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Questions Raised on Using Antiepilepsy Drug in Newborns

Karen Gale

Karen Gale, professor of pharmacology at Georgetown University Medical Center, was the senior investigator in a new study on the effects of phenobarbital.

May 11, 2012 – A new brain study in infant rats by Georgetown researchers shows that the antiepilepsy drug phenobarbital stunts neuronal growth in rat pups, which could prompt questions about using the drug in human newborns with epilepsy.

Annals of Neurology – Early View posted the study by Georgetown University Medical Center (GUMC) researchers online today.

The researchers say when the first-line drug is given to week-old rats it changes the way their brains are wired, causing cognitive abnormalities later in life.

“Our study is the first to show that exposure to phenobarbital – and just a single exposure – can prevent brain circuits from developing their normal connectivity,” says the study’s senior investigator, Karen Gale, a GUMC professor of pharmacology. “[That means] they may not be wired correctly, which can have long-lasting effects on brain function.”

Other Antiepilepsy Drugs

“The good news is not all antiepilepsy drugs have this disruptive effect in the animal studies," Gale says.

Use of the antiepilepsy drug levetiracetam did not stunt neuronal growth. Adding melatonin to phenobarbital prevented the toxic neural effects in the rats. Melatonin has been used clinically to protect cells from injury in human infants.

“Many clinicians have been advocating for a reexamination of the use of these drugs in infants, and our findings provide experimental data to support that need,” says the study’s lead investigator, Patrick A. Forcelli, a postdoctoral fellow in GUMC’s department of pharmacology and physiology.

“Phenobarbital has been used to treat seizures for over 100 years,” he adds, “well before a Food and Drug Administration approval process was established and for more than 50 years it has been the drug of choice in the treatment of seizures in neonates.”

Incidence of Seizures

According to the Epilepsy Foundation, epilepsy affects more than 300,000 Americans under the age of 15. Seizures in neonates are relatively common, according to the foundation, and seizure incidence peaks in the first year of life and remains at a high level up to age 4.

Recent studies of IQ and other measurements of cognitive function in children have suggested that exposure to certain antiepilepsy drugs in utero or infancy affects brain function, but the issue is highly controversial, Forcelli says.

“Seizures do not happen to a normal healthy brain,” he says. “They are typically associated with, or are a result of, an injury or another neurological condition. So the issue is what causes later deficits in function – the underlying condition, the seizures, or the drug used to treat the seizures or some combination of these? Our study in otherwise normal animals suggests that drugs by themselves can be a significant factor.”

Slow to Learn

The researchers also tested the effect of the drugs after the infant rats reached early childhood, and found that those treated with phenobarbital were slow to learn.

“This is an important bridge between molecules and behavior that helps us to understand how early life drug exposure can permanently alter behavioral function in later life of the rats,” Forcelli says.

The research group is now planning to investigate how the drugs affect brain development in infant animals that also have seizures.

Study co-authors include Megan Janseen and Stefano Vicini from the department of pharmacology and physiology at GUMC.

Study Qualifications

The Georgetown researchers say their study was designed to look directly at the effect of the different drugs on normal growth of brain neural networks in otherwise normal animals.

This kind of study can only be conducted with research in animals, they explain, in which each component (condition, seizure and drug) can be controlled and examined separately and in combination.

The researchers also say this type of study can only be performed in animal models in which drug effects can be examined separately from the effects of either seizures or other complications.

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