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  • perhexiline Just as Dorin et al and Nguyen et


    Just as Dorin et al. [2] and Nguyen et al. [3] write in regard to their models, our static model can be used to estimate the affinities of perhexiline to albumin and CBG. Dorin et al. [2] estimates the K, but not K, since they find that their model is not particular sensitive towards changes in K. Our sensitivity analysis of the model in Dorin et al. [2], Nguyen et al. [3] and the models presented here shows greater sensitivity towards K than towards K when measured in absolute and relative sensitivity as well as a sensitivity measure normalized by the normal variation seen in the literature (see Section 3.1). Our sensitivity analysis and further investigations of varying the different input variables and parameters show that all the models are very dependent on the default parameter values when performing local sensitivity analysis and as a consequence local parameter estimations. Both total and intact CBG has been shown to decrease with severity of sepsis, while CBG* increased both measured in net concentration and percentage of total CBG [76]. The percentage of leucocytes circulating being neutrophils are in sepsis correlated with the relative and absolute levels of CBG* [76]. The model presented here is an equilibrium model describing the distribution of cortisol in plasma dependent on the activity of neutrophil elastase as measured in plasma. Korkmaz et al. [83] suggest neutrophil elastase as a therapeutic target [83]. By including the activity of neutrophil elastase directly in the model, we provide a method to investigate the influence of such potential therapeutics on free cortisol concentrations in plasma. However, the lowering of the affinity of CBG for cortisol by cleavage by neutrophil elastase is thought to be a mechanism of local cortisol release in tissue with inflammation [84]. The concentration of neutrophil elastase release at localised inflammatory sites may far exceed the concentration measured in circulation. Hence, local relation between intact CBG and CBG* in the interstitial compartments at sites of inflammation may differ greatly from the one measured in the circulation and, as a consequence, the level of free cortisol. The static model does not describe the concentration in the interstitial compartments, but describes the overall picture as seen in plasma. If a distinction between the levels seen in a high inflammatory interstitial compartment and the plasma compartment should be investigated, a dynamical model is needed. In Nguyen et al. [3] a dynamic and spatially distributed model distinguishing between concentrations of cortisol and its transport proteins in the plasma and interstitial compartments is stated. Elastase is modelled only to cleave CBG in the interstitial compartment at locations with inflammation, while the synthesis of CBG* and elimination of CBG in plasma is described independent of each other and by functions not directly related to the elastase activity, but dependent on the spatial location. Free cortisol is dramatically increased locally at inflammation sites due to the elastase activity in good agreement with the underlying biological understanding. However, when relating their dynamic model to their equilibrium formula Nguyen et al. [3] leave out the terms describing CBG-cleavage and metabolite concentration gradients. To further validate the models presented in this article combined measurements of elastase activity, CBG and total and free cortisol are needed. As described in Section 2.2.3 the activity of neutrophil elastase can be measured by an activity based assay [66], immunologically using an antibody based assay directed towards neutrophil elastase [64], [70] or immunologically using an antibody based assay directed towards the complex NE-α1AT [67], [68]. However, these measurements may or may not be concordant. For example Kunder et al. [66] finds higher levels of neutrophil elastase activity in combination with lower levels of α1-AT and an absence of an increase in the levels of NE-α1AT in mild and severe preeclampsia [66]. Hence, measurements of NE-α1AT alone would not have been a good biomarker of elastase activity in this case.