A Dose‐ranging Study of the Antiplatelet Effect of Enteric Coated Aspirin in Man

Herd, Caroline M.; Rodgers, S. E.; Lloyd, John Uri; Bochner, Felix; Duncan, Elizabeth M.; Tunbridge, L.J.

doi:10.1111/j.1445-5994.1987.tb00040.x

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…Since thromboxane A2 is an important mediator of platelet aggregation it is not surprising that, in this study, a cumulative dose of 240 mg aspirin was able to inhibit totally platelet aggregation and ATP release induced by exogenous AA. These results are in agreement with many others (Bye et al, 1979;Herd et al, 1987;McLeod et al, 1986;Wilson et al, 1990) and also with current recommendations for the use of low-dose aspirin in the prophylaxis of cerebrovascular and cardiovascular disease (Bochner & Lloyd, 1986).…”

Section: Discussionsupporting

confidence: 92%

“…Many studies have demonstrated inhibition of AAand collagen-induced platelet activation by aspirin (Bye et al, 1979;Herd et al, 1987;McLeod et al, 1986;Siebert et al, 1983) but in many of these only a limited range of aspirin doses and stimulus concentrations have been used. Aspirin has also been shown to partially inhibit ex vivo PAF-induced platelet aggregation and ATP release (Lecrubier et al, 1983;Rao et al, 1982) .…”

Section: Introductionmentioning

confidence: 99%

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The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid.

Taylor

Misso

Stewart

et al. 1992

Brit J Clinical Pharma

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1. The effect of increasing doses of orally administered aspirin (30‐ 900 mg) on platelet aggregation and ATP release induced by arachidonic acid (AA), collagen and platelet activating factor (PAF) was assessed in 12 normal volunteers. 2. Aspirin ingestion was associated with a significant increase in EC50 for AA (P less than 0.0001) and collagen (P less than 0.0001) but not for PAF (P greater than 0.495) although the normal biphasic aggregation response for the latter was abolished. Maximum ATP release was reduced by aspirin for all three agonists. 3. The mean maximum degrees of inhibition of platelet aggregation induced by aspirin for AA, collagen and PAF were 100%, 48% and 21% of baseline, respectively. The corresponding mean maximum inhibition of ATP release was 100%, 63% and 57%. The minimum cumulative doses of aspirin producing these effects were 240, 240 and 90 mg for AA, collagen and PAF respectively. For collagen alone, there was a significant decrease in the degree of inhibition of aggregation between the last dose on day 1 (150 mg) and the baseline measurement on day 2. 4. Platelets from female subjects were more sensitive to collagen (P less than 0.05) and AA (P less than 0.01) stimulation compared with males. However, prior to aspirin ingestion, PAF produced a greater maximum response in platelets from females (P less than 0.02) while following aspirin ingestion PAF‐induced activation was inhibited to a greater degree in females (P less than 0.02). 5. These results indicate that collagen‐ and PAF‐induced platelet activation are only partially dependent on cyclo‐oxygenase and for PAF this seems related only to the second phase of aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid.

Taylor

Misso

Stewart

et al. 1992

Brit J Clinical Pharma

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“…Platelet aggregation induced by sodium arachidonate was the only aggregation response to be significantly inhibited by chronic ingestion of 100 mg aspirin/day. This contrasts with the findings in man where all aggregation responses were markedly inhibited by 20 mg/day (9). In our study, ingestion of 100 mg aspirin/day did not inhibit collagen-induced aggregation although thromboxane generation induced by collagen and sodium arachidonate was reduced to 11-33% of the control values.…”

Section: Discussioncontrasting

confidence: 99%

“…Aspirin may be more effective as an antithrombotic agent if the undesirable effect on the vessel wall could be minimised or avoided, while retaining the inhibitory effect of aspirin on platelets. This may be possible using enteric-coated or slow-release aspirin in doses of 100 mg or less which have been shown to maximally inhibit platelet function (8,9).…”

Section: Introductionmentioning

confidence: 99%

Measurement of Aspirin Concentrations in Portal and Systemic Blood in Pigs: Effect on Platelet Aggregation, Thromboxane and Prostacyclin Production

et al. 1989

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SummaryLow doses of enteric-coated aspirin were administered orally to pigs. Plasma aspirin concentrations measured in blood obtained simultaneously from permanent catheters in a systemic artery and portal vein for 6 hours after dosage showed a large variation in the plasma aspirin concentration : time profile between pigs. After 50 mg single dose the ratio of the arterial : portal area under the plasma concentration versus time curve (AUC) was 0.63 ± 0.08 (mean ± SE, n = 6). In three pigs which received all three dosage regimens, the arterial : portal AUC ratios were 0.48 ± 0.05 after 50 mg single dose, 0.52 ± 0.02 after 100 mg single dose and 0.47 ± 0.02 after 100 mg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65 mM) was completely abolished after chronic aspirin administration of 100 mg daily. Thromboxane production (pg/ 106 platelets) induced by this stimulus decreased from 536 ± 117 before aspirin to 57 ± 14 after aspirin (mean ± SE, n = 4; p = 0.03). Aortic prostacyclin synthesis, measured as 6-keto PGF1α (ng/disc after 10 min incubation), was 1.66 ± 0.28 (mean ± SE, n = 4) in untreated pigs and 0.95 ± 0.25 (n = 5) in treated pigs (p = 0.07). Results from this study support the idea that a difference between aspirin concentrations in the portal and systemic circulations can be achieved. Whether this can be translated into a clinically useful differential effect on the vessel wall compared to the platelet remains to be determined.

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“…The production of TXA2, 5 min after the -addition of agonist, was measured by radioimmunoassay of the stable end-product, TXB2, as previously described (Herd et al, 1987). The detection limit of the assay was 0.2 ng ml' PRP or 0.6 pg/106 platelets.…”

Section: Platelet Function Testsmentioning

confidence: 99%

Potentiation of ADP‐induced aggregation in human platelet‐rich plasma by 5‐hydroxytryptamine and adrenaline

Vanags

Rodgers

Duncan

et al. 1992

British J Pharmacology

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We have used dose‐response curves to quantitate the potentiation of adenosine 5′‐diphosphate (ADP)‐induced aggregation and thromboxane (TXA2) generation by 5‐hydroxytryptamine (5‐HT) and adrenaline in human citrated platelet‐rich plasma. We have also quantitated the inhibition of these responses by aspirin, ketanserin and yohimbine, singly and in pairs. Ketanserin (5 μm) inhibited TXA2 production and the second wave of platelet aggregation induced by a range of concentrations of ADP alone. This indicates that endogenous 5‐HT, released from the platelet dense granules, contributes significantly to responses induced by ADP. When 5‐HT (10 μm) was added before ADP, a lower concentration of ADP was required to cause 50% aggregation and TXA2 generation. The ratio of ADP concentrations (CR) to cause 50% aggregation in the presence and absence of 5‐HT was 2.1 when only added 5‐HT was considered, and 5.0 when endogenous 5‐HT was also taken into account. Potentiation of ADP‐induced aggregation by 5‐HT also occurred in the presence of aspirin, resulting in a CR of 2.3. As expected, ketanserin inhibited potentiation by 5‐HT in the presence and absence of aspirin. Although aspirin caused substantial inhibition of aggregation induced by ADP and 5‐HT (CR 3.4), further inhibition occurred when ketanserin was also present (CR 6.5). A subthreshold concentration of adrenaline (0.25 μm) caused substantial potentiation of ADP‐induced aggregation in the absence (CR 4.0) and presence (CR 2.0) of aspirin. As expected, yohimbine (9 μm) inhibited this potentiation. Maximum TXA2 generation induced by ADP increased from 32.5 to 59.4 pg per 106 platelets when adrenaline was present. Aggregation induced by ADP and adrenaline was markedly inhibited by aspirin (CR 5.1) but was further inhibited when yohimbine (9 μm) was also present (CR 10.0). Results from this in vitro study show ketanserin and yohimbine have the potential to be used in combination with aspirin as antithrombotic agents in vivo.

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A Dose‐ranging Study of the Antiplatelet Effect of Enteric Coated Aspirin in Man

Cited by 10 publications

References 22 publications

The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid.

The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid.

Measurement of Aspirin Concentrations in Portal and Systemic Blood in Pigs: Effect on Platelet Aggregation, Thromboxane and Prostacyclin Production

Potentiation of ADP‐induced aggregation in human platelet‐rich plasma by 5‐hydroxytryptamine and adrenaline

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