Direct response models

The standard effect-compartment model, usually characterized as an atypical indirect-link model, also constitutes an example of what we will call a direct-response model in contrast to the indirect-response models. Globally, the standard direct-response models are models in which c(t) affects all dynamic processes only linearly. 

In a direct-response model, the output of a linear dynamic model (the link model) with input c (t) drives a nonlinear static model (usually the Emax model) to produce the observed response. 

Direct response models are characterized by a direct correlation between the effect site concentration of the drug and the observed effect without time lag. Direct response models can comprise either a directly linked direct response model or an indirectly linked indirect response model. Indirect response models are models for drugs whose mechanism of action consists of either inhibition or stimulation of a physiological process involved in the elucidation of the clinical expression of the observed effect, as discussed in detail in the previous section. 

C Low dose effects usually not measurable directly In human or animal observations Need to extrapolate observed high dose effects to low or zero dose range by theoretical dose-response models ... 

When the concentration of a drug cannot be directly related to effect, indirect modeling is suggested. This will most aptly apply to situations where, for example, the response is not directly a result of action (e.g., binding a receptor site) as there may be several steps involved in between the action and response with their own specific mathematical relationships. Unlike the direct action models where any delay in the response is likely a result of PK phenomenon, fhe delay where indirecf models are used is a result of intrinsic nature of drug action and response relationship. Several models can be used in such instances ... 

When operating conditions were changed, transient phenomena were sometimes observed that first move in one direction and in the reverse direction on going to the final steady state. To study these transients and to design an improved control strategy for the unit, a dynamic response model was needed. With the inclusion of the fast coke in the model, it became possible to extend the steady-state model to obtain useful dynamic response results by the addition of time-dependent accumulation terms (Weekman et al., 1967). 

Fig. 14. Schematic description of pharmacokinetic and pharmacodynamic determinants of drug action. Distribution from the measurement site (Cp) to the biophase (Ce), determined by a distribution rate constant is followed by drug-induced inhibition or stimulation of the production (k ) or removal (A out) of a mediator (R), transduction of the response R and further transformation of R to the measured effect E, if the measured effect variable is not R. (Modified from Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6.)...

Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6. 

In the bond valence model quantum effects are treated classically by including them in the interatomic repulsion described by eqn (3.1) or (3.2). There are, however, a number of cases where quantum effects are directly responsible for deviations from the higher symmetry that would otherwise be expected. Such electronically distorted structures were discussed in Chapter 8. 

Adopting a social learning approach in the context of the transtheoretical model of change not only provides an understanding of addiction behaviour which accounts for the observed phenomena, it also informs and directs responses to produce a wide variety of interventions which are able to meet the demands of the whole spectrum of drug problems rather than the very select few currently catered for. 

Details concerning the model, which, for the water, was slightly different from that of Ref. 35, appear in Refs. 36 and 44.) These results show the electrostatic response of the first two, metallic and Stem, layers in Fig. 1. within the direct dynamics model. At distances of more than about 10 A, the ions... 

All chemical companies will have a person, or group of people, depending on their size, directly responsible for health, safety and environment (HSE) and for regulatory affairs. All model HSE management systems consist of a Plan, Do, Check and Review cycle as illustrated in Figure B13 [B-20]. The Check and Review stages enable any necessary corrective actions to be taken. 

When one looks into the basic functions of the link and indirect response models, it is clear that one of the differences resides in the input functions to the effect and the receptor protein site, respectively. For the link model a linear input operates in contrast to the indirect model, where a nonlinear function operates. For the link model the time is not directly present and the pharmacological time course is exclusively dictated by the pharmacokinetic time, whereas the indirect model has its own time expressed by the differential equation describing the dynamics of the integrated response. 

A very general scheme for relating effects to concentration, of which both the effect-compartment and the indirect-effect models are special cases, was outlined by Sheiner and Verotta [452], The models presented in the study can be considered to be a special case of that unified scheme. As judiciously presented by these authors, both direct-response and indirect-response models are composed of one nonlinear static submodel and one dynamic submodel, but the placement of the submodels in the global model differs ... 

Beside the consideration of the up-cycles in the stretching direction, the model can also describe the down-cycles in the backwards direction. This is depicted in Fig. 47a,b for the case of the S-SBR sample filled with 60 phr N 220. Figure 47a shows an adaptation of the stress-strain curves in the stretching direction with the log-normal cluster size distribution Eq. (55). The depicted down-cycles are simulations obtained by Eq. (49) with the fit parameters from the up-cycles. The difference between up- and down-cycles quantifies the dissipated energy per cycle due to the cyclic breakdown and re-aggregation of filler clusters. The obtained microscopic material parameters for the viscoelastic response of the samples in the quasi-static limit are summarized in Table 4. 

The second contribution in either the lattice or the van der Waals model is that originating from intermolecular attractions. This contribution is commonly referred to as the attractive energy term, the residual term, or the potential energy term. It is also known as the enthalpic contribution since the differences in interaction energies are directly responsible for the heats of mixing. This contribution is calculated by a product of a characteristic energy of interaction per contact and the number of contacts in the system. Van der Waals models use a similar expression for the interaction energy. 

In contrast to the aforementioned direct relationships/ the indirect response model shown in Figure 32.16 was used to describe the relationship between the administration of GH and IGF-1 in nonhuman primates (88). It was assumed in this model that the production of IGF-1 varied over time/ a reasonable... 

Many PK/PD models have been developed to characterize the exposure-response relationship for a variety of classes of drugs. In the following section we provide a brief discussion on some simple direct effect models that assume a rapid equilibrium between plasma... 

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