Preclinical Studies of a Kidney Safe Iodinated Contrast Agent.

BACKGROUND AND PURPOSE: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the use of iodinated contrast agents. This problem is particularly acute in interventional neurology and interventional cardiology, probably due to the intra-arterial route of injection, high contrast volumes, and preexisting risk factors of these patients. In an attempt to develop a contrast agent that is less damaging to the kidneys, we have studied the effects of adding a small amount of the substituted cyclodextrin, sulfobutyl-ether-ß-cyclodextrin (SBECD), to iohexol in rodent models of renal toxicity. METHODS: Renally compromised mice and rats were injected with iohexol and iohexol-SBECD via the tail vein. The renal pathology, creatinine clearance, and survival benefits of iohexol-SBECD were studied. The safety of direct intra-arterial injection of the iohexol-SBECD formulation was studied in a dog heart model system. Mechanism of action studies in cell culture model using a human kidney cell line was performed using flow cytometry. RESULTS: Nephrotoxicity was significantly reduced using iohexol-SBECD compared to iohexol alone, at mole ratios of iohexol:SBECD of 1:0.025. SBECD increased survival from 50% to 88% in a rat survival study. In the dog heart model, iohexol-SBECD was safe. Cell culture studies suggest that SBECD interferes with the early stages of contrast-induced apoptosis in a human renal cell line. CONCLUSION: We have shown that the addition of a small amount of SBECD (one molecule of SBECD per 40 iohexol molecules) significantly protects rodent kidneys from CI-AKI. Further development of this new formulation of iodinated contrast is warranted.

Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-beta, beta-carotene-4,4'-dione) by Captisol (sulfobutyl ether beta-cyclodextrin).

Carotenoids are the most widely distributed natural pigments, with over 600 individual compounds identified and characterized from natural sources. A few are commercially important molecules, having found utility as additions to animal feed in the aquaculture, poultry, and swine feed industries. The majority are lipophilic molecules with near zero inherent aqueous solubility. Many different methods have been developed to make the carotenoids "water dispersible," as true water solubility has not been described. Astaxanthin (3,3'-dihydroxy-beta, beta-carotene-4,4'-dione) is a commercially important oxygenated carotenoid that has gained wide acceptance as a feed additive in the $50 billion salmon and trout aquaculture industry. Recently, interest in the human health applications of astaxanthin has increased, with astaxanthin receiving approval as a dietary supplement in several countries, including the United States. Moving astaxanthin into a pharmaceutical application will require a chemical delivery system that overcomes the problems with parenteral administration of a highly lipophilic, low molecular weight compound. In the current study, the ability of sulfobutyl ether beta-cyclodextrin (sodium), as the Captisol(R) brand, to increase the aqueous water solubility of crystalline astaxanthin was evaluated. Complexation of crystalline astaxanthin with Captisol increased the apparent water solubility of crystalline astaxanthin approximately 71-fold, to a concentration in the 2 microg/mL range. It is unlikely that this increase in solubility will result in a pharmaceutically acceptable chemical delivery system for humans. However, the increased aqueous solubility of crystalline astaxanthin to the range achieved in the current study will likely find utility in the introduction of crystalline astaxanthin into mammalian cell culture systems that have previously been dependent upon liposomes, or toxic organic solvents, for the introduction of carotenoids into aqueous solution.