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One pill to make you smaller?

June 09, 2008|Melissa Healy | Times Staff Writer

For an activity that seems to come so naturally to so many Americans, getting fat is actually quite complicated. Not surprisingly, then, so is developing a pill that will help reverse that process.

Day after day, the appetite must be energized and the urge to eat activated -- frequently, and for the right foods. These foods must be eaten in volume, digested and rendered into usable form as fuel. Energy used in daily activity must not exceed available stores. And unused calories must be deposited as love handles, thunder thighs, double chins and pot bellies.

In principle, there's good news in that calculus. Disrupt that complex process at any step along the way and -- voila! -- the obese patient should begin inching his or her way toward a healthy weight. In the multibillion-dollar sweepstakes to discover or develop an effective medication to combat obesity, scientists and drug makers have many points to target.

For those awaiting weight-loss help from a physician's prescription pad, the result is a panoply of candidate medicines.

Since 1997, the FDA has approved only two weight-loss medications -- sibutramine (marketed as the prescription drug Meridia) and orlistat (marketed as the over-the-counter fat-blocker Alli). PhRMA, the drug manufacturers' trade association, counts about 35 more candidates under development -- from the embryonic to the nearly hatched. Many are in wide use to treat other conditions, including epilepsy, vertigo and high blood pressure. Some are variants of psychiatric drugs that are known to have weight loss as a side effect. A few are novel agents that may reverse weight gain -- and some of its medical consequences -- in ways never tried before.

Ken Johnson, senior vice president of PhRMA, says that drug developers and manufacturers are scrambling to find ways to lessen the health effects of obesity. Johnson underscores the importance of proper diet and lifestyle management in weight reduction and disease prevention. But, he adds, "Several new treatments in the research pipeline . . . may help."

Complex challenges

But the complexity of becoming overweight poses remarkably steep challenges to drug developers. With so many systems at work in the fat-making process, different people climb the BMI charts for different reasons.

A sweet tooth might be one person's biggest vulnerability. An inability to push the plate away -- say, because of inattention to feelings of fullness -- might be another's. A third might wring every calorie from food consumed, quickly storing the excess as fat.

In short, there are many different ways to gain weight and, likely, as many ways to lose it. And the pill that will work for one overweight patient may be no more effective than a sugar pill for another. There simply is no magic bullet, experts say.

Even if you could treat obesity one patient at a time, fighting fat is tough. The brain, endocrine system and gut work in close coordination to extract energy from food, store fat deposits and -- most important -- protect those energy stores from going, or staying, away.

With the neurological, metabolic and digestive processes so closely intertwined, it's hard for a pill to fool one system without another stepping in to preserve a person's body mass. Cap the sweet tooth and the engine may slow to resist the loss of weight. Rev up the fat-burning engine, and the "I'm full" light may take longer to come on. Tinker with the brain's reading of fullness sensations and the body's system of transporting fuel to organs could short-circuit.

"What happens when you mess with one of them is that the others sort of compensate," says Barbara Corkey, a biochemist and director of Boston University's Obesity Research Center. "That's why things so often don't pan out."

The reason the brain has so many ways to bypass whatever targets you're hitting is because fat has a survival value," Corkey adds. "Something in your system fights to regain any weight that is lost."

To circumvent the human body's guerrilla tactics against weight loss, scientists and drug developers will need to be crafty or lucky, experts say. They will need to find a mechanism that, when manipulated, will allow weight loss without alerting the body's forces of weight-preservation. Or they will have to combine forces -- devise combination therapies -- so that every end run against weight loss is denied.

"I don't think money is going to be enough" to crack the problem of obesity by pharmacological means, says Mike Cawthorne, director of metabolic research at the University of Buckingham's Clore Laboratory. "Fundamental research, insight, brilliant chemists and probably most of all, a sleight of luck will be necessary. And we will need to use a combination of drugs, in part to block the redundancy in the system."

In the pipeline

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