Direct link models

As is implicit from all the above, the measured concentration in plasma is directly linked to the observed effect for these simple mechanistic, pharmacokinetic-dynamic models. Accordingly, these models are called direct-link models since the concentrations in plasma can be used directly in (10.6) and (10.7) for the description of the observed effects. Under the assumptions of the direct-fink model, plasma concentration and effect maxima will occur at the same time, that is, no temporal dissociation between the time courses of concentration and effect is observed. An example of this can be seen in the direct-fink sigmoid Emax model of Racine-Poon et al. [418], which relates the serum concentration of the anti-immunglobulin E antibody CGP 51901, used in patients for the treatment of seasonal allergic rhinitis, with the reduction of free anti-immunglobulin E. 

Under the assumptions of the direct-link model, neither a counterclockwise (Figure 10.2) nor a clockwise hysteresis loop (Figure 10.4) will be recorded in an effect vs. concentration plot. In principle, the shape of the effect vs. concentration plot for an ideal direct-link model will be a curve identical to the specific pharmacodynamic model, relating effect with concentration, e.g., linear for a linear pharmacodynamic model, sigmoid for the sigmoid Emax model (cf. Table 10.1 and following paragraphs and sections), etc. 

In the direct-link model, concentration-effect relationships are established without accounting for the intrinsic pharmacodynamic temporal behavior, and the relationships are valid only under the assumption of effect site, prereceptor equilibrium H3. In contrast, indirect-link models are required if there is a temporal dissociation between the time courses of concentration and effect, and the observed delay in the concentration-effect relationship is most likely caused by a functional delay between the concentrations in the plasma and at the effect site. 

PK and PD can be linked directly through a measured concentration that is directly linked to an effect site. The direct link model does not work well when there is a temporal relationship between a measured concentration and effect, as when hysteresis is present. When this is the case, an indirect link between the measured concentration and effect must be accounted for in the model. This has been done in... 

Racine-Poon et al. provided an example for a direct link model by relating the serum concentration of the antihuman immunoglobulin E (IgE) antibody CGP 51901 for the treatment of seasonal allergic rhinitis to the reduction of free IgE via an inhibitory Emax-model [75]. Radwanski et al. used a similar approach to assess the effect of recombinant interleukin-10 on the ex vivo release of the proinflammatory cytokines TNE-a and interleukin-1(IL-1/3) in LPS-stimulated leukocytes [76]. 

This provides a very strong tool for communicating explanations, as the teacher can move between discussing the bench phenomena and the (sub-microscopic) explanatory models readily. By presenting an equation that describes the reaction (a macroscopic phenomena that students can see etc.) in a form that directly links to the molecules or other quanticles (ions, etc.) considered to be present at the sub-microscopic level, the symbolic representation acts as a referent to both levels and so at a meta-level also represents the relationship and mapping between substances and quanticles. 

In conclusion, the steady-state kinetics of mannitol phosphorylation catalyzed by II can be explained within the model shown in Fig. 8 which was based upon different types of experiments. Does this mean that the mechanisms of the R. sphaeroides II " and the E. coli II are different Probably not. First of all, kinetically the two models are only different in that the 11 " model is an extreme case of the II model. The reorientation of the binding site upon phosphorylation of the enzyme is infinitely fast and complete in the former model, whereas competition between the rate of reorientation of the site and the rate of substrate binding to the site gives rise to the two pathways in the latter model. The experimental set-up may not have been adequate to detect the second pathway in case of II " . The important differences between the two models are at the level of the molecular mechanisms. In the II " model, the orientation of the binding site is directly linked to the state of phosphorylation of the enzyme, whereas in the II" model, the state of phosphorylation of the enzyme modulates the activation energy of the isomerization of the binding site between the two sides of the membrane. Steady-state kinetics by itself can never exclusively discriminate between these different models at the molecular level since a condition may be proposed where these different models show similar kinetics. The II model is based upon many different types of data discussed in this chapter and the steady-state kinetics is shown to be merely consistent with the model. Therefore, the II model is more likely to be representative for the mechanisms of E-IIs. 

One of several general models for metabolite compart-mentation in which a central compartment is directly linked to or feeds from (hence the name) other compartments that do not communicate with each other aside from their connection to the central pool. See Catenary Model Compartmental Analysis... 

Figure 2. Model-2. Parkin is linked to sporadic PD as well as AR-JP. a-Syn, a-synuclein. For details including environmental stress, neurotoxin, ROS, qualitycontrolling E3, UCH-Ll, CHIP, UPR, CDCrel-1, initiation , and promotion , see text. In this model, impairment of protein degradation pathway downstream of ubiquitination results in accumulation of ubiquitinated protein(s) and non-ubiquitinated protein(s), i.e., aggregate formation (LB). At present, it is unknown whether parkin is involved in LB formation or LB causes dopaminergic neuron death, however it is currently clear that LB formation is not directly linked to neuronal death and pathogenesis of PD as shown by a dotted line (see text). Note that AR-JP can also be explained by model-2, if parkin operates as a qualitycontrolling E3.

The reason for this association of terms is physical. In a central-force problem, y. and y play roles that are similar in nature because measures the attraction of the valence electrons by the nucleus and y g the accompanying repulsion by the core electrons. This formulation is directly linked to the model adopted here, that of a charged inner sphere of radius surrounded by valence electrons. With... 

This section is organized as follows we first start with a discussion of the electrochemical behavior of the Roussin-type synthetic iron- sulfur clusters for their historic importance and as an interesting introduction to poly iron-sulfur centers redox chemistry. Then we review iron-sulfur centers in proteins and artificial models in the order of increasing iron content. Finally, biological iron-sulfur centers and artificial models directly linked to other inorganic centers, the so-called bridged molecular assemblies, are considered. 

A typical feature of this model is that on the one hand the supplier tries to sell more volumes (increasing revenue), on the other hand the user tries to control costs by buying less and/or at a cheaper price. So the basis of business is a purely economic consideration. Ecological aspects are only considered if they provide a more cost-efficient solution than the traditional one. In general, only purchasing costs are directly linked to a product, while all other expenditures are allocated to all other relevant entities as recurrent costs. 

Reducing the dimensionality of the descriptor space not only facilitates model building with molecular descriptors but also makes data visualization and identification of key variables in various models possible. Notice that while a low dimension mathematically simplifies a problem such as model development or data visualization, it is usually more difficult to correlate trends directly with physical descriptors, and hence the data become less interpretable, after the dimension transformation. Trends directly linked with physical descriptors provide simple guidance for molecular modifications during potency/property optimizations. 

Luedeking and Piret<56) proposed that the formation of microbial products could be described by a two parameter model. This was based on their studies of lactic acid fermentation using Lactobacillus delbruekii in which the accumulation of the acid is not directly linked to the growth rate. The function used was ... 

Regarding the chemical constitution of these monomers, the polymerizable, functional group was always directly linked to the rigid, voluminous mesogenic moieties. As space filling models indicate, polymers result, having a rigid main chain. This... 

With these three different examples it has been demonstrated that the systematics observed for the polymorphism of m-l.c. s is also valid for the side chain polymers, provided that a flexible spacer connects the rigid mesogenic moieties to the polymer main chain. Deviations from this behavior are observed, when the mesogenic moieties are directly linked to the backbone. Under these conditions, normally no liquid crystalline behavior is to be expected, according to the model considerations mentioned in Chap. 2.1. Some examples, however, proved l.c. properties for such systems, which are characterized by two striking properties Very high glass transition temperatures and only smectic structures even in case of short substituents... 

Classical anharmonic spring models with or without damping [9], and the corresponding quantum oscillator models seem well removed from the molecular problems of interest here. The quantum systems are frequently described in terms of coulombic or muffin tin potentials that are intrinsically anharmonic. We will demonstrate their correspondence after first discussing the quantum approach to the nonlinear polarizability problem. Since we are calculating the polarization of electrons in molecules in the presence of an external electric field, we will determine the polarized molecular wave functions expanded in the basis set of unperturbed molecular orbitals and, from them, the nonlinear polarizability. At the heart of this strategy is the assumption that perturbation theory is appropriate for treating these small effects (see below). This is appropriate if the polarized states differ in minor ways from the unpolarized states. The electric dipole operator defines the interaction between the electric field and the molecule. Because the polarization operator (eq lc) is proportional to the dipole operator, there is a direct link between perturbation theory corrections (stark effects) and electronic polarizability [6,11,12]. 

To assess the efficiency of the reactions listed in Table 7.2, Bolton et al. (1996) proposed a generally applicable standard for a given photochemical process. The proposed standard provides a direct link to the electrical efficiency. In this model, electrical energy per unit mass is calculated according to the quantum yield of the direct photolysis rate. Braun et al. (1997) calculated the quantum yield (O) according to Equation (7.13) ... 

Long time ago, theoretical works predicted that the feedback at IDAs is directly linked to the dimensions of the electrodes and the interelectrode distance (gap) [107,108] and, recently, the height of the electrodes was found to be another crucial parameter [109]. Different models have been developed to enhance the efficiency collection (Fig. 32.3) but the greatest advances were with nanometric dimensions [113]. In this way, IDAs have improved the analytical characteristics of current methodologies (as higher sensitive p-aminophenol detection [114] or capacitive biosensors [115,116]) and other applications have emerged [117]. 

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