Anti -Platelet Effects Of Ticlopidine Are Not Diminished By Efa Deficiency Cr Inecmet1Hacin Aemini Stoat Icn

1981 ◽  
Author(s):  
A L Willis ◽  
J M Fisher ◽  
D Donegan ◽  
D L Smith
Keyword(s):  
Fatty Acid ◽  
Guinea Pig ◽  
Platelet Function ◽  
Abdominal Aorta ◽  
Intraperitoneal Administration ◽  
Sprague Dawley ◽  
Inhibitory Effects ◽  
Final Dose ◽  
Endogenous Production ◽  
Induced Aggregation

It has been suggested that ticlopidine may act to sensitize platelets to the effects of anti-aggregatory prostaglandins ( I2, E1, D2) or enhance endogenous production of such PG’s. Rats (male, Sprague Dawley, 280-575g, Simonsen, Gilroy, CA) or guinea pigs, (male, Hartley strain, 330-410g, Simonsen) were dosed o rally with ticlopidine hydrochloride (RS 99847) at 100 mg/kg for 3 days. At 2h following the final dose, platelet function (ADP-induced aggregation, retention by glass beads) was examined within 5 min of blood withdrawal via the abdominal aorta. In rats chronically maintained on a fat-free diet, there is a deficiency in tissue levels of essential fatty acid (EFA) precursors for PG biosynthesis. Consequently, a marked (∼90%) reduction in platelet PG production and vascular PGI2 production was seen. Under such conditions, administration of ticlopidine hydrochloride inhibited platelet function in a manner indistinguishable from that in control animals. Similarly, in both guinea pig and rat, intraperitoneal administration of indcmethacin (100 mg/kg) lh before the final dose of ticlopidine failed to interfere with the anti-plate let effects of ticlopidine, even though vascular PGI2 production (in thoracic aorta) was shown to be virtually abolished. It is concluded that EFA’s and their PG metabolites are not necessary for the platelet inhibitory effects of ticlopidine to be exerted.

Unsaturated fatty acids inhibit ADP- arachidonate-induced platelet aggregation without affecting thromboxane synthesis

1986 ◽  
Vol 64 (9) ◽  
pp. 906-913 ◽  
Author(s):  
Ella Dratewka-Kos ◽  
D. O. Tinker ◽  
Brigitte Kindl
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Platelet Aggregation ◽  
Unsaturated Fatty Acids ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Fatty Acid Inhibition ◽  
Induced Aggregation ◽  
Protein Free Medium

The inhibitory effects of three cis-unsaturated C18 fatty acids (oleic, linoleic, and linolenic acids, sodium salts) on ADP- and sodium-arachidonate-induced aggregation of washed rabbit platelets were investigated. When the platelets were suspended in protein-free medium containing dextran, it was found that these fatty acids at very low concentrations (2–45 μM) were potent inhibitors of platelet responsiveness and the inhibitory effect occurred within seconds. The inhibition of ADP-induced aggregation was not affected by abolishing the activity of platelet cyclooxygenase using aspirin. Human serum albumin relieved the inhibition caused by fatty acids for both ADP- and arachidonate-induced aggregation. The inhibitory effect of fatty acids does not seem to be due to decreased thromboxane formation (except possibly in the case of linolenate), and the relief of fatty acid inhibition by albumin does not potentiate thromboxane B2 formation from exogenous arachidonate. It is suggested that the inhibitory effect of polyunsaturated fatty acids on platelet aggregation is specific and not related to a general surfactant effect, since inhibition occurs far below the critical micelle concentration of fatty acid soaps.

Inhibitory effects of H2-receptor antagonists on platelet function in vitro

1999 ◽  
Vol 18 (8) ◽  
pp. 487-492 ◽  
Author(s):  
K Nakamura ◽  
H Kariyazono ◽  
T Shinkawal ◽  
T Yamaguchi ◽  
T Yamashita ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Chemical Structure ◽  
Adenosine Diphosphate ◽  
Imidazole Ring ◽  
Inhibitory Effects ◽  
Receptor Antagonists ◽  
Induced Aggregation

1 To evaluate in vitro inhibitory effects of four types of histamine H2-receptor antagonist (H2-receptor antagonists), famotidine, roxatidine, cimetidine and ranitidine, on platelet function, we examined aggregating potency and P-selectin levels with agonist-induced aggregation. Ranitidine and cimetidine inhibited, in concentration of 0.35 mM, the secondary aggregation induced by 5 pM adenosine diphosphate (ADP), the aggregation induced by 1,g/mL collagen and 3 gM arachidonic acid. All of H2-receptor antagonists inhibited, in concentration of 1.4 mm, the aggregation induced by ADP, collagen and arachidonic acid. Ranitidine and cimetidine reduced markedly, in same concentration, P-selectin levels after induction of aggregation by 5 gm ADP, 1 ig/xmL collagen and 3 gM arachidonic acid. When classified by the strength of inhibitory action, ranitidine and cimetidine were strong, followed by famotidine and roxatidine. 2 It is considered that inhibitory effects of H.-receptor antagonists on platelet function are weaker than those of acetylsalicylic acid (ASA), since ASA inhibited platelet aggregation in concentration of 100 MM. 3 No relationship was observed between inhibitory effects of H2-receptor antagonists on platelet aggregation induced by above agonists and the presence or absence of imidazole ring in the chemical structure.

The Effect of Halofenate or Halofenate Free Acid on Human, Rat and Guinea Pig Platelet Aggregation

1976 ◽  
Vol 35 (02) ◽  
pp. 358-363 ◽  
Author(s):  
D.H Minsker ◽  
P.T Jordan ◽  
P Kling ◽  
A MacMillan ◽  
H.B Hucker ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Guinea Pig ◽  
Plasma Levels ◽  
Human Platelet ◽  
Free Acid ◽  
Secondary Phase ◽  
Inhibitory Effects ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

SummaryHalofenate free acid (HFA), the major metabolite of the hypolipemic agent halofenate, blocked the secondary phase of human platelet aggregation induced by ADP, epinephrine, or thrombin; higher concentrations of clohbrate free acid (CFA) were required to produce similar inhibitory effects on platelet aggregation. HFA and CFA inhibited collagen-induced aggregation of human, rat, or guinea pig platelets. Halofenate orally administered to rats caused inhibition of collagen-induced aggregation when plasma levels of HFA exceeded 300 μg/ml, a clinically achievable human plasma concentration. The platelet inhibitory effects of clofibrate administration were less than those observed with halofenate administration.

Roles Of Cyclic Nucleotides In The Inhibition Of Platelet Function By Nitroprusside And By Ascorbate

1981 ◽  
Author(s):  
M M L Davidson ◽  
R J Haslam
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Platelet Function ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Human Platelets ◽  
Dense Granule ◽  
Inhibitory Effects ◽  
Maximum Value ◽  
Induced Aggregation

The effects of nitroprusside and of ascorbate on the collagen-induced aggregation of washed human platelets and on the associated release of dense granule constituents were correlated with their effects on platelet cyclic GMP and cyclic AMP, which were measured either by radioimmunoassays or prelabelling methods. Nitroprusside at concentrations from 1 to 400 μM increased platelet cyclic GMP from 6 to 100-fold (maximum value approx. 50 pmol/109 platelets) and at concentrations above 10 μM also increased cyclic AMP about 2-fold (maximum value approx. 36 pmol/109 platelets). Platelet cyclic GMP reached a peak after an incubation period inversely related to the nitroprusside concentration and then declined. Collagen, which increased platelet cyclic GMP about 2-fold, enhanced the effect of nitroprusside on cyclic GMP but not cyclic AMP. Freshly prepared ascorbate (10 mM) increased platelet cyclic GMP about 8-fold. Storage of the ascorbate at pH 7 or simultaneous addition of 5 μM CuCl2 potentiated its action to give 15 to 20-fold increases in cyclic GMP and small increases in cyclic AMP. The results suggested that oxidation of the ascorbate was involved in these effects. In all the above studies, increases in platelet cyclic GMP greater than 6 to 10-fold were associated with measurable increases in cyclic AMP and with inhibitions of collagen-induced platelet responses that roughly correlated with the cyclic nucleotide changes. Addition of 100 μM 2',5'-dideoxyadenosine (an inhibitor of adenylate cyclase) blocked increases in platelet cyclic AMP but did not affect increases in cyclic GMP; this compound also decreased (but did not abolish) the inhibitory effects of nitroprusside and of ascorbate + CuCl2 These findings suggested roles for both cyclic GMP and cyclic AMP in mediating the inhibitions of platelet function by nitroprusside and ascorbate.

Platelet Aggregation in Finnish Men and Its Relation to Fatty Acids in Platelets, Plasma and Adipose Tissue

1985 ◽  
Vol 54 (03) ◽  
pp. 563-569 ◽  
Author(s):  
M K Salo ◽  
E Vartiainen ◽  
P Puska ◽  
T Nikkari
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Platelet Aggregation ◽  
Acid Composition ◽  
Saturated Fatty Acids ◽  
Free Living ◽  
Ω3 Fatty Acids ◽  
Induced Aggregation

SummaryPlatelet aggregation and its relation to fatty acid composition of platelets, plasma and adipose tissue was determined in 196 randomly selected, free-living, 40-49-year-old men in two regions of Finland (east and southwest) with a nearly twofold difference in the IHD rate.There were no significant east-southwest differences in platelet aggregation induced with ADP, thrombin or epinephrine. ADP-induced platelet secondary aggregation showed significant negative associations with all C20-C22 ω3-fatty acids in platelets (r = -0.26 - -0.40) and with the platelet 20: 5ω3/20: 4ω 6 and ω3/ ω6 ratios, but significant positive correlations with the contents of 18:2 in adipose tissue (r = 0.20) and plasma triglycerides (TG) (r = 0.29). Epinephrine-induced aggregation correlated negatively with 20: 5ω 3 in plasma cholesteryl esters (CE) (r = -0.23) and TG (r = -0.29), and positively with the total percentage of saturated fatty acids in platelets (r = 0.33), but had no significant correlations with any of the ω6-fatty acids. Thrombin-induced aggregation correlated negatively with the ω3/6ω ratio in adipose tissue (r = -0.25) and the 20: 3ω6/20: 4ω 6 ratio in plasma CE (r = -0.27) and free fatty acids (FFA) (r = -0.23), and positively with adipose tissue 18:2 (r = 0.23) and 20:4ω6 (r = 0.22) in plasma phospholipids (PL).The percentages of prostanoid precursors in platelet lipids, i. e. 20: 3ω 6, 20: 4ω 6 and 20 :5ω 3, correlated best with the same fatty acids in plasma CE (r = 0.32 - 0.77) and PL (r = 0.28 - 0.74). Platelet 20: 5ω 3 had highly significant negative correlations with the percentage of 18:2 in adipose tissue and all plasma lipid fractions (r = -0.35 - -0.44).These results suggest that, among a free-living population, relatively small changes in the fatty acid composition of plasma and platelets may be reflected in significant differences in platelet aggregation, and that an increase in linoleate-rich vegetable fat in the diet may not affect platelet function favourably unless it is accompanied by an adequate supply of ω3 fatty acids.

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.

scholarly journals Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function

eJHaem ◽  
2021 ◽  
Author(s):  
Bibian M.E. Tullemans ◽  
Mieke F.A. Karel ◽  
Valentine Léopold ◽  
Marieke S. ten Brink ◽  
Constance C.F.M.J. Baaten ◽  
...  
Keyword(s):  
Platelet Function ◽  
Inhibitory Effects ◽  
Btk Inhibitors

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor

2021 ◽  
pp. 019262332110104
Author(s):  
Marjolein van Heerden ◽  
Wendy Roosen ◽  
Sophie Lachau-Durand ◽  
Graham Bailey ◽  
Anthony Ndifor
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
In Utero ◽  
Histological Evaluation ◽  
High Dose ◽  
Lens Fiber ◽  
Sprague Dawley ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group. On histological evaluation of the lenses from fetuses with/without gross findings, primary lens fiber hypertrophy (swelling) and degeneration were observed across vehicle- and JNJ-42165279-exposed fetuses. In a follow-up study to investigate the progression or resolution of the fetal lens changes, animals exposed to suprapharmacological doses of JNJ-42165279 in utero had higher incidence of nuclear cataracts as detected via slit-lamp ophthalmic examinations on postnatal days 18 to 21 and 35 to 41. No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279.

Effect Of Solvents On Indium-111 Oxine Transport In Human Platelets And On Platelet Function In Vitro

1981 ◽  
Author(s):  
T Tsukada
Keyword(s):  
Platelet Function ◽  
Kinetic Constant ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Polysorbate 80 ◽  
Autologous Plasma ◽  
Indium 111 ◽  
Induced Aggregation ◽  
Water Space

Mechanism of Indium-111 oxine(In) transport in human platelets in buffered saline and the effect of In-labeling on platelet function were studied using In dissolved in 25% of ethanol in saline (In-ES) or 0.01% of polysorbate 80 in HEPES buffer(In-PH). Increase in temperature up to 37° C progressively enhanced the transport of In-ES, while transport of In-PH reached to plateau at 15°C. A states of equilibrium was not reached during 2 hr incubation at 22°C in In-ES. Uptake of In-PH reached to plateau after only 15 min of incubation. Distribution of In taken up by platelets in InES was 57% in cytosol and 27% in stroma, while in In-PH 69% in stroma and 22% in cytosol. 88% of In in cytosol was bound to lipids(46% in cholesterol and 27% in PS+PI). 82% of In in stroma was found in PS+PI fraction.The fact that the ratio of free In between the platelet water space and the outside medium after 30 min of incubation at up to 0.1 uM of In exceeded unity, suggests satura- , ble component of In transport prevails at this concentration in In-ES and In-PH. Kinetic constant could be calculated, Kt= 2nM, Vmax= 2.5 pmol/min/ml in In-ES, and Kt= InM, Vmax=0.7 pmol/min/ml in In-PH.Elution of In from radiolableled platelets in autologous plasma incubated at 37°C for 5 hr was less than 10% in the case of In-ES and 56% in the case of In-PH. Less than 3% of labeled-In was eluated from platelets in collagen-induced aggregation and 4-7% of In was eluated in thrombin-induced aggregation.Although 0.3% of ethanol and/or 6nM of oxine have no inhibitory effect of platelet aggregation, collagen-induced aggregation and release reaction of In-labeled platelet was impaired. 0.003% of polysorbate 80 itself abolished completely the aggregability of platelets by collagen or thrombin.It is concluded In-PH is unsuitable for platelet labeling. In-111 oxine also seems to have problems which Cr-51 has, i.e. inhomogenous distribution of In in a platelet population, elution of In from labeled platelets in circulation.

Sign in / Sign up

Export Citation Format

Share Document