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Direct Oral Anticoagulants: New Options
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The first clinically applied anticoagulants were heparin and vitamin K antagonists (VKA), both accidentally discovered. They proved to be very effective antithrombotics and have routinely been used for more than 50 years despite their respective shortcomings. With the development of various low molecular weight heparins (LMWH) in the 1980s, the short- and medium-time parenteral anticoagulation was much improved. In contrast, the long-term oral anticoagulation was limited to the VKA warfarin, phenprocoumon and acenocoumarol for further 30 years. Only in 2008, the first two direct oral anticoagulants (DOAC) (syn. non-vitamin K oral anticoagulants, NOAC) were approved by the European Commission (EC), namely the direct thrombin inhibitor (DTI) dabigatran etexilate (Pradaxa®) and the direct factor Xa inhibitor (DXI) rivaroxaban (Xarelto®). After the approval of the DXI apixaban (Eliquis®) in 2011 and the DXI edoxaban (Lixiana®) in 2015, there are currently four DOAC on the market and increasingly used in clinical practice.
Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Several thrombin inhibitors have been developed during the past couple of decades and proved their efficacy as anticoagulants. Hirudin is one of the most important, naturally occurring thrombin inhibitor molecule isolated from leach. Administration of hirudin has been associated with increased risk of bleeding as well as formation of non-neutralizing antibodies in patients (Hoppensteadt et al., 2008). Later, many thrombin inhibitors with better efficacy and therapeutic potential have been developed such as argatroban, bivalirudin, lepirudin, and dabigatran etexilate. The first used thrombin inhibitor is argatroban and it is now widely used in Japan. It was recommended as an alternate anticoagulant for patients suffering from HIT and its clinical use significantly reduced bleeding complications in comparison to heparin (Lewis et al., 2001, 2003). Bivalirudin is a bivalent reversible inhibitor and when compared to heparin and LMWHs, they declined the bleeding complications by almost 50%, whereas the efficacy remained same for all of them (Carswell and Plosker, 2002; Ahrens et al., 2007). Another thrombin inhibitor lepirudin was found to be marginally superior to heparin and more suitable for patients with previously reported HIT though continuous monitoring is required here also (Lubenow et al., 2004). Dabigatran etexilate is an oral prodrug that would get converted into active dabigatran, a direct thrombin inhibitor, upon intestinal absorption (Lee and Ansell, 2011). All those thrombin inhibitors described here are FDA approved for preventing various cardiovascular diseases.
Imaging of Cardiovascular Disease
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Aleksandra Kalinowska, Lawrence W. Dobrucki
Imaging enhancers targeted at factor XIII have been employed. When active, factor XIII acts as a glutaminase that cross-links selected substrates to extracellular matrix proteins. A radiolabeled substrate analogue, 111In-DOTA-FXIII, was applied, and after a short period of time, it gets accumulated in areas of increased factor XIII activity. A study in a murine model of MI has been conducted, where decreased levels of this 111In-labeled peptide substrate were noted in animals treated with dalteparin, a direct thrombin inhibitor. After dalteparin treatment, the animals showed increased risk of infarct rupture, while mice with injected factor XIII presented increased factor XIII activity in the infarct zone and increased collagen synthesis as well as capillary density, suggesting improved post-MI healing (Nahrendorf et al. 2008a).
Immobilizing argatroban and mPEG-NH2 on a polyethersulfone membrane surface to prepare an effective nonthrombogenic biointerface
Published in Journal of Biomaterials Science, Polymer Edition, 2019
Yanling Dai, Siyuan Dai, Xiaohui Xie, Jianping Ning
Argatroban (AG), a synthetic direct thrombin inhibitor that does not require a co-factor to impart activity, has been developed to provide superior nonthrombotic efficacy to heparin [7, 34–36]. First, AG can not only reversibly and selectively inhibit plasma-free and clot-bound thrombin but can also inhibit protein C, several procoagulant factors and platelet aggregation [37–39]. Second, as a homogeneous synthetic molecule, AG does not generate heparin/PF4 complex antibodies; thus, it cannot lead to heparin-induced thrombocytopenia, and it is a suggested treatment for patients with acute HIT who are undergoing hemodialysis [40–41].
Structural basis of different surface-modified fullerene derivatives as novel thrombin inhibitors: insight into the inhibitory mechanism through molecular modelling studies
Published in Molecular Physics, 2021
Zhijie Yang, Yongfeng Wan, Jingwen E, Zhijian Luo, Shanshan Guan, Song Wang, Hao Zhang
Thrombin inhibitors can block enzyme activity by binding to any of the three regions, including the active site, exosite I, or exosite II. For example, agatroban [19] acts as a competitive inhibitor by binding to the active site, hirudin [20] and bivalirudin [21] can interact with exosite I to inhibit thrombin, and exosite II is the region of action of heparin [22]. The inhibitors that act at the active site and the exosite I region are called direct thrombin inhibitors [23]. The anticoagulant response of direct inhibitors is predictable and unaffected by platelet factors and is the main direction of research and development [24].