抄録
The efficacy of AZ 1355 (300mg/kg, po) was compared with clofibrate (CPIB) using Triton hyperlipidemic mice. AZ 1355 reduced serum cholesterol and the magnitude of reduction was similar to that of CPIB.
AZ 1355 (50, 100mg/kg) and CPIB (100mg/kg) were given orally for 4 weeks to rats fed on either CE-2 or a lipid-rich diet. When the rats were fed on CE-2, CPIB reduced the serum cholesterol and triglyceride but AZ 1355 did not. But with the lipid-rich diet AZ 1355 was more effective than CPIB.
Both agents (100mg/kg) were given orally for 4 weeks to golden hamsters fed on either CE-2 or a 10% butter diet. With both diets AZ 1355 reduced the serum triglyceride more than CPIB did. The dose-response relationship of AZ 1355 was examined using hamsters. The serum triglyceride was reduced by doses above 25mg/kg. In addition, the highest dose (100mg/kg) elevated HDL-cholesterol.
In the rabbits fed on 1% cholesterol diet for 12 weeks, AZ 1355 at a dose of 80mg/kg inhibited an elevation of the serum cholesterol.
The effects of AZ 1355 and its major metabolite, AZ 1355F (having hypolipidemic activity weaker than that of AZ 1355) on platelet aggregation in vitro, arachidonic acid (AA) shock in rats and the formation of Prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) were studied. PGI2 and TXA2 were determined as 6-ketoPGF1α and TXB2, respectively.
AZ 1355 above 15μM partially prevented the aggregation induced by collagen or AA and completely inhibited the aggregation above 250μM. AZ 1355 weakly inhibited the aggregation.
AZ 1355 (po) and AZ 1355F (po, iv) dosedependently protected the rats from stroke death induced by AA. But the protective activity of both agents was weaker than that of aspirin.
AA is converted to TXB2 as the major product and 6-ketoPGF1α as the minor product, when incubated a mixture of rat platelets and swine aortic microsomes. AZ 1355 inhibited the TXB2 synthesis at concentration higher 13μM, but 6-ketoPGF1α formation was unaltered. AZ 1355F also inhibited TXB2 synthesis, but accelerated 6-ketoPGF1α production. AZ 1355 and AZ 1355F exerted activities similar to aspirin and imidazole, respectively. The properties of AZ 1355F concerning TXB2 and 6-ketoPGF1 are favorable as an anti-atherosclerotic agent.
