Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax)

Cardioprotection in humans by carotenoids has been inferred from observational and epidemiologic studies, however, direct studies of cardioprotection and myocardial salvage by carotenoids are lacking. In the current study, intravenous (I.V.) pre-treatment with a novel carotenoid derivative (disodium disuccinate astaxanthin; Cardax) was evaluated as a myocardial salvage agent in a Sprague-Dawley rat infarct model. Animals were dosed once per day I.V. by tail vein injection for 4 days at one of 3 doses (25, 50, and 75 mg/kg) prior to the infarct study carried out on day 5. The results were compared with control animals treated with saline vehicle. Thirty (30) minutes of occlusion of the left anterior descending (LAD) coronary artery was followed by 2 hours of reperfusion prior to sacrifice, a regimen which resulted in a mean infarct size (IS) as a percent (%) of the area at risk (AAR) of 59 +/- 3%. Area at risk was quantified by Patent blue dye injection, and infarct size (IS) was determined by triphenyltetrazolium chloride (TTC) staining. Cardax at 50 and 75 mg/kg for 4 days resulted in a significant mean reduction in IS/AAR to 35 +/- 3% (41% salvage) and 26 +/- 2% (56% salvage), respectively. Infarct size and myocardial salvage were significantly, and linearly, correlated with plasma levels of non-esterified, free astaxanthin at the end of reperfusion. These results suggest that parenteral Cardax may find utility in those clinical applications where pre-treatment of patients at risk for myocardial infarction is performed.     

Seven day oral supplementation with Cardax TM (disodium disuccinate astaxanthin) provides significant cardioprotection and reduces oxidative stress in rats

In the current study, the improved oral bioavailability of a synthetic astaxanthin derivative (Cardax^TM; disodium disuccinate astaxanthin) was utilized to evaluate its potential effects as a cardioprotective agent after 7-day subchronic oral administration as a feed supplement to Sprague-Dawley rats. Animals received one of two concentrations of Cardax^TM in feed (0.1 and 0.4%; ∼125 and 500 mg/kg/day, respectively) or control feed without drug for 7 days prior to the infarct study carried out on day 8. Thirty minutes of occlusion of the left anterior descending (LAD) coronary artery was followed by 2 h of reperfusion prior to sacrifice, a regimen which resulted in a mean infarct size (IS) as a percentage (%) of the area at risk (AAR; IS/AAR,%) of 61 ± 1.8%. The AAR was quantified by Patent blue dye injection, and IS was determined by triphenyltetrazolium chloride (TTC) staining. Cardax^TM at 0.1 and 0.4% in feed for 7 days resulted in a significant mean reduction in IS/AAR,% to 45 ± 2.0% (26% salvage) and 39 ± 1.5% (36% salvage), respectively. Myocardial levels of free astaxanthin achieved after 7-day supplementation at each of the two concentrations (400 ± 65 nM and 1634 ± 90 nM, respectively) demonstrated excellent solid-tissue target organ loading after oral supplementation. Parallel trends in reduction of plasma levels of multiple lipid peroxidation products with disodium disuccinate astaxanthin supplementation were observed, consistent with the documented in vitro antioxidant mechanism of action. These results extend the potential utility of this compound for cardioprotection to the elective human cardiovascular patient population, for which 7-day oral pre-treatment (as with statins) provides significant reductions in induced periprocedural infarct size.     

Plasma appearance and tissue accumulation of non-esterified, free astaxanthin in C57BL/6 mice after oral dosing of a disodium disuccinate diester of astaxanthin (Heptax)

Oral bioavailability of natural and synthetic carotenoids is generally poor in rodents, and this has limited the ability to test these antioxidant compounds in well-defined rodent models of human disease. Various strategies have been employed, with variable success, to increase the percentage of the total oral dose absorbed by the rodent GI tract. In the current study, a novel carotenoid derivative (the disodium disuccinate diester of astaxanthin; Heptax) was administered by oral gavage in a lipophilic emulsion to C57BL/6 mice. Plasma appearance and tissue accumulation of non-esterified, free astaxanthin was studied by HPLC over 72 h after single- and multiple-dose regimens. One-time dosing of Heptax in emulsion at 500 mg/kg resulted in significant appearance of free astaxanthin in plasma (Cmax=0.2 mg/l; 381 nM) and accumulation in solid organs (e.g. liver Cmax=0.9 mg/l; 1735 nM), levels not previously reported after single carotenoid doses in rodents. At each point in the concentration/time curve (AUC), free astaxanthin levels in liver were greater than the corresponding concentration in plasma, suggesting concentrative uptake by the liver. As the ED50 as an antioxidant for non-esterified, free astaxanthin in model systems is approximately 200 nM, the current results suggest that hepatoprotection against oxidative insults may be achieved after a single dose of Heptax in these animals. In humans, where the bioavailability of oral carotenoids ranges from 40 to 60% of the total dose when given in lipophilic vehicle, much smaller oral doses may be utilized for therapeutic benefit in a particular clinical application.