Induction of Diabetes Abolishes the Antithrombotic Effect of Clopidogrel in Apolipoprotein E–Deficient Mice

Sugidachi, Atsuhiro; Ohno, Kousaku; Jakubowski, Joseph A.; Ito, Yoshiharu; Tomizawa, Atsuyuki; Mizuno, Makoto

doi:10.1055/s-0037-1605361

Cited by 3 publications

(2 citation statements)

References 54 publications

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“…The animals (mice) were divided into 4 groups of 10 animals. The animals were administered GRS compound in 10 mg/kg dose or clopidogrel (Plavix®, 75 mg film-coated tablets, Sanofi Winthrop Industry, France, lot АА686, expiration date -01.04.2023) in median effective dose 10 mg/kg once orally for 3 days [4]. Control group rats received 0.5 % aqueous carboxymethyl cellulose solution.…”

Section: Thromboembolism Modelmentioning

confidence: 99%

Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Bykov

Bykova

Smol’yakova

et al. 2022

Razrabotka i registraciâ lekarstvennyh sredstv

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Introduction. The article presents the results of studying the antithrombotic activity of a novel drug, a soluble guanylate cyclase stimulator (codename -GRS), in experimental models of arterial and venous thrombosis and thromboembolism. Aim. Study the antithrombotic action of GRS compound in comparison with clopidogrel and rivaroxaban in the following models: arterial thrombosis induced by iron chloride application to carotid artery wall in rats; thromboembolism induced by intravenous administration of thrombin solution in mice; venous thrombosis induced by the ligature of inferior vena cava in rats. Materials and methods. Arterial thrombosis was modelled in rats by applying a pad soaked in iron chloride (FeCl 3 ) to the carotid artery, GRS compound was administered orally in median effective dose of 10 mg/kg once 3 hours before pad application. Blood flow in carotid arteries and blood clot mass were registered. Thromboembolism was induced in mice by intravenous administration of thrombin solution, GRS in dose 10 mg/kg or the reference drug clopidogrel were administered once orally daily for 3 days. Animal mortality, survival time and blood clot size were registered. Venous thrombosis was induced in rats by the ligature of inferior vena cava below renal veins, GRS in dose 10 mg/kg, reference drug rivaroxaban in 5 mg/kg dose or their combination in these doses were administered once orally 1 hour before vein ligature. The mass of dry and wet blood clots was registered. Results and discussion. In arterial thrombosis model GRS compound in 10 mg/kg, administered 3 hours before iron chloride application, increased the time to blood flow cessation in the carotid artery by 35 % and reduced the frequency of complete artery occlusion by 2 times compared to the control group (р < 0.05). 60 min after arterial thrombosis modelling complete occlusion was observed in 28 % of animals in GRS group and in 75 % of control animals, while after 24 hours the occlusion was observed in 14 % of animals in GRS group and in 50 % of control group animals (p < 0.05). In thrombin-induced thromboembolism model in mice GRS did not reduce the size of blood clots in pulmonary vessels, while clopidogrel reduced it by 48 %. In GRS group 80 % of animals died of thrombosis, compared to 30 % in clopidogrel group and 90 % in the control group. In ligature-induced venous thrombosis in rats GRS after single oral administration reduced the mass of dry blood clot, being as potent as rivaroxaban. Combined administration of GRS and rivaroxaban did not enhance their antithrombotic action. Conclusion. GRS after single oral administration in 10 mg/kg dose had potent antithrombotic action in models of arterial and venous thrombosis in rats, while not preventing pulmonary vessel thrombosis in mice after thrombin administration. Therapeutic action of GRS in experimental venous thrombosis was as potent as that of rivaroxaban. Antithrombotic action of GRS compound results not only from its antiplatelet action, but also from the alleviation of endothelial dysfuncti...

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Section: Thromboembolism Modelmentioning

confidence: 99%

Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Bykov

Bykova

Smol’yakova

et al. 2022

Razrabotka i registraciâ lekarstvennyh sredstv

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“…Finally, platelet inhibitory activity of clopidogrel was also shown to be reduced in DIO mice compared to controls [ 141 ]. In another preclinical study using wild-type apolipoprotein E (apoE) mice and diabetic apoE deficient mice, it was shown that platelet inhibition by clopidogrel was reduced in diabetic mice compared to wild-types [ 142 ].…”

Section: Clopidogrel: a Specific Example Of Phenoconversion In T2dmmentioning

confidence: 99%

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity

Darakjian

Deodhar

Turgeon

et al. 2021

IJMS

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Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

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Silibinin augments the effect of clopidogrel on atherosclerosis in diabetic ApoE deficiency mice

Zhang

Shi

et al. 2022

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BACKGROUND: Diabetes mellitus (DM) abolishes the antithrombotic effect of Clopidogrel. Here, we investigated the synergistic effect of Silibinin on Clopidogrel-mediated atherosclerosis treatment in diabetic mice. METHODS: ApoE–/– mice were fed with high-fat diet (HFD) to establish the atherosclerotic model with diabetes. Animals were treated with Clopidogrel, Silibinin, or the combined to evaluate the protective effects on atherosclerosis and diabetes through Oil-red-O staining, qRT-PCR, Western blot, and metabolic measurements. Platelet activation and aggregation ex vivo assays were performed to detect the anti-thrombotic effect of different administrations. RESULTS: Silibinin significantly enhanced the inhibitory effect of Clopidogrel on atherosclerosis in DM mice. Co-administration of Silibinin with Clopidogrel remarkedly reduced the aortic lesion, inflammation, and endothelial dysfunction in aorta roots, and diabetic symptoms were significantly improved by the Silibinin-Clopidogrel treatment in HFD-fed ApoE–/– mice. Interestingly, the anti-thrombotic effect of Clopidogrel was further augmented by the Silibinin treatment in atherosclerotic mice. CONCLUSION: In atherosclerotic mouse model, Silibinin significantly improves the effect of Clopidogrel on atherosclerosis.

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Induction of Diabetes Abolishes the Antithrombotic Effect of Clopidogrel in Apolipoprotein E–Deficient Mice

Cited by 3 publications

References 54 publications

Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity

Silibinin augments the effect of clopidogrel on atherosclerosis in diabetic ApoE deficiency mice

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