Anticoagulant modeling

One drawback of thrombolytic therapy is a high incidence of reocclusion. In a report using a canine model, inclusion of heparin [9005-49-6] (anticoagulant therapy) in the treatment prevented this side effect (158). The combination of aspirin [50-78-2] (antiplatelet therapy) and streptokinase (thrombolytic therapy) has also shown significant therapeutic advantages (78). Although additional work is needed to estabUsh the thrombolytic advantage of various combinations, preliminary results in this area indicate promise in terms of increased efficacy and reduced side effects. 

Dicoumarol is found in sweet clover and can cause hemorrhaging in cattle because of its anticoagulant action. It acts as a vitamin K antagonist and has served as a model for the development of warfarin and related anticoagulant rodenticides. 

Sarasin, F.P. and H. Bounameaux, "Decision Analysis Model of Prolonged Oral Anticoagulant Treatment in Factor V Leiden Carriers with First Episode of Deep Vein Thrombosis," BMJ, 316, 95-99 (1998). 

Using human physiology and in vitro data and clinically relevant input parameters (i.e., metabolic stability in human hepatocytes and microsomes as well as prothrombin time measured in various batches of human plasma) the model was extended to human. This human PK/PD model was then used to investigate the impact of the various physicochemical, pharmacokinetic and pharmacodynamic properties on the anticoagulant profile (i.e., prothrombin time) expected in man. 

Becker, C. F., Guimaraes, J. A., Mourao, P. A., and Verli, H. (2007). Conformation of sulfated galactan and sulfated fucan in aqueous solutions Implications to their anticoagulant activities. ]. Mol. Graph. Model. 26, 391-399. 

In contrast to unfractionated heparin, the factor Xa inhibitor tick anticoagulant peptide (TAP) effectively inhibited coronary arterial thrombosis in a canine electrolytic injury model (57). TAP was also effective in inhibition of the procoagulant properties of whole blood clots in vitro however, it was stated that TAP might be not optimal due to its slow binding kinetics (54). Meanwhile, several low molecular weight direct factor Xa inhibitors are in clinical development (Table I), some of them specifically for the treatment and secondary prevention of ACS. DX-9065a, ZK-807834 and otamixaban have been intensively characterized in vitro and in vivo and are in clinical investigations for the treatment of acute arterial thrombosis. 

Parallel-plate hemodialyzers using flat membranes, with several compartments in parallel, separated by plastic plates, are now only available from Hospal Co (Crystal and Hemospal models). Blood circulates between two membranes and the dialysate between the other side of membrane and the plastic plate. These parallel-plate dialyzers have a smaller blood-pressure drop than hollow-fiber ones and require less anticoagulants as flat channels are less exposed to thrombus formation than fibers, but they are heavier and bulkier and thus less popular. A recent survey of the state-of-the-art in hemodialyzers is given in [13]. 

Anticoagulant adapted to the animal model investigated (citrate buffer, carbonate buffer modified Alsever solution, etc.). 

It was found that rivaroxaban competitively inhibits human FXa and prothrombinase activity (/C50 = 2.1 nM). It inhibits endogenous FXa more potently in human and rabbit plasma (/C50 = 21 nM) than in rat plasma (/C50 = 290 nM). Rivaroxaban has demonstrated anticoagulant effects in human plasma, doubling the prothrombin time (PT) and activated partial thromboplastin time (APTT) at 0.23 and 0.69 pM, respectively. In vivo, rivaroxaban reduced venous thrombosis dose dependency (EDS0 = 0.1 mg/kg i.v.) in a rat venous stasis model. The pharmacological actions of rivaroxaban have been described in more detail by Perzbom et al.12... 

Modeling, Parameter Identification, and Adaptive Control of Anticoagulant Drug Therapy... 

The purpose of this paper is to illustrate how mathematical modeling and control theory can be applied to the problem of optimizing the administration of the anticoagulant drug heparin. 

A pharmacokinetic model which describes a patienf s response to the widely used anticoagulant drug, heparin, is discussed. The model contains several unknown parameters. A patients own past data can be used to identify these parameters and thus tailor-make a model for each individual under treatment. Once such a model is available it can be used to calculate optimum dosing policies to achieve a specified therapeutic goal. 

Ariens [432] was the first to describe drug action through indirect mechanisms. Later on, Nagashima et al. [433] introduced the indirect response concept to pharmacokinetic-dynamic modeling with their work on the kinetics of the anticoagulant effect of warfarin, which is controlled by the change in the prothrombin complex synthesis rate. Today, indirect-response modeling finds extensive... 

The cone-and-plate viscometer is an in vitro flow model used to investigate the effects of bulk fluid shear stress on suspended cells. Anticoagulated whole blood specimens (or isolated cell suspensions) are placed between the two platens (both of stainless steel) of the viscometer. Rotation of the upper conical platen causes a well-defined and uniform shearing stress to be applied to the entire fluid medium as described by Konstantopolous et al. (1998). The shear rate (y) in this system can be readily calculated from the cone angle and the speed of the cone using the formula i/ = where y is the shear rate in sec-1, mis the... 

A method for the direct observation of extracorporal thrombus formation has been introduced by Rowntree and Shionoya (1927). These first studies could provide evidence that anticoagulants like heparin and hirudin do inhibit thrombus development in arteriovenous shunts. Since today, the A-V-shunt thrombosis models have been often used to evaluate the antithrombotic potential of new compounds in different species including rabbits (Knabb et al. 1992), rats (Hara et al. 1995), pigs (Scott et al. 1994), dogs and cats (Best et al. 1938), and non-human primates (Yokoyama et al. 1995). 

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