Effect of Sulphinpyrazone (SP) Aspirin (ASA) and Dipyridamole (DP) on Plateletvessel Wall Interaction after Oral Administration to Rabbits

1979 ◽  
Author(s):  
J.A. Davies ◽  
V.C. Menys
Keyword(s):  
Clinical Trials ◽  
Platelet Aggregation ◽  
Vessel Wall ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Human Dose ◽  
Wall Interaction ◽  
Adhesion Of Platelets

Clinical trials of anti-platelet drugs have suggested that they may be useful in the prevention of thrombotic disease. While such drugs inhibit platelet function, those which act on cyclooxygenase also reduce PGI2 synthesis and may interfere with tne natural antithrombotic properties of the vessel wall. We studied the effects of SP, ASA and OP ex vivo on the platelet-vessel wall interaction. Rabbits were dosed by mouth with drug (at about twice the weight-adjusted human dose) or placebo for 5 days, then exsanguinated and aortas removed. Washed platelets prepared from the blood were labelled with 51Cr. and their adhesion to everted aortapr epared from treated or control rabbits was measured in a perfusion device. PGI2-like activity in aortic rings was assayed by its inhibitory effect on platelet aggregation to ADP. Adhesion of platelets to aort as from SP- treated rabbits was i ncreased (p < 0.025), PGI2 - like activity was partially inhibited, but over all adhesion of SP-treated platelets to aor tas f rom SP-treated animals reduced by 30% (p < 0.02). Adhesion to aortas of ASA- treated rabbits was sliahtly inc r ea=-.ed (p > 0 . 1) , PGI 2 - l ike act ivi ty abolished , and no overall reduc tion in platelet adhesion seen. DP had no effecton adhesion or PGI-like activity. These results support the evidence that cyclo-oxygenase inhibitors reduce the inherent resistance of the vessel wall to platelet adhesion. However with SP, inhibitory effects on platelets appear to be more important.

Platelet Adhesion to Subendothelial Structures under Flow Conditions: No Effect of the Lipoxygenase Product 13-HODE

1989 ◽  
Vol 62 (02) ◽  
pp. 802-806 ◽  
Author(s):  
Jacques C de Graaf ◽  
Hidde Bult ◽  
Guido R Y de Meyer ◽  
Jan J Sixma ◽  
Philip G de Groot
Keyword(s):  
Endothelial Cells ◽  
Hydroxy Fatty Acid ◽  
Vessel Wall ◽  
Platelet Adhesion ◽  
Direct Evidence ◽  
Inhibitory Effect ◽  
Flow Conditions ◽  
Physiological Concentration ◽  
Hydroxyoctadecadienoic Acid ◽  
Wall Interaction

SummaryIt has been shown that endothelial cells can convert linoleic acid to 13-hydroxyoctadecadienoic acid (13-HODE) and it has been suggested that 13-HODE has non-thrombogenic properties. However, no direct evidence has been presented that indicates that 13-HODE indeed modulates platelet-vessel wall interaction.In this study we have bound a purified 13-HODE to a thrombogenic surface and its effect on platelet adhesion was studied and compared to the effects of an analogous hydroxy fatty acid, 15-hydroxyeicosatetraenoic acid (15-HETE). The effect of 13-HODE on platelet adhesion was studied both under static and flow conditions. In this report we show that binding of up to 40 times the physiological concentration to a thrombogenic surface has no inhibitory effect on platelet adhesion under static or flow conditions. We conclude that 13-HODE is not an important regulatory substance in platelet-subendothelium interaction, although this does not exclude it has a putative anti-adhesive role on intact endothelium.

THE NEWLY SYNTHESIZED COMPOUND E-5510 IS A HIGHLY POTENT ANTIPLATELET AGENT

1987 ◽  
Author(s):  
K Harada ◽  
T Fujimori ◽  
M Kogushi ◽  
M Kogushi ◽  
I Yamatsu ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Human Subjects ◽  
Antiplatelet Agent ◽  
Antiplatelet Agents ◽  
Inhibitory Effect ◽  
Experimental Animals ◽  
Antiplatelet Effect

Our newly synthesized compound, 4-cyano-5,5-bis(methoxy-phenyl)-4-pentenoic acid (E-5510) has highly potent antiplatelet activity. In this paper, the effects of E-5510 on platelet functions in vitro and ex vivo in human and in various experimental animals are examined.E-5510 inhibited human platelet aggregation induced by collagen, arachidonate, ADP, PAF and epinephrine (IC50: 1.5, 0.7, 2.0, 1.6 and 1.1 uM, respectively). Thrombin-induced platelet aggregation, which was not inhibited by aspirin and U-53059 (lC50s: 100 uM), was also inhibited by this compound (IC50: 21uM). The IC50 of E-5510 in thrombin-induced ATP secretion fromhuman platelets was only 2 uM. Platelet adhesion to a collagen coated disk, whichwas measured by the method of Buchanan et al (Prost. Leuko. Med., 21, 157, 1986) was inhibited by E-5510 (IC50: 19.3 uM) butnot by aspirin and U-53059. In the PRP ofthe guinea pig, the beagle and the monkey, E-5510 inhibited collagen-induced platelet aggregation in vitro to the same degree as in human PRP(IC50: 1.2, 0.6 and 1.5 uM, respectively). After being administered orally to guinea pigs, E-5510 exhibited extremely potent ex vivo inhibitory effect in collagen-induced platelet aggregation with a very low ED50 of 0.05 mg/kg. In contrast, the ED50’s of ticlopidine, aspirin and U-53059 were 300 , 27.2 and 1.0 mg/kg, respectively. In beagles and monkeys E-5510 also showed ex vivo antiplatelet effects at 0.01 and 0.003 mg/kg, respectively. This effect continued for more than 8 hrs. and disappeared within 24 hrs. The antiplatelet effect in human PRP was highly correlated with that in PRP of experimental animals in which the ex vivo effects were confirmed at a very low dose. Thus, E-5510 will ensure to exert the antiplatelet effect after oral administration to human subjects.In summary, E-5510 is unique among the known antiplatelet agents since it has potent inhibitory effects on thrombin-induced platelet activation and platelet adhesion to collagen. It was also shown that this compound had an ex vivo antiplatelet effect at an extremely low ED50. Our results suggest that E-5510 will be a beneficial agent for antiplatelet therapy in humans.

Platelet-Vessel Wall Interactions In Experimentally Induced Hypercholesterolemia

1981 ◽  
Author(s):  
E Tremoli ◽  
E Aqradi ◽  
A Socini ◽  
A Petroni ◽  
C Galli
Keyword(s):  
Platelet Aggregation ◽  
Vessel Wall ◽  
Aortic Wall ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Lower Sensitivity ◽  
High Cholesterol ◽  
Simple Method ◽  
Wall Interaction ◽  
Wall Interactions

A simple method was developed to study platelet-vesseln wall interactions based on the perfusion of platelet rich plasma (PRP) through isolated segments obtained from the aorta of the same animal. The inhibition of aggregation of the perfused PRP, indicating prostacyclin (PGI2)-like material production by aortic wall, was quantified. The effect was not present when normal PRP was perfused through the vessels obtained from aspirin-treated animals. This experimental model was used in the study of platelet-vessel wall interaction in normal (N) and hypercholesterolemic (HC) rabbits (one month on a high cholesterol -2% W/W - diet).In the HC animals increased aggregating response coupled with reduced platelet sensitivity to the inhibitory effect of exogenous PGI2 was observed. When PRP of the two groups of animals was perfused through their own aortas, the inhibition of aggregation was significantly lower in HC samples, suggesting ever lower aortic production or lower sensitivity to the inhibitory effect of PGI2-like material in treated animals. In addition a lower inhibition of platelet aggregation occurred after perfusion of PRP from HC animals through aortas of N rabbits, indicating a decreased platelet sensitivity to the inhibitory effect of PGI2-like material released.It appears that in experimental HC rabbits, platelet aggregation and their sensitivity to the antiaggregatory effect of PGI2 are significantly affected. In our experimen tal conditions, production of PGI2-like material in the aorta is not reduced, but the overall outcome of plateletvessel wall interaction is a reduced inhibition of platelet aggregatory response.

Phospholipase C from Clostridium Perfringens Induces Human Platelet Aggregation in Plasma

1988 ◽  
Vol 59 (02) ◽  
pp. 236-239 ◽  
Author(s):  
Giovanna Barzaghi ◽  
Chiara Cerletti ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Phospholipase C ◽  
Clostridium Perfringens ◽  
Human Platelet ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Platelet Activating Factor ◽  
Inhibitory Effect ◽  
Thromboxane Receptor Antagonist

SummaryWe 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° C and the platelet aggregation was followed for 10 min. The threshold aggregating concentration (TAG) 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 endoper- oxide/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.

Abstract 2214: The Aptamer ARC1779 Is A Potent And Specific Inhibitor Of von Willebrand Factor (vWF) Mediated Ex Vivo Platelet Function In ST-elevation (STEMI) and non-ST elevation (NSTEMI) Acute Myocardial Infarction (AMI)

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Bernd Jilma ◽  
Florian B Mayr ◽  
Alexander O Spiel ◽  
Patricia G Merlino ◽  
Harold N Marsh ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Citrate Anticoagulation ◽  
St Elevation ◽  
A1 Domain ◽  
The Impact ◽  
Novel Therapeutic

Background: ARC1779 is an aptamer which blocks the A1 domain binding of the vWF A1 domain to platelet GPIb receptors that is now in development for the treatment of AMI. vWF is increased in the elderly and in the setting of AMI, as reflected in higher vWF levels in circulation and in increased shear-dependent platelet function as measured by the platelet function analyzer (PFA-100) and cone and plate analyzer (IMPACT). Conventional therapy of AMI partially reduces platelet activation and aggregation, but does not address excessive vWF activity or platelet adhesion. Methods: We studied the ex vivo dose response curves for ARC1779 on PFA-100 and IMPACT platelet function tests, agonist-induced platelet aggregation, and vWF activity (free A1 domain sites) of patients with AMI on standard treatment including aspirin and clopidogrel (n=40), young (n=20) and elderly controls (n=20). Results: ARC1779 fully blocked collagen ADP induced platelet plug formation as measured by PFA-100 with an IC100 of ~ 1–2 mcg/mL with citrate anticoagulation, and 3–5 mcg/mL with hirudin anticoagulation. ARC1779 fully blocked shear-dependent platelet adhesion measured by the IMPACT analyzer with an IC100 of ~ 1 mcg/mL with citrate anticoagulation. In contrast to GPIIb/IIIa antagonists, ARC1779 did not inhibit platelet aggregation by ADP, collagen or arachidonic acid at concentrations (10mcg/mL) that fully inhibited vWF dependent platelet function. ARC1779 fully blocked vWF activity ex vivo with an IC90 of ~ 1 mcg/mL in young controls and 6 – 8 mcg/mL in STEMI and NSTEMI patients. Conclusions: ARC1779 potently and specifically inhibits vWF activity and vWF dependent platelet function, even in the setting of AMI where vWF activity is increased. ARC1779 represents a novel therapeutic principle (vWF antagonism) and a novel therapeutic class (aptamers). Potent and specific inhibition of VWF makes ARC1779 a promising development candidate for patients with AMI. Results

Inhibition of collagen-induced platelet aggregation by anopheline antiplatelet protein, a saliva protein from a malaria vector mosquito

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2007-2014 ◽  
Author(s):  
Shigeto Yoshida ◽  
Toshiki Sudo ◽  
Masashi Niimi ◽  
Lian Tao ◽  
Bing Sun ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Malaria Vector ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Blood Feeding ◽  
Adhesion Assay ◽  
Type I ◽  
Subsequent Increase ◽  
Glycoprotein Vi ◽  
Vector Mosquito

During blood feeding, mosquitoes inject saliva containing a mixture of molecules that inactivate or inhibit various components of the hemostatic response to the bite injury as well as the inflammatory reactions produced by the bite, to facilitate the ingestion of blood. However, the molecular functions of the individual saliva components remain largely unknown. Here, we describe anopheline antiplatelet protein (AAPP) isolated from the saliva of Anopheles stephensi, a human malaria vector mosquito. AAPP exhibited a strong and specific inhibitory activity toward collagen-induced platelet aggregation. The inhibitory mechanism involves direct binding of AAPP to collagen, which blocks platelet adhesion to collagen and inhibits the subsequent increase in intracellular Ca2+ concentration ([Ca2+]i). The binding of AAPP to collagen effectively blocked platelet adhesion via glycoprotein VI (GPVI) and integrin α2β1. Cell adhesion assay showed that AAPP inhibited the binding of GPVI to collagen type I and III without direct effect on GPVI. Moreover, intravenously administered recombinant AAPP strongly inhibited collagen-induced platelet aggregation ex vivo in rats. In summary, AAPP is a malaria vector mosquito-derived specific antagonist of receptors that mediate the adhesion of platelets to collagen. Our study may provide important insights for elucidating the effects of mosquito blood feeding against host hemostasis.

Amino acid Sequence of a Peptide from Type III Collagen Involved in Platelet Adhesion

1979 ◽  
Author(s):  
F. Fauvel ◽  
Y.J. Legrand ◽  
H. Bentz ◽  
G. Pignaud ◽  
K. Kühn ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Cyanogen Bromide ◽  
Platelet Adhesion ◽  
Type Iii Collagen ◽  
Salt Precipitation ◽  
Type Iii ◽  
Imino Acid ◽  
Precipitation Type ◽  
Adhesion Of Platelets

The probable importance of the role of type III collagen in the initiation of thrombosis is due to its localization in the subendothelial layers of the vessel wall.The adhesion of platelets to type III has been therefore quantified by a method based on the filtration of non-adhesive 14C 5HT-labe11ed platelets through a Sepharose 2B column.Type III collagen was purified from calf skin by pepsin extraction and salt precipitation. Type III collagen was cleaved by cyanogen bromide and the adhesion induced by the resulting peptides was measured. The activity was attached to the central alpha l(III) CB4 peptide which was further cleaved by hydroxy lamine, chymotrypsin and trypsin. An adhesive potency was linked to three fragments (HA 1 obtained by hydroxylamine, C2 by chymotrypsin and T2 by trypsin) which possess a common portion of 9 amino-acids, localized in the central part of the alpha l(III) CB4 peptide and of the entire alpha 1(III) Chains, which probably represents the active part of type III collagen. Its activity could be due to a particular sterical conformation linked to the presence of 3 imino acid residues in the sequence Gly-Lys-Hyp-Gly-Glu-Hyp-Gly-Pro-Lys of this fragment.

Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time

2006 ◽  
Vol 96 (08) ◽  
pp. 167-175 ◽  
Author(s):  
Yutaka Matsumoto ◽  
Hisao Takizawa ◽  
Kazuhiro Nakama ◽  
Xiaoqi Gong ◽  
Yoshihisa Yamada ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
Bleeding Tendency ◽  
Fab Fragment ◽  
Dose Escalation Study ◽  
Cynomolgus Monkeys ◽  
Induced Aggregation

SummaryRecent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (>80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0. 2 mg/kg with a slight prolongation of bleeding time (1. 3 times baseline value). Furthermore, at 18. 8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1. 9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5. 0 times at 0. 35 mg/kg, the lowest effective dose on platelet aggregation. Ina pharmacodynamic study,a bolus injection of OM2 at 0. 4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exerta potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.

scholarly journals Thrombospondin inhibits adhesion of platelets to glass and protein- covered substrata

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1096-1099 ◽  
Author(s):  
J Lahav
Keyword(s):  
Platelet Adhesion ◽  
Binding Capacity ◽  
Inhibitory Effect ◽  
Adsorbed Protein ◽  
Platelet Binding ◽  
Platelet Spreading ◽  
Glass Surfaces ◽  
Adhesion Of Platelets

Abstract Glass and protein-covered surfaces when treated with the platelet- secreted glycoprotein thrombospondin lose their capacity to bind unstimulated platelets. In comparison to the number that bind to fibronectin-covered glass surfaces, less than 3% bind to thrombospondin- covered glass surfaces. When the fibronectin-covered surface is incubated with thrombospondin, it loses 87% of its binding capacity for platelets. The inhibitory effect of thrombospondin on platelet binding increases with increasing amounts of the adsorbed protein and reaches maximal values at 65% saturation of the adsorption of thrombospondin to the surface. Platelet spreading on the surface is also completely inhibited by thrombospondin. These data suggest that thrombospondin is nonthrombogenic and can modulate platelet adhesion to the subendothelium.

Effects Of Aspirin And Sulfinpyrazone On Platelets, Vascular Cells And Their Interactions

1981 ◽  
Author(s):  
M R Buchanan ◽  
M J Vazquez ◽  
M A Gimbrone
Keyword(s):  
Growth Rate ◽  
Cell Growth ◽  
Dna Synthesis ◽  
Vessel Wall ◽  
Culture Medium ◽  
Platelet Adhesion ◽  
Thymidine Incorporation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Final Density

Sulfinpyrazone (SUL) and aspirin (ASA) are potentially useful antithrombotic drugs. Both drugs are thought to exert this effect by inhibiting the platelet enzyme, cyclooxygenase (C-0), thus preventing thromboxane A2 synthesis. Recent data, however, suggest that these drugs also may affect vessel wall cells. To study this further, we examined the effects of SUL and ASA on i) the adhesion of 3H-adenine-labelled washed human platelets to cultured bovine endothelial (EC) and smooth muscle cells (SMC), ii) EC and SMC DNA synthesis (3H-thymidine incorporation) and iii) cell growth. Pretreatment of platelets with 100μM ASA or 250μM SUL (concentrations sufficient to inhibit C-0), did not affect platelet adhesion to untreated EC or SMC. However, adhesion of untreated, ASA- and SUL-platelets was increased 25,28 and 44% resp. when EC were pretreated with 650μM SUL for 24 hr. In contrast, adhesion of ASA-platelets to EC pretreated with lOOμM ASA (sufficient to inhibit prostacyclin), was unaffected. Platelet adhesion to SMC pretreated with 650μM SUL for 24 hr was decreased when platelets also were pretreated with ASA (20%, p<0.05) or SUL (27%, pc 0.02). Pretreatment of SMC with SUL for only 2 hr had no effect. DNA synthesis in EC and SMC treated with 62.5 and 250μM SUL for 24 hr, was inhibited >35% and >95% resp. Preliminary data suggest that this inhibitory effect may last longer in SMC. To study the effect of SUL on cell growth, EC and SMC were plated at 2 × 104 cells/ cm2 and fed with culture medium containing 0, 62.5 or 625uM SUL on day 0, 1, 3 and 4.5. EC growth rate and final density were unaffected over 7 days. SMC growth rate also was unaffected, but the final density of SMC treated with 650μM SUL was 31 μ 2% less than untreated SMC at 7 days (p<0.01). These data indicate that SUL has direct effects on EC and SMC that may influence i) platelet-vessel wall interactions and ii) vascular cell proliferation.

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