CLINICAL-EVALUATION ON COMBINED ADMINISTRATION OF ORAL PROSTACYCLIN ANALOG BERAPROST AND PHOSPHODIESTERASE INHIBITOR CILOSTAZOL

Among various oral antiplatelets, a combination of a novel prostacycli n analogue beraprost (BPT) and a potent phosphodiesterase inhibitor ci lostazol (CLZ) may result in untoward clinical effects due to possible synergistic elevation of intracellular cAMP (cyclic adenosine 3',5'-m onophosphate). Thereby, a clinical study of the combined administratio n of the two agents was attempted. Twelve healthy volunteers were assi gned to take BPT/CLZ in the following schedule; BPT: 40 mu g at day 1 and 120 mu g t.i.d. from day 7 to 14, CLZ: 200 mg t.i.d. from day 3 to 14. At various time intervals, physical examination and blood collect ion for ex vivo platelet aggregation and determination of intraplatele t cAMP were performed. Throughout the observation period, no significa nt alteration in vital signs was observed. Seven out of 12 subjects ex perienced headache of a short duration accompanying facial flush in on e and nausea in one, especially after ingestion of CLZ. All of these s ymptoms, probably caused by the vasodilating effect of the two agents, were of mild degree and no special treatment was required. Intraplate let cAMP content was gradually but significantly increased to 9.84+/-4 .59 pmol per 10(9) platelets at day 14 in comparison with the initial value (6.87+/-2.25 pmol). The platelet aggregability was significantly suppressed at various time intervals but no additive or synergistic i nhibitory effect by the combined administration was noted. In conclusi on, the combined administration of BPT/CLZ is safe at doses used in th e study, though the beneficial clinical effect of the combined adminis tration has yet to be elucidated.