DRUG MAKERS SEE A RISKY NEW ROLE FOR NICOTINE

Cigarette makers may be facing an unusual rival as long-term suppliers of
nicotine fixes: the pharmaceutical industry.

For the past 14 years, drug companies have sold nicotine patches and gums
with the single-minded goal of helping people quit smoking. Now the drug
makers

are talking with federal regulators about promoting their nicotine products
to those among the nation's 50 million smokers who merely want to cut down
on cigarettes.

With new research revealing that nicotine is more benign than previously
thought, some executives envision sustaining cigarette addicts with
pharmaceutical nicotine for years, even decades.

"Nicotine, caffeine and alcohol are cultural drugs, and I don't think we
can get rid of them," says Karl Fagerstrom, former director of scientific
information for Pharmacia & Uplohn Inc., which makes smoking-cessation
products, including Nicorette nicotine gum. "If it's the nicotine people
want, why not give it to them?"

In the past year, Pharmacia, Smith~ Kline Beecham PLC, which markets
Nicorette in the U.S., and others have quietly commissioned research to
explore the potential health benefits of simply cutting back on cigarettes
smoked, as opposed to quitting altogether.

Meanwhile, for people still struggling to quit, they also hope to persuade
the Food and Drug Administration to extend the recommended dosage period
for gums and patches to as much as six months from the current six to 12
weeks.

According to people close to SmithKline, the company began talking to the
FDA about its new strategy in late 1996, and it has been exploring the
issue with division-level officials on a regular basis ever since.

The drug makers' new strategy has some obvious advantages. "There will be
less environmental smoke," says Neal Benowitz, a nicotine expert at the
University of California at San Francisco who was one of the scientific
editors of the landmark surgeon general's report of 1988 that concluded
that nicotine is addictive. "I'd much rather see people dependent on
nicotine than on tobacco," he adds.

But the approach also raises troubling ethical questions: Will smokers
merely cut down rather than quit? Will former smokers be lured back into
the habit? Should people be perpetually maintained with nicotine?

George Crane, a 77-year-old retired math researcher in Palo Alto, Calif.,
chomps on about a dozen pieces of Nicorette gum a day - and has chewed them
faithfully ever since he snuffed out his last cigarette six years ago. "I'm
going to be on nicotine all my life," Mr. Crane says. "I think we need to
take care of people who've become so addicted to nicotine that there's
nothing you can do but give them a maintenance drug."

It's certainly a sensitive topic for the drug makers. SmithKline, according
to scientists familiar with the company, is petrified that people will
accuse it of profiting from addiction, as they do the tobacco companies. "I
don't want people to misconstrue our intentions here." says George
Quesnelle, vice president of medical marketing and sales at SmithKline.

"We're not a cigarette company; we're a health-care company."

That may be, but drug makers also know there is much room for growth.

Over-the-counter smoking-cessation aids, which generated sales of about
$700 million last year, have barely been tapped by smokers, who spent $25
billion on cigarettes. According to a soon-to-be-published study
co-authored by John Pinney, a consultant for SmithKline, only an estimated
13% of all smokers try to quit using a nicotine patch or gum. Of those,
only 8% stay off cigarettes for at least a year.

The company that stands to gain the most is SmithKline, which dominates the
U.S. over-the-counter market with its Nicorette gum and NicoDerm CQ
patches. The company has already benefited from smokers who defy the
product label in search of a nicotine substitute. Last year, SmithKline
says, sales of its NicoDerm CQ patch and Nicorette gum swelled 30%, to $448
million, partly because more smokers were using the products to avoid
nicotine cravings in non-smoking places.

"To be crass about it, virtually every pharmaceutical company sees a
tremendous market here," says David Sachs, director of the Palo Alto Center
for Pulmonary Disease Prevention in California, which conducts clinical
studies on smoking-cessation products.

Just a few years ago, the mere suggestion that a drug company would
encourage people to use nicotine would have been treated as heresy. Most
experts believed the addictive substance was dangerous to the heart, and
news reports in 1992 announced an apparent link between smoking while using
the nicotine patch and heart attacks.

But new nicotine research has caused scientists to rethink their
objections. A major study by the National Institutes of Health, which
tracked smokers using nicotine gum between late 1986 and May 1994, found no
increase in heart problems. Another, conducted between November 1994 and
June 1995 and funded by Hoechst

Marion Roussel, found that those who smoked while using a patch were no
more likely to suffer ill effects than smokers who didn't wear a patch.

While some researchers still believe nicotine may not be good for the heart
most scientists now think the critical addictive agent in cigarettes is
relatively benign in low doses compared with cigarette tar, which has
dozens of carcinogens, or cancer-causing agents.

To distance themselves from cigarette makers, whose sales are perpetuated
by nicotine dependence, SmithKline's Mr. Quesnelle says drug companies must
remain committed to helping people overcome nicotine addiction. He says his
company is interested only in pursuing "exposure reduction" - that is,
selling aids to smokers who want to cut back in order to eventually quit.

"We're not in the business of saying 'use this for the rest of your life,'
" Mr. Quesnelle says. "It's too much like cigarettes."

SmithKline's biggest rival in the market, Glaxo Wellcome PLC, says it is
studying whether prolonged use of its smoking cessation drug, Zyban, will
keep ex-smokers from relapsing. Zyban, which was initially developed as an
antidepressant contains no nicotine but appears to alleviate
nicotine-withdrawal symptoms. After repackaging the drug for smokers last
year, Glaxo has been advertising it heavily. It has side effects, including
dry, mouth and insomnia; the company says they are mild and often subside
within a few weeks.

For weaning people from cigarettes, non-nicotine products like Zyban are
better than nicotine-based ones, contends J. Andrew Johnston, head of the
psychiatry clinical research group of Glaxo Wellcome. But, he adds, "I
would support long-term nicotine use through some administration other than
cigarettes."

It's likely to be many months be fore the drug makers formally petition the
FDA to extend the approved period for nicotine alternatives. But last
summer the FDA signaled an interest in nicotine after natives. One
official, Curtis Wright, said a~ a meeting, "We can shift our attitude . .

to accept the reality that there are some patients that are going to need
prolonged treatment with nicotine-replacement ther apy, and approach that
as something we can gather information about rather than try to prevent."

(Mr. Wright, formerly director of the FDA's division of anesthetic,
critical care and addiction drug products, left the agency last year.)

People close to the agency say it is having a tough time grappling with any
regulatory change on nicotine, worried about the consequences to millions
of people who are addicted to cigarettes. "The experts don't know all the
right questions to ask, and it's a painstakingly slow process," says a
person familiar with the agency's thinking. "But the agency can't afford to
make any mistakes."

Representatives of Philip Morris Cos. RJR Nabisco Holdings Corp. and B.A.T
Industries PLC's Brown & Williamson tobacco unit declined to comment on
drug makers' plane.

Brown & Williamson once toyed with the idea of getting into the
nicotine-patch business itself. According to internal documents, in 1992
the company was concerned about the impact nicotine patches would have on
smoking. A couple of memos even suggested that the patches might simply be
regarded as "an alternative to smoking as a vehicle for delivering
nicotine." But a spokesman for Brown & Williamson maintains that the memos
discussing patches were anticipating how tobacco opponents, rather than the
company itself, would regard them.

As it moves forward, the FDA has reason to be cautious. In 1994, Kabi
Pharmacia Inc. sought approval for a nicotine nasal spray, which sends
nicotine to the brain more quickly than patches or gum. Though the vast
majority of smokers reported no problems, a handful grew so addicted to the
spray that they started to give themselves dozens of "hits" a day. Dne
woman insisted on using her spray even when she had nosebleeds; another
used hers after developing a nasal ulcer. Such incidents were very rare,
though, and the FDA ultimately approved the spray.

Certainly, the FDA's choices aren't easy. Scientists are convinced that
smoking fewer cigarettes is better than not cutting back, but not as
beneficial a quitting altogether. So if drug companies, manage to encourage
smokers only to cut back, will they indirectly discourage then from
quitting? "It's a difficult and painful question," says Dr. Wright, the
former FDA official.