小时的再灌注。使用氯化三苯基四氮唑（TTZ）组织化学染色测定梗死面积，并表示为危险区域面积的百分比（IS/AAR）。对照组的IS/AAR为20.9 +/- 1.6%（平均值 +/- 标准误），在闭塞前2小时仅静脉注射一次的狗中降至11.0 +/- 1.7%（挽救率47.3%；p < 0.01），在治疗4天的狗中降至6.6 +/- 2.8%（挽救率68.4%；p < 0.001）。在慢性治疗组中，血浆中非酯化虾青素浓度高于1微摩尔的三只狗中有两只的IS/AAR为0%（心脏保护率100%）。这些结果表明，Cardax在啮齿动物和犬类中都具有显著的心脏保护特性。因此，Cardax可能是一种新型且强大的新方法，可用于预防与选择性和/或紧急心脏手术干预（如冠状动脉成形术和支架置入术以及冠状动脉旁路移植术（CABG））相关的心肌损伤和/或坏死。
