Biomedical Engineering Reference
In-Depth Information
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Analogue syntheses of the most active compounds, planned after careful examination of
literature and patents. More elaborated pharmacology in order to elucidate mode of action,
efi cacy, acute and chronic toxicity, and genotoxicity. Studies of ADME characteristics.
Planning of large scale synthesis and initiation of formulation studies. Application for pat-
ent protection.
These i rst project phases, which typically last 4-5 years, are followed by very time- and resource-
demanding clinical, regulatory, and marketing phases, which normally last about 10 years:
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Phase I clinical studies, which include safety, dosage, and blood level studies.
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Phase II clinical studies focusing on efi cacy and side effects.
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Phase III clinical studies, which involve studies of range of efi cacy and long-term and rare
side effects.
Regulatory review.
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Marketing and phase IV clinical studies focusing on long-term safety.
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Very large-scale synthesis.
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Distribution, advertisement, and education of marketing and information personnel.
After these project stages from initiation to successful therapeutic application after approval,
the patent protection expires, normally after 17-25 years, and generic competition becomes a
reality.
This outline of a drug development project illustrates that, at best, it takes many years to intro-
duce a new therapeutic agent, and it must be kept in mind that most projects are terminated before
marketing, even at advanced stages of clinical studies.
I.5 DISCOVERY OF DRUG CANDIDATES
Prehistoric drug discovery started with higher plant and animal substances, and this continues today
to be a fruitful source of biologically active molecules frequently belonging to unanticipated struc-
tural types. Adding to the long list of classical plant products that are still used in modern medicine,
one can list many substances of more recent origin, including antibiotics such as penicillins, cepha-
losporins, tetracyclines, aminoglycosides, various glycopeptides, and many others (Chapter 25).
Anticancer agents of natural origin comprise taxol, camptothecin, vinca alkaloids, doxorubicin, and
bleomycin (Chapter 23). Among immunosuppressant agents, cyclosporine and tacrolimus deserve a
special mention.
I.5.1 N
ATURAL
P
RODUCTS
—R
OLE
IN
T
ARGET
I
DENTIFICATION
Various biologically active natural products have played a key role in the identii cation and charac-
terization of receptors, and such receptors are often named after these compounds (Chapter 12).
Morphine is a classical example of a natural product used for receptor characterization. Radiolabeled
morphine was shown to bind with high afi nity to receptors in the nervous system, and these recep-
tors were, and still are, named opiate receptors. Some three decades ago, the physiological relevance of
these receptors was documented by the i ndings that endogenous peptides, notably enkephalins and
endorphins, served as receptor ligands (agonists). Analogues of morphine have been useful tools for
the demonstration of heterogeneity of opiate receptors (Chapter 19) (Figure I.3).
The very toxic and convulsive alkaloid, strychnine, has been extensively studied pharmacologi-
cally. Using electrophysiological techniques and tritiated strychnine for binding studies, strychnine
was shown to be an antagonist for the neuroreceptor mediating the inhibitory effect of glycine, pri-
marily in the spinal cord. This receptor is currently named the strychnine-sensitive glycine receptor
or the glycine
A
receptor.
