SHELVED SOLUTIONS

Eight years ago at a laboratory in Texas, Warner-Lambert Co. began testing a
possible cure for the methamphetamine epidemic: a new and improved cold
medicine that could not be turned into the illicit stimulant.

The company was worried that federal regulators would soon ban or
restrict sales of pseudoephedrine, the main ingredient used to make
meth and Warner-Lambert products such as Sudafed, Actifed and
Benadryl. Warner-Lambert's meth-proof alternative showed promise in
animal testing, conducted at a university lab in Fort Worth. The
company quickly applied for a patent.

But that is where the product's development ended. Former company
officials said they saw little chance of making a profit on the product.

Federal approval of a new drug, which includes lengthy human trials,
costs as much as $800 million, according to industry estimates.
Warner-Lambert's top-selling cold remedy, Sudafed, was grossing less
than $100 million a year. "It would be a long road and an expensive
road," said Robert G. Flynn, a former research vice president at the
company. A cold pill that could not be used to make meth would offer
huge public benefits if it replaced existing products.

Past constrictions in the flow of meth ingredients have radically
altered the trade, disrupting the supply of meth for as long as a
year, The Oregonian's analysis of federal data shows. Federal
authorities never offered the pharmaceutical industry financial or
other incentives to develop such a pill. By the time Warner-Lambert
had its patent, the threat of a ban on pseudoephedrine had receded.

In 2000, Pfizer Inc. took over Warner-Lambert and did not pursue the
new cold medicine. Jay Kosminsky, a Pfizer spokesman, said
Warner-Lambert's formula was not enough of an improvement over
existing products to merit further research. Instead, Pfizer tried
mixing Sudafed with chemicals that would make it harder for meth
traffickers to extract pseudoephedrine. The company chose ingredients
already approved for human use, which made it possible to avoid the
lengthy testing required for new drugs. After seven years of research,
the company abandoned that project as unworkable this past summer,
Kosminsky said. Warner-Lambert's new decongestant is a close chemical
sibling of pseudoephedrine, the bulk of which is manufactured in nine
overseas factories. Executives at two of the largest pseudoephedrine
makers -- India's Emmellen Biotech and Malladi Drugs -- say they could
supply the new chemical if the vast U.S. market demanded it. "I can
supply large quantities, in tons," said V.N. Gopalakrishnan, technical
director at Malladi. Fear of a ban Pharmaceutical companies have known
that cough and cold remedies could be misused ever since the federal
government first threatened tighter regulations to deal with the meth
problem. "All manufacturers of these types of products are aware that
these decongestant ingredients are related, on a technical, chemical
basis, to more powerful abuse drugs," Robert N. Anderson, an attorney
for Nyquil maker Richardson-Vicks, wrote to Congress in September
1987. But Anderson said Vicks' research indicated that it would be
impractical for meth cooks to extract ingredients from
over-the-counter cold medicine because it "unnecessarily complicates
the chemical process, and raises the cost dramatically." In fact, meth
cooks did find it economical to extract the ingredients. The U.S. Drug
Enforcement Administration responded in the 1990s with more attempts
to control meth ingredients. James D. Cope, former president of the
Consumer HealthCare Products Association, said he warned the trade
group's members that the DEA would make pseudoephedrine a controlled
substance unless they prevented their products from being misused. "If
you can put some chemical in to make it impossible or almost
impossible, that's a way of avoiding the federal sanctions," Cope
recalled telling the group, formerly known as the Proprietary
Association. "Warner-Lambert was the leader in this." Warner-Lambert
entered a joint venture with Burroughs Wellcome in the mid-1990s to
market Burroughs Wellcome's Sudafed and Actifed.

In a 1995 letter to DEA officials, David Long, Warner-Lambert's vice
president for regulatory affairs, said it was unlikely the company's
products would be used in meth labs. At the same time,
Warner-Lambert's scientists were studying how easily meth cooks could
extract pseudoephedrine -- and how to counteract that. Some
Warner-Lambert cold medicines combined pseudoephedrine and painkillers
with inactive ingredients. In a November 1995 memo to Long, one
company scientist explained that it was "rather straightforward"
chemistry to dissolve the tablets and obtain pure pseudoephedrine.
Former Warner-Lambert executives say the company, which took over the
two Burroughs Wellcome product lines in 1996, wanted to come up with a
meth-proof cold medicine in case of a ban. "The impetus of the
research was related to finding decongestants that could not be
manipulated," said Flynn, the former research vice president. "We
obviously were well aware of what was going on relative to the
methamphetamine issue," said Lester Isbrandt, a former Warner-Lambert
research vice president. "We immediately became concerned about it
because of its impact on the sale of Sudafed." Warner-Lambert "had a
huge pseudoephedrine franchise," said a source familiar with the
research program. "This was an insurance policy." The mirror image The
idea for the new decongestant came from the study of molecules.
Ephedrine, pseudoephedrine and methamphetamine are close molecular
cousins; meth, in fact, is ephedrine minus a single oxygen atom. As a
result, their effects on the body are similar.

All three shrink blood vessels in the nose and dilate airways in
lungs, while unleashing adrenaline that stimulates the heart. With
meth, the latter effect is most pronounced. Removing the oxygen atom,
it turns out, makes the molecule fit receptor cells in the human brain
"like a key in the lock," said Paul Doering, a professor of pharmacy
at the University of Florida. Each of the three related molecules also
has a twin: a mirror image of the same atoms.

Flipping the atomic pattern can have a huge effect on how a drug
works. Mirror images can sometimes be even more effective than the
original drug, producing the desired outcome with fewer side effects.
Drug companies also introduce mirror images to extend the life of an
existing drug with a patent that's close to expiring.

For example, AstraZeneca created Nexium, the purple pill that fights
indigestion, using a molecular mirror image of its product Prilosec,
also marketed in purple. At Warner-Lambert, a team led by researcher
Anthony R. Booth was exploring ways to apply the mirror-image concept
to improving the performance of ephedrine, pseudoephedrine and other
drug ingredients that affect the central nervous system. Booth's team
came up with a unique insight: Mirror-image pseudoephedrine could only
be used to make mirror-image methamphetamine, a benign incarnation of
the street drug with few stimulant effects.

No amount of processing or lab magic could change that. And, the new
drug appeared to be a better cold medicine. Warner-Lambert hired a
team of researchers at the University of North Texas to test the drug
in dogs and rats. The team found the drug remained an effective
decongestant but had significantly fewer side effects, such as
elevated blood pressure. The research was complete by December 1997,
said Michael Forster, one of the Texas researchers. "It was
essentially devoid of nervous system effects, as far as we could
tell," Forster told The Oregonian. "And yet it retained the nasal
decongestant effects very well." Steep price Back at Warner-Lambert
headquarters in Morris Plains, N.J., executives discussed what to do
next. They filed an initial patent application in July 1998, records
show. But they were not sure whether to pursue additional research.
Sudafed was a hugely popular and safe product.

Changing the formula would be costly, former executives said. The U.S.
Food and Drug Administration requires three phases of testing on
thousands of human subjects.

The FDA can impose even more extensive tests for over-the-counter
products because consumers use them without a doctor's guidance. To
make the new pseudoephedrine commercially viable, Warner-Lambert
executives considered pitching it to the FDA as part of an anti-meth
program. If the FDA required companies to sell only mirror-image
pseudoephedrine, Warner-Lambert could reap substantial benefits. "If
you had the patent on the only drug that was effective for sinuses, I
think it could be lucrative, especially if you had the patent, and
everybody else had to come to you," said Isbrandt, the former
Warner-Lambert vice president. "That is kind of a pharmaceutical drug
researcher's dream." But the company never made that pitch with
Booth's idea.

Going to Plan B

While Booth's mirror-image molecule was being tested in Texas, a
second team, headed by Warner-Lambert scientist William Bess, went
down another avenue. Bess' team mixed Sudafed with harmless
ingredients such as guar gum, a common ice-cream thickener, that would
create a sticky mess when meth cooks tried to extract the
pseudoephedrine. On this project, the company worked closely with the
DEA. "We had meetings in Washington," said Isbrandt, "and we would be
sending samples back and forth." Researchers tested the formula using
a popular meth recipe found on the Internet. Ordinary Sudafed yielded
89 percent pure pseudoephedrine, but with the additives, no usable
pseudoephedrine could be extracted. Another bonus was that the
additives were already FDA-approved chemicals, executives said. Unlike
Booth's decongestant, which would be considered a new drug, a cold
medicine made with additives would not require costly clinical trials.

The company could move the product quickly to market. Keeping the
costs low was important because executives had no guarantees from the
government that they would be rewarded for their investment. "We never
had any strong indication coming back from the DEA or other sources
saying if we had solved the problem, we would have owned the market,"
Isbrandt said. Warner-Lambert applied for a patent on the additives in
April 1997. That November, a Warner-Lambert spokeswoman told a British
magazine that the company was "now at the final stages of research
into a global solution" to the pseudoephedrine problem. But there was
an obstacle.

The harder researchers made it for meth cooks to extract
pseudoephedrine from Sudafed, the harder it was for digestive fluids
to break down the pills and absorb the decongestant. "We were trying
to do a balancing act, to make it difficult for a chemistry lab to get
at it, but at the same time make it easy for the body to get at it,"
Isbrandt said. "We kept trying to get at that sweet spot." At the same
time, the original pressure on Warner-Lambert -- the possibility that
regulators might ban pseudoephedrine -- was fading.

Industry lobbyists persuaded Congress to exempt from regulation cold
products in foil blister packages, which were considered harder for
meth cooks to open in volume. The DEA, which had been a major force
behind previous pseudoephedrine rules, stopped pushing for additional
powers. Research ceases The company received patents on both ideas:
the additives in October 2000 and Booth's mirror-image pseudoephedrine
in December 2002. Kosminsky, the Pfizer spokesman, said the Booth
project ended before the company took over Warner-Lambert in 2000. He
said Pfizer gave up on the additives that Bess' team had studied after
spending $12 million. Pfizer plans to introduce a cold medicine in
January made with the decongestant phenylephrine, which cannot be
converted to meth. Kosminsky said the product will offer consumers an
alternative in states that restrict retail sales of pseudoephedrine
products. The company will continue selling Sudafed nationwide. Today,
the National Institute of Drug Abuse spends $1 billion a year, much of
it on developing drugs that will fight addiction to substances such as
meth. Yet in the past 15 years, Congress has never seriously debated
financing research into a cold remedy that cannot be turned into meth.
Pfizer's patent on the mirror-image pill is a public record.

Yet lawmakers have never discussed making it easier for Pfizer to get
federal approval for its new drug. Kosminsky said Pfizer would be open
to such a proposal. For now, experts say, drug companies have little
incentive to pursue pseudoephedrine alternatives. "If tomorrow there
was no such thing as Sudafed," Doering said, "people would probably be
working 24/7 looking for something that could fill that need."