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Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
Beneficial effects of TP receptor inhibition have been attested by many animal studies. Daltroban, a TP receptor antagonist, was found to decrease the progression of atherosclerosis in cholesterol-fed rabbits (Metz et al., 1991). Terutroban, another antagonist, exhibited antithrombotic action by inhibiting fibrinogen and platelet deposition in a porcine model (Osende et al., 2004; Vilahur et al., 2007). The regression of atherosclerotic lesions has been observed in a rabbit atherosclerosis model after 6 months of terutroban treatment (Viles-Gonzalez et al., 2005). In an earlier study, terutroban was found to reduce serum levels of the stable metabolite of TxA2, TxB2, and significantly decreased serum levels of ICAM-1 and aortic root-lesion formation in mice (Cayatte et al., 2000).
Antiplatelet therapy in interventional cardiology
Published in John Edward Boland, David W. M. Muller, Interventional Cardiology and Cardiac Catheterisation, 2019
Thromboxane receptors, which mediate thromboxane A2‐induced platelet activation, have been an area of interest, as despite aspirin blockade of COX-1, platelets continue to be exposed to thromboxane A2.63 Various thromboxane receptor antagonists (picotamide, ridogrel, terutroban) have been trialled with overall disappointing results. 64–66
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Because of their role in thromboxane synthesis, TBXAS1 inhibitors and thromboxane A2 receptor antagonists have been a great interest for many years for their potential use in preventing platelet aggregation. Drugs with dual action, such as dual TBXAS1 inhibitors/thromboxane A2 receptor antagonist and dual COX-1/thromboxane A2 receptor antagonists, are currently in clinical development with the hope of providing a better, more complete inhibition of the thromboxane A2 pathway. For example, ifetroban is a potent and selective thromboxane A2 receptor antagonist; dipyridamole antagonizes this receptor too; picotamide has activity both as a TBXAS1 inhibitor and as a thromboxane A2 receptor antagonist. These inhibitors often contain a basic nitrogen atom that binds to the CYP5A1 heme. Terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial fails to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke (Bousser et al. 2011).
The antithrombosis effect of dehydroandrographolide succinate: in vitro and in vivo studies
Published in Pharmaceutical Biology, 2022
Bowen Yin, Shuhua Zhang, Yuxi Huang, Yuanzhu Long, Yiguo Chen, Shiyun Zhao, Aiqun Zhou, Minghua Cao, Xiaoming Yin, Daya Luo
In current clinical treatment, certain side effects have been observed during the use of commonly employed antiplatelet agents for targeted primary hemostasis, such as thrombin inhibitors, ADP receptor inhibitors, and cyclooxygenase (COX) inhibitors. For example, because of the non-selective inhibition of COX by aspirin, low reactivity, serious side effects, gastrointestinal haemorrhage, and other problems may occur during treatment (Group et al. 2018). The thromboxane receptor inhibitor terutroban exerts a secondary preventive effect on patients with thrombotic cerebral ischaemia, but the haemorrhagic side effects of terutroban are still slightly higher than those of aspirin (Bousser et al. 2011; Lee and Ovbiagele 2011). Clopidogrel also has the problem of low reactivity and bioavailability in some patients. Aspirin combined with clopidogrel is often used for antiplatelet aggregation therapy; however, the risk of haemorrhage has not been effectively improved (Yusuf et al. 2001; Bates et al. 2011; Katsanos et al. 2015), and in some patients, this treatment also causes problems such as decreases in the numbers of neutrophils and platelets and aplastic anaemia (Maurício et al. 2014). Therefore, demand for antiplatelet aggregation drugs with high efficiency, low toxicity, a low haemorrhage risk, and low prices in clinical practice is still great.
Cilostazol for treatment of cerebral infarction
Published in Expert Opinion on Pharmacotherapy, 2018
Kensuke Noma, Yukihito Higashi
In a meta-analysis that was conducted in 2015 by analyzing the results of 24 randomized trials that included 85,667 patients [55], Xie et al. showed that cilostazol treatment significantly reduced recurrence of stroke compared with that in patients who received aspirin (odds ratio, 0.66; 95% CI, 0.44–0.92) and that in patients who received dipyridamole (odds ratio, 0.57; 95% CI, 0.34–0.95). Cilostazol treatment also significantly reduced the rate of recurrence of intracranial hemorrhage compared with the rates of recurrence in patients who received aspirin, clopidogrel, terutroban, ticlopidine, aspirin plus clopidogrel, and aspirin plus dipyridamole. They concluded that long-term monotherapy is a better choice than long-term dual therapy and that cilostazol has the best risk-benefit for long-term secondary prevention after stroke or TIA.