Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury

E. S. Baskin-Bey, K. Washburn, S. Feng, T. Oltersdorf, D. Shapiro, Mi Ra Huyghe, L. Burgart, M. Garrity-Park, F. G.I. Van Vilsteren, L. K. Oliver, C. B. Rosen, G. J. Gores

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. The aim of the current study was to assess the utility of the pan-caspase inhibitor IDN-6556 on CI/WR injury during human liver transplantation. This report is a post hoc analysis of a Phase II, multi-center, randomized, placebo-controlled, double-blinded, parallel group study. Subjects were assigned to four treatment groups: Group 1 (Organ storage/flush: Placebo - Recipient: Placebo); Group 2 (Organ storage/flush: 15 μg/mL - Recipient: Placebo); Group 3 (Organ storage/flush: 5 μg/mL - Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 μg/mL - Recipient: 0.5 mg/kg). Liver cell apoptosis was assessed by serum concentrations of the apoptosis-associated CK18Asp396 ('M30') neo-epitope, TUNEL assay and caspase 3/7 immunohistochemistry. Liver injury was assessed by serum AST/ALT determinations. Serum markers of liver cell apoptosis were reduced in all groups receiving drug as compared to placebo. However, TUNEL, caspase 3/7 positive cells and serum AST/ALT levels were only consistently reduced in Group 2 (drug exposed to organ only). This reduction in serum transaminases was significant and observed across the study. In conclusion, IDN-6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR-mediated apoptosis and injury. However, larger studies are required to confirm these observations.

Original languageEnglish (US)
Pages (from-to)218-225
Number of pages8
JournalAmerican Journal of Transplantation
Volume7
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Apoptosis
  • Clinical trial
  • Cold ischemia/warm reperfusion injury
  • Neutrophil infiltration

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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    Baskin-Bey, E. S., Washburn, K., Feng, S., Oltersdorf, T., Shapiro, D., Huyghe, M. R., Burgart, L., Garrity-Park, M., Van Vilsteren, F. G. I., Oliver, L. K., Rosen, C. B., & Gores, G. J. (2007). Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. American Journal of Transplantation, 7(1), 218-225. https://doi.org/10.1111/j.1600-6143.2006.01595.x