Novel Anticoagulant Therapy: Principle and Practice

Mousa, Shaker A.

doi:10.1007/978-1-60761-803-4_5

Cited by 27 publications

(6 citation statements)

References 75 publications

(57 reference statements)

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“…Oral anticoagulant drugs and platelet inhibitors have been developed to prevent thrombotic events in high-risk patients. Parenteral anticoagulant drugs have been developed for surgical procedures [3] , [5] , [6] . The causes of thrombosis are manifold and treatment thus requires adapted approaches employing distinct medications and combinations thereof.…”

Section: Introductionmentioning

confidence: 99%

Exploring potential anticoagulant drug formulations using thrombin generation test

Zavyalova

Копылов

2016

Biochemistry and Biophysics Reports

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SummaryMany anticoagulant drugs inhibiting proteins of the coagulation cascade have been developed. The main targets of anticoagulant drugs are thrombin and factor Xa; inhibiting these factors delays thrombus growth, thus preventing thrombosis while increasing bleeding risk. A balance between thrombosis and bleeding is ensured in the ‘therapeutic window’ of the anticoagulant drug concentration range. Novel anticoagulant drugs and combinations thereof are being developed. We rank coagulation factors as potential anticoagulant drug targets in combination with thrombin inhibitors, aptamer HD1 and bivalirudin, providing a background for several promising dual target treatment strategies.The thrombin generation test was used to assess the whole coagulation cascade in normal and factor-deficient human blood plasma. Potential therapeutic windows were estimated for coagulation factors, ranking them as targets for anticoagulant drugs. Thrombin and factor Xa have been revealed as the most promising targets, which fully agrees with the current drug development strategy. Inhibitors of factors Va and VIIa are expected to have narrow therapeutic windows. Inhibitors of factors VIIIa and IXa are expected to have a moderate anticoagulant effect. Factors XI and XII are poor targets for anticoagulant drugs. Compared with plasma that is deficient in factor II, the thrombin inhibitors bivalirudin and aptamer HD1 had increased activity. Both inhibitors were tested in deficient plasma providing a model of potential drug combination. The most promising combinations were anti-thrombin with anti-V/Va and also anti-thrombin with anti-IX/IXa. Each combination had an incremental dose-effect dependence that is promising from the standpoint of the therapeutic window.

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Section: Introductionmentioning

confidence: 99%

Exploring potential anticoagulant drug formulations using thrombin generation test

Zavyalova

Копылов

2016

Biochemistry and Biophysics Reports

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“…The discovery of safe, selective, and orally available anticoagulants has proved to be a challenging endeavor, primarily due to the serious side effects (e.g. bleeding and liver toxicity) of the compounds considered so far, limiting their therapeutic application [1]. Therefore, the development of new synthetic direct thrombin inhibitors (DTI) has been the focus of intense research [2], [3].…”

Section: Introductionmentioning

confidence: 99%

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

et al. 2012

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The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both l- and d-amino acids, with the general sequence d-Phe(P3)-Pro(P2)-d-Arg(P1)-P1′-CONH2. The P1′ position was scanned with l- and d-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P1′ position. The lead tetrapeptide, d-Phe-Pro-d-Arg-d-Thr-CONH2, competitively inhibits α-thrombin's cleavage of the S2238 chromogenic substrate with a Ki of 0.92 µM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P1′ l-isoleucine (fPrI), l-cysteine (fPrC) or d-threonine (fPrt)) in complex with human α-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the d-Arg residue in position P1 and thrombin are similar to those observed for the l-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 d-Arg and a bulkier P1′ residue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational constrains imposed by the d-stereochemistry of the residues at positions P1 and P1′.

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“…This question is all the more crucial because the use of VKAs is widespread in older adults. Clinical trials are now warranted to explore the effect on cognition of the use of VKAs in large samples of adults, against that of DOACs, whose indications are similar, but whose mechanism does not interfere with vitamin K [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin K Antagonists and Cognitive Decline in Older Adults: A 24-Month Follow-Up

et al. 2018

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Vitamin K participates in brain physiology. This study aimed to determine whether using vitamin K antagonists (VKAs), which interfere with the vitamin K cycle, were (i) cross-sectionally associated with altered cognitive performance, and (ii) independent predictors of cognitive changes in older adults over 24 months. Information was collected on the use of VKAs (i.e., warfarin, acenocoumarol, and fluindione) among 378 geriatric outpatients (mean, 82.3 ± 5.6 years; 60.1% female). Global cognitive performance and executive functions were assessed with Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores, respectively, at baseline and after 12 and 24 months of follow-up. Age, gender, body mass index, mean arterial pressure, disability, gait speed, comorbidities, atrial fibrillation, stroke, carotid artery stenosis, leukoaraiosis grade on computed tomography (CT) scan, psychoactive drugs, antidementia drugs, blood-thinning drugs (i.e., anticoagulants other than VKAs, antiplatelet medications), serum creatinine levels, and vitamin B12 concentrations were considered as potential confounders. Using VKAs was associated with lower (i.e., worse) FAB score at baseline (adjusted β = −2.1, p = 0.026), and with a decrease in FAB score after 24 months (adjusted β = −203.6%, p = 0.010), but not after 12 months (p = 0.659). Using VKAs was not associated with any change in MMSE score at baseline (p = 0.655), after 12 months (p = 0.603), or after 24 months (p = 0.201). In conclusion, we found more severe executive dysfunction at baseline and incident executive decline over 24 months among geriatric patients using VKAs, when compared with their counterparts.

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Novel Anticoagulant Therapy: Principle and Practice

Cited by 27 publications

References 75 publications

Exploring potential anticoagulant drug formulations using thrombin generation test

Exploring potential anticoagulant drug formulations using thrombin generation test

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

Vitamin K Antagonists and Cognitive Decline in Older Adults: A 24-Month Follow-Up

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