From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents

Abstract

The potential consequences of a major radiological event are not only large-scale external radiation exposure of the population, but also uncontrolled dissemination of, and internal contamination with, radionuclides. When planning an emergency response to radiological and nuclear incidents, one must consider the need for not only post-exposure treatment for contaminated individuals, but also prophylactic measures to protect the workforce facing contaminated areas and patients in the aftermath of such events. In addition to meeting the desired criteria for post-exposure treatments such as safety, ease of administration, and broad-spectrum efficacy against multiple radionuclides and levels of challenge, ideal prophylactic countermeasures must include rapid onset; induce minimal to no performance-decrementing side effects; be compatible with current military Chemical, Biological, Radiological, Nuclear, and Explosive countermeasures; and require minimal logistical burdens. Hydroxypyridinone-based actinide decorporation agents have shown the most promise as decorporation strategies for various radionuclides of concern, including the actinides plutonium and americium. The studies presented here probe the extent of plutonium decorporation efficacy for two chelating agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), from early pre-exposure time points to a delay of up to 7 days in parenteral or oral treatment administration, i.e., well beyond the first hours of emergency response. Despite delayed treatment after a contamination event, both ligands clearly enhanced plutonium elimination through the investigated 7-day post-treatment period. In addition, a remarkable prophylactic efficacy was revealed for 3,4,3-LI(1,2-HOPO) with treatment as early as 48 hours before the plutonium challenge. This work provides new perspectives in the indication and use of experimental actinide decorporation treatments.

Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents

“…Deposition in the skeleton is the ultimate fate of a substantial fraction of the retained contaminant. However, consistent with previous studies on the decorporation of other f-elements such as 238 Pu 4+ 21 , 22 , 241 Am 3+ 19 , or 152 Eu 3+ 7 , HOPO is more effective than DTPA at reducing the overall skeletal content of the heavy metal, even when administered up to 48 h post-contamination. In comparison, administration of DTPA only 1 h post-contamination cannot prevent Gd accumulation in the skeleton as efficiently.…”

“…These simulations provide excellent rationale for the elevated levels of urinary Zn (zincuria) that have been observed in both human and animal studies 13 , given that our findings indicate urinary clearance of the M n + -DTPA complexes 7 , 19 , 21 , 22 . It then seems likely that Zn transmetallation of GBCAs in the kidneys could be implicated as an underlying cause of NSF.…”

“…This octadentate ligand binds metal ions through the eight oxygen donor atoms of its four bidentate binding units, and is ideally suited to the larger f-block cations, while disfavoring complexation of transition metals and Group I or II ions ubiquitous in biology. In fact, the maximum tolerated dose of HOPO in rats was determined to be in excess of 100 μ mol kg −1 d −1 over 28 days of daily oral administration 9 , 19 , 22 . The higher acidity of HOPO (highest p K a = 6.6) compared to DTPA (10.4) or DOTA (11.2) makes it more resistant to intrinsic competition between ligand protonation and metal binding at low concentrations.…”

Toxic heavy metal – Pb, Cd, Sn – complexation by the octadentate hydroxypyridinonate ligand archetype 3,4,3-LI(1,2-HOPO)

“…The methods of sample collection, preparation, radioactivity measurements, and data reduction have been published previously. [27][28][29][30] The experimental data are reported as radionuclide fractions, expressed as percent of recovered 210 Pb (%RD), and values are arithmetic means AE SD. When comparing values between groups, the term ''significant'' is used in the statistical sense, indicating p o 0.05 by one-way analysis of variance (ANOVA) followed by a post hoc Dunnett's multiple-comparison test to compare groups of treated to the control group that was administered saline.…”

Multiple Patients With Burn Injury Induced by a Chemical Explosion Managed by Physician-Staffed Helicopters

“…The fire department initially believed they were responding to a fire incident and did not recognize the incident as a CBRNE incident. 7,8 In CBRNE incidents, it is standard for the first responders to wear special personal protect equipment, such as a positive-pressure self-contained breathing apparatus with a fully encapsulating protective suit, and to detect or measure chemical, biological, radioactive, and/or explosive materials and then establish zones. 7,8 Because some types of terrorist attacks are more likely to be unsuspected or covert than others, a high suspicion for terrorism is important.…”