Modeling clotting time

An important aspect of PD models is the link between the pharmacokinetics and the pharmacodynamic model, i.e. which concentration drives the drug effect. For empirical models there are many different PK/PD link approaches described and the theory is presented in several review papers [33-35]. The two most popular approaches are described in the following and are also illustrated in Fig. 17.7. The direct link approach assumes that a change in the measured concentration is directly reflected in a change in the measured P D. This is most often observed if the site of PK measurement and the site of PD measurement are identical (e.g. PK measurement in plasma and clotting time as PD measurement). 

Since AT-III is so important to heparin s action, it is proposed to model its dynamic behavior, and to attempt to incorporate its concentration into an equation for clotting time. Thus, one equation which is proposed for describing clotting time is... 

Figure 3. Optimum dosing policy and clotting time response for heparin model. (-----------) optimum...

The general drawback of the Wessler model is the static nature of the venous thrombus development. To overcome this problem some investigators have developed more dynamic models with reperfusion of the occluded vessel segments after clot development. Depending on the time of test compound administration (pre- or post-thrombus initiation), the effect on thrombus growth and fibrinolysis can be evaluated. Levi et al. (1992) have used this model to assess the effects of a murine monoclonal anti-human PAI-1 antibody and Biemond et al. (1996) compared the effect of thrombin and factor Xa inhibitors with a low molecular weight heparin. 

An alternative model, including a lag-time to allow for distributional effects embedded in the observed time delay of the onset of the effect after warfarin administration, was published by Pitsui et al. (1993). Setting the baseline value of clotting factor activity in the absence of warfarin (P0) to a fixed mean of three predose measurements, the program can estimate that parameter. 

Figure E. Total thrambin as a function of time with an initiatiog TF conceniration of 25 pAf (figure courtesy of M. F. Hockin et al.. A Model for the Stoichiometric Regulation of Blood Coagulation." Thr /ounio/ of Biotogical ChtmisiTy, 277(21], pp. 18322-18333 [2002]). Full blood clotting cascade.

As reference values, Table 3b also presents the amounts of C oxidized after 30 or 120 min for pure tannic acid pp and for the C-pp model. It is evident that, in the absence of an efficient complexing cation, the whole amount of organic C is definitively oxidized within 120 min. Interestingly, in the C-pp model, the large amount of C already oxidized after 30-min could be ascribed to a possible priming catalytic effect by the clay mineral differently, the flakes of pure pp probably clotted, thus needing more time to be completely oxidized [15]. 

These findings have led us to conclude that the matrix to which the cells are attached in vitro would be one of the most important variables of our system as we continued to search for the ideal polymer matrix. The hepatocyte-polymer scaffolds, created as described above, were tlaen implanted into the omentum, the interscapular fat pad, or the mesentery of the recipient animal for varying periods of time. We avoided surgical trauma as much as possible, because any fibrin clot or hematoma formation would decrease the ability to nourish the cells by diffusion. The rat was used as the animal model for hepatocyte transplantation, because there existed several models of metabolic deficiency states representative of human liver disease. 

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