Drug discovery pharmacological responses

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

More complex integrated PK/PD models are necessary to link and account for a possible temporal dissociation between the plasma concentration and the observed effect. Four basic attributes may be used to characterize PK/PD models First, the link between measured concentration and the pharmacological response mechanism that mediates the observed effect (direct versus indirect link) second, the response mechanism that mediates the observed effect (direct versus indirect response) third, the information used to establish the link between measured concentration and observed effect (hard versus soft link) and, fourth, the time dependency of the involved PD parameters (time variant versus time invariant) (Danhof et al., 1993 Steimer et al., 1993 Aarons, 1999 Lees et al., 2004). The expanded and early use of PK/PD modeling in drug discovery and development is highly beneficial for increasing the success rate of drug discovery and development and will most likely improve the current state of applied therapeutics. 

During the first half of the century, there was virtually an exclusive reliance on animal testing as the primary model for drug discovery and development. New chemical entities were administered to rodents in the primary screen assay, and the appropriate responses were monitored for indications of therapeutic potential. Compounds meeting the appropriate potency and efficacy criteria were promoted to more diverse and sophisticated animal models to characterize their pharmacological profile. The responses that were monitored included blood pressure (hypotensives), latency to respond to painful stimuli (analgesics), attenuation of seizure propensity (antiepileptics) and other responses that were intuitively and pharmacologically valid indicators of medicinal potential or toxicity. Some of these methods were semiautomated and quite sophisticated for their time, particularly for cardiovascular indications [1]. 

These aspects stimulated our decision to publish this volume as a counterpart to Drug Discovery and Evaluation. Pharmacological Assays (Second Edition Springer Verlag 2002). The current book contains three sections. Dr. Franz Jakob Hock shares with me the responsibility for the section Safety Pharmacology Dr. Jochen Maas took over the responsibility for the section Safety Pharmacokinetics and Prof. Dr. Dieter Mayer for the section Safety Toxicology . 

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