We are developing a novel small molecule cytoprotective drug (R-100) for the prevention of contrast- induced nephropathy (CIN) following IV radiocontrast media (CM) injection. R-100 is a novel cell- permeable redox-active agent formed from the covalent fusion of 2 chemical moieties: 1) an organic nitrovasodilator that donates nitric oxide, and 2) a pyrrolidine nitroxide that acts as a trifunctional degradation catalyst of reactive oxygen species. In rats subjected to renal ischemia/reperfusion injury (RIRI), IV administration of R-100 prior to reperfusion reduced the 6 h elevations in serum creatinine, serum NGAL, tissue myeloperoxidase, and histologic score by 75-90% (p<10-14) and restored the reduction of creatinine clearance from 90% to 50% (p<0.01). In a murine RIRI model, 24 h creatinine elevations were entirely eliminated by a single dose of R-100 prior to reperfusion (p<0.01).
Aim #1 : Establish the pharmacodynamic (PD) profile of R-100 in models of CIN in healthy and diabetic rodents under conditions of normal hydration and aggressive volume loading Rats will be subjected to dehydration, prostaglandin synthetase inhibition, and an IV challenge of CM. A sham injury group will be compared to treatment of CM-challenged healthy rats with 3 dose levels of IV R-100, N-acetyl-cysteine (NAC), or vehicle control initiated 10 min before CM administration and continued for 48 h. Rats will then be evaluated at 48 h for renal function (and parameters reflecting renal injury, including protein release into the blood (NGAL, KIM-1), pro-inflammatory transcription factor expression (cytoplasmic I?B? degradation, nuclear p65 translocation), histologic damage, and nuclear damage and DNA repair (PARP activation and nitrosative stress as noted by poly(ADP-ribose) and 3-nitrotyrosine (3-NT) tissue immunoreactivity). In order to better model the patient population at greatest risk of CIN, the optimal dose of R-100 will then be further evaluated, using the same experimental approach and design as before, but in rats previously rendered diabetic 2 weeks earlier by injection of streptozotocin (STZ). Finally, we will investigate whether further benefit may be obtained in the diabetic setting by combining the administration of R-100 with aggressive volume resuscitation.
Aim #2 : Establish the pharmacokinetics (PK) of R-100 in a rodent model of CIN We will carry out PK studies in rodents exposed to the same conditions utilized to generate CIN as in Aim #1. A full PK profile will be generated, to define plasma half-life, clearance, and volume of distribution. The exposure to cumulative plasma concentrations of R-100 and the renal tissue concentration of R-100 will be correlated with the morphologic, immunologic, and functional endpoints detailed in Aim #1, in order to construct a PD profile relating drug exposure to effect. The proposed studies will provide a rational foundation for advanced commercial development of R-100, with the intent that this product will serve as first-line prophylaxis in high-risk diabeic patients undergoing CM injection.
Radiocontrast imaging is an invaluable and frequently used diagnostic modality for but its use is complicated by the subsequent development of kidney injury, often to the extent of requiring dialysis, particularly in populations at greatest risk, suh as the elderly, diabetic, and those with preexisting renal impairment. There are no approved pharmaceutical therapies to prevent this complication. We are developing a novel prophylactic agent that protects the kidney from radiocontrast administration by directly protecting kidney cells from injury. We now propose to test this agent in a clinically-relevant small animal model of radiocontrast-induced kidney failure.