DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Drug Invention and the
Pharmaceutical Industry
Suzanne M. Rivera and
Alfred Goodman Gilman ∗
The first edition of this textbook, published in 1941, is
often credited with organizing the field of pharmacology,
giving it intellectual validity and an academic identity.
That first edition began: “The subject of pharmacology
is a broad one and embraces the knowledge of
the source, physical and chemical properties, compounding,
physiological actions, absorption, fate, and
excretion, and therapeutic uses of drugs. A drug may be
broadly defined as any chemical agent that affects living
protoplasm, and few substances would escape inclusion
by this definition.” These two sentences still serve us
well. This first section of the 12th edition of this textbook
provides the underpinnings for these definitions by
exploring the processes of drug invention and development
into a therapeutic entity, followed by the basic
properties of the interactions between the drug and biological
systems: pharmacodynamics, pharmacokinetics
(including drug transport and metabolism), and pharmacogenomics.
Subsequent sections deal with the use
of drugs as therapeutic agents in human subjects.
We intentionally use the term invention to describe
the process by which a new drug is identified and brought
to medical practice, rather than the more conventional
term discovery. This significant semantic change was suggested
to us by our colleague Michael S. Brown, MD, and
it is appropriate. In the past, drugs were discovered as natural
products and used as such. Today, useful drugs are
rarely discovered hiding somewhere waiting to be found;
rather, they are sculpted and brought into being based on
experimentation and optimization of many independent
properties. The term invention emphasizes this process;
there is little serendipity.
∗
Alfred G. Gilman serves on the Board of Directors of Eli Lilly
& Co. and Regeneron Pharmaceuticals, and acknowledges
potential conflicts of interests.
FROM EARLY EXPERIENCES WITH
PLANTS TO MODERN CHEMISTRY
Man’s fascination—and sometimes infatuation—with
chemicals (i.e., drugs) that alter biological function is
ancient and arose as a result of experience with and
dependence on plants. Most plants are root-bound, and
many have become capable of elaborate chemical syntheses,
producing harmful compounds for defense that
animals learned to avoid and man learned to exploit.
Many examples are described in earlier editions of this
text: the appreciation of coffee (caffeine) by the prior of
an Arabian convent who noted the behavior of goats that
gamboled and frisked through the night after eating the
berries of the coffee plant, the use of mushrooms or the
deadly nightshade plant (containing the belladonna alkaloids
atropine and scopolamine) by professional poisoners,
and a rather different use of belladonna (“beautiful
lady”) to dilate pupils. Other examples include the uses
of the Chinese herb ma huang (containing ephedrine)
for over 5000 years as a circulatory stimulant, curarecontaining
arrow poisons used for centuries by South
American Indians to paralyze and kill animals hunted
for food, and poppy juice (opium) containing morphine
(from the Greek Morpheus, the god of dreams) for pain
relief and control of dysenteries. Morphine, of course,
has well-known addicting properties, mimicked in some
ways by other problematic (“recreational”) natural products—nicotine,
cocaine, and ethanol.
While many terrestrial and marine organisms
remain valuable sources of naturally occurring compounds
with various pharmacological activities, especially
including lethal effects on both microorganisms
and eukaryotic cells, drug invention became more allied
with synthetic organic chemistry as that discipline
flourished over the past 150 years. This revolution