scholarly journals Semi-Mechanistic Modeling of HY-021068 Based on Irreversible Inhibition of Thromboxane Synthetase

2020 ◽  
Vol 11 ◽  
Author(s):  
Ping Li ◽  
Jie Huang ◽  
Donghao Geng ◽  
Peihua Liu ◽  
Zhaoxing Chu ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Oral Administration ◽  
Prediction Interval ◽  
Visual Predictive Check ◽  
Mechanistic Modeling ◽  
Photometric Method ◽  
Beagle Dogs ◽  
Irreversible Inhibition ◽  
Thromboxane Synthetase

Background: HY-021068 [4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate], developed by Hefei Industrial Pharmaceutical Institute Co., Ltd. (Anhui, China), is a potential thromboxane synthetase inhibitor under development as an anti-platelet agent for the treatment of stroke. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the PK of HY-021068 and its platelet aggregation inhibitory effect in beagle dogs.Method: Beagle dogs received single oral administration of 2.5 mg/kg HY-021068 or consecutively oral administration of 5 mg/kg HY-021068 once daily for 7 days. The plasma concentration of HY-021068 and the platelet aggregation rate (PAR) were determined by liquid chromatography tandem-mass spectrometry (LC‐MS/MS) assay and a photometric method, respectively. The PK/PD data was sequentially fitted by Phoenix NLME. The PK/PD parameters of HY-021068 in beagle dogs were estimated by 2.5 and 5 mg/kg dosing on the 1st day, and then used to simulate the PAR of HY-021068 on the 7th day after 5 mg/kg dosing daily.Result: A one-compartment model with saturable Michaelis-Menten elimination was best fitted to the PK of HY-021068. A mechanistic PD model based on irreversible inhibition of thromboxane synthetase was constructed to describe the relationship between plasma concentration of HY-021068 and PAR. Diagnostic plots showed no obvious bias. Visual predictive check confirmed the stability and reliability of the model. Most of PK/PD observed data on the 7th day after 5 mg/kg dosing fell in the 90% prediction interval.Conclusion: We established a semi-mechanistic PK/PD model for characterizing the PK of HY-021068 and its anti-platelet effect in beagle dogs. The model can be used to predict the concentration and PAR under different dosage regimen of HY-021068, and might be served as a reference for dose design in the future clinical studies.

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 Lipid peroxidation, prostacyclin and thromboxane A2 in pigs depleted of vitamin E and selenium and supplemented with linseed oil

1995 ◽  
Vol 74 (3) ◽  
pp. 369-380 ◽  
Author(s):  
Maeve R. Nolan ◽  
Seamus Kennedy ◽  
W. John Blanchflower ◽  
D. Glenn Kennedy
Keyword(s):  
Lipid Peroxidation ◽  
Arachidonic Acid ◽  
Vitamin E ◽  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Linseed Oil ◽  
Thromboxane A2 ◽  
Dietary Factors ◽  
Biochemical Effects ◽  
Skeletal Myopathy

In a 2×2 balanced factorial experiment the biochemical effects on pigs of two dietary factors were investigated. The first factor was α-tocopherol and Se supplementation and the second factor was supplementation with α-tocopherol-stripped linseed oil. In pigs fed on diets depleted of α-tocopherol and Se, increases in concentrations of markers of lipid peroxidation (4-hydroxynonenal and hexanal) were observed. However, skeletal myopathy was only observed in those pigs fed on diets depleted of α-tocopherol and Se and supplemented with oil. In those pigs, increased lipid peroxidation was observed in heart and supraspinatus muscle. The plasma concentration of thromboxane B2 was increased in pigs fed on diets depleted of α-tocopherol and Se, suggesting an increased tendency towards platelet aggregation. However, this change was reversed in pigs depleted of α-tocopherol and Se, but supplemented with oil. This may have been a consequence of loss of arachidonic acid, the substrate for thromboxane formation, as a result of lipid peroxidation.

scholarly journals High molecular weight kininogen inhibits thrombin-induced platelet aggregation and cleavage of aggregin by inhibiting binding of thrombin to platelets

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 500-507 ◽  
Author(s):  
RN Puri ◽  
F Zhou ◽  
CJ Hu ◽  
RF Colman ◽  
RW Colman
Keyword(s):  
Molecular Weight ◽  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Human Plasma ◽  
Shape Change ◽  
Dependent Manner ◽  
Normal Human Plasma ◽  
High Molecular Weight Kininogen ◽  
Normal Human ◽  
Dose Dependent

In this study we show that high molecular weight kininogen (HK) inhibited alpha-thrombin-induced aggregation of human platelets in a dose-dependent manner with complete inhibition occurring at plasma concentration (0.67 mumol/L) of HK. HK (0.67 mumol/L) also completely inhibited thrombin-induced cleavage of aggregin (Mr = 100 Kd), a surface membrane protein that mediates adenosine diphosphate (ADP)- induced shape change, aggregation, and fibrinogen binding. The inhibition of HK was specific for alpha- and gamma-thrombin-induced platelet aggregation, because HK did not inhibit platelet aggregation induced by ADP, collagen, calcium ionophore (A23187), phorbol myristate acetate (PMA), PMA + A23187, or 9,11-methano derivative of prostaglandin H2 (U46619). These effects were explained by the ability of HK, at physiologic concentration, to completely inhibit binding of 125I-alpha-thrombin to washed platelets. As a result of this action of HK, this plasma protein also completely inhibited thrombin-induced secretion of adenosine triphosphate, blocked intracellular rise in Ca2+ in platelets exposed to alpha- and gamma-thrombin, inhibited thrombin- induced platelet shape change, and blocked the ability of thrombin to antagonize the increase in intracellular cyclic adenosine monophosphate (cAMP) levels induced by iloprost. Because elevation of cAMP is known to inhibit binding of thrombin to platelets, we established that HK did not increase the intracellular concentration of platelet cAMP. Finally, HK did not inhibit enzymatic activity of thrombin. To study the role of HK in the plasma environment, we used gamma-thrombin to avoid fibrin formation by alpha-thrombin. Platelet aggregation induced by gamma- thrombin was also inhibited by HK in a dose-dependent manner. The EC50 (concentration to produce 50% of the maximum rate of aggregation) of gamma-thrombin for washed platelets was 7 nmol/L and increased to 102 nmol/L when platelets were suspended in normal human plasma. The EC50 for platelet aggregation induced by alpha-thrombin in plasma deficient in total kininogen was 40 nmol/L. When supplemented with HK at plasma concentration (0.67 mumol/L), the EC50 increased to 90 nmol/L, a value similar to that for normal human plasma. These results indicate that (1) HK inhibits thrombin-induced platelet aggregation and cleavage of aggregin by inhibiting binding of thrombin to platelets; (2) HK is a specific inhibitor of platelet aggregation induced by alpha- and gamma- thrombin; and (3) HK plays a role in modulating platelet aggregation stimulated by alpha-thrombin in plasma.

scholarly journals Prodrugs of 2',3'-dideoxyinosine(DDI): Synthesis and plasma concentration of DDI in rats via oral administration of an oil formulation.

1992 ◽  
Vol 7 (3) ◽  
pp. 203-207
Author(s):  
Takeo Kawaguchi ◽  
Tetsuya Hasegawa ◽  
Toshinobu Seki ◽  
Kazuhiko Juni ◽  
Yasunori Morimoto ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Oil Formulation

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.

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