THE HUNT IS ON FOR AN ANTIFAT PILL Scientists are testing a plateful of anti-obesity compounds with few if any side effects. They could mean new hope for the hefty, and fat profits for drug makers.
(FORTUNE Magazine) – THE VENDING MACHINE stood in the research ward, ready to dispense its goodies whenever someone had the urge for a snack. Half the food slots contained protein-rich fare: barbecued chicken wings, lean corned beef wrapped around cheese. The other half held some of the sinful delights -- miniature Snickers bars, pecan cookies, peanut cream patties -- treasured by the test subjects, all of whom were obese, self-confessed carbohydrate addicts. At first the volunteer subjects chose carbohydrates over protein more than 80% of the time. But once they began taking an experimental drug called dextro-fenfluramine, their tastes began to shift. Eventually they cut their carbohydrate snacking by 40%, and the pounds dropped off. Researchers at MIT have been conducting such experiments for several years. Along with many other recent studies at clinics throughout the U.S. and abroad, the MIT research has shown encouraging results with a new generation of anti-obesity drugs. Amphetamines, used to treat obesity in the past, are addictive and can cause personality changes. So far the new drugs appear to be nonaddictive and to have few serious side effects. Combined with new theories and genetic studies about the causes of obesity, they promise far more effective treatment. Several of the new drugs should be finding their way to the marketplace before long, and the drug companies that will sell them are quietly anticipating hefty profits. After all, Americans already spend $200 million annually on various over-the-counter nostrums to battle the bulge -- not to mention the billions they lay out for everything from fat farms to Jane Fonda exercise tapes. The new drugs will not be sold over the counter and are intended for people with serious weight problems. By clinical definitions, however, that category includes plenty of people who may think of themselves as merely pudgy. Specialists in weight control consider anyone obese who exceeds his or her ideal weight by 20% or more. The 200-pound man who should weigh 165 (see table) would probably be a candidate for the new drugs. Wall Street analysts speculate that the U.S. market for these new antifat compounds could grow to $600 million by 1990. Most of these new drugs are based on recent research that demonstrates the link between brain chemistry and eating habits. Says Dr. Jerrold G. Bernstein, director of training at MIT's clinical research center and an expert on the effects of antidepressant drugs: ''What we've learned is that you can alter the status of various important chemicals in the brain by what you eat or by taking a drug. It really is a breakthrough.'' Some of the drugs counteract depression that can lead to overeating; others block the effects of chemicals in the brain that trigger appetite. The first of the new drugs to hit the U.S. market will probably be fluoxetine, developed as an antidepressant drug. Eli Lilly & Co. is waiting for approval from the Food and Drug Administration and should bring its fluoxetine product, Prozac, to market early in 1987. Like several of the other new anti-obesity drugs, fluoxetine inhibits appetite by affecting chemicals in the brain called neurotransmitters. These chemicals allow an electrical impulse to travel from one nerve ending to the next; then they become inactive. Fluoxetine prolongs the active phase of a neurotransmitter called serotonin, an important regulator of both appetite and mood. Since the serotonin in the brain remains active longer, the person taking the drug is less likely to sink into a depression or indulge in destructive eating binges. Serotonin levels may influence cravings of all kinds, so fluoxetine could someday be used to help people quit smoking or withdraw from alcohol addiction. Prozac's side effects appear relatively mild, although some patients have experienced nervousness or difficulty sleeping. ADJUSTED FOR A SPLIT, Lilly's stock price has jumped from about $44 a year ago to $74 recently, partly because of enthusiastic reports about the company's fluoxetine research. But industry analysts are divided over how big a bonanza Prozac will be. Some sales estimates range as high as $400 million annually by 1990. ''A lot depends on the doctors,'' says Jonathan S. Gelles of the Wertheim & Co. brokerage firm in New York. ''There are four classes. Those who won't prescribe no matter what. Those who got burned from bad experiences with amphetamines. The innovative physicians who will try it. And those who will overprescribe.'' Though fenfluramine compounds like those used in the MIT study are further from the marketplace than Prozac, they interest scientists because they seem to reduce the craving for carbohydrates -- the downfall of many obese people. The MIT research, mostly conducted by obesity specialists Richard and Judith Wurtman, traced the brain chemistry of both animal and human subjects. As with fluoxetine, the serotonin neurotransmitter appears to be crucial. The Wurtmans' research suggests that a serotonin deficiency may lead to a craving for carbohydrates. Their subjects gorged on sweets and starches, apparently in order to raise the insulin levels in their blood. Insulin helps an amino acid called tryptophan pass through the bloodstream to the brain. Tryptophan is an important building block for serotonin and a number of other neurotransmitters. In effect the obese patients were consuming excess carbohydrates in order to produce serotonin. With fenfluramine, which raises serotonin levels, the Wurtmans stifled the intense carbohydrate craving, and the patients fell into more normal eating habits. Fenfluramine's commercial potential is difficult to estimate. A.H. Robins Co. put a fenfluramine compound called Pondimin on the U.S. market about 15 years ago with much fanfare. Industry analysts predicted annual sales of up to $100 million, but the drug turned out to be a bad trip for Robins; last year sales were negligible. The culprit: side effects. ''It's like a sedative hypnotic,'' says Robert Benezra, a drug industry analyst at the Alex. Brown & Sons office in Boston. ''People were dazed when they took it.'' But proponents of the drug say that new forms of fenfluramine now being tested produce far fewer side effects and still help retard overeating. Groupe Servier, the French drug company that developed Pondimin, has been selling dextro-fenfluramine under the name Isomeride for eight months and hopes to enter the U.S. market at some point. An intriguing compound called NPC-168 is under development at Nova Pharmaceutical Corp., a small, publicly held drug company in Baltimore. The drug acts to block the effects of substances called opioids that attach to receptors throughout the body and produce a response like that of morphine. Among other things, opioids relieve pain and affect bowel activity. Some opioids found in the hypothalamus, part of the brain, also appear to stimulate appetite. In tests on rats NPC-168 seemed to block the effect of the opioids, so the animals ate less. Nova's compound is especially long-lasting. Rats injected with NPC-168 cut their food intake by 20% over a six-hour period and continued to eat less than usual for as long as 24 hours. A HOST of other anti-obesity drugs are in preliminary stages of testing around the U.S. on animals and in some cases on people. At the University of ! Washington, animals reduced their food intake and lost weight when researchers injected insulin directly into the brain. The method is risky, however, and for it to work safely in people would require development of a synthetic hormone that acts like insulin and can be taken as a pill -- a process that could take years. Another group of drugs, thermogenics, appears to aid weight loss by stimulating a protein that increases the rate at which the body burns fat. Unfortunately thermogenics also increase the heart rate, heightening the risk of coronary problems, to which overweight people are already vulnerable. Still another compound, chlorocitrate, under study at St. Luke's-Roosevelt Hospital Center in New York and elsewhere, produces weight loss by delaying the passage of food through the digestive system. Other drugs being tested coat the intestines or otherwise retard the absorption of fats by the body. Finally, researchers are studying how a combination of drugs could affect weight maintenance. ''You may need several different drugs working at different levels of the body's regulatory mechanism,'' says Dr. Ann Sullivan, an obesity specialist with Hoffmann-La Roche, which is testing a full platter of weight-control drugs. ''Someone, for example, may need a compound that reduces food intake as well as a compound that accelerates the using up of body fat.'' Some recent studies have helped explain why excess weight is such an intractable problem for many people. For one thing, genetics apparently plays a far greater role in determining body weight than had been previously recognized. A team of University of Pennsylvania researchers led by obesity specialist Dr. Albert Stunkard demonstrated such a link earlier this year by studying 540 Danish adults who had been adopted at birth and separated from their natural parents. (The Danish group was used because unusually complete medical histories were available.) Stunkard and his colleagues found a close correlation in body size between the children and their natural parents, but none whatever between the children and their adoptive parents. The Penn researchers followed up that study with another, reported just this July, that tracked the body size of 1,974 identical and 2,097 fraternal twins. Identical twins, who share the same genes, were about twice as likely to share a weight problem as fraternal twins, whose genes differ. The study found that about 80% of the differences in body size are attributable to genetic factors, though the authors think the actual correlation is not quite that high. At the same time, some weight-control experts have developed theories about a ''set point'' that helps determine how much body fat each person accumulates. According to these theories a complex system of hormones, chemicals, and nerve signals influences food intake, physical activity, and metabolic rate. The body sends messages that induce a person to consume food in order to maintain a particular level of fat stores that varies with each individual. One person's body may signal him to stop eating after a modest repast, while other people's bells may not ring until they have laid waste to a gargantuan feast. Dr. William I. Bennett, editor of the Harvard Medical School Health Letter and an expert in the field, likens the set point to a thermostat. ''The person who is fat is responding to exactly the same signals as a person who is thin,'' says Bennett. ''The signals are just set at different levels.'' Over a ten-year period beginning in the mid-1960s, researchers at the University of Vermont conducted a historic experiment involving set-point theory. They had a group of state prisoners of normal weight overeat to gain large amounts of weight, while continuing their regular daily routine. Some of the men had difficulty increasing their body size, and once they did, some were forced to consume 7,000 calories or more per day to maintain the increased weight. Nearly all of them dropped back to their previous weight once the experiment ended. Some of the new anti-obesity drugs appear powerful enough to lower the set point and even to help some patients whose genes virtually doom them to lifelong skirmishes with excess weight. But experts in the field also emphasize that drugs alone won't bring about the slimming of America. People with a predisposition toward poundage must of course eat sensibly and, even more important, get proper exercise. Harvard's Bennett points to research showing that American men are fatter than they were 100 years ago even though they consume fewer calories per day. The reason, he says, is today's more sedentary life. Says Bennett: ''Gasoline has a lot more to do with obesity than ice cream or French fries.'' CHART: TEXT NOT AVAILABLE. |
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