Preclinical Studies of a Kidney Safe Iodinated Contrast Agent

Abstract

BACKGROUND AND PURPOSEContrast‐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‐β‐cyclodextrin (SBECD), to iohexol in rodent models of renal toxicity.METHODSRenally 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.RESULTSNephrotoxicity 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.CONCLUSIONWe 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.

AS1411 Aptamer-Anionic Linear Globular Dendrimer G2-Iohexol Selective Nano-Theranostics

“…In that research, it was concluded from the results that a nonionic radiocontrast such as Iohexol cause acute renal failure 58 . In another study in 2016, acute kidney injury of Iohexol was considered and using a new complex consisted of sulfobutyl-ether-β-cyclodextrin (SBECD) and Iohexol, the toxicity decreased from 50% to 12% in a rodent model compared to the Iohexol alone 59 . Hence, it is of great importance to find an alternative to the conventional radiocontrast agents.…”

MRI and CT contrast media extravasation

“…Although the currently available contrast agents are considered to be safe, their use is not completely without risk [ 4 ] and considerable attention has been focused on allergic reactions, physiologic reactions, nephrotoxicity, nephrogenic systemic fibrosis, and gadolinium deposition in tissues. [ 4 , 5 – 11 ]…”

A nephroprotective iodinated contrast agent with cardioprotective properties: A pilot study

“…SBECD is widely used in marketed drug formulations to increase solubility, including remdesivir, one of the few approved treatments for Covid‐19 37 . However, in our studies, only one molecule of SBECD per 40 molecules of iohexol is necessary for nephroprotection, ruling out a solubilization mechanism in this case 36 …”

“…As we previously reported in this journal, SBECD (trade name Captisol, Ligand Pharmaceuticals, Inc, San Diego, CA) was shown to mitigate CI‐AKI in laboratory animals 36 . A reformulation of iohexol with SBECD is now in phase II clinical trials in the United States, for prevention of CI‐AKI in vulnerable patients undergoing elective coronary angiography.…”