A generic drug with a spotty record is getting increasingly serious scrutiny as a possible adjunct to Tamiflu in the event of a bird flu pandemic.

The drug, amantadine, was created in the 1970s and used to treat seasonal flu. After bird flu re-emerged in humans in late 2003, most scientists believed the virus was resistant to amantadine because the strains that infected the first victims in Southeast Asia seemed to be resistant to the drug. Now, evidence of amantadine's potential against some forms of the avian flu virus is mounting, and some health authorities and prominent scientists are taking a fresh look.

Of the approximately 130 strains of H5N1 whose sequences have been analyzed by the World Health Organization, about a quarter are sensitive to the older drugs, a WHO official says, adding that other labs have probably reviewed more sequences. That dovetails with a recent finding that H5N1 may have evolved into several distinct subgroups, some of which are resistant to the older antivirals and some of which are not. The H5N1 strains found in Vietnam, Thailand and Cambodia seem to be mostly resistant, according to experts who have reviewed the data. But those from China, Indonesia and Turkey seem to be somewhat sensitive to the drugs.

Health authorities worry that if a pandemic erupts, putting millions of lives at risk, a single-minded reliance on Tamiflu, made by Roche Holding AG of Switzerland, could backfire. Amantadine and its older cousin, rimantadine, are produced by many generic-drug makers, offering huge supply potential at a cost far below Tamiflu's. Forest Laboratories Inc. in New York, for instance, makes a branded version of rimantadine, and Endo Pharmaceuticals Holdings Inc. of Chadds Ford, Penn., makes a version of amantadine marketed as Symmetrel.

Amantadine isn't in the same league as Tamiflu, largely because most strains of H5N1 -- the viral strain of avian flu that concerns scientists most -- may still be resistant to it, as well as to rimantadine. The two drugs also have more side effects than Tamiflu and appear likelier to spawn drug-resistant strains of the virus. And the evidence in favor of the older drugs remains ambiguous because so few strains have been analyzed.

Still, the new research has "created this conundrum for everybody," says Keiji Fukuda, acting coordinator of the global influenza program at the WHO in Geneva. "Should amantadine be stockpiled? Should it be used? What is its role, both for avian influenza and for pandemic influenza?"

Avian flu, which has spread widely among birds in Asia and has now breached the borders of Europe and Africa, can pass from birds to humans through close contact. If the virus became readily transmissible from person to person, threatening a pandemic, authorities would use antiviral drugs to control its spread until a vaccine was ready for wide use.

This month, the WHO is planning to gather a group of experts at its headquarters to review the WHO's guidance on antivirals, including the older drugs, in fighting bird flu, Dr. Fukuda says. "It's under consideration to say something about the possibility of using amantadine in stockpiles" of antiviral drugs, another WHO official adds. "But currently, we're sticking with Tamiflu."

Martina Rupp, a Roche spokeswoman in Basel, Switzerland, says that all the strains of H5N1 that have been examined so far would be susceptible to Tamiflu. She adds that research indicates that those viruses that develop resistance to Tamiflu don't multiply and pass between people as easily as the others.

If governments have enough information about the viruses in their country, "and they all turn out to be amantadine-sensitive," says Michael L. Perdue, a bird flu expert at the WHO, "I don't see why they shouldn't consider amantadine as a second drug to have available" in addition to Tamiflu.

Tim Uyeki, a medical epidemiologist in the influenza branch at the U.S. Centers for Disease Control and Prevention in Atlanta, says amantadine's potential to fight bird flu is "something that we have looked at, and will continue to look at."

"A lot of scientists are changing their minds" about the drug, says a senior Chinese scientist who has analyzed the genetic sequences of H5N1 viruses in China and found that many would be sensitive to amantadine. "In the meetings, they don't think Tamiflu is the only one," the scientist adds, referring to calls for a reappraisal of the older drugs by senior virologists at recent scientific conferences.

Last year, when bird flu began spreading quickly in poultry and infecting dozens of people, raising fears that a pandemic could be near, governments scrambled to stockpile antiviral drugs. They bypassed amantadine and turned directly to Tamiflu. Hundreds of millions of dollars were spent -- driving sales of Tamiflu to surge last year to $1.2 billion -- as countries moved to stock supplies of the drug.

In January, the CDC in Atlanta announced that the vast majority of seasonal flu strains circulating in the U.S. were resistant to amantadine and rimantadine, and it advised doctors against the use of those drugs. That the drugs didn't work on regular flu didn't necessarily mean they were useless against H5N1, but the announcement cast further doubt on the value of the older drugs.

In a recent re-examination of amantadine, a group of health experts brought together by the WHO discussed with Turkish doctors the possibility of trying a combination of Tamiflu and amantadine on bird flu patients. This "cocktail" would be somewhat similar to the complicated regimen of drugs used successfully for years to fight HIV, the virus that causes AIDS. "There's clearly no consensus on whether to do that or not," says Dr. Fukuda. "It's also clearly an issue that people are very interested in."

The U.S. has stockpiled five million rimantadine treatments, which had been on hand for years before bird flu broke out, but has none of amantadine. It has also purchased about five million courses of Tamiflu, and plans to buy more from Roche.

The CDC would make the call on whether to use the older antivirals against bird flu in the U.S. "We are not currently recommending amantadine or rimantadine to be stockpiled for pandemic planning stockpile purposes," says Dr. Uyeki. "But these viruses need to be continually monitored."