THE PLATELET ANTIAGGREGATORY EFFECT OF ILOPROST IS ENHANCED BY ASPIRIN:IN VITRO AND EX VIVO STUDIES IN HUMAN SUBJECTS.

1987 ◽  
Author(s):  
E Tremoli ◽  
P Maderna ◽  
S Colli ◽  
L Mannucci ◽  
C R Sirtori ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Human Subjects ◽  
Selective Inhibition ◽  
Blood Collection ◽  
Inhibition Of Platelet Aggregation ◽  
Iloprost Infusion

To evaluate whether the activity of Iloprost, a chemically stable prostacyclin analog, on platelet aggregation could be potentiated by aspirin (ASA), in vitro and ex vivo studies in human volunteers were performed. In vitro studies were carried out in human platelet rich plasma (PRP) incubated with different concentrations of ASA (25-150 μM). For ex vivo studies Iloprost (0.5 ng.Kg−1.min−1 for 30 min) was given intravenously to healthy volunteers. After 20 hour wash out a single 50 mg ASA dose was given to the same subjects. Two hours after ASA intake, a second infusion of Iloprost was carried out. Blood was collected at appropriate time intervals thereafter. Platelet aggregation and thromboxane B2 (TXB2) formation were determined in collagen stimulated PRP. ASA, in vitro , dose dependently reduced the concentrations oF Iloprost required to achieve 50% inhibition of platelet aggregation (IC50) in PRP stimulated by 1 g/ml collagen. Also, the IC50S for Iloprost were significantly reduced (p<0.01) in PRP of subjects who ingested ASA two hours before blood collection. Iloprost infusion (0.5 ng.Kg−1.min−1 for 30 min) only minimally affected the concentrations of collagen eliciting 50% aggregation (AC50) and was ineffective on TXB2 synthesis. ASA, administered after a 20 hour wash out period did not significantly affect the AC s for collagen, whereas it inhibited TXB2 synthesis by more than 50%. The mean AC50 for collagen, evaluated at the end of Iloprost infusion in PRP of subjects who previously ingested ASA, was signicantly greater than that evaluated after the two single treatments. No significant changes in hemodynamic and ECG parameters were detected during the study. These findings, indicating an in vivo potentiating effect of ASA on the antiaggregatory activity of Iloprost, observed at doses of Iloprost with no effect on hemodynamic parameters, may be of relevance for the design of treatment schedules aimed to the selective inhibition of platelet aggregation.

The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

1989 ◽  
Vol 67 (9) ◽  
pp. 989-993 ◽  
Author(s):  
A. W. Ford-Hutchinson ◽  
Y. Girard ◽  
A. Lord ◽  
T. R. Jones ◽  
M. Cirino ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Guinea Pig ◽  
Receptor Antagonist ◽  
Competitive Inhibition ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Prostaglandin Endoperoxide ◽  
Induced Aggregation

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 × 10−9 M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 × 10−7 M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A2, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.

Lu 23051, A New Potent Inhibitor Of Platelet Aggregation

1981 ◽  
Author(s):  
H D Lehmann ◽  
J Gries ◽  
D Lenke
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Coronary Vessels ◽  
Inhibitory Effect ◽  
Spontaneously Hypertensive ◽  
Dependent Inhibition ◽  
Induced Aggregation

6- [p-(2-(Chiorpropionylamino)phenyl] -4.5-dihydro-5-methyl-3(2H)-pyridazinone, LU 23051, is primarily characterized by its strong inhibition of platelet aggregation under in vitro and in vivo conditions. In vitro there is a concentration-dependent inhibition of ADP and collagen induced aggregation in platelet rich plasma of man, rat and dog. The inhibitory concentration EC 33 % is 0.0010-0.030 mg/1 (man: ADP-0.030, col 1.-0.013 mg/l) depending on species and type of aggregation. When administered orally in ex vivo experiments on rats and dogs the substance is found to have a dose-dependent antiaggregatory effect in the range from 0.1-3.16 mg/kg. The ED 33 % is 0.27-0.63 mg/kg.-In addition after oral administration the substance has a good inhibitory effect in models being based on intravascular platelet aggregation. Thus, a dose of 1 mg/kg inhibits laser-induced aggregation in mesenteric venules of rats. Mortality after i.v. injection of collagen in mice is reduced by 50 % after a dose of 0.02 mg/kg. A dose of 0.039 mg/kg prolongs the bleeding time of rats by 50 %. The aggregation-inhibiting action is of long duration (0.1 mg/kg p.o.∼24 h). The substance does not interfere with clotting.Besides its effect on platelet aggregation LU 23051 acts as vasodilatator as well. Dilatation of coronary vessels by 100 % is seen in isolated guinea-pig hearts at a concentration of 0.1 mg/l. In spontaneously hypertensive rats the substance has an anti hypertensive effect. The ED 20 % is 0.36 mg/kg p.o.The combination of antiaggregatory and vasodilatatory effects opens up interesting aspects with respect to the pharmacotherapeutic use of the new substance

Inhibition of platelet aggregation and thromboxane production by low concentrations of aspirin in vitro

1988 ◽  
Vol 74 (5) ◽  
pp. 491-497 ◽  
Author(s):  
D. Sils ◽  
S. E. Rodgers ◽  
J. V. Lloyd ◽  
K. M. Wilson ◽  
D. M. Siebert ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Critical Concentration ◽  
Significant Inhibition ◽  
Inhibit Platelet Aggregation ◽  
Prolonged Incubation ◽  
Inhibition Of Platelet Aggregation ◽  
Low Concentrations

1. The aspirin concentrations previously reported to inhibit platelet aggregation in vitro (40–500 μmol/l) are much greater than those required in vivo in man (5 μmol/l). 2. Human platelet-rich plasma was incubated with buffer or various aspirin concentrations at 37°C for up to 4.5 h. Platelet aggregation and thromboxane generation were measured in response to collagen (0.4–6.3 μg/ml) and adenosine 5′-pyrophosphate (0.5–4 μmol/l). 3. The concentration of aspirin needed to inhibit platelet aggregation in response to a critical concentration of aggregating agent (lowest concentration to cause greater than 50% aggregation) was lower than that required for higher concentrations of aggregating agent. 4. With more prolonged incubation times with aspirin, lower concentrations of aspirin inhibited platelet aggregation. 5. Inhibition of platelet aggregation and thromboxane formation by 10 μmol/l aspirin was maximal by 90 min. There was progressive inhibition by 3 μmol/l aspirin during incubation for 270 min. By the end of this time there was also significant inhibition by 1 μmol/l aspirin. 6. The apparent discrepancy between inhibitory aspirin concentrations in vivo and those observed in vitro in previous studies appears to have been resolved by extending the incubation time of platelets with low aspirin concentrations, thus mimicking the conditions in vivo.

scholarly journals The effect of chlorin e6 drug on platelet aggregation activity

2019 ◽  
Vol 8 (3) ◽  
pp. 4-10 ◽  
Author(s):  
N. N. Petrishchev ◽  
M. A. Galkin ◽  
T. G. Grishacheva ◽  
I. N. Dementjeva ◽  
S. G. Chefu
Keyword(s):  
Platelet Aggregation ◽  
Laser Irradiation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Dependent Manner ◽  
Functional Changes ◽  
Aggregation Activity ◽  
Dose Dependent

The goal of the study is to evaluate the effect of Radachlorin (OOO “RADA-PHARMA”, Russia) (RC) on platelet aggregation in ex vivo and in vivo experiments. The experiments were conducted on male Wistar rats. Platelet aggregation activity was determined in platelet-rich plasma (PRP) using a turbidimetric method and the aggregation inducer was ADP at a final concentration of 1.25 μM. PRP samples containing RC were irradiated with ALOD-Granat laser device (OOO “Alkom Medika”, Russia) at 662 nm wavelength with 0.05 W/cm2 power density. After a 5-minute incubation of PRP with RC in the dark, dose-dependent inhibition of platelet aggregation was observed. Laser irradiation (12.5 J/cm2 and, especially, 25 J/cm2) increased the inhibitory effect of RC. 3 hours after intravenous administration of RC, the rate and intensity of platelets aggregation did not change, while disaggregation slowed down significantly. Irradiation at a dose of 5 J/cm2 did not affect the platelets aggregation kinetics, and disaggregation slowed down even more at 10 J/cm2, and at 20 J/cm2 the rate and intensity of platelets aggregation decreased, and no disaggregation occurred.In vitro, RC inhibited the ADP-induced platelet aggregation in rats in a dose-dependent manner; after laser irradiation, this effect was enhanced significantly. The effect of RC on circulating platelets leads to a change in their functional state, which manifests in slowing down the disaggregation after exposure to ADP. After laser irradiation (10 J/cm2 and, especially, 20 J/cm2), the severity of the functional changes increases. The role of decreasing the disaggregation activity of platelets in the mechanism of vascular thrombosis in the affected area of photodynamic therapy (PDT) is discussed.

scholarly journals Inhibition of Platelet Aggregation by Brinolase Degradation Products of Fibrinogen and Serum Albumin

1977 ◽  
Author(s):  
W. H. E. Roschlau
Keyword(s):  
Platelet Aggregation ◽  
Serum Albumin ◽  
Degradation Products ◽  
Platelet Rich Plasma ◽  
Biological Effects ◽  
Response Curves ◽  
Human Fibrinogen ◽  
Inhibition Of Platelet Aggregation

Brinolase (fibrinolytic enzyme from Aspergillus oryzae) was observed to possess significant platelet aggregation inhibitory properties during and after thrombolytic therapeutic use. These platelet effects were found in vitro to be caused in part by intermediate products of fibrinogen digestion, namely low-molecular-weight peptides of approx. MW 2500. Human fibrinogen peptides were isolated, purified, and shown to have high inhibitory activity in platelet-rich plasma. Quantitative comparisons of attainable platelet inhibition in vitro and observed responses in vivo during administration of equivalent enzyme doses, however, suggested that total available fibrinogen, even if it were entirely converted to degradation products (which it is not), would be insufficient to account for observed platelet effects of brinolase therapy.Human serum albumin is also readily degraded by brinolase. Albumin degradation products were prepared in vitro by optimal incubation with the enzyme. Dose-response curves of inhibition of platelet aggregation were obtained with lyophilized peptides in platelet-rich plasma in vitro, and significant inhibition of platelet aggregation was observed in vivo following infusion of albumin degradation products into rabbits. The enzyme doses and amounts of substrates employed in all experiments were equivalent to the conditions of therapeutic fibrinolysis.Thus, albumin degradation products are considered to contribute a significant, if not the major, portion of platelet-active intermediates during clinical brinolase therapy. Albumin cleavage, which is unique to brinolase amongst clinical fibrinolytic enzymes, was shown to have biological effects of its own, but it may also serve to protect coagulation proteins from enzymatic destruction through competition for the enzyme during systemic brinolase therapy.

On the Action of Intravenously Applied Acetylsalicylic Acid (ASA) on Platelet Functions, a Kinetic Study

1975 ◽  
Author(s):  
D. Loew ◽  
H. Vinazzer
Keyword(s):  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Single Intravenous Dose ◽  
Inhibition Of Platelet Aggregation ◽  
Rapid Action ◽  
Vitro Effect ◽  
Kinetics Of ◽  
Platelet Functions

There is general agreement that ASA inhibits platelet aggregation, adhesion and release reactions when given orally. In the present study, 10 individuals received a single intravenous dose of 500 mg ASA to examine the kinetics of the influence on platelet functions. Blood was drawn prior to ASA and at intervals between 2 minutes and 72 hours after injection.Collagen induced platelet aggregation as well as PF 3 and PF 4 release started to decrease 2 minutes after ASA and reached a minimum after 1 hour. A full ASA effect could still be observed after 24 hours though ASA had disappeared from plasma by that time. Simultaneously, in-vitro examinations with ASA were carried out. ASA was added to fresh platelet rich plasma in a concentration correspondent to the in-vivo dose. The inhibition of platelet aggregation and PF 4 release had a lag time of 1 hour and was considerably less distinct than in vivo. No inhibition of PF 3 release could be observed. The results demonstrate a rapid action of ASA when given intravenously while the in-vitro effect is much less distinct. A probable explanation is a direct effect of ASA on the platelet membrane. The enhancement in vivo is supposed to be caused by splitting of the acetylic group from ASA.

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.

Reaction of Acetaldehyde with Human Platelets

1992 ◽  
Vol 67 (01) ◽  
pp. 126-130 ◽  
Author(s):  
Olivier Spertini ◽  
Jacques Hauert ◽  
Fedor Bachmann
Keyword(s):  
Platelet Aggregation ◽  
Inhibitory Action ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
Reaction Medium ◽  
Human Platelets ◽  
Membrane Glycoproteins ◽  
Neutral Ph

SummaryPlatelet function defects observed in chronic alcoholics are not wholly explained by the inhibitory action of ethanol on platelet aggregation; they are not completely reproduced either in vivo by short-term ethanol perfusion into volunteers or in vitro by the addition of ethanol to platelet-rich plasma. As acetaldehyde (AcH) binds to many proteins and impairs cellular activities, we investigated the effect of this early degradation product of ethanol on platelets. AcH formed adducts with human platelets at neutral pH at 37° C which were stable to extensive washing, trichloracetic acid hydrolysis and heating at 100° C, and were not reduced by sodium borohydride. The amount of platelet adducts formed was a function of the incubation time and of the concentration of AcH in the reaction medium. At low AcH concentrations (<0.2 mM), platelet bound AcH was directly proportional to the concentration of AcH in the reaction medium. At higher concentrations (≥0.2 mM), AcH uptake by platelets tended to reach a plateau. The amount of adducts was also proportional to the number of exposures of platelets to pulses of 20 pM AcH.AcH adducts formation severely impaired platelet aggregation and shape change induced by ADP, collagen and thrombin. A positive correlation was established between platelet-bound AcH and inhibition of aggregation.SDS-PAGE analysis of AcH adducts at neutral pH demonstrated the binding of [14C]acetaldehyde to many platelet proteins. AcH adduct formation with membrane glycoproteins, cytoskeleton and enzymes might interfere with several steps of platelet activation and impair platelet aggregation.This in vitro study shows that AcH has a major inhibitory action on platelet aggregation and may account for the prolonged ex vivo inhibition of aggregation observed in chronic alcoholics even in the absence of alcoholemia.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Inhibition of Fibrinolytic Activity In-Vivo by Dexamethasone Is Counterbalanced by an Inhibition of Platelet Aggregation

1992 ◽  
Vol 68 (01) ◽  
pp. 069-073 ◽  
Author(s):  
J J J van Giezen ◽  
J W C M Jansen
Keyword(s):  
Platelet Aggregation ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Dose Range ◽  
Coagulation System ◽  
Loop Model ◽  
Prothrombotic State ◽  
Inhibition Of Platelet Aggregation ◽  
Pai 1

SummaryDexamethasone decreases the fibrinolytic activity in cultured medium of several cell types by an induction of PAI-1 synthesis. As a result of this enhanced PAI-1 synthesis a prothrombotic state is expected in patients treated with dexamethasone. However, such a prothrombotic state is not reported as a major adverse effect. We have studied the effects of dexamethasone (dose range: 0.1–3.0 mg/kg) on the fibrinolytic system of rats after a 5 day pretreatment period. It appeared that dexamethasone dose dependently decreased the fibrinolytic activity (a dose of 1 mg/kg showed a reduction of about 40%). This reduced fibrinolytic activity could be functionally translated into an increased thrombus size as measured with a venous thrombosis model: thrombus size was increased by 50% with 1 mg/kg dexamethasone. No effects could be measured on the coagulation system, but it appeared that ex-vivo measured platelet aggregation was dose dependently inhibited by dexamethasone treatment. This effect resulted in-vivo in prolonged obstruction times as measured with a modified aorta-loop model. These results indicate that the expected prothrombotic state due to a diminished fibrinolytic activity caused by dexamethasone is counterbalanced by an inhibition of platelet aggregation.

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