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  • In conclusion Factor Xa inhibitors edoxaban and rivaroxaban

    2022-01-14

    In conclusion, Factor Xa inhibitors (edoxaban and rivaroxaban) reduced PVs and SAN spontaneous activities in a concentration-dependent manner. FXa inhibitors may modulate occurrence of atrial fibrillation through PAR1 inhibition and INa-late reduction in PVs.
    Introduction Enzymes play crucial functional roles in all biological processes, such as modulation of cellular activities [1]. Enzyme activities are naturally linked to disease states such as cancer [2], Alzheimer's disease [3], human immunodeficiency virus (HIV) [4] and diabetics [5]. Therefore, diltiazem hcl have become one of the most attractive drug targets [6]. The importance of enzymes has led to extensive efforts in the screening of their inhibitors as potential drugs. Disorders of coagulation are pathological states which can contribute to bleeding or thrombosis. Thrombosis is one of the most common causes of cardiovascular-associated death in the developed world [7], [8], [9]. Inhibition of abnormal thrombus formation is important in the prevention and treatment of such thromboembolic disorders. One of the strategies to treat thrombotic diseases implies the treatment by anticoagulants targeting the coagulation cascade [10]. The coagulation cascade is a complex process, mediated by a group of tightly regulated plasma proteases and cofactors. In theory, the inhibition of any enzyme in the coagulation cascade should reduce the formation of thrombus. Thus, targeting the proteases and cofactors by small molecular regulators provides an opportunity for the development of therapeutics for the treatment of thrombotic disease [11], [12]. Among the enzymes in the cascade, thrombin and factor Xa (FXa) have been intensively investigated [13]. Thrombin plays a key role as a procoagulant by converting fibrinogen to active fibrin [14]. FXa, a trypsin-like serine protease, is positioned at a common junction of the intrinsic and extrinsic pathways in the blood coagulation cascade. It has been demonstrated that the selective inhibition of FXa could provide an anticoagulant effect by blocking the amplified formation of thrombin without influencing the existing level of circulating thrombin [15]. For these reasons, thrombin and FXa represent valid drug targets for the design of new anticoagulants and significant efforts have been made in developing inhibitors of these coagulation factors [16]. Several assays for the determination of the activity of thrombin and FXa and screening of inhibitors have been established. The majority of these assays are based on fluorescent or chemiluminescent detection techniques [17], [18], [19]. Although these fluorescence-based assays are very convenient, reproducible and fast for measuring enzyme activities, they have the disadvantage of potential interference from the autofluorescence of compounds which may result in false positive or false negative results [20], [21]. An accurate, rapid, and cost-effective methodology for enzyme inhibitor assays is still highly needed to screen the efficacy of compounds at the molecular level. In the past decade, mass spectrometry (MS) has been extensively reported for measuring the conversion of substrates to products for enzyme assays and assaying inhibition of enzyme-mediated reactions [21], [22], [23], [24]. Kinetic studies and inhibition assays of various enzymes were performed using combinations of chromatographic and electrophoretic separation methods with ESI-MS, such as liquid chromatography (LC)/MS [25], [26], LC/tandem mass spectrometry (MS/MS) [27], [28], gas chromatography (GC)/MS [29], frontal affinity chromatography (FAC)/MS [30], or capillary electrophoresis (CE)/MS [31], [32]. Recently, several groups have developed integrated analytical approaches which combined the separation of mixtures with liquid chromatography and the identification of thrombin and FXa inhibitors in the mixture with a mass spectrometer in parallel [33], [34]. The development of screening assays that can simultaneously detect inhibition of multiple enzymes could provide a method to rapidly identify active compounds against targets of anticoagulants. To our knowledge, a simultaneous method for measuring the activity of anticoagulant enzymes has not been reported. The lack in existing assays for the rapid multi-target screening of anticoagulant prompted us to develop a dual-target enzyme assay upon mass spectrometry.