Biomedical Engineering Reference
In-Depth Information
is more likely to identify intracellular targets, such as regulatory, structural, and metabolic proteins,
and has been most extensively deployed in oncology. In recent years, there has been a signii cant
shift toward the molecular approach in an attempt to identify new targets through an understanding
of the cellular mechanisms underlying disease phenotypes of interest.
The systems approach is geared toward target discovery through the study of diseases in whole
organisms. In general, this information is derived from the clinical sciences and in vivo animal stud-
ies in physiology, pathology, and epidemiology. The systems approach has been traditionally the main
target discovery strategy and this remains the case for many diseases, including obesity, arteriosclero-
sis, heart failure, stroke, behavioral disorders, neurodegenerative diseases, and hypertension, in which
the relevant phenotype can be only detected at the organismal level. For these historical reasons, the
majority of current drugs was identii ed through this strategy and includes those that act against both
disease phenotypes and intracellular/extracellular targets. Interestingly, because many of these drugs
are directed against targets which were identii ed from physiological studies, rather than being directly
implicated in the disease mechanism, they would probably not have been identii ed by the molecular
approach. For example, although changes in
β
2
-adrenoreceptor expression/activity in airway smooth
muscle have not been implicated in the mechanism of allergen hyperreactivity that produces airway
contraction in asthma; these symptoms are commonly treated with
β
2
-agonist.
The incidence of many chronic diseases is strongly correlated with age, and such diseases are
thought to be inl uenced by both genomic and environmental factors. The overall contribution of
genomic factors is still unknown, although it is believed that many diseases are inl uenced by the
presence of susceptibility genes. With the exception of smoking, the role of environmental factors is
controversial, although a number of studies have indicated the importance of infection/inl ammation
and diet in diseases such as arteriosclerosis, central nervous system (CNS) disease, and cancer.
In undertaking target discovery, one would ideally perform clinical studies and obtain cell/
tissue samples using normal and diseased human patients. In reality, this is usually unethical and/or
impractical, which means we must rely on cellular and/or animal models. However, such models
often suffer from a number of signii cant problems which make them poor predictors of human
disease. In the case of cell models, the central problem lies in simulating the complexity of the in vivo
biological interactions, particularly as many of these are unknown. This problem of complexity
makes it increasingly difi cult to predict the role of a protein as one proceeds from the cellular level
to tissue and organism. In addition, the use of immortalized cell lines to overcome the problems
of availability prompts the questions regarding their biochemical similarity with primary cells. To
overcome the problems of complexity, we often use animal models. However, although these models
may reproduce a particular disease phenotype, genomic differences (related to species and strain),
and the difi culty of identifying and replicating the long-term environmental inl uences, imply that
the underlying causes could be different.
I.4 THE DRUG DEVELOPMENT PROCESS—AN OUTLINE
The stages through which a drug discovery/development project proceeds from inception to market-
ing and beyond are illustrated in the following text. From this outline, the complexity of the task of
i nding new therapeutic agents is evident:
•
Identii cation of target disease, establishment of a multidisciplinary research team, selec-
tion of a promising approach, and decision on a sufi cient budget. Initiation of chemistry,
which normally involves synthesis based on available chemicals or collection of natural
product sources. Start of pharmacology, includes suitable screening methods and choice of
receptor binding and/or enzymatic assays.
Coni rmation of potential utility of initial class(es) of compounds in animals, focusing on
•
potency, selectivity, and apparent toxicity.
