U researcher
develops new way to test pharmaceutical drugs
By Veronica Pineda
Approving
a new drug takes a minimum of 500 million dollars and years of clinical
research. Despite this large investment, about 73 percent of pharmaceuticals
drugs fail clinical trials, and 10
percent are recalled after FDA approval due to unforeseen harmful side effects.
What’s the flaw? One
possible reason could be that pharmaceutical testing overlooks the harmful side effects that show up on unexpected organ systems.
University
of Utah scientist, Shannon Gaukler, believes her lab has developed a drug
testing methodology called the Organismal Performance Assay (OPA) that may be
capable of revealing drug toxicities that are often missed by other pharmaceutical
tests.
The OPA
utilizes semi-natural enclosures to test the performance of wild mice. Measures
of performance include reproductive success, survivorship, and male dominance.
“I come
from an ecology background, and this is what animals in the environment do.
They compete for mates and resources that are essential for survival,” said
Gaukler.
Pharmaceutical
safety and efficacy are assessed in both in vivo and in
vitro studies. In vivo studies
are conducted in animals, typically inbred strains, to determine if the drug causes cancer, birth defects, or genetic
mutation. In vitro studies are usually conducted in tissue culture, cells from an organism grown in a flask that are used as
the experimental model instead of an animal.
One major downside to in vitro testing is that this approach ignores the synergy, or
interaction, between the many physiological systems in the body. The drug might be designed to affect one
body system, though the drug could affect various physiological systems.
“If you
determine that a particular drug is safe for the heart, (it) does not mean that
it will be safe for other organs and organ systems,” said Gaukler. “A lot of
drug failures are due to toxicities that emerge in unexpected organ systems.”
One way
that the pharmaceutical approval process could be improved is through the use
of the OPA. The OPA utilizes genetically diverse wild mice that compete for
limited resource in semi-natural enclosures. Since humans are genetically
diverse, it is best to test in genetically diverse animals. Typically,
preclinical trials are conducted in genetically inbred strains that are housed
in a stress-free caged environment.
“By
housing our wild mice in semi-natural environments, we are challenging mice to
be mice,” she said.
Gaukler
has used the OPA to test paroxetine (Paxil), a selective serotonin reuptake
inhibitor (SSRI), and an antidepressant. At the moment, Paxil is available on
the market and is suspected of causing birth defects in babies born to mothers
who take the drug during pregnancy.
GlaxoSmithKline*
now warns pregnant women against taking the drug. Studies reveal that women who took Paxil
during the first three months of pregnancy were about one and a half to two
times more likely to have a baby with a heart defect, such as murmurs, than
women who received other antidepressant medication or women not on
antidepressant medication. The FDA approved Paxil after
successful preclinical and clinical trials.
Paxil
was incorporated into rodent food so that each mouse would ingest approximately
30 mg/kg/day, which is about 10 times the human therapeutic dose. Breeding
pairs are exposed to the drug in a caged environmental. The offspring produced
by these breeders are the test individuals that go into the OPA.
Gaukler found that Paxil litters
were significantly skewed towards female offspring (p=0.0021) and that the offspring weighted significantly less (p<0.0001) than
litters in the control treatment. Gaukler also found that pregnancy was
significantly delayed (p=0.05) in the Paxil breeders.
Once the
offspring are approximately two months old, they are released into semi-natural enclosures. Each population
consists of 24 individuals: eight males, four from the control treatment and four
from the Paxil treatment; and 16 females, eight from the control treatment and
eight from the Paxil treatment.
Each enclosure consists
of six territories. Four of the territories contain dark nesting sites, in
which males compete for. The remaining two territories contain open nesting
areas in which the losers are then forced into.
The males constantly
fight to either obtain or defend the optimal territories, while females continually
gestate and nurse new young.
“Unlike caged animals
used in preclinical studies, mice competing in these semi- enclosures require
high performance from most of their physiological systems to establish social
dominance and become successful individuals,” said Gaukler.
Paxil- exposed males
were significantly less dominant (p<0.0001) and had approximately 50 percent fewer sons (p=0.0236) than
control males. Paxil-exposed females had approximately 25 percent fewer
offspring (p=0.1014) that control females.
However, there
were no significant differences in terms of survivorship between treatments
Gaukler said.
“These results tell us
that Paxil is really impacting the overall fitness of these animals. We do not
know the mechanisms that are responsible for these fitness declines, but they
could be determined in future studies,” she said.
One possible mechanism
of fitness declines could be how Paxil interferes with serotonin levels. Serotonin,
known as the happy drug, impacts a region of the brain called the hypothalamus,
a gland within the endocrine system.
The endocrine system is
responsible for regulating hormones in the body, including testosterone,
estrogen, and progesterone. Alterations to these hormone levels could explain
why males have reduced dominance and why females have a reduced number of
offspring, said Gaukler.
In addition to Paxil, Gaukler
has also used the OPA to test the safety of Baycol (cerivastatin), a drug that
was prescribes to reduced cholesterol.
Gaukler has detected
significant fitness declines in Baycol-exposed mice as well.
The results from these
two studies suggest that the OPA is a superior approach to assessing the safety
of pharmaceutical drugs according to Gaukler.
“If OPA’s were
implemented as a tool in preclinical testing, there is the potential to save
millions of dollars and reduce human suffering by identifying drug toxicities
early in development and prior to clinical trials,” said Gaukler.
