TINY FROG OFFERS MAJOR NEW PAINKILLER, DRUG RESEARCH FINDS

QUITO, Ecuador -- Epibpedobates tricolor seems a big name for something so
small.

Little longer than a fingernail, the tiny frog can easily hide in the heart
of a flowering plant, a bright jewel of red and green with shining black eyes.

The brilliant color is a warning. The frog's skin secretes a deadly poison,
which Ecuador's rain forest dwellers have long used to coat blowgun darts
for hunting. When the poison enters the bloodstream of a monkey or sloth,
the animal quickly dies.

Soon, however, Epibpedobates tricolor also may become a boon for mankind.

Abbott Laboratories of North Chicago has just completed initial human
trials in Europe of a painkilling drug based on a derivative of the frog's
poison. While the results have not yet been made public and the company is
hesitant to talk about ABT-594, as the chemical is known, scientists say
the drug is 200 times as powerful as morphine, lacks morphine's addictive
problems, and might one day take that drug's place as the world's leading
treatment for intense and chronic pain.

"Abbott, I think, was very lucky to be able to separate the toxicity from
the desired analgesic effect," said John Daley, a scientist at the National
Institutes of Health who initially identified the chemical structure of the
frog poison.

With many drugs derived from natural substances, such as digitalis used in
the treatment of heart problems, "nobody's been able to get rid of the
toxicity. That's usually the problem," he said.

ABT-594, however, has passed its initial human trials, which determine
whether the drug produces problem side effects in healthy users. Phase II
trials, in which the drug will be tested on pain sufferers, are being
scheduled, said Melissa Brotz, an Abbott spokeswoman.

"We'll probably try a broad brush on a few different types of pain," she said.

Years of research into compounds from rain forest plants, animals and
insects are beginning to pay off for companies such as Abbott, which
synthesized up to 500 variations of the Epibpedobates frog poison before
deciding to go forward with ABT-594.

Scientists say they expect to see a growing number of drugs coming out of
the world's tropical rain forests. What is more worrying is whether the
rain forest and its animals will still be there to provide their
potentially miraculous compounds in the future.

The tiny frog that gave birth to Abbott's new painkiller is endemic to
lowland rain forest slopes in southwestern Ecuador, near the town of Loja.
Today, less than 6 percent of the frog's original habitat remains intact.

When Daley first came to Ecuador in the late 1970s to collect samples of
the frog, he was able to take home more than 750. Within a few years, road
building and human settlement put the frog on Ecuador's threatened species
list and further collecting was outlawed.

"Human competition is their worst problem," said Maria Elena Baragan,
director of Quito's vivarium, which displays a collection of the tiny
poison dart frogs.

Today, the frog has managed somewhat of a comeback by adapting to life in
Ecuador's coastal banana plantations, where it is commonly found. The
problem is that in its altered habitat or in captivity the frog no longer
produces its poison.

Scientists have not yet determined what it is about the frog's forest
habitat that allows it to produce the vital chemical. "There just are no
studies," Baragan says. But work on some of the other 100 or so species of
poison dart frogs suggests it is probably some ant, millipede or beetle in
the frog's diet.

"The frog without its intact surroundings is useless," said Roderick Mast,
a vice president and frog expert at Washington-based Conservation
International. "It's a wonderful conservation flagship species. You have to
conserve its entire habitat to conserve it."

Whether the frog and its habitats will be protected, however, remains in
question, in part because Abbott's new drug, a variation of the natural
frog poison, can be synthesized in the laboratory without the frog.

That ability is a blessing for native frog populations that might otherwise
be decimated by collecting for medical purposes and a curse in that their
protection is no longer key to development of the drug.

Countries such as Ecuador, which are only now working on laws to claim
intellectual property rights on the genetic variety in their forests,
generally get no share in the profits of new drugs produced from their
plants or animals.

Other countries have passed laws that patent the genetic material but not
derivatives of it, the case with ABT-594.

That has left many South American countries with little money for or direct
interest in promoting conservation of their rain forest species.

Mast calls that shortsighted and says part of the answer is for countries
such as Ecuador, Colombia, Brazil and Peru to begin strengthening their
drug industries to take advantage of their resources.

"Our basic understanding of biodiversity is pathetic," he said. "We barely
know what species are out there let alone the alkaloids they have in their
skin or what they might be good for.

"How many chemicals are out there? We have no idea. What we do know is that
we're only scratching the surface."

When the chemical structure of the Epibpedobates frog poison was determined
in 1990, Daley found that the chemical worked as a powerful painkiller but
not through the same opioid receptors targeted by morphine.

Abbott's non-toxic derivative focuses instead on nicotine receptors,
raising the possibility that other kinds of addiction might be a problem.
So far, however, the company has reported no addiction problems and early
testing in rats showed animals taken off the painkiller suffered no lack of
appetite, a normal withdrawal sign.

The drug also appears to make users alert, rather than sedating them, as is
the case with morphine.

"Abbott got the jump on everyone else on this because they have been
working on nicotine derivatives forever," Mast said. "They weren't
particularly looking for painkillers but as a good chemical company they're
always on the lookout. This popped up as something with potential."

If the drug eventually wins U.S. approval from the Food and Drug
Administration, a process Abbott says is still years away, it could
potentially snare a major share of what is a $40 billion a year worldwide
industry in treating long-term or severe pain not affected by aspirin or
other basic painkillers.

In the U.S., the company estimates 30 million to 40 million people suffer
pain that might be treated by ABT-594.

Mast calls the promising new drug reason enough to step up conservation of
rain forests, where he and others believe many other new wonder drugs lurk.

"My view is the only logical action is to conserve as much intact for as
long as possible," he said. "Otherwise, there will be nothing to study and
we could be losing something not only with economic value but with
significance to every other living thing on the planet."

Checked-by: Pat Dolan