Platelet actions of stable carbocyclic analogues of prostacyclin

Abstract

The mechanisms underlying peripheral vasodilation, as demonstrated by facial flushing or increased blood flow to the extremities in the absence of a marked fall in blood pressure, as seen with prostacyclin, 9β-methyl-carbacyclin, or other analogues, warrant further investigation and point to potential therapeutic utilities of these compounds, including the treatment of peripheral vascular diseases. Although the carbacyclin analogues described thus far offer the advantage of being more chemically stable than prostacyclin, the development of well-tolerated, orally effective compounds of long duration of activity for use in man is still awaited. Although there is some evidence from experimental studies of a change in selectivity away from the vasodepressor actions of prostacyclin, there is as yet no stable analogue that has a highly selective action on platelets in vivo. Claims for such selectivity in an analogue will require support from rigorous comparisons with prostacyclin in several experimental preparations in different species. The definitive separation of the platelet and cardiovascular properties in further analogues, if demonstrated in man, will have extensive therapeutic possibilities and will also allow a closer analysis of the mechanism of action of prostacyclin in such clinical situations as peripheral vascular disease. The rational design of the pharmacologic profile of such analogues will, however, depend on the clinical experience gained with prostacyclin itself.