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Prostaglandin E1 incorporated in lipid microspheres (lipo-PGE1) was evaluated following intravenous administration as an inhibitor of ADP-induced thrombus growth rate and as a thrombus disaggregating agent following vascular damage in the microcirculation of the hamster cheek pouch. The drug was shown to be significantly more active and longer acting than PGE1 in the first experiment. Following vascular damage lipo-PGE1 was very efficacious as a thrombus disaggregating agent and was significantly more effective when infused after, rather than before, vascular damage. These data suggested that the drug might be targeted to the site of damage. When incorporated in lipid microspheres, PGE1 appeared to be more stable, longer acting and more efficacious than PGE1 alone.

Isocarbacyclin, (+)-9(O)-methano-delta 6 (9 alpha)-PGI1 (TEI 7165) and its methyl ester (TEI 9090) were incorporated in lipid microspheres (LM) with a diameter of 0.2 micron, in an attempt to increase their efficacy, possibly by way of targeting the drugs to the site of vascular damage. When the two LM-preparations were incubated in 2% bovine serum albumin solution, it was shown that TEI 7165 was released rapidly from LM, while the release of TEI 9090 was slow. Thus, TEI 9090 in LM, injected intravenously, may not be released largely in plasma before the distribution of LM to the target sites. The antithrombotic activity of the LM preparation of TEI 9090 was then compared with that of TEI 9090 as such in the hamster cheek pouch model. It was found that TEI 9090 incorporated in LM was more than 500 times more potent as an inhibitor of ADP-induced thrombus growth. These data suggest that prostacyclin analogues incorporated in LM may be used safely as potent antithrombotic agents in the clinical application.

Sodium dl-4-[1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro- 2-hydroxy-1-[(3S,4RS)-3-hydroxy-4-methyl-oct-6- yne-(E)-1-enyl]-5-cyclopenta[b]benzofuranyl]butyrate (TRK-100) is a stable analogue of prostacyclin (epoprostenol, PGI2). The drug was shown to be a potent inhibitor of platelet aggregation in vitro, induced by adenosine diphosphate (ADP), using platelet-rich plasma (PRP) from human and several animal species. The inhibitory activity of TRK-100 using human platelets was half that of PGI2 and eight times that of PGE1. There was a marked tendency for platelet clumps to disaggregate following secondary aggregation in the presence of TRK-100 at final concentrations higher than 1 ng/ml. This activity was similar to PGI2 and more than 30 times that of PGE1. TRK-100 was shown to induce the disaggregation of a pre-existing thrombus in the microcirculation of the hamster cheek pouch. A dose-dependent response was obtained following oral administration of the drug at levels of 50-200 micrograms/kg. Optimal activity was observed 30-60 min after dosing and activity was sustained throughout the experimental period. TRK-100 was more active than PGE1 in the test system and appeared to be of a similar potency to PGI2. Since this drug is stable, orally active and without the hypotensive activity of PGI2, it is considered to be a potentially useful agent for antithrombotic therapy.

1-(6-Methoxy-4-quinolyl)-3-(3-vinyl-4-piperidyl)-1-propanone (viquidil, Desclidium) when administered parenterally was a potent inhibitor of thrombus formation in the microvasculature of the hamster cheek pouch. The drug was active at a minimum dose level of approximately 2.5 X 10(-4) mg/kg and appeared to be more potent than papaverine in the same test system. Papaverine was shown to be toxic at higher dose levels with intermittent vasodilatation and haemorrhage. Viquidil, however, appeared to be approximately twice as potent as papaverine and was apparently without toxic side-effects.

1-(7-Theophyllinyl)-2-ethyl-[2-(p-chlorophenoxy)-isobutyrate] (etofylline clofibrate, theofibrate, Duolip) was shown to possess substantial thrombus disaggregating activity in the microcirculation of the hamster cheek pouch following minor vascular damage by electrical stimulation. At 12 mg/kg p.o. the moderate effect of a single dose (12% reduction in disaggregation time) increased to a maximum reduction of 31 and 43% following 5 and 7 consecutive daily applications, respectively. Etofylline clofibrate was more active than other drugs already tested in this test system, but less than the prostaglandins PGE1 and PGI2. The antithrombotic efficacy found in both in vivo tests, thrombus formation and disaggregation, suggests as mode of action of etofylline clofibrate an agonistic interaction with intimal PGI2. This could be by enhancement of its production or by a synergistic interaction with this prostanoid, rather than inhibition of thromboxane A2 synthetase.