Lockwood Samuel F, Gross Garrett J
Hawaii Biotech, Inc., 99-193 Aiea Heights Drive, Suite 200, Aiea, HI 96701, USA.
Cardiovasc Drug Rev. 2005 Fall;23(3):199-216. doi: 10.1111/j.1527-3466.2005.tb00166.x.
Disodium disuccinate astaxanthin (Cardax), DDA) has cardioprotective effects in the rat, rabbit, and canine models of experimental infarction. It is highly effective by parenteral administration in subchronic and acute dosing regimens. Unpublished data in rats suggest that oral cardioprotection is also readily achievable. DDA-induced myocardial salvage in the canine can reach 100% with a 4-day subchronic dosing regimen. At a single i.v. dose DDA is cardioprotective, when given 2 h before experimental coronary occlusion, but the protection is on the average two-thirds of that achieved with the subchronic regimen in dogs. In conscious animals DDA has no effects on hemodynamic parameters. The primary mechanism of cardioprotection appears to be antioxidant activity involving direct scavenging of superoxide anion, the lynchpin radical in ischemia-reperfusion injury. In addition, modulation of serum complement activity, as well as the reduction in the levels of C-reactive protein (CRP) and the membrane attack complex (MAC) in infarcted tissue suggest a significant antiinflammatory component in the mechanism of cardioprotective action of DDA. Stoichiometric binding of the meso-form of the compound to human serum albumin (HSA) has been demonstrated in vitro. This binding capacity overcomes the supramolecular assembly of the compound in aqueous solution, which by itself improves the stability and shelf life of aqueous formulations. Non-esterified astaxanthin readily enters cardiac tissue after either oral or parenteral administration, providing a reservoir of a cardioprotective agent with a significant half-life due to favorable ADME in mammals. Due to the well-documented safety profile of non-esterified astaxanthin in humans, disodium disuccinate astaxanthin may well find clinical utility in cardiovascular indications in humans following successful completion of preclinical and clinical pharmacology and toxicology studies.
虾青素二琥珀酸钠（Cardax，DDA）在大鼠、兔子和犬类实验性梗死模型中具有心脏保护作用。在亚慢性和急性给药方案中，通过肠胃外给药它具有高效性。大鼠的未发表数据表明口服心脏保护作用也很容易实现。在犬类中，采用4天亚慢性给药方案时，DDA诱导的心肌挽救率可达100%。在实验性冠状动脉闭塞前2小时静脉注射一次DDA具有心脏保护作用，但这种保护作用平均只有犬类亚慢性给药方案所达到效果的三分之二。在清醒动物中，DDA对血流动力学参数没有影响。心脏保护的主要机制似乎是抗氧化活性，包括直接清除超氧阴离子，这是缺血再灌注损伤中的关键自由基。此外，血清补体活性的调节，以及梗死组织中C反应蛋白（CRP）和膜攻击复合物（MAC）水平的降低表明DDA心脏保护作用机制中存在显著的抗炎成分。该化合物的内消旋形式与人血清白蛋白（HSA）的化学计量结合已在体外得到证实。这种结合能力克服了该化合物在水溶液中的超分子组装，这本身提高了水性制剂的稳定性和保质期。非酯化虾青素在口服或肠胃外给药后很容易进入心脏组织，由于在哺乳动物中具有良好的吸收、分布、代谢和排泄特性，可提供具有显著半衰期的心脏保护剂储备。由于非酯化虾青素在人类中的安全性记录良好，在成功完成临床前和临床药理学及毒理学研究后，虾青素二琥珀酸钠很可能在人类心血管疾病适应症中找到临床应用。
