Peripheral Venous Plasma Aspirin Concentrations and Platelet Aggregation Inhibition Produced by Enteric-Coated Aspirin Formulations

1986 ◽  
Vol 55 (02) ◽  
pp. 222-227 ◽  
Author(s):  
Roslyn A Brandon ◽  
J A G Emmett ◽  
M J Eadie ◽  
A C W Curran ◽  
I H Bunce
Keyword(s):  
Platelet Aggregation ◽  
Peripheral Circulation ◽  
Systemic Circulation ◽  
Inhibition Of Platelet Aggregation ◽  
Enteric Coated Aspirin ◽  
Aggregation Inhibition ◽  
Enteric Coated ◽  
Adult Volunteers ◽  
Chronic Use ◽  
Venous Plasma

SummaryIn a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P <0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P >0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

SECRETION OF PROGESTERONE DURING GESTATION IN THE RAT

1978 ◽  
Vol 79 (2) ◽  
pp. 179-190 ◽  
Author(s):  
MRINAL K. SANYAL
Keyword(s):  
Abdominal Aorta ◽  
Primary Source ◽  
Solvent System ◽  
Peripheral Circulation ◽  
Systemic Circulation ◽  
Maternal Circulation ◽  
Secondary Importance ◽  
System Hexane ◽  
Venous Plasma

The concentrations of progesterone and 5α-pregnane-3,20-dione in ovarian and uterine venous plasma and in the systemic circulation were measured during gestation in the rat. The steroids were quantified by radioimmunoassay after separation on silicic acid microcolumns with the solvent system hexane: ethyl acetate (5: 2, v/v). The concentration of progesterone in the systemic circulation was highest on days 3–4 and 13–17 of pregnancy; throughout gestation, the concentration of 5α-pregnane-3,20-dione was low in relation to that of progesterone and showed no marked changes as gestation proceeded. The level of progesterone in ovarian venous effluent was 10–20 times higher than that in the uterine vein and 20–50 times greater than that in the systemic circulation. The rate of secretion of progesterone by the ovary was highest during days 13–17 of gestation and ovariectomy during this period markedly reduced the levels of progesterone in the peripheral circulation. The concentration of progesterone in the uterine venous effluent was raised compared with the concentration in plasma from the abdominal aorta, especially on days 7 and 9 of pregnancy. These results suggest that, in vivo, the rat placenta synthesizes small amounts of progesterone and secretes it into the maternal circulation. The ovary is the primary source of progesterone during pregnancy and the placental contribution is of secondary importance. Although 4-ene-5α-reductase enzyme(s) is present in the ovary and placenta, significant quantities of the reduced progestin 5α-pregnane-3,20-dione are not secreted into the systemic circulation during gestation in the rat.

PRESYSTEMIC DEACETYLATION OF LOW DOSES OF ENTERIC COATED ASPIRIN IN A PIG MODEL

1987 ◽  
Author(s):  
J V Lloyd ◽  
S E Rodgers ◽  
D M Siebert ◽  
F Bochner ◽  
G H McIntosh ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Portal Vein ◽  
High Performance ◽  
Time Curve ◽  
Before And After ◽  
Enteric Coated Aspirin ◽  
Thromboxane Production ◽  
Enteric Coated ◽  
Prostacyclin Production

The antithrombotic effect of aspirin might be enhanced if platelet cyclooxygenase could be inhibited in the portal ciculation while sparing cyclooxygenase in the systemic vascular endothelium. This might be achieved by modifying the dose and formulation to maximise presystemic aspirin clearance by the liver. To test this hypothesis low dose enteric coated aspirin (Astrix, 50mg single dose, lOOmg single dose and lOOmg daily for 1 week) was orally administered to pigs with permanent indwelling arterial and portal vein catheters. Plasma aspirin concentrations were measured by high performance liquid chromatography in blood obtained simultaneously from the artery and portal vein for 6 hours after dosage. Platelet aggregation and thromboxane generation were measured in 4 pigs before and after the lOOmg chronic dosage regimen. Aortic prostacyclin production was measured in aspirin treated (lOOmg daily for 1 week) and untreated pigs after sacrifice. After the 50mg single dose the arterial:portal areas under the plasma concentration versus time curve (AUC) ratio was 0.63±0.09 (n=6). In 3 pigs which received all 3 dosage regimens the arterial:portal AUC ratios were 0.48±0.05 after 50mg single dose, 0.52±0.02 after lOOmg single dose and 0.47+0.03 after lOOmg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65mM) was completely abolished after chronic aspirin administration. Thromboxane production (pg/106 platelets) by this stimulus decreased from 536±117 before aspirin to 57±14 after aspirin (n=4; p=0.017). Aortic prostacyclin synthesis (ng/disc after 10 min incubation) was 1.66±0.28 (n=4) in untreated pigs and 0.97±0.25 (n=4) in treated pigs (p=0.06).With this slow release aspirin formulation there was substantial but incomplete clearance of aspirin by the liver. This may not be sufficient to spare cyclooxygenase in the systemic vessels from the effect of aspirin.

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

1989 ◽  
Vol 61 (02) ◽  
pp. 211-216 ◽  
Author(s):  
F Bochner ◽  
D M Siebert ◽  
S E Rodgers ◽  
G H McIntosh ◽  
M J James ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Time Profile ◽  
Time Curve ◽  
Systemic Artery ◽  
Enteric Coated Aspirin ◽  
Study Support ◽  
Thromboxane Production ◽  
Enteric Coated ◽  
Prostacyclin Production

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.

Single-Dose Effect of Enteric-Coated Aspirin on Platelet Function and Thromboxane Generation in Middle-Aged Men

1993 ◽  
Vol 27 (4) ◽  
pp. 405-410 ◽  
Author(s):  
Hiroshi Mohri ◽  
Takao Ohkubo
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Bleeding Time ◽  
Adenine Nucleotides ◽  
Adenosine Diphosphate ◽  
Platelet Factor 4 ◽  
Middle Aged ◽  
Platelet Factor ◽  
Enteric Coated Aspirin ◽  
Enteric Coated

OBJECTIVE: To evaluate the effect of a single dose of enteric-coated aspirin (ECA) in three different dosages on platelet function and thromboxane generation in middle-aged men. DESIGN AND METHODS: In a nonblind, nonplacebo-controlled, crossover study, a single dose of ECA (50, 250, or 1000 mg) was given in a tablet form to a group of healthy, middle-aged men. Ten subjects, aged 50–67 years, volunteered to participate in this study. Platelet functions including bleeding time, platelet aggregation, adenine nucleotides, beta-thromboglobulin, platelet factor 4, thromboxane generation, and aspirin measurement were determined. RESULTS: Before ECA ingestion, the intracellular adenine nucleotides (adenosine triphosphate, adenosine diphosphate) were decreased, and both beta-thromboglobulin and platelet factor 4 were increased. These observations suggested that platelets were activated in vivo in middle-aged men. These findings returned to normal within 8 hours after the ingestion of ECA, and maintained normal for at least two days. Bleeding time was significantly prolonged at 8 and 24 hours compared with that before ingestion of ECA 1000 mg (p<0.05). The generation of platelet thromboxane was maximally inhibited by approximately 40 percent in the samples 8 hours after ECA ingestion. Abnormal values of adenine nucleotides, beta-thromboglobulin, and platelet factor 4 returned to normal within 8 hours. Arachidonic acid-induced platelet aggregation was inhibited compared with that before treatment (p<0.01) and the inhibitory effect was maintained for at least three days. Adenosine diphosphate- and epinephrine-induced aggregations were less inhibited than those induced by arachidonic acid. Inhibitory effects of ECA on platelet aggregation were dose dependent. CONCLUSIONS: Our study indicates that platelets are activated in middle-aged men and that a single dose of ECA 50 mg is safe and can inhibit thromboxane synthesis and platelet aggregation. These results suggest that a daily dose of ECA 50 mg may be useful for blocking platelet activation and preventing thrombosis.

Enhancement by Ticlopidine of the Inhibitory Effect on In Vitro Platelet Aggregation of the Glycoprotein IIb/IIIa Inhibitor Tirofiban

1997 ◽  
Vol 78 (05) ◽  
pp. 1381-1384 ◽  
Author(s):  
K Umemura ◽  
K Kondo ◽  
Y Ikeda ◽  
M Nakashima
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Inhibitory Effect ◽  
Clinical Effects ◽  
Percent Inhibition ◽  
Inhibition Of Platelet Aggregation ◽  
Prolonged Bleeding Time ◽  
Period 2 ◽  
Aggregation Inhibition

SummaryWe determined the effects of combining the glycoprotein IIb/IIIa inhibitor tirofiban (MK-383, Aggrastat) and ticlopidine on inhibition of ADP-induced platelet aggregation, inhibition of collagen-induced platelet aggregation, and prolongation of bleeding time in 5 healthy male volunteers. The study consisted of 2 periods. In period 1, tirofiban was administered intravenously as a bolus injection at a dose of 5.0 µg/kg for 5 min, then as a continuous infusion at a rate of 0.05 µg/kg/min for 5 h 55 min. In period 2, ticlopidine was given orally at a dose of 200 mg once daily for 4 days, after which tirofiban was administered in the same manner as in period 1, starting 2 h after the last dose of ticlopidine. The percent inhibition of platelet aggregation induced by ADP 5 µM at the end of tirofiban infusion in periods 1 and 2 was 73.6 ± 2.6 and 87.1 ± 5.7% (mean ± SD), respectively. The corresponding values for inhibition of platelet aggregation induced by collagen 2 µg/ml were 45.4 ± 36.1 and 82.8 ± 27.0%, respectively. In contrast, the percent inhibition of platelet aggregation induced by ADP and collagen after treatment with ticlopidine alone was 15.8 ± 20.2 and p ± 4.8%, respectively. Compared with tirofiban alone, the combination of tirofiban and ticlopidine significantly enhanced inhibition of platelet aggregation induced by both ADP and collagen (p <0.02 and p <0.012, respectively). The inhibitory effects of ticlopidine alone were not statistically significant. Tirofiban prolonged bleeding time both in period 1 and in period 2. However, tirofiban and ticlopidine combined did not affect bleeding time. Ticlopidine administration did not alter the pharmacokinetics of tirofiban. In conclusion, at the doses of tirofiban and ticlopidine used in this study, the combination of the two drugs enhanced inhibition of platelet aggregation but did not prolong bleeding time, suggesting that appropriate doses of tirofiban can be used concomitantly with ticlopidine with no further safety concerns but with potential additional clinical effects.

Effect of alternate-day regular and enteric-coated aspirin on platelet aggregation, bleeding time, and thromboxane A2 levels in bleeding-time blood

1986 ◽  
Vol 81 (3) ◽  
pp. 400-404 ◽  
Author(s):  
Meir J. Stampfer ◽  
Joseph A. Jakubowski ◽  
Daniel Deykin ◽  
Andrew I. Schafer ◽  
Walter C. Willett ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thromboxane A2 ◽  
Enteric Coated Aspirin ◽  
Enteric Coated

A Physiologic Regulator of Collagen-Induced Platelet Aggregation: Inhibition by Clq

1981 ◽  
Vol 45 (02) ◽  
pp. 110-115 ◽  
Author(s):  
György Csákó ◽  
Eva A Suba
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Platelet Reactivity ◽  
High Specificity ◽  
Turbidimetric Method ◽  
Specific Manner ◽  
Aggregation Inhibition ◽  
Different Tissues

SummaryPlatelet aggregations were studied by a turbidimetric method in citrated human platelet-rich plasmas (PRP) in vitro. Human Clq inhibited the aggregations caused by collagens derived from different tissues and species. Clq was needed by weight in comparable quantities to collagen for neutralizing the aggregating effect. The dependence of the inhibitory reaction on the preincubation of platelets with Clq and the differences in the occurrence of aggregating substances in supernatants of PRP triggered with collagen in the presence or absence of Clq, confirmed that Clq exerts its effect by preventing fixation of collagen to platelets. In addition, the high specificity of the inhibitory action of Clq for collagen-induced platelet aggregation was demonstrated by results obtained for testing a variety of aggregating agents in combination with Clq and/or collagen.Since normal concentrations of Clq in the blood are in the range of inhibitory doses of Clq for collagen-induced platelet aggregations in vitro and upon activation of complement Clq is known to dissociate from Cl, it is proposed that Clq may participate in a highly specific manner in regulating platelet reactivity to collagen in vivo.

Some Effects of Fibrinogen Degradation Products (FDP) on Blood Platelets

1966 ◽  
Vol 15 (03/04) ◽  
pp. 413-419 ◽  
Author(s):  
Z Jerushalmy ◽  
M. B Zucker
Keyword(s):  
Platelet Aggregation ◽  
Connective Tissue ◽  
Degradation Products ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Serotonin Release ◽  
Fibrinogen Degradation Products ◽  
Inhibition Of Platelet Aggregation

Summary“Early” fibrinogen degradation products are more potent inhibitors of thrombin-induced clotting than “late” products and also interfere with the ability of thrombin to release serotonin from platelets. “Early” and “intermediate” FDP cause moderate inhibition of platelet aggregation induced by adenosine diphosphate or connective tissue particles. Serotonin release by connective tissue particles is probably not inhibited by FDP.

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