TY - JOUR
T1 - Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury
AU - Baskin-Bey, E. S.
AU - Washburn, K.
AU - Feng, S.
AU - Oltersdorf, T.
AU - Shapiro, D.
AU - Huyghe, Mi Ra
AU - Burgart, L.
AU - Garrity-Park, M.
AU - Van Vilsteren, F. G.I.
AU - Oliver, L. K.
AU - Rosen, C. B.
AU - Gores, G. J.
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Clinical trial
KW - Cold ischemia/warm reperfusion injury
KW - Neutrophil infiltration
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UR - http://www.scopus.com/inward/citedby.url?scp=33845654847&partnerID=8YFLogxK
U2 - 10.1111/j.1600-6143.2006.01595.x
DO - 10.1111/j.1600-6143.2006.01595.x
M3 - Article
C2 - 17227570
AN - SCOPUS:33845654847
SN - 1600-6135
VL - 7
SP - 218
EP - 225
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 1
ER -