Significant Reduction of Radiation-Induced Death in Mice Treated with PrC-210 and G-CSF after Irradiation.

The search for single or combined radiation countermeasures that mitigate the development of Acute Radiation Syndrome (ARS) after radiation exposure remains a prominent goal of the U.S. government. This study was undertaken to determine whether PrC-210 and G-CSF, when administered 24-48 h postirradiation, would confer an additive or synergistic survival benefit and mitigate ARS in mice that had received an otherwise 96% lethal radiation dose. Our results show that optimum systemic doses of PrC-210 and G-CSF, when administered 24 h or later after a 96% lethal dose of whole-body irradiation, conferred: 1. strong individual survival benefits (PrC-210 44%, P = 0.003), (G-CSF 48%, P = 0.0002), 2. a profound combined 85% survival benefit (P < 0.0001) when administered together, and on day 14 postirradiation, 3. peripheral white blood cell/lymphocyte counts equal to unirradiated controls, 4. dense bone marrow cell density (>65% of unirradiated controls), 5. jejunal villi density that equaled 90% of unirradiated controls, and 6. spleen weights that equaled 93% of unirradiated controls. Our results show that PrC-210 and G-CSF given together 24 h after irradiation confer strong additive efficacy by protecting the immune system, and enabling recovery of the bone marrow, and they work synergistically to enable recovery of peripheral white blood cells in circulating blood.

Significant Reduction of Total-Body Irradiation-Induced Death in Mice Treated with PrC-210 24 Hours Postirradiation.

The search for radiation countermeasures that can serve as: i. a pre-exposure agent to protect against subsequent irradiation, and/or ii. a post-exposure agent to mitigate the development of Acute Radiation Syndrome after radiation exposure, remains a prominent goal of the U.S. Government. This study was undertaken to determine whether PrC-210, when administered once, 24 h postirradiation, would provide a survival benefit and would mitigate Acute Radiation Syndrome in mice that had received an otherwise 95-100% lethal radiation dose. Our results show that a single intraperitoneal dose of PrC-210 (0.3-0.4 MTD, 151-201 ug/gm body weight) administered 24 h postirradiation, conferred: i. a 45% survival advantage (P = 0.002) in outbred ICR mice and a 25% survival advantage (P = 0.037) in inbred C57Bl/6 mice, ii. a significant increase in body weight in surviving mice (P = 0.012), iii. a discernible protection of intestinal structure by MRI imaging of live mice, iv. visibly denser jejunal villi and surface epithelium and v. visible bone marrow population in PrC-210-treated mice versus saline controls. The ability of PrC-210 to suppress 100% of radiation-induced death when administered minutes before irradiation, or roughly half of this effect (45%) when administered 24 h postirradiation is noteworthy. Determining the multiple paths by which PrC-210 protection is conferred is a process; the results in this report showing protection of two of the major systems central to Acute Radiation Syndrome damage, is a good first step. This was the first study of PrC-210 administered postirradiation; it conferred substantial survival benefit and suppression of Acute Radiation Syndrome. This outcome supports the continued development of PrC-210 to protect humans exposed to ionizing radiation.

Suppression of Inflammation-Associated Kidney Damage Post-Transplant Using the New PrC-210 Free Radical Scavenger in Rats.

Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process-from organ donation, through transportation, re-implantation and the post-operative inflammation-to minimize acute and chronic rejection.