Tuesday, March 19, 2013

U researcher develops new way to test pharmaceutical drugs


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.

     

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