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Drug Cure in Sight for Obesity
Three very
fat Turkish people, all cousins, got very lucky this year, when they
spent a few months in Los Angeles getting injections of leptin, the
“satiety” hormone discovered in 1994 and immediately hailed as the
long-awaited magic bullet to cure obesity. The three, a
27-year old man who weighed 312 pounds, a 35-year old woman who weight
253 pounds and a 40 year old woman who weighed 194 pounds, were all
miserable. The man was
so fat, he said through an interpreter, that he couldn’t get a job, or
a girlfriend. One woman had to work at home as a seamstress because
people made fun of her if she went out. The other had given up her
dreams of marriage, devoting herself to taking care of her parents. By the time
they headed back to Turkey in July after their treatments, they had each
lost roughly half of their body weight, says the researcher who treated
them, Dr. Julio Licinio, professor of psychiatry and medicine at the
David Geffen School of Medicine at UCLA. A pair of
obese Pakistani cousins living in England, both born, like the Turkish
family, with defective genes for leptin, also lost significant amounts
of weight with leptin injections. And that’s
pretty much it, folks. That’s the good news: A handful of obese people
who get better with leptin, and -
let’s be generous here- maybe several thousand
more helped modestly and temporarily by other drugs. After all the
hoopla, all the hype, all the hope and all the research, anti-obesity
drugs, at least so far, have largely been a bust. And barring some
secret miracle concoction now in development, there will simply not be a
pharmaceutical fix for fatness in the near future. It’s all
rather depressing. Two-thirds of
Americans are now overweight, the latest government figures show, and
one in every three is obese. Obesity is defined as having a Body Mass
Index (BMI) of 30 or more and being overweight, by having a BMI of 25 to
30. (To calculate your BMI, multiple your weight in pounds by 703; then
divide that number by your height in inches squared.) Yet, aside
from repeating the old mantra of diet and exercise, and maybe a mention
of gastric bypass surgery, there’s still very little that doctors have
to offer the millions of Americans stuck in weight loss hell. “There is
certainly nothing on the horizon in terms of a drug that will solve
obesity,” says Dr. Eric Colman, medical team leader for the metabolic
and endocrine division at the US Food and Drug Administration. “It would
be wonderful if there were something that was highly effective and
without side effects. But nobody should be waiting for that pill to
arrive,” adds Dr. Walter Willett, chairman of the department of
nutrition at the Harvard School of Public Health. The more
researchers try to find a magic bullet for weight loss, the more they
are discovering that the biochemical pathways in the brain that control
appetite and weight maintenance are devilishly complicated. At the
moment, for instance, there are only two prescription weight-loss drugs
on the market that are approved for long term use – Meridia (sibutramine)
and Xenical (orlistat). Meridia works
promotes a feeling of satiety by increasing levels of serotoninn,
norepinephrine and dopamine, chemical messengers in the brain. But, as
the Harvard Heart Letter of March, 2002, notes, the drug only works as
long as you take it, and even then, only modestly, resulting in a 5 to
10 percent weight loss. This amount of weight loss can help lower blood
pressure and cholesterol but may not make a huge dent in what you see in
the mirror. Nor is
Xenical a magic answer. It acts in the digestive tract to stop
absorption of fat from foods by blocking enzymes called lipases. Like
Meridia, it can result in a 5 to 10 percent weight loss, but all that
unabsorbed fat can cause uncontrollable bowel movements, messy underwear
and frequent passing of fatty gas. There used to
be more choices, but they weren’t terrific either. In 1997, the US
Food and Drug Administration asked manufacturers to remove two highly
popular anti-obesity drugs from the market, fenfluramine (part of the
combination called “fen-phen”) and dexfenfluramine (Redux) because
of an apparent increase in the risk of heart disease and serious lung
problems. There still
are a few other weight-loss drugs on the market, including those
containing phentermine (the “phen” of the old fen-phen combo). But
these aren’t approved for long term use (which obese people need) and
many are stimulants that can cause nervousness, rapid heartbeat and
similar symptoms. These drugs can trigger brief spurts of minor weight
loss, but they often lose their effectiveness over time. So where does
this leave the millions of Americans who are either overweight or obese?
Still fat and still desperate. Some people
resort to gastic bypass operations – surgery to reduce the size of the
stomach, which limits the amount of food a person can take in.
In 2000, 40,000 Americans underwent this procedure, almost double
the number performed five years earlier, reports Ellen Ruppel Shell,
co-director of the Knight Center for Science Journalism at Boston
University, in her highly-readable new book “The Hungry Gene.” But the costs
are high. “Gastric bypass surgery kills one out of every hundred
patients on the operating table, and not everyone recovers from the
complications,” notes Shell. On the other
hand, gastric surgery may work not just by limiting stomach volume –
but biochemically as well, according to a recent paper in the New
England Journal of Medicine. Cells in the stomach produce a chemical called ghrelin that has been shown to stimulate feeding and obesity in animals. Unlike the weight loss induced by dieting, weight loss induced by gastric bypass may lead to longer term maintenance of weight loss because of reduced ghrelin levels, note Drs. Jeffrey Flier, an endocrinologist and chief academic officer at Beth Israel Deaconess Medical Center and Eleftheria Maratos-Flier, director of the obesity section at the Joslin Diabetes Center in Boston in an editorial accompanying the research. This suggests that a grehlin-blocking drug might work where others have failed. And someday,
there may be other pharmaceutical options. Some scientists are hopeful that a drug now in clinical trials called CNTF, for ciliary neurotrophic factor, may work out. Others are looking at a compound called MLN 4760, made by Millenium Pharmaceuticals in Cambridge, MA, which has been working on obesity drugs for years. So far, says Lou Tartaglia, vice president of metabolic diseases, none of the drugs in the works are yet ready for marketing, but MLN 4760 is now in early human safety trials. The company will not say exactly how it works except that it block an enzyme called carboxypeptidase. Farther back in the Millenium pipeline is a drug that would activate a receptor molecule called MC4 that seems to act in the brain, at least in mice, to decrease body weig Tartaglia thanks that the reason that drugs marketed so far have failed is that they are crude and act essentially “by hitting the brain with a hammer.” New drugs could work better because they are targeted to more specific molecules in the brain. But even then, there are no guarantees. Take leptin, for exaple, a highly specific drug. Amgen, a company based in Thousand Oaks, Calif., has been trying for years to develop a leptin-based drug, with no success. Company spokeswoman Barbara Bronson Gray says Amgen researchers have conducted several trials but the drug “did not achieve clinical or commercial hurdles needed for an obesity drug in this population.” Why? For one thing, obese people often turn out to have perfectly normal or even higher than normal levels of leptin, which is made in fat cells and travels to the brain to deliver “satiety” or “I’m full, stop eating” signals. The Turkish cousins were genuinely – and genetically – leptin-deficient, so giving leptin to them worked. But most obese people are not leptin deficient, perhaps in part because of the sheer number of their fat cells. These fat cells, which never go away, even when a person loses weight, keep cranking out leptin but, obese people, one current theory goes, may become resistant to their own leptin, much as people susceptible to diabetes can become insensitive to their own insulin. Maybe, some day, the growing understanding of all the biochemistry involved in appetite and weight regulation will result in a magic pill. Until then?
It’s same old, same old: Diet and exercise. Turn off the TV and take a
walk instead. Don’t adopt a “low fat” diet that allows you to eat
endless carbohydrates. Eat more veggies and less processed junk. At the
very least, if you are already overweight, don’t give up and let the
problem get even worse.
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