Corrigendum to ‘Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro’ [Biochem. Pharmacol. 148 (2018) 288–297]

2区 · 医学

Article

作者: Farndale, Richard W ; Prakash, Prem ; Aggarwal, Hobby ; Bihan, Dominique ; Dikshit, Madhu ; Kumar, Sachin ; Misra, Ankita ; Prakash Pandey, Chandra ; Pugh, Nicholas ; Dhankani, Priyanka ; Kumar Barthwal, Manoj ; Kumar Dikshit, Dinesh

2018-02-01·Biochemical Pharmacology2区 · 医学

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

2区 · 医学

Article

作者: Dikshit, Dinesh Kumar ; Prakash, Prem ; Farndale, Richard W ; Aggarwal, Hobby ; Barthwal, Manoj Kumar ; Bihan, Dominique ; Dikshit, Madhu ; Kumar, Sachin ; Misra, Ankita ; Pugh, Nicholas ; Dhankani, Priyanka ; Pandey, Chandra Prakash

Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2-fold) and maintained a sustained blood flow velocity for >30 min. Comparatively, clopidogrel showed significant prolongation in TTO (1.3-fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained hemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7-fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300 µM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV₅₀ (53.4 ± 5.7%). Mechanistically, S007-867 (10-300 μM) inhibited collagen-induced ATP release, thromboxane A₂ (TxA₂) generation, intra-platelet [Ca⁺²] flux and global tyrosine phosphorylation including PLCγ2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings.

2015-06-03·Xenobiotica4区 · 医学

Pharmacokinetics and tissue distribution study of novel potent antiplatelet agent S007-867 in mice using HPLC-MS/MS

4区 · 医学

Article

作者: Dinesh K. Dikshit ; K. S. Anil Kumar ; Tulsankar Sachin Laxman ; Yashpal S. Chhonker ; Yarra Durga Prasad ; Hardik Chandasana ; Rabi S. Bhatta

1. S007-867 is a novel antiplatelet agent that shows promising in vitro and in vivo efficacy. For further development and better pharmacological elucidation, we characterized pharmacokinetics and tissue distribution of S007-867 in a mouse model. 2. A sensitive, selective and robust LC-MS/MS method was developed and validated in the mouse plasma and tissue for quantification of S007-867. The chromatographic separation was performed on Waters Symmetry Shield C18 column (150 × 4.6 mm, 5 µm) using methanol and ammonium acetate buffer. 3. S007-867 was rapidly absorbed and distributed to various tissues. Following single oral administration of S007-867 in the mouse, the concentration was in the order of C intestine > C liver > C kidney > C heart > C spleen > C lungs > C brain. Tissue to plasma area under the plasma curve ratio suggested that the maximum amount of drug was found in the intestine and liver. Half life of S007-867 was found longer in the heart (8.08 h), spleen (∼ 7.94 h) and kidney (∼ 15.41 h) as compared with other tissues. 4. The preclinical pharmacokinetics and tissue distribution data obtained using this LC-MS/MS method are expected to assist the future clinical investigations of S007-867 as a promising antiplatelet agent.

100 项与 S-007-867 相关的药物交易

登录后查看更多信息