Antiplatelet effects of combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia

Antiplatelet effects of combination therapy with aspirin and ticlopidine were investigated in comparison with single aspirin or ticlopidine therapy in 62 patients with cerebral thrombosis or transient ischemic attack. The 14, 21 and 27 patients were given orally daily aspirin 300mg, ticlopidine 200mg and aspirin 81mg with ticlopidine 100mg, respectively. Various platelet function tests were performed before and a week after medication. They included platelet aggregation (PA) to adenosine diphosphate (ADP), arachidonic acid (AA) and platelet activating factor (PAF) with turbidimetry, plasma beta-thromboglobulin (beta TG), platelet factor 4(PF4), thromboxane B2(TXB2) and 6keto-prostaglandin-F1 alpha(6keto PGF1 alpha) with radioimmunoassay, bleeding time with Simplate device, and platelet survival and lysis with Indium-111-tropolone-labelled platelets. Aspirin inhibited PA to ADP and AA but not to PAF, while ticlopidine inhibited PA to ADP and PAF but not to AA. In contrast, aspirin with ticlopidine inhibited PA to all of these agonists despite their smaller doses used. Aspirin reduced plasma TXB2 but not beta TG or PF4, while ticlopidine reduced beta TG and PF4 but not TXB2. On the contrary, aspirin with ticlopidine reduced TXB2 as well as beta TG and PF4. 6keto PGF1 alpha tended to be reduced by aspirin 300mg alone but not by ticlopidine with or without aspirin 81mg. Bleeding time was significantly prolonged by aspirin or ticlopidine alone, although most prolongation was produced by combination of aspirin and ticlopidine. Platelet survival and lysis remained unaltered in 4 patients treated with aspirin or ticlopidine alone, whereas platelet survival was prolonged and platelet lysis was reduced in 4 patients treated with both aspirin and ticlopidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ticlopidine selectively inhibits human platelet responses to adenosine diphosphate.

Platelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrinogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPII b/III a monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their Kd were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.     

Ex vivo response to aspirin differs in stroke patients with single or recurrent events: a pilot study

The dose of aspirin for secondary stroke prevention and the clinical meaning of ex vivo platelet abnormalities are debated. We assessed prospectively 39 noncardioembolic stroke patients in which 300 mg/day aspirin had proved effective (n=24) or ineffective (n=15) to prevent recurrent ischemic events. We evaluated platelet aggregation induced by arachidonic acid, adenosine diphosphate and epinephrine, and the sensitivity of platelets to increasing concentrations of the synthetic thromboxane mimetic U46619. Aggregation studies were repeated while subjects received 300 (study phase 1), and 600 (study phase 2) mg/day aspirin, respectively. Overall, arachidonic acid-induced platelet aggregation was less effectively inhibited during study phase 1 compared to phase 2. Arachidonic acid and epinephrine promoted a stronger platelet aggregation in aspirin nonresponders than in aspirin responders while taking 300 mg/day aspirin. On the other hand, 600 mg/day effectively inhibited platelet function in both clinical groups. A lower sensitivity to thromboxane receptors was also found during phase 1 of the study, although the response was similar between aspirin responders and nonresponders. This pilot study suggests that 300 mg/day aspirin is less effective than 600 mg/day to block the cyclooxygenase pathway in noncardioembolic stroke and, incomplete cyclooxygenase inhibition is associated with recurrent thromboembolic events despite adequate aspirin compliance. It is likely that patients could receive a more efficacious stroke prevention if the dose of aspirin is tailored to individual needs as reflected by laboratory findings.     

Effect of berberine on arachidonic acid metabolism in rabbit platelets and endothelial cells

The antiplatelet effect of berberine has been demonstrated in both laboratory research and clinical trials. In the present study, we show ex vivo that berberine significantly inhibited rabbit platelet aggregation induced by adenosine diphosphate, arachidonic acid, collagen or calcium ionophore A23187. The most potent inhibition was observed in collagen-induced platelet aggregation. Using radioimmunoassay, we show in vitro that berberine significantly inhibited synthesis of thromboxane A(2) in rabbit platelets induced by adenosine diphosphate, arachidonic acid or collagen in which collagen-induced thromboxane A(2) synthesis was also most potently inhibited. In our in vivo study using radioimmunoassay, the plasma prostacyclin level was reduced by 34.6% during a 30-min period after intravenous administration of 50 mg/kg of berberine. These results suggest that berberine might inhibit arachidonic acid metabolism in rabbit platelets and endothelial cells at two or more sites: cyclooxygenase in the arachidonic acid cascade and possibly the enzyme(s) for arachidonic acid liberation from membrane phospholipid(s).     

小剂量阿司匹林和噻氯匹定合用在缺血性脑血管病中抗聚效果的观察

目的 :观察阿司匹林 (ASA)和噻氯匹定 (TIC)合用对ICVD患者血小板聚集功能的影响。方法 :用花生四烯酸 (AA)、二磷酸腺苷 (ADP)、肾上腺素 (EPN)和胶原 (COL)做诱导剂检测ICVD患者合用ASA +TIC组与单用TIC或ASA组的血小板聚集率。结果 :合用组对EPN、COL、AA诱导聚集的抑制与TIC组比较差异有显著性 ,对ADP诱导聚集的抑制与ASA组比较差异有显著性 ,P均 <0 0 1。结论 :两者合用后的抗聚效果有相加及协同作用。对需加强抗聚的患者 ,在监测下小剂量的ASA和TIC合用有较好的价 /效比 ,可做为高危ICVD二级预防的一种选择。     

Inhibitory effect of vitamin E (alpha-tocopherol) on spontaneous platelet aggregation in whole blood

Vitamin E (D-alpha-tocopherol) inhibited spontaneous human platelet aggregation in whole blood in the 20-200 micrograms/ml range. When alpha-tocopherol (20 micrograms/ml) and aspirin (0.5 mM), or alpha-tocopherol and the mixture of phosphocreatine (1.5 mM) and creatine phosphokinase (50 U/ml) (CP/CPK) were added to this reaction system, a synergic inhibitory effect on aggregation was observed. On the other hand, when both alpha-tocopherol and the specific inhibitor of platelet activating factor (CV-3988; 0.38 mM) were added to this system, the inhibition was the same as that caused by the addition of CV-3988 alone, suggesting there was no synergism, i.e., that the effect of alpha-tocopherol is related to the inhibition of platelet activating factor (PAF)-induced platelet aggregation in whole blood. However, alpha-tocopherol (20 or 50 micrograms/ml) did not inhibit PAF (10 nM) induced platelet aggregation in platelet rich plasma (PRP). These results suggest that the inhibition of platelet aggregation in whole blood by alpha-tocopherol is due to the inhibition of PAF synthesis, and is unrelated to adenosine diphosphate (ADP) or thromboxane A2.     

Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia

We tested the antiplatelet effects of low-dose aspirin in patients with occlusive cerebrovascular disease, because conventional dosage aspirin inhibits vascular synthesis of prostacyclin at the same time that it inhibits platelets. The effects on platelet function and thromboxane A2 synthesis of 40 mg of aspirin daily or 40 mg aspirin plus dipyridamole were measured in 23 patients starting within a week after the onset of cerebral ischemia. All patients had normal baseline platelet aggregation responses to four stimuli: arachidonate, epinephrine, adenosine diphosphate and collagen. The generation of thromboxane A2 by platelets, measured as serum thromboxane B2, was also normal. After 3 to 7 days of low dose aspirin therapy, platelet aggregation responses were suppressed to the extent observed with higher dosage aspirin. Serotonin release during platelet aggregation was inhibited by more than 95% and thromboxane B2 levels in clotted blood fell by more than 95%. Responses to aspirin treatment were similar in patients with transient ischemic attacks and in those with stroke and were also similar in both sexes. No differences in platelet responses were observed between patients receiving aspirin alone and aspirin plus dipyridamole. Thus 40 mg aspirin daily inhibited platelet responses as effectively as higher doses of aspirin in patients who had recent cerebral ischemia and showed a cumulative antiplatelet effect.     

Inhibition of platelet aggregation in whole blood by dipyridamole and aspirin

We have examined the effects of dipyridamole on platelet aggregation in whole blood both in vitro and after administration to man. The effects of dipyridamole ex vivo were compared with those of aspirin and a combination of dipyridamole and aspirin. In vitro dipyridamole was most effective as an inhibitor of platelet aggregation induced by platelet activating factor (PAF) and low concentrations of arachidonic acid (AA). Its inhibitory effect was always potentiated by adenosine suggesting that its effect on aggregation may be via inhibition of adenosine uptake into blood cells. Ex vivo, dipyridamole, aspirin and the combination of these drugs inhibited the platelet aggregation induced by PAF and AA. Again, adenosine increased the degree of inhibition. These results stress the importance of measuring platelet aggregation in the natural whole blood environment for detection of the inhibitory effects of dipyridamole and suggest a mode of action for the drug.     

Inhibitory effect of vitamin E (α -tocopherol) on spontaneous platelet aggregation in whole blood

Vitamin E (D-α-tocopherol) inhibited spontaneous human platelet aggregation in whole blood in the 20–200 μ g/ml range. When α -tocopherol (20 μ g/ml) and aspirin (0.5 mM), or α -tocopherol and the mixture of phosphocreatine (1.5 mM) and creatine phosphokinase (50 U/ml) (CP/CPK) were added to this reaction system, a synergic inhibitory effect on aggregation was observed. On the other hand, when both α -tocopherol and the specific inhibitor of platelet activating factor (CV-3988 : 0.38 mM) were added to this system, the inhibition was the same as that caused by the addition of CV-3988 alone, suggesting there was no synergism, i.e., that the effect of α -tocopherol is related to the inhibition of platelet activating factor (PAF)-induced platelet aggregation in whole blood. However, α -tocopherol (20 or 50 μ g/ml) did not inhibit PAF (10 nM) induced platelet aggregation in platelet rich plasma (PRP). These results suggest that the inhibition of platelet aggregation in whole blood by α -tocopherol is due to the inhibition of PAF synthesis, and is unrelated to adenosine diphosphate (ADP) or thromboxane A2.     

Effect of increasing doses of aspirin on platelet aggregation among stroke patients

BACKGROUND AND PURPOSE: Aspirin has been shown to reduce the risk of myocardial infarction and stroke. Some investigators believe that low-dose aspirin inhibits platelet aggregation to the same degree as high-dose aspirin. Our study aimed to assess the effect of increasing doses of aspirin on the degree of platelet aggregation induced by collagen and adenosine diphosphate (ADP) among stroke patients. METHODS: Sixteen poststroke patients were prescribed aspirin at daily doses of 40, 80, 160, 325, 650, and 1,300 mg, each dose to be taken for 14 days (total duration 12 weeks). Platelet aggregation studies using 2 microgram/ml collagen and 2 microM ADP were performed on platelet-rich plasma at baseline and on the 14th day of each dose. RESULTS: Platelet aggregation studies using 2 microgram/ml collagen at the start of treatment and at the 14th day of each dose revealed dose-dependent inhibition by aspirin starting at 40 mg/day, but was optimal at 80- 160 mg/day. ADP-induced platelet aggregation inhibition appears to be dose dependent up to 1,300 mg/day. CONCLUSION: Inhibition of collagen-induced platelet aggregation by aspirin appears to be optimal at 80-160 mg/day, while ADP-induced platelet aggregation inhibition by aspirin appears to be dose dependent up to 1,300 mg/day in our poststroke patients, albeit to a less remarkable degree at higher doses.     

Effect of three nonsteroidal anti-inflammatory agents on platelet function and prostaglandin synthesis in vitro

Effects on platelet aggregation in citrated, human, platelet-rich plasma (PRP) of nonsteroidal anti-inflammatory agents naproxen (Nap.), ibuprofen (Ib.) and aspirin (ASA) showed that the second wave of aggregation induced by adenosine diphosphate (ADP) or adrenaline was inhibited by all three drugs whereas the first wave of aggregation was not. Inhibition was dose-dependent and the agents were equipotent. With collagen- induced aggregation the delay-phase was prolonged and there was dose-dependent inhibition of curve height by the three drugs with Ib. being less potent than ASA or Nap. Using washed human platelet lysates, all three drugs were shown to inhibit prostaglandin (PG) synthesis. Inhibition by Nap. and Ib. was competitive in nature while inhibition by ASA was uncompetitive. Nap. and Ib. were more potent than ASA at all concentrations of drug and substrate (arachidonic acid) employed. The anti-platelet effect of these drugs may be due to their ability to inhibit PG synthesis in platelets.     

Evaluation of a porcine model to study in vivo platelet activation

INTRODUCTION: In order to investigate if decompression sickness involves platelet activation an animal model was evaluated. MATERIALS AND METHODS: Twenty-four thiopentone-midazolam-fentanyl-anaesthetized pigs in four groups received 5-min infusions of adenosine diphosphate (25 mg/kg) or platelet activating factor (0.4 microg/kg). Groups 1 and 2 (adenosine diphosphate, n=6 and platelet activating factor, n=6) were studied for 30 min and then sacrificed. Groups 3 and 4 (adenosine diphosphate, n=6 and platelet activating factor, n=6) were sacrificed immediately afterwards to study short-term changes. Haemodynamics, platelet counts and post mortem lung platelet aggregates were registered. Groups 1 and 2 also had indium platelet labelling, lung scintigraphy and platelet accumulation index calculations performed. RESULTS: Adenosine diphosphate induced immediate and more profound transient shocks. Platelet and leukocyte count decreases and occurrences of post mortem lung platelet aggregates were significantly more profound in the 5-min adenosine diphosphate group (Group 3) than in the platelet activating factor group (Group 4). With platelet labelling there were positive platelet accumulation index trends in the 30-min adenosine diphosphate group (Group 1). Adenosine diphosphate also produced platelet aggregation in platelet-rich porcine plasma. Only adenosine diphosphate (an intermediate platelet agonist) showed signs of platelet activation when considering all platelet parameters. The model should be further evaluated with different bolus doses of adenosine diphosphate, but may be used to evaluate if gas bubbles introduced into the circulation (as with decompression sickness), or possibly if clinical drugs, might produce platelet activation in vivo.     

ME3277, a GPIIb/IIIa antagonist reduces cerebral infarction without enhancing intracranial hemorrhage in photothrombotic occlusion of rabbit middle cerebral artery.

GPIIb/IIIa antagonists are expected to have a beneficial effect on acute cerebral infarction, however, the occurrence of intracranial hemorrhage has not been as widely investigated. A rabbit focal thrombotic occlusion model of the middle cerebral artery was established by creating a photochemical reaction between green light and Rose Bengal. Hemorrhagic transformation was common in the area of cerebral infarction. Using this model, the effect of a GPIIb/IIIa antagonist, ME3277 (low dose, (L); 0.15 mg/kg + 0.125 mg/kg x h, middle dose, (M); 0.3 mg/kg + 0.25 mg/kg x h and high dose, (H); 0.6 mg/kg + 0.5 mg/kg x h), aspirin (20 mg/kg) and sodium ozagrel (thromboxane A2 synthase inhibitor, 1 mg/kg + 2 mg/ kg x h) were evaluated. Drugs were intravenously administrated 30 minutes after the photochemical reaction for 24 hours. Aspirin inhibited the ex vivo platelet aggregation induced by arachidonic acid and collagen but not by adenosine diphosphate (ADP), while sodium ozagrel only inhibited the arachidonic acid-induced aggregation. ME3277 dose-dependently inhibited the platelet aggregation induced by all the inducers (approximately 60% in L, 80% in M, and 90% in H). At 24 hours of middle cerebral artery (MCA) occlusion, infarct volume was significantly reduced by aspirin and each dose of ME3277. These agents improved neurologic deficits, with ME3277 being more potent than aspirin. Sodium ozagrel did not alter the infarct volume nor neurologic deficits. No drug was found to worsen hemorrhage volume despite increasing bleeding time (2-3 fold) in the skin. In this model, the occluded artery was spontaneously recanalized and re-thrombosed frequently. One mechanism by which antiplatelet agents reduced infarct volume was inhibition of rethrombosis of the MCA. These results suggest that treatment with a GPIIb/IIIa antagonist is a useful intervention for acute cerebral infarction prolonging dose bleeding time to 3 times the basal value.     

ADP plays a key role in thrombogenesis in rats

The relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR 4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose- and time-dependent antiplatelet effects of aspirin

Aspirin is widely used, but dosages in different clinical situations and the possible importance of "aspirin resistance" are debated. We performed an open cross-over study comparing no treatment (baseline) with three aspirin dosage regimens--37.5 mg/day for 10 days, 320 mg/day for 7 days, and, finally, a single 640 mg dose (cumulative dose 960 mg)--in 15 healthy male volunteers. Platelet aggregability was assessed in whole blood (WB) and platelet rich plasma (PRP). The urinary excretions of stable thromboxane (TxM) and prostacyclin (PGI-M) metabolites, and bleeding time were also measured. Platelet COX inhibition was nearly complete already at 37.5 mg aspirin daily, as evidenced by >98% suppression of serum thromboxane B2 and almost abolished arachidonic acid (AA) induced aggregation in PRP 2-6 h after dosing. Bleeding time was similarly prolonged by all dosages of aspirin. Once daily dosing was associated with considerable recovery of AA induced platelet aggregation in WB after 24 hours, even after 960 mg aspirin. Collagen induced aggregation in WB with normal extracellular calcium levels (hirudin anticoagulated) was inhibited <40% at all dosages. TxM excretion was incompletely suppressed, and increased <24 hours after the cumulative 960 mg dose. Aspirin treatment reduced PGI-M already at the lowest dosage (by approximately 25%), but PGI-M excretion and platelet aggregability were not correlated. Antiplatelet effects of aspirin are limited in WB with normal calcium levels. Since recovery of COX-dependent platelet aggregation occurred within 24 hours, once daily dosing of aspirin might be insufficient in patients with increased platelet turnover.     

Phospholipase C from clostridium perfringens induces human platelet aggregation in plasma

We studied the aggregating effect of different concentrations of phospholipase C (PLC) (extracted from Clostridium perfringens) on human platelet-rich plasma (PRP). PRP was preincubated with PLC for 3 min at 37 degrees C and the platelet aggregation was followed for 10 min. The threshold aggregating concentration (TAC) of PLC was 3-4 U/ml. We also studied the potentiation of PLC with other stimuli on platelet aggregation. Potentiating stimuli, such as arachidonic acid (AA), ADP. Platelet Activating Factor (PAF) and U-46619 (a stable analogue of cyclic endoperoxides) were all used at subthreshold concentrations. We also studied the possible inhibitory effect of aspirin, apyrase, TMQ, a prostaglandin endoperoxide/thromboxane receptor antagonist and BN-52021, a PAF receptor antagonist. Only aspirin and apyrase were able to reduce aggregation induced by PLC alone and PLC + AA and PLC + ADP respectively. TMQ and BN-52021 were inactive. In ex vivo experiments oral aspirin (500 mg) partially inhibited platelet aggregation induced by PLC alone, PLC + AA and PLC + ADP 2 and 24 h after administration. Aspirin 20 mg for 7 days also reduced aggregation induced by PLC + AA.     

p-Aminobenzoic acid and its metabolite p-acetamidobenzoic acid inhibit agonist-induced aggregation and arachidonic acid-induced [Ca2+]i transients in human platelets.

We have previously found that the naturally occurring amine p-aminobenzoic acid (PABA) inhibits the thrombin-induced thromboxane B2 production in human platelets. In this report we show that PABA and its acetylated metabolite p-acetamidobenzoic acid (PACBA) inhibit platelet aggregation induced by agonists such as adenosine diphosphate (ADP) and arachidonic acid (AA). Both substances were equipotent to acetylsalicylic acid regarding inhibition of ADP-induced aggregation and approximately 50% as potent as acetylsalicylic acid regarding arachidonic acid-induced aggregation. Although not significantly inhibiting collagen aggregation, PABA and PACBA reduced the concomitant adenosine triphosphate (ATP) secretion by approximately 30 and 20%, respectively. The antiaggregatory effect does not seem to be mediated through cyclic adenosine monophosphate (cAMP) increase because in our experiments PABA and PACBA did not significantly affect cAMP levels. However, we have found that PABA and PACBA inhibit the intracellular aequorin indicated Ca2+ transient upon arachidonic acid stimulation. Our results describe a hitherto unknown effect of PABA and PACBA on platelet aggregation.     

An evaluation of the effect of flurbiprofen (2-(2-fluoro-4-biphenylyl) propionic acid) on platelet behaviour.

Flurbiprofen, a potent anti-inflammatory agent, has been shown to inhibit human platelet aggregation induced $\text{in vitro}$ by adenosine diphosphate (ADP), adrenaline, collagen and thrombin. The compound was active at concentrations as low as 10^?7 M. Single oral doses as low as 4 mg in man (approximately 0.06mg/kg) had a marked inhibitory effect on the second phase of ADP-induced platelet aggregation. The drug effect reached a peak at 2 to 4 hours after dosing and had disappeared after 24 hours. In a short-term repeated-dose study, 10 mg given orally to 12 human volunteers daily for 8 days inhibited the irreversible phase of platelet aggregation induced by ADP. Platelet adhesiveness and thrombus formation time were not affected. Platelet aggregation induced by all four agonists was also markedly suppressed in 7 out of 8 rheumatic patients treated orally with the drug for up to 2 years. Template bleeding times and platelet counts were normal in all of these subjects.     

A new approach to antithrombotic therapy--evaluation of combined therapy of thromboxane synthetase inhibitor and very low dose of aspirin

The effect of a selective thromboxane (TX) synthetase inhibitor (OKY-046), alone and in combination with a very low dose of aspirin, on the platelet function was studied in healthy and diseased subjects. A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease (CVD) and healthy volunteers. TXB2 generation and platelet aggregation were measured before and at 1, 4, 6 and 8hr after dosing. In addition, after the administration of a very low dose of aspirin (0.1-0.25 mg/kg/day) for at least one month, a single dose of OKY-046 was given to CVD patients. TXB2 generation and platelet aggregation were measured in the same manner as OKY-046 alone. The effect of OKY-046 on platelet aggregation induced by arachidonic acid (AA) was different in each subject whereas platelet TXB2 generation was almost completely inhibited in all of the patients and healthy volunteers. OKY-046 had a slight inhibitory effect on collagen induced aggregation. A combination of OKY-046 with a very low dose of aspirin, on the other hand, produced additional inhibition of the platelet aggregation induced by both AA and collagen. The present results suggest that the accumulation and metabolism of cyclooxygenase products that accumulate when TX synthetase is blocked, differ in each subject, additional inhibition is caused by the combined use of TX synthetase inhibitor and a very low dose of aspirin because the very low dose of aspirin partially reduces the proaggregatory cyclooxygenase products that accumulate when TX synthetase is blocked.(ABSTRACT TRUNCATED AT 250 WORDS)