The long
time it takes to develop new treatments can generate understandable impatience in
patient groups. Why does it take so long? What goes on when
these drugs are in your body? How does your body react to the exotic
molecules?
A drug's job is to interfere with a disease pathway or symptoms.
Some drugs are very familiar and some have been around for a long
time. Aspirin, for example, can help with pain by dealing with
inflammatory enzymes. Some painkillers lock up neural receptors to
reduce the sensation of pain. An antibiotic, such as the
well-known penicillin, may clobber the bacteria of infection.
Infection, pain and cancers have always plagued us. People have used
plants, minerals and animal parts as medicine from time immemorial.
Even today, there is some interest in using herbs without an
understanding of how or if they work. (See
sidebar on NATURAL MEDICINES.)
Before aspirin there was willow bark. Opium and
cocaine gave pain relief to our primitive ancestors. Early
scientists extracted and purified the active ingredients from such
early drugs. Then clever organic chemists delighted in fragmenting
these molecules in order to find their structures.
Aspirin and penicillin have been around for a long time, but the
drugs that stop and kill cancer cells are among the newest drugs
being discovered and fine-tuned.
How do scientists develop them? ... How do
we know what happens when a drug is received in the body, introduced
by mouth, IV drip, or by patch? Briefly, the
investigation most go through three phases: preclinical, clinical
(human testing), and regulatory assessment.
The first task in in the preclinical phase is to
find a promising compound and then to determine how much of the drug
is needed to do the job. The necessary concentration is determined
in preclinical experiments involving cell cultures as in the
well-known Petrie dish, or with animals.
(NOTE: This phase is essential to credible
drug research. Homeopathy - using very minute doses of compounds
to treat medical conditions - has not been validated as affective
in any blinded randomized trials.)
In the body the drug interacts with, binds to, or
disrupts, some process underlying the disease. Targets of the
compound can be cell membranes; enzymes, structures or carriers -
all proteins - or any one of the cellular chemicals or processes
that have been hijacked to keep the disease going.
The fit between a drug and a body molecule or
diseased cell structure is known as affinity. One
important goal of therapy related to affinity is specificity
... that the compound binds as exclusively possible to the target of
treatment and minimally impairs normal processes.
The interaction between drug and disease is known
as mechanism of action.
However, even well targeted drugs, such as the
cancer drug Gleevec, can have significant side effects, emphasizing
the need for caution in the testing of new drugs in human subjects.
A relatively new drug target is found on the surface
of cancer cells. These are molecular binding sites. One, known
as CD20, is targeted by the drug Rituxan. Here a man made
antibody binds to the CD20 receptor which can cause the cell to
self destruct, or leads to killing of the cell by immune cells.
The field of identifying new potential drug
targets is accelerating at a rapid pace. Targets may be within
the cell, such proteins or genes that prevent cell death, on
the cell surface as described above, or the target may be other
"normal" cells that contribute to the survival and
expansion of the malignant cells in the tumor microenvironment.
Many chemotherapy drugs exploit the overt behavior
of cancerous cells - rapid cell division. The dividing cell
more readily takes up the drug, which leads to damage of its DNA
(the vital information that determine cell behavior and
functions). ...
Source: http://www.nih.gov/sigs/aig/
... The cell, detecting the damage to
its DNA , self destructs in a process called apoptosis.
An everyday example of apoptosis is peeling skin that results from
sunburn.
Pharmacokinetics, or PK for short, is yet another
essential part of new drug development and assessment in the
clinical phase. It's the study of what your body does to a
drug. The initial PK research is carried out on animals and then
ever so slowly and carefully in humans.
How long the drug remains in the bloodstream, and
at what concentration, are vital to the safety and effectiveness of
drug, which are determined by Absorption, Distribution,
Metabolism and Excretion. (ADME for
short).
The organs that have a major impact on ADME are
the liver and the kidneys. Individual
differences in patients can result in faster or slower clearance of
the drug from the body. Differences in clearance rates can affect
the course of treatment and severity of side effects. (See
also the side bar on HETEROGENEITY.)
If the drug remains in the blood too long it can increase side
effects. Conversely, a drug that's excreted or cleared too rapidly
will not be around long enough, or at the proper concentration, to
do its job well.
Moreover, interaction with other drugs or herbs can affect how drugs
are absorbed or cleared from the body.
Yet another aspect of the drug development and
testing is the called pharmacodynamics, or PD, which
is the
Source: http://www.gmhc.org/health/treatment/ti/ti1507.html
The larger the window the more likely the drug can
be administered in a safe and effective protocol.
Finally, if the new drugs shows reasonable safety
and activity in early phases of clinical trials, it is then tested
against approved therapies in large randomized controlled clinical
trials. The goal of these phase III studies is to objectively
determine the safety and efficacy in a way that minimizes bias,
which can result from patient selection in smaller non-randomized
studies.
Only 1 in 5,000 new compounds evaluated in the
preclinical stage makes it to the clinic ... and about 1 in 5 new
therapies that reach phase III clinical testing.
It's worth noting the regulatory evaluation of the
data for approval does not take very long ... about 6 months. The
preclinical and clinical testing phase can take ten years or longer.
The cost to the sponsor can reach 1 billion dollars.
~ John Dixon and Karl Schwartz
