thromboxane-a2 and bisantrene

Bisantrene, (9,10-anthracenedicarboxaldehyde bis [(4,5-dihydro-1H-imidazol-2yl)hydrazone] dihydrochloride) is one of a series of anthracene dicarboxaldehyde compounds in Phase II trials. Preliminary studies suggested that bisantrene has anti-platelet activity. Therefore, in vitro studies of its effects on platelets were undertaken. Bisantrene in clinically attainable concentrations of 0.625 - 10 microM, caused a 95 +/- 1% decrease in maximal platelet aggregation to collagen (1 microgram/ml), and epinephrine (5-40 microM) and 90 +/- 10% inhibition of arachidonic acid (50 micrograms/ml) induced aggregation. Collagen induced platelet shape change was not affected. Aggregation to calcium ionophore A23187 was inhibited by 10-30%. No effect on ADP induced aggregation was seen at clinically relevant bisantrene concentrations. This inhibition was time dependent, reaching a maximum when platelets were preincubated with bisantrene for 10 minutes before exposure to agonist. Inhibition persisted after bisantrene was removed by washing. To determine the mechanism of platelet inhibition, platelet prostaglandin metabolism, oxygen consumption and release reaction were measured. In the presence of drug: normal cyclooxygenase activity was demonstrated by O2 consumption studies and normal secondary wave ADP (3.2 microM) aggregation; lipoxygenase activity, by O2 consumption was also normal. There was 30-50% inhibition of thromboxane A2 synthesis induced by arachidonic acid or collagen; ADP, collagen and AA induced release of serotonin was decreased by 30-60% but was never abolished. No effect on basal platelet cAMP levels nor additive effect on PGE1 induced elevation of platelet cAMP was detectable. These data demonstrate that bisantrene has potent antiplatelet activity probably mediated by several different mechanisms. The inhibition may have important clinical and theoretical consequences.

Topics: Anthracenes; Blood Platelets; Cyclic AMP; Humans; Oxygen Consumption; Platelet Aggregation; Secretory Rate; Serotonin; Thromboxane A2