Ataprost

The effect of OPC-6535 was investigated on graft livers subjected to warm ischemia during swine liver transplantation under condition that model liver transplantation from a non-heart-beating-donor.Subjecting liver grafts to warm ischemia for 30 min results in the disappearance of thrombomodulin from sinusoidal endothelial cells by 2 h after reperfusion, and this disappearance was associated with accumulation of leukocytes and severe congestion in sinusoidal spaces.Combined administration of OP-41483 and OPC-6535 before the warm ischemic insult and after reperfusion had a protective effect, as demonstrated by maintained expression of thrombomodulin after reperfusion, a marked reduction of leukocyte accumulation and congestion, diminished postoperative hyperbilirubinemia, and low mortality.

Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage.

Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed.

Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension.

These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.