Direct action 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 ... 

In the mass action model the micellar system can be described by only one parameter, and despite this simplicity, a good qualitative description of the main physical properties is obtained, for example the onset of cmc (critical micelle concentration), as shown in Figure 9.7. Notice that the formation of micelles becomes appreciable only at the cmc, and after that, by increasing further the surfactant concentration, all added surfactant is transformed directly into micelles, so that the surfactant concentration in solution remains constant at the level of cmc. 

From these various analyses, it is clear that dopamine regulation of the striatum does not simply control detailed movement, but is involved in the selection and initiation of appropriate goal directed actions (Dunnett and Robbins, 1992 Robbins and Everitt, 1992), as influenced by motor learning (i.e. the acquisition of skills and habits Mishkin et al., 1984 Jog et al., 1999), in the context of motivational information related to needs and rewards (Suri and Schultz, 1999). Theoretical formulations of this process have moved away from the neuropsychological theory, although still conceptually useful, to mathematical and neural network modeling (Houk et al., 1995 Servan-Schreiber et al., 1998), which is beyond the scope of the present review. 

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. 

Butler AE, Janson J, Soeller WC, Butler PC. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes. 2003 52(9) 2304-2314. 

FIGURE30.8 Central nervous s)rstem (CNS) stimulation results in direct effects and indirect effects on CNS neurons, (a) Two-dimensional maps of thresholds for indirect (synaptic) and direct activation of neurons in the red nucleus [from Baldissera et al., 1972]. (b) Complex polyphasic changes in the firing rate of a cortical neuron in response to extracellular stimulation [firom Butovas and Schwarz, 2003]. (c) Transmembrane potential in the axon (top trace) and cell body (bottom trace) of a model thalamocortical neuron before, during (black bar at bottom), and after extracellular stimulation [from McIntyre et al., 2004]. Extracellular stimulation results in simultaneous inhibition of the cell body, as a result of activation of presynaptic terminals and subsequent indirect effects, and excitation of the axon, as a result of direct action potential initiation in a node of Ranvier. (d) Firing rate in the cell body and axon during extracellular stimulation of a model thalamocortical neuron [modified from McIntyre et al., 2004]. The firing rate in the cell body is lower than that in the axon, as a result of simultaneous indirect synaptic effects on the soma, and direct excitation of the axon. 

Now that the mass-action model has been supported by a number of observations, we move to the thermodynamics of micelle formation based on this model. As would be predicted from the above discussion, micelle formation can be well expressed by a single association constant, even though the process strictly involves multiple association equilibria. The error is less than 5%, for example, for micelles having an aggregation number more than 50. For nonionic surfactants, the standard free energy change AG° per mole of surfactant molecules follows directly from the equilibrium constant and is given from (4.21) and [S] = Q by... 

In the previous chapters, the dissolution and micellization of surfactants in aqueous solutions were discussed from the standpoint of the degrees of freedom as given by the phase rule. The mass-action model for micelle formation was found to be better for explaining the phenomena of surfactant solutions than the phase-separation model. Two models have similarly been used to explain the Krafft point, one postulating a phase transition at the Krafft point and the other a solubility increase up to the CMC at the Krafft point. The most recent version of the first approach is a melting-point model for a hydrated surfactant solid. The most direct approach to the second model of the Krafft point rests entirely on measurements of the solubility and CMC of surfactants with temperature. From these mesurements the concept of the Krafft point can be made clear. This chapter first reviews the concepts used to relate the dissolution of surfactants to their micellization, and then shows that the concept of a micelle temperature range (MTR) can be used to elucidate various phenomena concerning dissolution... 

The concept of "repressors" and "prorepressors" appeared initially as a model (hypothesis) based on the analysis of genetic data for localization of regulator genes and operators, and discovery of the invalidity of other schemes of induction and repression assuming the direct action of metabolites on structural genes. 

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