[Clinical application of cyclosporin A].
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Biomedical subjects
Publications and source records attributed to M Monden.
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The protective effect of prostaglandin I2 (PGI2) on ischemia-induced liver cell injury was investigated during 60-min, 75-min, and 90-min liver ischemia. Vehicle-treated rats tolerated the 75-min hepatic ischemia poorly. Only 25% of the rats in this group survived more than 7 days. However, the survival rate of PGI2-treated rats (350 ng/kg/min) significantly improved to 67%. Liver cell organelles were well-preserved by the PGI2 treatment. Adenosine triphosphate levels in the liver of the PGI2-treated rats were significantly higher than those of vehicle-treated rats at 60 min of reoxygenation following 75-min ischemia. Cyclic 3'-5' adenosine monophosphate levels markedly increased during 60-min PGI2 infusion. Cyclic 3'-5' guanosine monophosphate levels also significantly increased during the PGI2 infusion and were still higher than those of vehicle-treated rats at the end of the 75-min ischemia. Although the exact cytoprotective mechanism of PGI2 at the cellular level is still unclear, our results demonstrate that elevated ATP and cyclic nucleotides levels play an important role in liver cell preservation during ischemia.
To clarify whether the reactivity of A cells is regulated by B cell function in the pancreas, plasma glucagon (IRG) responses to insulin-induced hypoglycemia and to arginine infusion were evaluated in streptozotocin (STZ; total 40 mg/kg) treated and control dogs. There was no significant rise in plasma IRG levels during the insulin-induced hypoglycemia in the STZ-treated dogs. In contrast, arginine enhanced the IRG secretion from the pancreas to a similar extent in the two groups. This was deduced from the difference between IRG levels in the pancreaticoduodenal and peripheral veins. Neither intravenous glucose nor arginine infusion resulted in a significant rise in plasma insulin (IRI) levels in the STZ-treated dogs. IRI content in the pancreas of STZ-treated dogs was significantly reduced to 5 percent below the levels in the control dogs. The IRG content for control and STZ-treated dogs did not differ. These results indicate that while the responsiveness of A cells to hypoglycemia may depend on the secretory capacity of B cells, such is not the case with arginine.
Transcatheter arterial chemo-embolization (chemo-embolization) for treatment of unresectable liver cell cancer has now been widely used. Histological appraisal of chemo-embolization had been reported by us and many of cancers thus treated fell into complete necrosis. The present report deals with histological examination on 14 resected specimen of hepatocellular cancer in order to clarify the prevention from intrahepatic spread and therefore to elucidate the justification of preoperative chemo-embolization. One year actuarial survival rate of chemo-embolization followed by hepatic resection was 83%, while that of hepatic resection was 46% and that of chemo-embolization was 59%. Capsular invasion was observed in 83% of cases, but complete necrosis of the capsular invasion was seen in 60% of cases. Eighty-three percent of small cancer, less than 5 cm in diameter, showed completed necrosis of the capsular invasion. This necrotizing effect is beneficial for prevention from the recurrence of the resected stump when local excision is underwent in high risk patients. But once the bulky tumor emboli embedded and grew extensively in the portal vein, they could not be erased .
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In the present study we examined the effect of a recently isolated hexacyclodepsipeptide, Cyclomunine (Servier, France), on certain parameters which assess cellular and humoral immunity in the rat and dog. Our data establish Cyclomunine as a potent in vitro inhibitor of 3H-thymidine incorporation by lymphocytes. The concentrations of Cyclomunine required to abrogate mitogen or allogeneic lymphocyte stimulated 3H-thymidine incorporation was greater in the dog than in the rat, 15 micrograms/ml versus 10 micrograms/ml, respectively, to achieve greater than 99% inhibition. Little cytotoxicity was noted at concentrations below 25 micrograms/ml. Oral administration of Cyclomunine to rats (50 mg/kg dissolved in corn oil) did not significantly alter white blood cell count, lymphocyte-polymorphonuclear cell differential, body weight, or histological architecture of the liver, spleen, lymph node or kidney. Our results show that in vitro, Cyclomunine is highly effective in suppressing lymphocyte proliferation. In vivo, Cyclomunine appears to have little myelosuppressive effect a property shared with Cyclosporin A. Cyclomunine may hold promise as a clinically useful immunosuppressive agent.
Orthotopic liver transplantations were performed by one team in 18 dogs using a cuff method to anastomose the portal vein, the suprahepatic vena cava and the infrahepatic vena cava without external or internal shunts. Total and warm ischemic times of donor liver averaged 124 and 32 minutes, respectively. The average occlusion time of the portal vein and the infrahepatic vena cava were 9.7 and 13.9 minutes, respectively. During this time, uncontrolled hypotension, petechiae or hemorrhagic enterogastritis did not develop. Sixteen of 18 dogs survived more than five days, and five dogs lived more than three weeks. The cause of death was not related to the cuff method in any instance. This approach proved to be a technically simple and satisfactory procedure.
Canine livers were preserved by simple hypothermic storage using modified Sacks' solution and prostacyclin. Orthotopic liver transplantation was then carried out. Five of six and three of five livers preserved for 24 and 48 hours, respectively, were able to sustain life for more than five days.
Antilymphocyte serum (ALS) was raised in rabbits immunized by administration of lymphoid cells from Sprague-Dawley (SpD) rats. The ALS was rendered specific for the SpD strain by complete absorption by Wistar rat lymphoid cells. The specificity was considered to be predominantly directed to SpD Ir gene-associated (Ia) antigens, since absorption by SpD erythrocytes failed to abolish lymphocytotoxic activities. Alloantibody production by Wistar rats sensitized with SpD spleen cells was completely inhibited by simultaneous injections of SpD-specific ALS. This effect was specific as normal alloantibody production occurred when Wistar rats were immunized with ACI cells, as a third party. Although this ALS exhibited restricted enhancing ability on skin allograft survival, it was capable of significantly prolonging the survival of heart allografts from SpD to Wistar rats. The ALS showed blocking activities on mixed lymphocyte culture (MLC) but had no effect on cell-mediated cytotoxicity (CMC). The enhancing activity was thus considered to be mediated by an afferent blockage of immune responses.
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