New Class of Drugs Might Cause Congenital Heart Defects

Lithium is only such drug on market, but more powerful versions are in development, researcher warns

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By Ed Edelson
HealthDay Reporter

THURSDAY, Oct. 2 (HealthDay News) -- An animal study raises a warning sign that a new class of drugs that shows promise against a variety of ailments ranging from cancer to Alzheimer's disease might cause congenital heart defects, researchers report.

"We have no idea if there will be any risk, but the study suggests we should be aware of the possibility," said Dr. Thomas Force, a professor of medicine at Thomas Jefferson University in Philadelphia and lead author of an online report in the October issue of the Journal of Clinical Investigation.

The drugs are aimed at a gene that produces a protein called glycogen synthase kinase-3 (GSK-3). The only drug now on the market that targets GSK-3 is lithium, given to treat bipolar disorder. It is a relatively weak GSK-3 inhibitor. Because of the wide range of GSK-3 protein activity, there is active research on molecules that inhibit that activity.

The study was done on mice bred to lack two forms of the gene, GSK-3-alpha and GSK-3-beta. Mice lacking GSK-3-alpha were born with normal hearts, but those lacking GSK-3-beta all died before birth. Some died halfway through gestation of severe liver degeneration. Most died at a later stage of development, with numerous heart defects, including abnormally thick heart muscle caused by overgrowth of the muscle cells.

"It has been suggested in the past that lithium might cause birth defects," Force said. "It is not clear whether that is the case. The data from our paper suggest that newer agents with much more potent GSK-3 inhibitory action could raise the level of danger."

It is difficult to get detailed information on the development of new GSK-3 inhibitors, because drug companies try to keep that information to themselves, Force said. "These are proprietary compounds, so they are not talking about what they are doing," he explained.

But there appears to be time to investigate the danger of birth defects, because none of the new agents seem to be in human trials yet, Force said. "I have checked on clinical trials, and I did not see anything there yet," he said.

The kind of animal study that his group has done can help determine whether there is danger, Force said. "Probably more work needs to be done on the basic level with these agents and their effect on embryonic development before we start giving them to women of childbearing age," he said. "Before they are given to women of childbearing age, they should be tested in animal models."

There are published reports of various GSK-3 inhibitors showing promise against diabetes, pancreatic cancer, leukemia, Alzheimer's disease and other dementias. Those reports do not mention human trials, planned or ongoing, that would require assessment of the risk of birth defects.

"The last thing I want to do is scare people," Force said. "I'm saying this is something we should be aware of as these drugs come out."

One expert said having a mouse model for this purpose should prove useful.

"It's always important to have tools like this mouse model to look at teratogenicity [birth defects], irrespective of specific drug families," said Dr. Peter J. Nelson, an assistant professor of medicine at New York University. His research centers on compounds that affect both GSK-3 and another family of proteins, cyclin-dependent kinases.

"We're looking primarily at renal disease," Nelson said. "It's in a very preclinical state."

More information

Use and known side effects of lithium are described by the U.S. National Library of Medicine.

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