THE NEW MIRACLE DRUG?

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The big test for Barbara Dorsett, a Buford, Georgia, homemaker, came on a visit to the local Red Lobster last month. Dorsett, 50, had tried low-carbohydrate diets and the Scarsdale diet and plenty of other weight-loss schemes in an effort to shed the extra 100 lbs. she carried on her 5-ft. 9-in. frame. But the weight had always been hard to take off and had always come back. This time seemed different. In her first two months on her new regimen, Dorsett had dropped 40 lbs., and she swore she would lose 60 more by the end of the year. If she was going to fall off the wagon, though, it would probably be here, at one of her favorite restaurants. But try as she might, Dorsett couldn't even finish her potato, the most tempting part of the meal. "You don't want as much to eat," she explains. "Now I leave food on my plate. I'm full."

Stories like Dorsett's have become increasingly common over the past several months. People are dropping 20 lbs. or more in a matter of weeks. And it's not through willpower or exotic diets or Olympian exercise routines, but largely because, for the first time in their lives, they have simply lost interest in eating. The reason for this astonishing transformation: Redux, approved by the FDA last April as the first new diet drug in the U.S. in 23 years.

Naturally, these remarkable results have created a great buzz. Word of mouth is big in some circles in Southern California, for example, where washboard abs and buns of steel are practically residency requirements. National weight-loss clinics, including Jenny Craig and Nutri/System, are scrambling to work Redux into their programs. Last week Sheldon Levine, a New Jersey diet doctor, began a high-profile nationwide publicity campaign to flog his new book, The Redux Revolution (Morrow; $20), a 222-page paean to what is being promoted as "the most important weight-loss discovery of the century."

At the same time, physicians, including thousands of general practitioners, are being chatted up by sales agents for Wyeth-Ayerst Laboratories, a division of American Home Products, which is marketing Redux. And in October, according to doctors and industry analysts, the company will begin a widespread advertising campaign to promote the drug directly to the public. (The company begs to differ: it claims it is planning only to "educate" the public about obesity.) Just three months after the introduction of Redux, doctors are writing 85,000 prescriptions a week. Says David Crossen, an analyst for Montgomery Securities in San Francisco: "What we have here is probably the fastest launch of any drug in the history of the pharmaceutical industry. Our projection is that this product will hit $1 billion in sales in five years."

Not bad for a drug that's new only in a sense. In fact, Redux is essentially just a refined version of a compound called fenfluramine, which is usually taken along with another drug, phentermine, in a combination known popularly as fen/phen. Like fenfluramine, Redux stimulates the production and availability of the neurotransmitter serotonin in the brain. Serotonin is responsible for, among other things, the physical and emotional sense of being satisfied, of having had enough. Serotonin also triggers a more general feeling of well-being (antidepressants like Prozac work on the serotonin system as well); some experts think the mood-elevating effect of Redux and fen/phen probably helps with weight loss.

So does that make Redux, in its stylish sweater-striped capsule, the ideal drug for our look-good, feel-good era? Hardly. Like any other medication, Redux has side effects. Some are merely annoying: fatigue, diarrhea, vivid dreams, dry mouth. But some are patently dangerous. The drug has caused significant, possibly permanent brain damage in lab animals--though not, as far as anyone knows, in humans. It can trigger a rare but frequently fatal human disorder called primary pulmonary hypertension, which destroys blood vessels in the lungs and heart. European research on fen/phen shows that using such drugs for more than three months boosts the risk of pph from the normal 1 or 2 in 1 million patients to 18 in 1 million. A study published three weeks ago in the New England Journal of Medicine suggests the rate is actually as high as 46 per 1 million patients.

That risk, of course, and the still unquantified chance of brain damage have to be weighed against the danger of remaining fat, which is considerable. Severe obesity puts people at risk for heart disease, diabetes and some cancers, and in the U.S. contributes to 300,000 deaths each year. If Redux can help these people get thin, it might be worth the risk.

For the merely overweight, though, Redux probably poses an unacceptable danger. While the drug is intended to be taken only by the clinically obese for a limited time, in conjunction with an ongoing diet and exercise program, there is no guarantee that this scenario will be followed. Predicts David Nichols, a Purdue University pharmacologist: "This drug will ultimately be overprescribed by every bumpkin doctor who has patients who perceive themselves to be slightly overweight."

That's already proved true with fen/phen, as Betty Moore, 64, a registered nurse living in Los Angeles, found out. Shortly after starting on the drug, she began experiencing noticeable mood shifts. "I kind of knew that it had something to do with the medication," she says, "because a couple of times when I went off it for a few days, it was almost like going off amphetamines." Moore had obtained the drug at a weight-loss clinic whose presiding doctor was rarely available to talk to patients. Such problems could be more widespread with Redux, which will be marketed not only to diet specialists but also to general practitioners--and the general public.

Americans are certainly primed to respond. The U.S. is one of the fattest countries on earth, and at the same time the most obsessed with slimness. Some 58 million citizens, nearly a fourth of the nation's population, are clinically obese--at least 20% above their ideal body weight. For a 5-ft. 3-in. woman, that's 162 lbs. or more. Millions more are significantly overweight. All told, Americans are carrying around tons of excess fat, and we are desperate to lose it.

We will try just about anything--short of giving up our overeating, couch-potato habits. Just three weeks ago, a U.S. Department of Agriculture researcher presented a fat substitute made from the hulls of oats, corn and soybeans. If it is remotely palatable, it is sure to sell. History suggests, however, that it won't make much difference. Despite the arrival of Olestra last winter, despite NutraSweet and 1% milk, despite an estimated $33 billion spent every year on diet books, over-the-counter medications, health-club memberships and low-calorie foods, the flab still remains, entrenched solidly on waists, hips and thighs. News of a truly effective weight-loss drug will have people beating down doctors' doors, despite the worrisome side effects.

This marks a striking change in attitude. The idea of using drugs to treat excess weight was anathema 20 years ago, when M.I.T. neurologist Dr. Richard Wurtman first learned about the compound fenfluramine. At the time, the term diet pill was synonymous with amphetamines, and conjured up an image of sleazy feel-good doctors getting patients hooked on speed. Pharmaceutical companies wanted nothing to do with the weight-loss business.

But Wurtman was convinced that obesity must to some degree have a physiological basis. He had been doing research on the relationship between serotonin and appetite. Carbohydrates in the blood can help produce elevated levels of serotonin in the brain; Wurtman and his wife Judy, a nutritionist, theorized that eating high-carbohydrate food might be an unconscious attempt to elevate mood by giving the brain extra jolts of serotonin. "We reasoned," says Wurtman, "that people were using these foods as drugs." And because the best-tasting high-carbohydrate foods--ice cream, French fries, potato chips--are high in fat, the calories and pounds pile up.

If the Wurtmans were right, then a chemical that could generate a similar serotonin jolt might be highly effective for weight control. Wurtman began combing the medical literature for such a substance and discovered that the French pharmaceutical company Servier had discovered one called fenfluramine. "We tested it," he says, "and we found that it worked in selectively suppressing carbohydrate overeating."

Unfortunately, there was a rather dramatic and unpleasant side effect. Like many organic molecules, fenfluramine comes in both a left-handed and a right-handed version. The molecules are like a pair of gloves, with identical composition and structure except that they are mirror images of each other. That gives them different chemical properties. In this case, the right-handed molecule, dexfenfluramine, was an appetite suppressant. But the left-handed version, levofenfluramine, made people uncontrollably drowsy. And Servier didn't have a commercially viable way to separate the two.

As a result, fenfluramine went nowhere for years. In the late 1980s, though, pharmacologist Dr. Michael Weintraub of the University of Rochester hit on the idea of adding a mild amphetamine-like drug, phentermine, to fenfluramine. The combination, dubbed fen/phen, didn't put most people to sleep; if anything, it perked them up. And in 1992 Weintraub and colleagues published a series of studies that showed fen/phen to be an astonishingly effective appetite suppressant. Patients lost an average of 30 lbs. within a matter of months, while those who took a placebo and exercised and dieted rigorously didn't come close.

These dramatic results kicked off a fen/phen fad. But there were a few problems with the combination. Some patients still got drowsy, and others suffered from depression, loss of sexual appetite, headaches, diarrhea and dry mouth. The same serious medical problems now being ascribed to Redux--pulmonary hypertension and possible brain damage--began showing up as well. Moreover, fen/phen worked for only so long. Patients usually stopped losing weight after a few months and began to regain it once they stopped taking the drugs.

Meanwhile, Servier had finally figured out how to produce pure dexfenfluramine, without its mirror-image molecule. This was a potentially profitable discovery, since the patent on fenfluramine was about to run out, and the new formulation could be considered a novel, patentable drug. Servier approached Wurtman in the late 1970s with a proposal that he purchase the U.S. rights to dexfenfluramine. Wurtman tested the drug, found it was indeed effective and agreed. The actual purchaser would be Interneuron Pharmaceuticals, a company co-founded by Wurtman to market discoveries by M.I.T. scientists. Interneuron subsequently licensed the drug to Wyeth-Ayerst for marketing.

Then Interneuron went after and got FDA approval--a ruling that critics charge was made with unseemly--and perhaps even unprofessional--haste. Says Lewis Seiden, a University of Chicago pharmacologist who testified before the FDA advisory committee: "The procedures were loose, to be mild about it."

What Seiden and others claim is that the FDA glossed over evidence that both Redux and the older drug fenfluramine cause significant brain damage in laboratory animals, from mice to baboons. The problem, they say, is that after the drugs are withdrawn, serotonin levels plummet and stay low for weeks at least. The effect is similar to one caused by the recreational drug Ecstasy, a distant chemical cousin of the fenfluramine family, and the cause is evidently the same: neurotoxicity, or more plainly, the killing of brain cells. An overdose of Redux makes the neurons that produce serotonin swell, then wither, then die, according to Johns Hopkins neurologist Dr. Mark Molliver. Eventually some of the cells regenerate, but they are often malformed. Moreover, the overdose doesn't have to be huge. All Molliver had to do was double the dosage required for weight loss. In humans, such an overdose could presumably happen if a patient simply took two pills by accident instead of one.

This potential danger, when combined with the generally acknowledged risk of pph, was enough to persuade the FDA advisory committee to reject Redux by a 5-to-3 vote on the question of safety when it first came up for consideration a year ago. But a few hours later, FDA official Dr. James Bilstad reopened the discussion after some committee members had left the meeting. Since there was no longer a quorum, a new meeting was called for two months later, in November.

When that time came, however, the anti-Redux forces were missing. The meeting had been scheduled--all too conveniently, they suggest--to coincide with an international neurosciences conference in San Diego. And at the second meeting, Redux won approval by a one-vote margin. That, along with the fact that Interneuron sent a high-profile member of its board of directors, Alexander Haig, to the November meeting in what was perceived as a high-pressure lobbying effort, led to charges that Redux was moved through improperly.

Not so fast, counters the FDA's Bilstad. Yes, he did reopen the issue after last September's no vote. But that, he says, is because it became clear that the vote to reject was invalid: at least one member had misunderstood the wording of the question on the table. "Obviously," says Bilstad, "we wanted a nonambiguous recommendation from the committee." Some members had left the meeting, though, and without a quorum he couldn't proceed. He considered polling the absentees by phone, but the FDA counsel advised against doing so.

Hence the November meeting. Bilstad acknowledges that the schedule conflicted with the San Diego neurosciences conference. But since Seiden and other Redux opponents had thoroughly aired their views in September and had no new findings, Bilstad decided to go ahead. Says he: "We weighed the idea of putting off the decision for several months, until those experts could be there. Since the committee had heard their presentations before and were given transcripts, we decided that we had the benefit of their comments on the issues. It was a judgment call."

In fact, there is more than one way to interpret the neurotoxicity research. For one thing, observes Wurtman, animals don't necessarily respond to drugs the way humans do. The toxic dose of Redux in a monkey is only twice the therapeutic dose, but the therapeutic dose in a monkey is much higher to start with--as much as 10 times that of a human. It's therefore highly unlikely, he says, that a human user would OD.

Besides, says Bilstad, dexfenfluramine has been available in Europe for 10 years, with some 10 million users. "It is highly unlikely," he says, "that there is anything significant in toxicity to the drug that hasn't been picked up with this kind of experience."

The advisory committee's recommendation wasn't legally binding on FDA Commissioner David Kessler. Last December 22 neuroscientists, including Seiden and Dr. George Ricaurte of Johns Hopkins, asked the FDA to "forgo a final decision on dexfenfluramine until more information is available on its serotonin-neurotoxic potential in humans." Nevertheless, Kessler gave the go-ahead for Redux last spring.

That doesn't mean the FDA has declared Redux to be entirely safe. As a condition of approval, the agency is requiring Wyeth-Ayerst to do follow-up testing. "We're concerned," says Bilstad, "that there could be subtle effects that you can pick up only in a clinical study." Among the possibilities: troubling changes in mood, like depression and aggressiveness, that might derive from a serotonin deficit.

The FDA's conditional approval, though, is based on the assumption that Redux will be doled out by well-informed physicians and will be used as intended--by the truly obese, for a limited time, in conjunction with a diet and exercise program. That seems rather naive, considering the history of fen/phen. In the four years since the older treatment has been on the market, clinics have sprung up all over the U.S., especially in the Los Angeles area, to distribute Redux to eager customers. One chain alone, California Weight Loss Medical Associates, has 19 centers and a catchy toll-free number (1-888-4FEN-FEN) that it advertises in the Los Angeles Times, the Los Angeles Daily News and on Howard Stern's syndicated radio show. Some places offer discounts for customers who buy in bulk. Many, says Dr. Michael Myers, an obesity expert in Los Alamitos, California, hand out prescriptions for fen/phen "like cheap Halloween candy."

Predictably, they have started to do the same with Redux. "In Europe," says Dr. Stuart Rich, a cardiologist at Chicago's Rush-Presbyterian-St. Luke's Medical Center and a co-author of the recent New England Journal study, "the majority of people who have taken Redux were looking to lose 10 lbs. to 20 lbs. You can just imagine how popular this medication is going to be here."

If general practitioners and weight-reduction chains get into the act, the problem of inappropriate use could get even worse. Says Dr. Brian A. Joseph, a Naperville, Illinois, physician who is chairman of the ethics committee of the American Society of Bariatric (obesity) Physicians: "These are legitimate medications when used in a responsible manner, as an adjunct to a weight-loss program, by trained physicians." But in the hands of nonspecialists, Joseph fears, these drugs could be misprescribed.

Some general practitioners are certainly enthusiastic. Culver City, California, doctor Ben Krentzman, a family physician, came out of retirement in 1993 to spread the gospel about fen/phen. He now treats some 300 patients--and so far has tallied 63,000 visitors to his Science of Obesity and Weight Control Website. Krentzman's contrarian advice, based on several months of library work and an ongoing experiment begun last year: take the pills instead of worrying about diet and exercise. Says Krentzman: "Dieting and exercise without fen/phen don't keep people slender, so why should they work with fen/phen?"

Most weight-loss experts insist that the reason diet and exercise don't work is that people don't stick with them. But because fen/phen and Redux can be dangerous if they're used too long, and they lose their effectiveness after a few months anyway, patients will eventually have to take up regular exercise and change their eating habits. Neither fen/phen nor Redux alone can "cure" obesity.

What they can do, say the experts, is give obese patients a powerful head start on weight loss. Redux is revolutionary, explains author Levine, because "it overcomes the loss of confidence in one's own diet. The feeling that the drug gives you is the key." That's the attitude of Barbara Dorsett, the Red Lobster survivor: "I'm just so thankful they discovered this stuff," she says. "I felt so old and decrepit. It's like a new lease on life."

But Redux is revolutionary in a deeper sense as well: it represents a profound change in the way medical science looks at obesity. "There is an increasing consensus," says Dr. Michael Lowe, a weight- control expert at Philadelphia's Allegheny University of the Health Sciences, "that obesity is at least a chronic condition and maybe even a chronic disease that is in many ways indistinguishable from diabetes and hypertension."

Diabetes and hypertension are treated with medication that is essentially lifelong and, in the view that many physicians are coming to accept, this is the model that will be needed for obesity. At the same time, scientists are beginning to unravel the biological basis of overweight. Molecular biologists, for example, have identified five genes in mice that control food metabolism and that, if damaged, can lead to chubby rodents. In humans, physiologists are beginning to track the multiple hormones that conspire to keep fat people fat and thin people thin. And as Redux and fen/phen demonstrate, neurologists are beginning to sort out the brain chemistry involved in appetite.

All these lines of research are making it clear that attacking obesity as a physiological disorder is scientifically sound and that Redux--imperfect though it may be--is a step in the right direction. Says Yale psychologist Kelly Brownell: "We're at a historic moment in the treatment of obesity. The drugs themselves are less important than the fact that drugs for obesity are again on the scene." A new generation of antiobesity medicines is in the pipeline, under active development by drug companies, and yet another generation is sure to follow. As popular as Redux may be, both it and fen/phen represent just the first, crude attempts to attack obesity at its very source.