The New Miracle Drug May Be Smog?

Eight years ago, at a medical meeting in Rochester, N.Y., two American scientists suggested that human blood vessels spew out nitric oxide gas--the very same toxic chemical in car exhaust fumes and smog. They were greeted by near-unanimous skepticism. But not from Dr. Salvador Moncada, head of British research for Wellcome PLC. To him, the notion suggested a tantalizing path for drug development. He immediately phoned his London team, insisting on crash confirmation.

Back at Wellcome, Moncada's crew started sleuthing for NO in blood vessels with crude environmental-lab machines that measure toxins in car fumes. Put to the test, blood vessels showed enough evidence of NO to persuade Wellcome to make its own souped-up NO detector--1,500 times as sensitive as the others. "Every time we stimulated cells, they released NO," says Moncada. He was convinced this "simple and beautiful" substance lurked all over the body.

In the years since, NO--not to be confused with nitrous oxide (N2O), or laughing gas--has been found everywhere in the body and tied to an array of major diseases. Today, researchers believe either boosting or blocking NO production could help combat such killers as heart disease and cancer, and treat such ailments as impotence, asthma, and rheumatoid arthritis. Those add up to a colossal potential market, considering the 1.2 million people in the U.S. alone who are diagnosed annually with cancer, the 1.5 million who have heart attacks, and the additional 500,000 who suffer strokes.

It's no surprise, then, that major drugmakers have begun to chase NO-based cures. Thanks to Moncada's prescience, Wellcome is exploring NO treatments for coronary artery disease, asthma, and rheumatoid arthritis, plus a slew of neurological diseases. Ciba-Geigy and Cassella, a subsidiary of Germany's Hoechst, are targeting cardiovascular drugs, while giant Merck is studying NO's role in the brain, the heart, and the immune system. Meanwhile, at least three U.S. startups, Guilford Pharmaceuticals, NitroMed, and Apex Bioscience, have pinned their futures on NO-based treatments for everything from septic shock and AIDS-related dementia to brain disorders. The payoff is likely to "be significant, considering the nature of the diseases involved," predicts Dr. Trevor M. Jones, director-general of the Association of the British Pharmaceutical Industry.

Plenty of people think he's wrong. "It's a revolutionary concept" for drug development, agrees Dr. Jeffrey M. Drazen, chief of pulmonary medicine and an NO investigator at Harvard Medical School. "But if I bought stock in drug companies, and I don't, I probably would not be heavily invested in nitric oxide." He worries that while NO can have important beneficial effects, such as lowering blood pressure, it may prove to have toxic effects, too. "We don't know if this is another thalidomide," he warns. Besides, since drugmakers need to solve a few problems--targeting the right amount to treat specific conditions, for instance--it is likely to be a decade before significant drugs come to market.

TICKLING VEINS. Still, it's clear that NO is no longer viewed as merely a pollutant. Toxicologists began to change the view of it in the 1980s, when they started exploring how smog wreaks havoc in the body. They spotted excess NO, way beyond the amount that would be expected from pollution--the first clue that the body might be making its own supply. Then, immunologists led by University of Utah School of Medicine's Dr. John B. Hibbs Jr. zeroed in on NO in macrophages, an immune-system cell, which suggested that NO can fight infections and possibly tumors. About the same time, Louis J. Ignarro, professor of molecular pharmacology at the University of California, Los Angeles School of Medicine, and Robert F. Furchgott, professor emeritus of pharmacology at the State University of New York Health Science Center at Brooklyn College of Medicine, proposed that wisps of NO tickle the inner lining of blood vessels, prompting them to relax. That was the finding that sent Moncada racing to the phone. Any substance that could do that, he knew, could be valuable because so many diseases are tied to narrowed blood vessels, including cardiovascular disease.

NO's ubiquity is both an asset and a drawback. "With the involvement of this molecule in so many functions, the risk is that [drugmakers] may be working in the wrong area," says Duncan Moore, a health-care analyst at Morgan Stanley & Co. in London. Indeed, to develop successful NO-based treatments, scientists first have to figure out NO's role in a disease, whether it's helpful or harmful, then figure out how to take advantage of or avoid the effect. Then they need to deliver NO precisely where it's needed, and in just the right dose.

GOOD NEWS, BAD NEWS. The effort to treat impotence shows how difficult this can be. Many scientists think the condition is caused by lack of NO in the nervous system. In initial attempts in 1992, University of California at San Francisco researchers injected NO into the penis to relax blood vessels and get blood rushing to the site. The men did get erections, but they also fainted because this first attempt used long-lasting NO drugs that lowered blood pressure.

Despite such obstacles, drugmakers are forging ahead. Wellcome, NitroMed, and Apex are targeting septic shock, potentially fatal low blood pressure caused by massive infections that generate excess NO. Roughly 600,000 people in the U.S. develop sepsis each year, and 100,000 die. In recent years, three high-profile potential treatments have failed. Analysts say a drug that helps could bring in as much as $1 billion a year in the U.S. alone.

In September, Wellcome launched clinical trials for its drug, L-NMMA, which inhibits enzymes that make NO. Meanwhile, Apex Bioscience Inc. in Durham, N.C., has won a patent for a potential septic-shock therapy. Its goal is to use a recombinant hemoglobin that would mop up excess NO caused by infections. In Cambridge, Mass., NitroMed researchers are gambling on a different approach. Their patented method aims to block NO receptors on cells to keep the chemical at bay. None of these drugs would cure the underlying infection, but they might restore blood pressure, keeping patients alive until the original illness can be controlled, says Joseph DeAngelo, vice-president of research at Apex.

Moncada's 1986 phone call was crucial in unleashing NO research. Today, he insists, research into the workings of NO "is moving faster than any other field of research." Still, it will be a while before NO becomes more than just smog.

Nitric Oxide: How It Helps And Hurts
      The primary ingredient in smog, NO also plays many roles in the body
              Nervous                Circulatory             Immune
              system                 system                  system
      GOOD    NO helps relay         NO relaxes blood        NO boosts the body's
              messages               vessels and eases       ability to fight
              between nerve          blood flow, keeping     viruses, bacteria,
              cells in the brain     blood pressure in       fungal infections,
              and elsewhere.         check.                  and possibly tumors.
      BAD     High NO levels         Too much NO,            Too much NO seems
              caused by stroke       caused by massive       to be linked to
              can kill brain cells.  infections,             arthritis, multiple
              And scientists think   dramatically lowers     sclerosis, asthma,
              low levels of it can   blood pressure,         and transplant
              lead to impotence.     leading to shock.       rejection.

Randi Hutter Epstein in London

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