Antithrombotic Effects of Montelukast by Targeting Coagulation Factor XIa
Dong WangYang ZhouYingying QiMeiru SongHuiqiao YaoChristopher LiaoHaili LinMeijuan HuangDexiang ZhuoLongguang JiangCai YuanYuanzhong ChenMingdong HuangJinyu LiPeng Xu
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Abstract Current oral anticoagulants prescribed for the prevention of thrombosis suffer from severe hemorrhagic problems. Coagulation factor XIa (FXIa) has been confirmed as a safer antithrombotic target as intervention with FXIa causes lower hemorrhagic risks. In this study, by a high-throughput virtual screening, we identified Montelukast (MK), an oral antiasthmatic drug, as a potent and specific FXIa inhibitor (IC 50 = 0.17 µM). Compared with the two mostly prescribed anticoagulants (Warfarin and Apixaban), MK demonstrated comparable or even higher antithrombotic effects in three independent animal models. More importantly, in contrast to the severe hemorrhage caused by Warfarin or Apixaban, MK did not measurably increase blood loss in vivo . In addition, MK did not affect the hemostatic function in plasma from healthy individuals. In contrast, MK suppressed clot formation in clinical hypercoagulable plasma samples. This study provides a lead compound of anticoagulants targeting FXIa, and suggests the exploratory clinical researches on antithrombotic therapies using MK.Keywords:
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This study was designed to compare effectiveness and safety of warfarin, direct thrombin inhibitor dabigatran, Xa factor inhibitors rivaroxaban and apixaban used to prevent stroke in 280 elderly patients in patients with age-specific non-valvular atrial fibrillation. The treatment of patients aged 65-74 and 75-80 yearsfor 2 years with dab itragan (110 mg b.i.d), apixaban (5 mg b. i. d), and rivaroxaban (20 mg once daily) prevented stroke as effectively as warfarin therapy but less frequently caused severe intracranial hemorrhage. It is concluded that these new anticoagulants can be used as alternative medication for antithrombotic therapy of elderly patients with age-specific non-valvular atrialfibrillation.
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The fundamental treatment of atrial fibrillation is based on maintenance of sinus rhythm or control of ventricular rate and preventing arterial thromboembolism. Warfarin has been the anti-thrombotic agent of choice for the last 50 years. However multiple interactions with other drugs and certain types of food and vegetables with high Vitamin K content complicate its use. It also requires multiple blood tests to adjust the dose in order to reach adequate and stable anticoagulation. Three new, di-fferent anti thrombotic agents are described. They are as or more effective than Warfarin with decreased incidence of hemorrhagic events. Dabigratan is a direct antithrombotic inhibitor, Rivaroxaban and Apixaban inhibits factor Xa. Their use will probably depend on their cost effectiveness in the population at risk for thromboembolic events.
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We compared efficacy and safety of warfarin with those of direct thrombin inhibitor dabigatran, factor Xa inhibitors rivaroxaban and apixaban used for stroke prevention in 280 patients aged 65-80 years with non-valvular atrial fibrillation. Treatment for two years with dabigatran (110 mg twice daily), apixaban (5 mg twice daily) or rivaroxaban (20 mg/day) prevented strokes no less successfully than warfarin, but more rarely caused severe intracranial hemorrhages. When selecting antithrombotic therapy in geriatric patients with non-valvular AF new oral anticoagulants may be regarded as an acceptable alternative to warfarin.
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Venous thromboembolism (VTE) is a major public health concern since the incidence of VTE rises substantially with age. Furthermore, the diagnosis can be elusive since patients can present differently, causing delay in diagnosis and initiation of treatment and resulting in major morbidity and mortality. In addition to accuracy and precision in diagnosis, antithrombotic therapies are the cornerstones of VTE management. In traditional paradigm, vitamin K antagonists (warfarin), indirect factor Xa inhibitors, and heparin are the foundation in management of VTE. Warfarin has been the only available oral anticoagulant therapy for several decades. Although warfarin is effective in both treatment and prophylaxis against VTE, there are several limitations. Therefore, the novel anticoagulation therapies, including rivaroxaban, apixaban, and dabigatran etexilate, have apparent advantages over warfarin in terms of clinical efficacy and adverse effects. The objective of this review is to describe the background and clinical implications of these novel anticoagulants.
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Abstract Rationale, aims and objectives The decision‐making around antithrombotics in atrial fibrillation requires comprehensive risk versus benefit assessment. In view of the availability of novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban and apixaban, a decision support tool designed to assist the selection of antithrombotics has been modified to consider both warfarin and NOACs. This study aims to pre‐test this modified decision support tool. Methods The decision support tool was modified to consider either warfarin or NOACs as first‐line therapy and applied to data pertaining to a cohort of 393 patients in New South Wales. Results Overall, 380 (96.7%) patients were eligible for oral anticoagulants. In the scenario of warfarin being recommended as first‐line therapy, the Computerised Antithrombotic Risk Assessment Tool version 2.0 ( caratv2.0 ) recommended warfarin for 360 (91.6%) patients, any NOAC for 5 (1.3%) patients, either rivaroxaban or apixaban for 6 (1.5%) patients and apixaban for 9 (2.2%) patients. In the scenario of NOACs as first‐line therapy, caratv2.0 recommended any NOAC for 279 (70.9%) patients, either rivaroxaban or apixaban for 80 (20.4%) patients, apixaban for 9 (2.3%) patients and warfarin for 12 (3.1%) patients. Key reasons for caratv2.0 to recommend a change from warfarin (patients' current therapy) to NOACs included known warfarin allergy/adverse reaction, a history of intracranial bleeding, and previous gastrointestinal bleeding. Key predictors for caratv2.0 to consider that patients are more suitable for NOACs over warfarin were a diagnosis of other gastrointestinal diseases, more co‐morbidities and high risk of falls. Conclusions According to this decision support tool, both warfarin and NOACs are viable treatment options in majority of the patients, but there is a scope for better rationalization of therapy.
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The capabilities of antithrombotic therapy to prevent systemic thromboembolic events in nonvalvular atrial fibrillation (AF) are substantially extended after clinically introducing novel oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, and apixaban. World clinical experience with NOACs in AF has confirmed their efficacy and safety in both primary and secondary stroke prevention. At the same time, apixaban additionally reduces the risk of fatal outcomes and it is the safest among the NOACs against hemorrhagic events. The low risks of intracranial hemorrhage typical of NOACs should be taken into account when choosing oral anticoagulant therapy after hemorrhagic stroke in patients at high risk for thromboembolic events due to AF. Whether NOACs may be used in acute myocardial infarction and during coronary stenting in the presence of nonvalvular AF, left ventricular thromboses, and cardiomyopathies is considered. In real clinical practice, nonvalvular AF may be accompanied by different cardiovascular diseases, by creating the situations where there are no specific guidelines for the use of NOACs. The results of comparing the clinical efficiency of different antithrombotic therapy regimens, the subanalysis of randomized trials, and experts’ opinions may assist a physician to substantiate their decisions. Thus, just a few NOACs that are similar and/or superior to warfarin in efficacy and safety have emerged to date. There are grounds to believe that many physicians will prefer direct anticoagulants to warfarin not only because of their proven efficacy, but also the rapid onset of their anticoagulant effect, neither interaction with a number of foods or drugs, and above all, nor need for regular laboratory blood testing. World post-marketing surveillance and new clinical tests will be helpful in better estimating the benefits and risks of treatment with NOACs and in expanding indications for their use, which will considerably enhance the possibilities of preventing thromboembolic events in cardiac pathology in the period ahead.
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