Thromboxane-Synthetase Inhibitors Could Be “Large Spectrum” Anti-Aggregating Agents

1981 ◽  
Author(s):  
C Bonne ◽  
B Martin
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Rat Aorta ◽  
The Other ◽  
Vascular Tissues ◽  
Synthetase Inhibitor ◽  
Compound C ◽  
Thromboxane Synthetase ◽  
Dependent Pathway

“Large spectrum”anti-aggregating activity could be only achieved by agents which increased the c AMP content of platelets. Cyclo-oxygenase inhibitors could only block the Thromboxane (Tx)- dependent pathway of platelet aggregation. Conversely, Tx-synthetase inhibitors could deviate the endoperoxides metabolism to anti-aggregating prostaglandins in particular in the presence of vascular tissues. In this study we have investigated the effect of CBS634 (1-(3-hydroxy- 1 - octenyl)-imidazole nicotinic ester, dichlorhydra- teD, a potent inhibitor of T×A2 synthesis, both on the production of anti-aggregating prosta- glandins and on the simultaneous c AMP synthesis in platelets.Rat aorta fragments pretreated with aspirin were incubated with rat platelet rich plasma in the presence or absence of tested compound, c AMP, T×B2, PGE2 and 6-keto-PGFF1α were determined by radioimmunoassays.In the presence of CBS63U (50μM), T×B2 formation was reduced from 17 ± 2 to 0.2 ng/ml/min. In parallel, PGE production in controls was 1.4 ± 0.6 and 8 ± 1 ng/ml/min in the presence of the drug. On the other hand, 6-keto-PGF1α formation, very low in controls, rose to 4 ±1.2 ng/mV min in the presence of CBS63U. Radiochemical assays performed with c14C)-arachidonate confirmed that metabolic deviation. The increased level of c AMP formed in the presence of T×A2-synthetase inhibitor supports the hypothesis that such a drug could present a “large spectrum”antiaggregating activity.

The Effect On Serum-Thromboxan B2 Production, Platelet Aggregation, Serotonin Release, PF-4 And 6-Keto-PGF1αOf A Novel Specific Thromboxan A2 Synthetase-Inhibitor In Patients With Hyperactive Platelets

1981 ◽  
Author(s):  
J B Knudsen ◽  
A Juhl ◽  
J Gormsen
Keyword(s):  
Platelet Aggregation ◽  
Fold Increase ◽  
Rat Aorta ◽  
Serotonin Release ◽  
Human Umbilical Cord ◽  
Synthetase Inhibitor ◽  
Thromboxane Synthetase ◽  
Effective Inhibition ◽  
Before And After ◽  
Acid Hydrochloride

A novel, specific Thromboxan A2-synthetase inhibitor 4-1-2- (1 H-imidazol-l-yl)ethoxy-benzoic acid hydrochloride was given to nine patients with hyperactive platelets (defined by an aggregation threshold 0.05 ug/ml epinepherine) and nine controls. The effects on serum Thromboxan B2, platelet aggregation, serotonin release, PF-4, and 6-keto-PGF1 were evaluated in sequential blood samples from h to 24 h after single dose of loo mg. The serum-thromboxan production measured by RIA was reduced 96% ± 4.3 sd 1/2 h to 2 h after dosing. Platelet+aggregation was reduced 89 ± lo.2% with epinephrine, 92 ± 11.4% with collagen and 56 ± 14.3% with ADP. Serotonin release induced by ADP was reduced 65 ± 9.8%, while PF-4 showed no consistant changes. When crushed rat aorta or microsome preparations from human umbilical cord arteries were incubated with PRP from patients before and after dosing, and aggregation induced by 16 uM ADP, a 6 fold increase in 6-keto PGF1α production measured by RIA was observed. The Ivy-bleeding time was prolonged by 65±14sd %.Conclusion: Specific inhibition of the platelet thromboxane synthetase in patients induces a highly effective inhibition of thromboxane production, and inhibition of platelet aggregability and serotonin release and an increase in Endoperoxide availability which by rat and human endothelial cell prostacycline synthetase can be utilized for increase prostacyclin production.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

A Thiazole Compound with Potential Antithrombotic Activity

1982 ◽  
Vol 47 (02) ◽  
pp. 173-176 ◽  
Author(s):  
E E Nishizawa ◽  
A R Mendoza ◽  
T Honohan ◽  
K A Annis
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Development Program ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thiazole Derivative ◽  
Cyclooxygenase Activity ◽  
Drug Development Program

SummaryA thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

Inhibition of Platelet Aggregation by Human Placenta

1985 ◽  
Vol 54 (02) ◽  
pp. 431-437 ◽  
Author(s):  
M J Dembélé-Duchesne ◽  
A Laghchim Lahlou ◽  
H Thaler-Dao ◽  
A Crastes de Paulet
Keyword(s):  
Fatty Acid ◽  
Platelet Aggregation ◽  
Human Placenta ◽  
Cyclooxygenase Inhibitor ◽  
Synthetase Inhibitor ◽  
Inhibition Of Platelet Aggregation ◽  
Thromboxane Synthetase ◽  
Rabbit Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryHuman placental cytosol inhibits platelet aggregation induced by high doses of collagen. The aim of this study was to investigate whether this anti-aggregating activity was caused only by the presence of various activities already described in the placenta (an ADP-consuming enzyme, a fatty acid cyclooxygenase inhibitor, and a thromboxane synthetase inhibitor) or whether another factor was present.Heating the cytosol at 50° C for 6 min destroyed the inhibitor of collagen-induced aggregation. ADPase and the AA pathway inhibitors were not modified by this treatment. We therefore show the presence of an additional anti-aggregating factor: it is destroyed by heating at 50° C.We also tested for the presence of an inhibitor of AA release in the placental cytosol using three different methods (rabbit platelets in PRP, washed rabbit platelets, and NRK fibroblasts) but no inhibition could be evidenced.We conclude that this new anti-aggregating factor, which is probably a protein, acts neither through AA release inhibition nor AA cascade inhibition.

Prostaglandins and Platelet Function in Diabetes

1979 ◽  
Author(s):  
J. García-Conde ◽  
J.A. Amado ◽  
J. Merino ◽  
I. Benet
Keyword(s):  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Normal Subjects ◽  
Inhibitory Effect ◽  
Rat Aorta ◽  
Diabetic Group ◽  
Diabetic Patients ◽  
Prostaglandin I2 ◽  
Induced Aggregation ◽  
Normal Controls

We have studied platelet aggregation induced by 0,5 mM. Araquidonic acid (AA) addition to platelet-rich-plasma (PRP) from 21 insulin treated diabetic patients and in 21 non-diabetic controls. The velocity of aggregation was significantly higher in the diabetic group. There was no differences in the velocity of aggregation in patients with or without retinopathy.The incubation of PRP of normal subjects at 37- during 5 minutes with 5,8 10-4 M. Imidazole changed the pattern of aggregation: The velocity of aggregation was slower and appeared a wave of disaggregation. Imida zole had not effect on aggregation in the diabetic group. This data add support to the findings published by COLWLLL showing that platelets from diabetics have hyperactive AA metabolism. Prostaglandin I2 (PGI2) obtained from rat aorta shows an inhibitory effect on ADP or AA induced aggregation. This effect is less marked in diabetic PRP than in PRP of normal controls. PGI2 release in platelet-poor-plasma from diabetics is normal. This can represent a resistance ot diabetic platelet to the anti aggregating effect of PGI 2. A similar finding was also appreciated with the PGE1 in three out of six patients so tar stu

Platelet Reactions and Immune Processes

1971 ◽  
Vol 25 (01) ◽  
pp. 086-097 ◽  
Author(s):  
F Jobin ◽  
F Lapointe ◽  
F Gagnon
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Light Chains ◽  
Marked Enhancement

SummaryWe have studied the effect of IgG, IgA, IgM, lambda light chains, Fc fragments, heat-aggregated gammaglobulin, albumin and fibrinogen on the interaction of latex, Kaolin, celite or bentonite particles with human platelet-rich plasma.1. Marked enhancement of platelet aggregating activity was produced by preincubating these particles with IgG at an appropriate concentration. Excess IgG abolished this platelet aggregating property.2. Platelet aggregation could also be induced by betamethasone acetate particles. The latter and IgG-coated latex, Kaolin or bentonite particles were inhibited by chymotrypsin substrates and inhibitors.3. Heat-aggregated IgG produced platelet aggregation in platelet-rich plasma only when adsorbed onto (Kaolin) particles.4. Results obtained with fibrinogen-coated Kaolin suggest that the particles thus acquired a slightly increased platelet clumping activity.5. The other proteins studied failed to enhance the platelet aggregating activity of Kaolin particles, and could even inhibit the formation of IgG-coated Kaolin particles able to readily aggregate platelets.

Possible Mode of Action of Ticlopidine: A Novel Inhibitor of Platelet Aggregation

1979 ◽  
Author(s):  
H. Johnson ◽  
J. B. Heywood
Keyword(s):  
Platelet Aggregation ◽  
Mode Of Action ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Thromboxane Synthetase ◽  
Sustained Effect ◽  
Dependent Inhibition

Ticlopidine (T) is weakly active in vitro, but is a potent inhibitor of platelet aggregation induced by ADP, collagen, thrombin, adrenaline, arachidonic acid, prostaglandin (PG) endoperoxide and thromboxane A2 with a sustained effect, when administered to a variety of animal species, including man. Platelets from treated animals were normal in ultrastructure and 14C-ADP binding was not modified by T. Basal PG synthesis was unaffected, whereas aspirin (A) had a marked inhibitory effect. Platelet cyclo-oxygenase and thromboxane synthetase activities were 90.6±12.9 and 96.1±5.3% of control following T treatment. In contrast to A, T had no effect on vascularprostacyclin (PGI2) synthesis, this being 1.4±0.1, 0.5±0.1 and 1.3±0. 3ng/mg wet weight aorta in T and A-treated and control animals respectively. Platelets from T-treated rats were significantly more responsive to inhibition by exogenous PGI2 (0.2-4 ng/ml) and PGE1 (4- 20 ng/ml). when compared with controls. T administration (30-300 mg/kg) resulted in a dose-dependent inhibition of ADP-induced platelet aggregation (26.0- 87. 5%) and enhancement of platelet reactivity to PGI2 (37.0-159.8%). There was a good correlation between these parameters (r=+0.994). T is a potent inhibitor of platelet aggregati on with a novel mode of action. It is not aspirin-like, but may act to potentiate endogenous PGI2 in vivo, possibly through an effect on platelet adenylate cyclase.

Effects of Dabigatran, a Direct Thrombin Inhibitor, as Compared to the Direct Factor Xa Inhibitors, Rivaroxaban and Apixaban, on Tissue Factor-Induced Human Platelet Aggregation in Platelet Rich Plasma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1884-1884 ◽  
Author(s):  
Joanne van Ryn ◽  
Monika Kink-Eiband ◽  
Norbert Hauel ◽  
Henning Priepke ◽  
Wolfgang Wienen
Keyword(s):  
Platelet Aggregation ◽  
Tissue Factor ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Direct Factor ◽  
Direct Factor Xa Inhibitors

Abstract Direct thrombin inhibitors (DTIs) have been shown to be very potent inhibitors of platelet function when platelets are activated with thrombin. This action does not occur by direct binding of the DTI to the platelet PAR-1/-4 receptor, but indirectly, by reducing thrombin concentrations and thereby reducing the interactions of thrombin with its receptor on the platelet. It was hypothesized that both thrombin and factor Xa inhibitors could inhibit platelet aggregation, if the stimulus to initiate aggregation was higher in the cascade than factor Xa, such as tissue factor. Thus, dabigatran, a DTI, and the direct factor Xa inhibitors, rivaroxaban and apixaban were tested. Free flowing whole blood (60 ml) was obtained from an antecubital vein using an 18 gauge needle from healthy human volunteers. Blood was collected in tubes containing 3.13% sodium citrate (1 in 10 dilution with whole blood). Blood was centrifuged at 200x g to obtain platelet rich plasma (PRP). Samples (300 μL PRP) were placed in a 6-channel aggregometer, equilibrated for 5 min at 37°C and calibrated with PPP from same individual (0–1 Volts). Photometric tracings were continuously digitally recorded over 5 min following the addition of tissue factor and curves were evaluated as AUC over this time interval. Each PRP sample was incubated with 2 mg/ml Pefabloc®FG (Gly-Pro-Arg-Pro) to prevent fibrin polymerisation, 5 mM CaCl2 and increasing concentrations of dabigatran or factor Xa inhibitor. Tissue factor stimulus (range, 5–27 μl of 10 ml Innovin solution) was tailored for each individual, so that the minimum concentration that resulted in maximum aggregation was used. As positive controls, aggregation was also performed after stimulating with ADP (10 μM), collagen (2 μg/ml), TRAP (20 μM) or ecarin (0.1 U/ml). All substances inhibited tissue factor-induced platelet aggregation in a concentration-dependent manner. Dabigatran was the most potent inhibitor of platelet aggregation among the substances tested, with an IC50 of 35 nM, rivaroxaban and then apixaban followed, with IC50s of 312 and 817 nM, respectively. All substances had no effect on platelet aggregation induced by ADP, collagen and TRAP. Dabigatran was a potent inhibitor of ecarin-induced platelet aggregation, while the factor Xa inhibitors had no effect, as expected from their mechanism of action. Thus, these studies demonstrate that both direct thrombin inhibitors (by inhibiting thrombin) and direct factor Xa inhibitors (by preventing thrombin generation) indirectly inhibit platelet aggregation, though dabigatran was more potent than rivaroxaban and apixaban under these experimental conditions. Thus, these substances may not only be effective in venous/stasis thrombotic episodes where fibrin formation plays an important role, but may also be effective in more platelet dominant, arterial thrombosis settings.

scholarly journals Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1460-1466
Author(s):  
V Bertele ◽  
A Falanga ◽  
M Tomasiak ◽  
C Chiabrando ◽  
C Cerletti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Normal Subjects ◽  
Gas Chromatography Mass Spectrometry ◽  
Thromboxane Synthetase ◽  
High Resolution Gas Chromatography ◽  
Pharmacologic Inhibition

Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2 (TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich plasma from 16 normal subjects. Inhibition of TxB2 synthesis was accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high- resolution gas chromatography-mass spectrometry. Even at dazoxiben concentrations (40–80 microM) above those inhibiting TxB2 synthesis, platelet aggregation induced by threshold concentrations of arachidonic acid was inhibited in only 4 of 16 subjects, referred to as responders. The remaining 12 individuals were defined as nonresponders. The aggregating effect of arachidonic acid and of the prostaglandin- endoperoxide analog U-46619 was potentiated by PGE2 and prevented by PGD2 at concentrations within the range of those detected in dazoxiben - treated platelet-rich plasma. The antiaggregating effect of dazoxiben was counteracted by PGE2 (in responders) and was potentiated by PGD2 (in nonresponders). Platelets from responders and nonresponders did not differ in the amount of immunoreactive PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded that inhibition of thromboxane synthetase does not per se prevent platelet aggregation. The functional result of thromboxane suppression appears to be modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and PGD2, which are formed in excess.

Sign in / Sign up

Export Citation Format

Share Document