Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury.
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 microg/mL-Recipient: Placebo); Group 3 (Organ storage/flush: 5 microg/mL-Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 microg/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.
Baskin-Bey
E S
ES
William J. von Liebig Transplant Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Washburn
K
K
Feng
S
S
Oltersdorf
T
T
Shapiro
D
D
Huyghe
Mira
M
Burgart
L
L
Garrity-Park
M
M
van Vilsteren
F G I
FG
Oliver
L K
LK
Rosen
C B
CB
Gores
G J
GJ
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D004796:Clinical Enzyme Tests; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010421:Pentanoic Acids / Q000008:administration & dosage*; D020011:Protective Agents / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control; D000637:Transaminases / Q000032:analysis
C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids; D020011:Protective Agents; D000637:Transaminases