New uses for existing drugs

REPRINTED FROM THE NEW YORK TIMES

Housed in a row of white freezers in a nondescript laboratory at the Johns Hopkins University School of Medicine in Baltimore are more than 3,000 of the estimated 10,000 drugs known to medicine. There is no sign on the door to indicate that this is perhaps the largest public drug library available to researchers interested in finding new uses for old and often forgotten drugs.

Already, researchers have used the library to discover that itraconazole, a drug used for decades to treat toenail fungus, may also inhibit the growth of some kinds of tumors and may forestall macular degeneration. Another drug, clofazimine, used more than a century ago to treat leprosy, may be effective against autoimmune disorders like multiple sclerosis and psoriasis.

“It takes 15 years and costs close to a billion dollars to develop a new drug,” said Jun O. Liu, professor of pharmacology and director of the Johns Hopkins Drug Library. “Why not start with compounds that already have proven safety and efficacy?”

He and his colleagues have been building the collection since 2002 and hope to have it complete by 2011. They acquire the drugs through donations, purchases and sometimes lab synthesis. And they will send researchers a complete set — minuscule amounts of every drug in the library — for $5,000, which covers the cost of shipping and replenishment.

Since the toenail and leprosy drugs are approved for use in the United States and are no longer under patent protection, clinical trials to test their new uses are either under way or close to regulatory approval, Dr. Liu said.

Drugs still under patent protection are more complicated; patent holders seldom allow independent research on alternative uses. “The drug companies haven’t been too keen on helping us,” Dr. Liu said.

There are other drug libraries, both commercial and noncommercial. Commercial suppliers offer considerably fewer drugs than Johns Hopkins (though they may have medicines it does not), and they charge much more. Noncommercial drug libraries include those at the National Institutes of Health; the University of California, San Francisco; and McMaster University in Hamilton, Ontario. But they will usually not send drugs to unaffiliated researchers. And like the commercial libraries, their holdings are smaller and composed largely of compounds from Hopkins.

Regardless of the source, researchers typically order copies of entire collections rather than individual drugs they think may work in their experiments.

“We’ve found drugs that are active in ways no one would have ever hypothesized,” said Marc G. Caron, a professor of cell biology at Duke who is using the Johns Hopkins library to find drugs that might quell the cravings of substance abusers.

Testing of these compounds has become much easier in recent years as a result of an automated technology called H.T.S., for high-throughput screening. The drugs are dissolved in a solution and stored in rectangular, compartmented plates reminiscent of ice trays; they can then be delivered to researchers for testing of their efficacy against various diseases, or disease mechanisms like inflammation.

Computerized droppers, plate agitators and microscope image readers can now accomplish in days what it once took bench scientists years to do.

Although H.T.S. has been around for at least a decade, it is just within the last five years that the technology has been widely available. Previously, only big pharmaceutical companies could afford to screen thousands of compounds; now more public and academic institutions are doing so, and their emphasis tends to be on rediscovering or tweaking the chemical structure of old drugs rather than developing new ones.

“The instrumentation to do sophisticated, large-scale screening of drugs has gotten significantly better and cheaper,” said Michelle Arkin, associate director of the Small Molecule Discovery Center at U.C. San Francisco.

Some institutions, like McMaster in Ontario and Rockefeller University in New York City, allow outside researchers to use their H.T.S. facilities for $10,000 to $20,000, depending on the complexity of the project.

Access to such facilities has increased demand for compounds, particularly already approved and off-patent drugs, to analyze. Johns Hopkins and commercial suppliers report a surge in orders over the last two years — because there are more H.T.S. laboratories, they said, and because of efforts to find cheaper therapies against third world scourges like malaria and tuberculosis.

“Old drugs are the low hanging fruit in terms of finding safe and inexpensive treatments for these diseases,” said Carl Nathan, chairman of microbiology at Weill Cornell Medical College in New York. Dr. Nathan receives plates of drugs from Johns Hopkins as well as commercial suppliers and does high-throughput screening at Rockefeller, which has a partnership with Weill.

“I’m addicted to it,” he said.