Judy Foreman

Nationally Sindicated Fitness, Health, and Medicine Columnist

Rushing Off Antidepressants Can Bring On More Distress

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At first, Zoloft seemed like “manna from heaven,” says this 53-year-old woman, a teacher who lives in Watertown.

It was the summer of 1999 and, for reasons she still doesn’t fully understand, she had slipped into a “terrible slump.” Her doctor suggested Zoloft, America’s second most popular antidepressant, after Prozac. And for a while, it was great, says the woman, who does not want her name used.

But after nearly a year on the drug, she developed a twitch in her left eyelid. It may not have been related to the Zoloft, but since she was feeling fine, she decided to stop taking the drug.

And, unlike many people who quit antidepressants, she did it the right way: very slowly – cutting the dose little by little over six weeks.

Even so, she wound up with three months of withdrawal hell, or discontinuation syndrome, the term psychiatrists prefer because withdrawal suggests that antidepressant drugs are addictive (like cocaine or heroin), which they are not.

Discontinuation syndrome is not a recurrence of the original depression, though that can happen, too. It’s a brand new set of problems, in this woman’s case, bad headaches, vertigo, and dizziness. At one point during a walk, she says, “my body felt like it was tipping to one side. I had to keep lying down. It was terrible.”

Could a drug that was no longer in her system somehow be causing weird symptoms she’d never had before?

“That was the thing that got me the most creeped out,” she says. “The drug clearly is out of your body. So what was it  that lasted for three months?”

What lasted so long for this teacher, and many others who stop taking antidepressant drugs, is what scientists now think of as a prolonged period of re-adjustment during which the chemistry of the brain settles into a kind of new, non-depressed normal.

To be sure, many of the millions of people worldwide who take antidepressants experience no withdrawal symptoms when they stop. But some studies suggest that one in every 10 have some symptoms and one in 20 suffer significant distress, says Dr. Jerrold Rosenbaum, chief of psychiatry at Massachusetts General  Hospital.

Others, among them Dr. Andrew Leuchter, director of the division of adult psychiatry at the UCLA Medical Center, believe the actual figures are much higher.

Yet even doctors who should be on the lookout for withdrawal symptoms – such as dizziness, increased nervousness, irritability, insomnia, and a dramatic increase in vivid dreams – often aren’t paying close attention.

A 1997 study in the Journal of Clinical Psychiatry showed that 70 percent of general practitioners and, surprisingly, a third of psychiatrists don’t know that significant withdrawal symptoms can occur when people stop  taking antidepressants called selective serotonin reuptake inhibitors, or SSRIs, including Prozac, Zoloft, Paxil, Luvox, Celexa, and a similar drug, Effexor. (Withdrawal syndromes can also occur with antidepressants that work differently from the SSRIs, including older drugs such  as Elavil and Tofranil)

“It’s an under-recognized problem,” says Leuchter, because when people stop taking a drug and then develop new symptoms, they can’t believe it has”anything to do with the medicine because, if they’re not taking it, how can it affect them?”

But withdrawal clearly does happen, though researchers still aren’t sure why. The basic thinking is that depression is caused by a deficiency of serotonin, a key neurotransmitter in the brain. SSRIs boost serotonin by stopping its re-absorption into brain cells, thus keeping more serotonin where it’s needed, in the synapses, or gaps, between nerve cells.

As the brain adapts to increased levels of serotonin, some neuroscientists think there is a decline in either the number or sensitivity of the brain’s molecular gateways that can put serotonin to work. Then, when SSRIs are discontinued, withdrawal symptoms may occur as the nervous system, now primed for lots of serotonin, isn’t getting enough, says Dr. Alexander Bodkin, chief of clinical psychopharmacology research at McLean Hospital in Belmont.

One thing researchers are sure of is that the severity of withdrawal symptoms from SSRIs is closely correlated with how long the drug remains in the body. The longer the drug or its active metabolic breakdown products stay in the body, the less severe the withdrawal.

“The faster-clearing the drug, the worse the withdrawal,” says Dr. Michael Craig Miller, a psychiatrist who edits the Harvard Mental Health Letter.

Prozac is least likely to cause withdrawal because its metabolic breakdown products linger in the body for as long as five weeks. In fact, precisely because of this, one strategy for people who have trouble getting off other SSRIs is to switch to Prozac and  then taper slowly off of that.

By contrast, Paxil, Luvox, and Celexa may trigger withdrawal because they are faster-clearing, lingering in the body for just four to five days. Zoloft lingers slightly longer. Effexor, a variant of standard SSRIs, has the shortest half-life of all, about 5 hours, which means it is highly likely to cause withdrawal symptoms.

Recent studies have bolstered the idea that faster-clearing drugs lead to worse withdrawal.

In 1998, Rosenbaum of MGH and his team studied 220 patients and found that those who abruptly stopped taking Paxil, and to a lesser extent, Zoloft, had significant withdrawal symptoms, while those who stopped taking Prozac did not. Another study published last year in the British Journal of Psychiatry found  essentially the same pattern.

Yet another study, sponsored by Lilly Research Laboratories (Eli Lilly makes  Prozac) and published last year in Psychoneuroendocrinology, showed that people  who suddenly stopped taking Paxil had a significant increase in heart rate and stress hormone levels, while those taking Zoloft or Prozac did not.

The bottom line is that if you want to wean yourself from antidepressants, do so slowly, by decreasing your dose by half every one to two weeks. It may take weeks or even months to discontinue completely, but that doesn’t really matter.

“There’s never a rush in getting off these medications,” says Leuchter of UCLA. “What’s the hurry? If you have been on them for six to 12 months and you’re tolerating them well, there’s no point in going too quickly.”

And if you do develop withdrawal symptoms despite tapering off slowly, try going back to the previous dose, then switching to Prozac and weaning yourself from that.

The most important lesson, says the teacher from Watertown, who is now symptom-free, is that antidepressants – despite the recent backlash in the media – significantly help millions of people. “I would never say, `Don’t go on it,’ ” she says. “I would just say be very aware that when you want to get off it, go to a doctor who knows about this.”

A ‘Cure’ For Osteoporosis May Be Near

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Scientists who normally shy away from words like “cure” or “breakthrough” say researchers are on the verge of what could be a revolution in the treatment of osteoporosis, the dangerous bone-thinning condition that is responsible for 1.5 million fractures in the United States each year.

Thanks to a vast improvement in scientific understanding of the process by which bone is created and destroyed, researchers have developed a new class of drugs that can actually trigger the formation of significant new bone to replace that lost to the disease. These drugs, based on human parathyroid hormone, reverse damage from osteoporosis far more effectively than any drugs currently on the market.

“Something that actually increases the formation of bone is the holy grail of osteoporosis research,” said Joan McGowan, a bone specialist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, which is part of the National Institutes of Health. “This is the first approach to having that kind of agent.”

Ten million Americans – most of them women over 50 – have osteoporosis, and another 18 million are at risk because they have low bone mass. Of greatest concern are the 300,000 broken hips that result each year, which can be devastating. One in every five people with a broken hip dies within a year from complications, such as blood clots induced by immobility. Half never walk again without assistance; more than a quarter need long-term care.

And while women are more likely than men to develop osteoporosis because they lose bone-building estrogen at menopause, 20 percent of those with osteoporosis are men. All together, hospitalization and nursing care for osteoporosis costs a staggering $13.8 billion a year, according to the National Osteoporosis Foundation.

Currently available medications such as estrogens and Evista(raloxifene) can help prevent the onset of osteoporosis, but they increase bone density only slightly. As a result, public health officials focus on preventing the disease through exercise and a diet rich in vitamin D and calcium.

The first of the new parathyroid drugs, called FORTEO, could reach the market as soon as the fall, and a major study showing its effectiveness in building new bone is scheduled for publication soon in a leading medical journal. Dr. Robert Neer, the lead author and director of the osteoporosis center at Massachusetts General Hospital, declines to give specifics, but the researchers have already shared some of the impressive results with other scientists.

Based on a study of 1,637 postmenopausal women, FORTEO (also called PTH 1-34) reduces the risk of spine fractures by 65 percent and of other fractures (including broken hips) by 54 percent when taken for one to two years. This summer, the US Food and Drug Administration is expected to convene an expert panel to review the drug for approval. Another still-unpublished study – by Dr. Claude Arnaud, professor of medicine emeritus at the University of California at San Francisco – showed that when taken in combination with estrogen, PTH increases bone density in the spine by 27 percent and in the hip by 9 percent. Two other studies, presented at scientific meetings last year, support these findings. “Most physicians don’t even want to breathe the word `cure’ because it makes them look like tonic salesmen,” Arnaud said.  “But this is about as close to a cure as you can possibly get. We don’t know for sure that [bone] returns to normal, but bone is made, and it acts like normal bone in the sense that it’s strong.”

Skeptics point out that Eli Lilly, the maker of FORTEO, had to stop the Neer study early because research in rats showed that PTH could cause bone cancers, although the rats got higher doses of PTH than humans would and rats are highly susceptible to bone tumors in general. By the time the study was stopped in late 1998, though, Neer’s team had already collected much of its data. They also looked for signs of bone cancer in their human subjects, and found none.

In fact, Neer said, “there has never been osteosarcoma in any patients who ever received PTH anywhere, in any country.”

Other researchers agree that one of the most attractive features of the new PTH drugs is that they appear to be safe as well as effective.

“We are in a new era for osteoporosis treatment,” said Dr. Meryl LeBoff, director of skeletal health and osteoporosis at Brigham and Women’s Hospital who is studying a different form of the drug called PTH 1-84. What has made this new era possible is a more detailed understanding of the intricate biochemical processes that shape bones. While many people imagine bone to be like cement – an inert substance that is simply there for structural support – it is actually a dynamic tissue that is always being turned over, or remodeled.

The tearing down of bone tissue, done by cells called osteoclasts, takes about two weeks; the rebuilding, by cells called osteoblasts, takes three months, though, at any given point, different bones are in different stages of the process. If there were no tearing down process, bones would get so big and heavy it would be impossible to walk.

Scientists now know that osteoblasts, the bone builders, are the key to the entire process because they also tell the osteoclasts, through chemical signals, when to become activated and start destroying bone. Estrogen, in turn, regulates the osteoblasts, slipping into the bone-building cells through special receptors.

Because estrogen is so crucial, it has long been the mainstay of osteoporosis prevention for women at menopause, when natural estrogen levels decline sharply. Estrogen therapy prevents further bone loss, but does not significantly increase new bone formation.

Estrogen is important for men’s bones, too. Two recent studies showed that the male hormone testosterone does not protect men against osteoporosis, meaning they, too, rely on the estrogen that their bodies make for protection, noted endocrinologist Dr. Michael F. Holick, director of the bone health care clinic at Boston University Medical Center.

Two other drugs – Fosamax (alendronate) and Actonel (risedronate) – work differently, Holick stated. Rather than boosting osteoblasts, as the hormonal therapies do, these so-called bisphosphonate drugs kill the bone-destroying osteoclasts. Some people get upset stomachs on Fosamax, but a new once-a-week version, approved last year, seems to reduce that problem.

Still, the problem with all the drugs currently on the market is that they basically block the destruction of bone. The bisphosphonates do yield a 2 to 3 percent increase in bone density per year, which over time produces as much as a 50 percent reduction in spinal and hip fractures.

But parathyroid hormone increases bone density far more quickly – up to5 percent a year.

Here’s how it works: When secreted normally by the parathyroid gland in the neck, PTH has one job – to keep blood calcium levels normal. “The body cares more about calcium than anything else,” Holick said. When blood calcium drops, PTH signals osteoblasts to signal osteoclasts to destroy bone, thus releasing calcium to where its needed most – in the blood.

The new PTH drugs “trick the system,” Holick said. By giving PTH in a single blast once a day, the osteoblasts become very active (thus building more bone), but don’t have time to stimulate the osteoclasts, which would tear bone down. The net result is new bone growth.

Despite its promise as a drug, PTH has its drawbacks. That it must be given by injection “will limit its appeal,” said Dr. Bess Dawson-Hughes, chief of the calcium and bone metabolism lab at the USDA Nutrition Center at Tufts University.

Research is underway on variants of PTH that could be taken in pill form, as a nasal spray or as a cream .

PTH probably will not become a substitute for estrogen in low-risk women at menopause. That’s because, as long as women have normal bone mass, which estrogen protects, there’s no need to build bone further. For women who do need PTH, taking that plus estrogen may ultimately prove the best bet.

Judy Foreman is a Lecturer on Medicine at Harvard Medical School. Her column appears every other week. Past columns are available on www.myhealthsense.com.

 

SIDEBAR: Some Drugs From Nature Show Promise

Although drug researchers haven’t hit the jackpot, they are developing some promising medicines from plants, insects, marine organisms, soil bacteria and other natural products.

Researchers from Abbott Laboratories are now conducting trials in human volunteers of a painkiller called ABT-594, which the company believes is about 50 times better than morphine in relieving both chronic and acute pain, yet is not addictive. Abbott scientists had already synthesized ABT-594 for other uses when they learned that John Daly of the National Institutes of Health already had discovered the powerful painkiller in the skin of a tiny Ecuadoran tree frog.

An Argentine soil microorganism has already been turned into an approved drug that fights antibiotic-resistant bacteria, Syncercid. And Neurex Corp. is working on a painkiller made from cone snails that live in tropical oceans.

Meanwhile, researchers at Arizona State University have begun human testing for a cancer-fighting drug, bryostatin, made from a marine weed that grows off the California coast. The researchers also see anti-cancer promise in a blue-green algae found near Guam, and have begun safety testing of a drug derived from it.

Finally, a Malaysian plant may produce a potential drug to combat AIDS, called calanolide A, which is now in human testing.

For more information, a good source is  “Medicine Quest” by Mark J. Plotkin (Penguin Putnam Inc. New York) or check out www.amazonteam.org.

Moisturizer Madness

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So, there it sits on the desktop, this ridiculous, ever-growing collection of moisturizers, seemingly endless bottles and stand-up tubes that rise like little mountain peaks amid the stacks of floppy disks and piles of papers.

There’s the tall squirt bottle of Keri lotion, billed as “moisture-rich therapy,” which might be true, judging by the way it makes fingers slide off the keyboard. There’s the oh-so-cutesy Nivea spray, whose nozzle could drive a woman crazy the way it spins around, spraying the room instead of dry skin.

And, for sheer kinkiness, there’s “Udderly Smooth,” a moisturizer originally designed for cows, whose directions begin, “Wash udder and teat parts thoroughly . . .”

American women spend billions a year on moisturizers in hopes of looking younger, healthier and more smooth-skinned.

Are they wasting their money?

Not completely, dermatologists say, at least in the narrow sense that it’s a good health practice to keep skin moist. Skin is a crucial barrier against infection that is more easily invaded once it becomes dry or cracked. Of more concern to most people, well-hydrated skin does look and feel better to the touch.

But moisturizers can indeed be a waste of money in the sense that something that costs $30 or more an ounce may not keep skin any moister than a big glob of Vaseline, though the high-priced spread may go on more easily and smell nicer. In fact, a January report in the Wellness Letter at the University of California-Berkeley, as well as an extensive Consumer Reports investigation last year, reached just that conclusion.

Why don’t moisturizers, like wines, generally get better the more they cost? Because most moisturizers, despite their baffling array of ingredients, work basically the same way: They trap water that’s already inside the skin, as opposed to adding moisture from the outside.

“Moisturizers help seal things off and allow less moisture to escape,” said Dr. Tom Rohrer, a dermatologist at the Boston University School of Medicine.

To accomplish this, moisturizers are made up of “some combination of oil and water,” said Dr. Richard Glogau, a dermatologist at the University of California at San Francisco. “You can go from pure oil at one end to pure water at the other.” The more oil it contains, the better the moisturizer is at trapping trap water beneath it. The more water it has, the lighter and easier it is to rub in and disappear.

“Once you get away from the basic combination of those two agents,” Glogau said, “everything else is aimed at making a moisturizer feel better to the skin at touch or making it smooth on better. . . . But that doesn’t really affect the way a moisturizer prevents evaporation of water.”

If it’s so simple, why, then, do moisturizer manufacturers bombard us with technical-sounding words like liposomes, humectants and the like? The answer, of course, is marketing, or as the US Food and Drug Administration, which regulates the cosmetics industry, puts it, “cosmetic puffery.”

“The average consumer has no idea what these things mean,” said one FDA spokesman who asked not to be named. “People throw out these terms because they seem mystical or magical.” And the FDA lets such pseudo-scientific hype slide, he said, unless it can prove in court that the cosmetic labels are downright “false or misleading.”

Dr. Melanie Grossman, a dermatologist in private practice in New York City, puts it more bluntly: “The FDA doesn’t regulate this stuff. So companies can claim whatever they want.”

How, then, does a winter-wizened or sun-scorched consumer begin to unravel the mysteries of moisturizers? One good place to start, perhaps surprisingly, is the industry itself, specifically, Martin Rieger, an organic chemist who consults for the Cosmetic, Toiletry and Fragrance Association, a trade group based in Washington.

Asked how moisturizers work, Rieger pulls no punches:  “Moisturizers are stupid materials. They have no brains. They pick up water from wherever they can find it, steal that water and hold onto it. They will not let this water go and give it back to skin cells, no matter how attractive that concept may appear. They don’t really penetrate the skin. I take a very dim view of some of the claims made for moisturizers.”

Take humectants, substances such as glycerine that attract water and hold it against the skin. “I have very little faith in humectants,” Rieger said, though dermatologists, Rohrer of BU among them, say humectants can make the skin somewhat more moist in some people.

Occlusives, on the other hand, substances like petroleum jelly and oils, are quite effective. “They are heavy, greasy and work precisely because they sit on top of the skin and preclude evaporation of water,” Rieger said. The downside is that, because they coat the skin so well, occlusives can leave a residue that many people don’t like, said Dr. Diane Berson, a dermatologist at New York University School of Medicine. They can also clog pores and lead to acne.

In addition to humectants and occlusives, moisturizers often contain emollients and other ingredients designed to make the skin feel slick and soft, though they have nothing to do with moisturizing per se. Some manufacturers add silicone, for instance, to make a moisturizer more slippery; others add dispersing agents like soaps to make the oil in a moisturizer break down into smaller particles.

Some manufacturers also add liposomes, delivery vehicles whose job it is to bring a substance into the skin. The trouble is, if liposomes are too big to penetrate the skin – and many are – whatever product they are carrying won’t get in, either.

Many moisturizers also contain collagen. In its natural form, this fibrous, connective tissue is important for maintaining firm, healthy-looking skin. But collagen that’s taken from cows and then slathered on human skin does not penetrate because the molecules are too big. The same goes for elastin.

“It would be wonderful if we could replace old, damaged collagen and elastin with a cream. But, unfortunately, at this point, it is physically impossible,” Rohrer said.

Sadly, the news on wrinkle reducers and anti-aging creams is no cheerier. Moisturizers that claim to get rid of wrinkles or reduce the appearance of age really don’t – all they do is plump up the skin momentarily, despite manufacturers claims of clinical trials to the contrary, Rohrer said.

What does help with wrinkles is Retin-A, or Renova, dermatologists say, but that is a genuine drug that is regulated as such by the FDA and is only available by prescription.

On the plus side, there are ingredients in moisturizers that may be genuinely effective. Vitamins E and C, for instance, are antioxidants that combat the oxygen free radicals that can damage skin. They may also penetrate the skin and combat free radicals from the inside.

Alpha hydroxy agents such as glycolic acid work, too, dermatologists say, penetrating the skin and making it look more moist and healthy by helping it slough off dead cells on the surface. That’s particularly important for older people since their skin has less ability to slough off dead cells on its own.

As for that cheap old trick, drinking water to make your skin look better? Go ahead, dermatologists say. But water probably only makes your skin look better if you were dehydrated to begin with, and most people aren’t.

The bottom line, Rohrer said, is that “most moisturizers don’t penetrate your skin. They only penetrate your pocketbook.”

That doesn’t mean you shouldn’t use them, said Grossman. But don’t break the bank to do it. Buy something that you will really use, she said, nothing too thick and goopy. And nothing that will wind up in the garbage. Or behind the piles of papers on your desk.

Drug Hunters Can’t See Rainforest For The Medicines

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TORTUGUERO NATIONAL PARK, Costa Rica – Carlos Bettancurt cuts the motor and we glide soundlessly toward the bank of the Parismina lagoon, part of the vast network of rivers and canals that crisscross this wildlife sanctuary.

Doused liberally with DEET to ward off mosquitoes and swathed in hats, longsleeved shirts and pants, we step ashore and follow Carlos, a trained Costa Rican naturalist-guide, along the path that he originally hacked out of this steamy jungle six years ago.

We are hunting on this sweltering January afternoon, not for the elusive jaguar or for the huge crocodiles we spotted earlier along the riverbank, but for something both less dangerous and potentially far more valuable – medicinal plants, which grow in abundance in rainforests all over the world.

Most of what Carlos knows about jungle medicine he learned from his grandmother, who is in her 90s now and unable to accompany us. As we alternately take notes and swat bugs, Carlos shows us a platanilla plant, which, when made into a tea, is said to induce abortions. He points out a type of sour cane that, when chewed, is supposed to help with liver and lung problems. And a broom tree, parts of which are said to stop bleeding.

So, why haven’t the big pharmaceutical companies been able to find medicines in the jungle as easily as Carlos? Despite the seeming promise of”bioprospecting” for drugs in rainforests, professional drug hunters have reported no blockbuster drugs after 10 years of looking. Merck & Co. even terminated its landmark bioprospecting contract with Costa Rica in 1999 after producing no commercially viable products – though the company says it’s still analyzing samples.

The difficulties are somewhat ironic, in light of the fact that human beings have always used natural products as medicine, and 80 percent of people in developing countries still do. Chimpanzees and other animals, too, eat certain types of foliage when they’re sick that they wouldn’t ordinarily eat as food, noted tropical ecologist Dan Janzen of the University of Pennsylvania.

Indeed, about 50 percent of all human pharmaceuticals in use today – from simple aspirin to powerful cancer chemotherapy drugs such as vincristine and Taxol – originally came from natural sources.

But modern “bioprospecting” in rainforests, coral reefs, deserts and other exotic locales has been slow going so far. It’s partly because modern drug development is such a costly, plodding process, often taking a decade or more to complete testing and regulatory approvals before the first prescription is written.

But the rainforest fizzle also may reflect unrealistic expectations about companies’ abilities to turn the folk remedies of people such as Carlos’ grandmother into the safe, reliable medicines that Western consumers expect.

Bioprospecting took off in earnest in 1991 amid great hopes when Merck entered into an agreement with Costa Rica’s National Biodiversity Institute, a private, nonprofit group that had been co-founded in the late1980s by Janzen. Under that novel agreement, Merck gained access to some plants, fungi and environmental samples from Costa Rica’s protected rainforests, and the Costa Ricans got the right to royalties if any marketed drugs resulted.

The romantic ideal of bioprospecting gained more steam in 1992, when 177 nations (although not the United States) ratified the Biodiversity Convention, an agreement that outlined ways for rich nations hunting for medicinal gold to share the wealth with cash-poor, plant-rich nations; and just as important, preserve natural habitats and indigenous populations in the process.

The need to protect such habitats was – and still is – acute, said Katy Moran, executive director of The Healing Forest Conservancy, a nonprofit group based in Washington. The equivalent of a football field of rainforest is lost every second  to industries such as logging, cattle raising, and oil and mineral extraction,  she said.

Bioprospecting has helped to preserve some of the land, said botanist Joshua Rosenthal, who heads the International Cooperative Biodiversity Group program, an effort started in 1993 at the National Institutes of Health to enable American scientists to work with other countries in bioprospecting ventures.

In Surinam, for instance, combined efforts by the US government, Bristol Myers-Squibb, conservationists and scientists from Virginia Polytechnic Institute and the Missouri Botanical Gardens helped the Surinam government set aside 4 million acres as the Central Surinam Reserve a year and a half ago, Rosenthal said.

The disappointing news, however, is that so far – and it really is too soon to judge – bioprospecting has yielded no major new drugs. Some are believed to be in the pipeline, but pharmaceutical companies remain close-mouthed.

“If they  get a lead, they won’t tell you,” Janzen said.  “They don’t want the competition to know what area they are looking in. 

The industry trade group, Pharmaceutical Research and Manufacturers of America, has acknowledged that companies may be reticent to talk about bioprospecting in part because they don’t want to be perceived as stealing the flora or the intellectual property of indigenous people. But the lack of publicized results also reflects the fact that companies are putting more effort into high-tech drug discovery using genomics to design drugs from scratch  rather than combing nature for medicine.

In comparison to lab-based genetic research, bioprospecting is a hit-or-miss proposition fraught with obstacles, as biologist Steven King, chief operating officer of Shaman Pharmaceuticals in South San Francisco, can attest.

Shaman Pharmaceuticals started up in 1989, armed with a short list of a dozen promising medical plants that company officials knew grew in specific regions, such as the  northwest Amazon basin in South America. One plant in particular, which contained a molecule the Shaman scientists dubbed SP303, seemed to be highly effective against diarrhea, just as indigenous healers had said it was.

Encouraged by the US Food and Drug Administration to do the research that could get this extract approved quickly as a prescription drug, the company launched human studies, including one on 400 patients at 25 US medical centers. The results were encouraging, King said, but apparently not quite good enough. The FDA demanded another study, but Shaman didn’t have the $15 million to $20 million to do it.

The result? Shaman is now reorganizing in the face of bankruptcy and has decided to market its once-promising prescription drug as a dietary supplement, for which prior FDA approval is not necessary. The product is now sold in health  food stores, under the rather drab name, NSF, for normal stool formula. The good news for Shaman, King said, is that the food supplement seems to combat not just traveler’s diarrhea, but irritable bowel syndrome as well.

Despite such bumps in the road, there is still considerable optimism that bioprospecting will yield new pharmaceuticals because of the sheer numbers of plant species in the world, many of which are as genetically complex as humans.

“Plants contain enormous numbers of genes and, if you multiply the number of  species times the genes, the number is huge,” said biochemist Malcolm Morville, who runs Worcester-based Phytera Inc., a biotech company.

“Plants can’t move,” he said, which means the only way plants can adapt to threatening changes in their environment is by turning on or off certain genes. “That’s why plants are of interest because, genetically and chemically, they’re some of the most sophisticated species on Earth.” Sponges and some other marine organisms use the same defenses.

“Nature produces many wonderful molecules for various reasons as a form of chemical defense,” said Gordon Cragg, chief of the natural products branch at the National Cancer Institute, which has been testing extracts from nature as potential cancer-killing agents for 45 years.

“You comb through nature, collect a whole range of plants, marine organisms and microorganisms, and then test extracts of these substances to see if they kill cancer cells in the test tube. The extracts often are mixtures of hundreds or thousands of chemicals. You have to try to isolate the one or two chemicals that are responsible for killing cancer cells.”

This, not surprisingly, can be a long and tedious process, and one that may seem far removed from the muggy, buggy reality of a Costa Rican rainforest.

But it is a path well worth pursuing, said Mark Plotkin, a Tufts University-trained ethnobotanist who now heads the Amazon Conservation Team, a Virginia-based group dedicated to protecting biological and cultural diversity.

“Western medicine is the most successful, sophisticated method of healing ever devised, but it doesn’t have all the answers,” he said. “Rainforest shamans claim they can cure – not just treat, but cure – some of the things we can’t. Doesn’t it make sense to go ask these guys what they have?”

SIDEBAR: Some Drugs From Nature Show Promise

Although drug researchers haven’t hit the jackpot, they are developing some promising medicines from plants, insects, marine organisms, soil bacteria and other natural products.

Researchers from Abbott Laboratories are now conducting trials in human volunteers of a painkiller called ABT-594, which the company believes is about 50 times better than morphine in relieving both chronic and acute pain, yet is not addictive. Abbott scientists had already synthesized ABT-594 for other uses when they learned that John Daly of the National Institutes of Health already had discovered the powerful painkiller in the skin of a tiny Ecuadoran tree frog.

An Argentine soil microorganism has already been turned into an approved drug that fights antibiotic-resistant bacteria, Syncercid. And Neurex Corp. is working on a painkiller made from cone snails that live in tropical oceans.

Meanwhile, esearchers at Arizona State University have begun human testing for a cancer-fighting drug, bryostatin, made from a marine weed that grows off the California coast. The researchers also see anti-cancer promise in a blue-green algae found near Guam, and have begun safety testing of a drug derived from it.

Finally, a Malaysian plant may produce a potential drug to combat AIDS, called calanolide A, which is now in human testing.

For more information, a good source is  “Medicine Quest” by Mark J. Plotkin (Penguin Putnam Inc. New York) or check out www.amazonteam.org.

A New Weapon Against Memory Loss?

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After creeping corpulence, perhaps the most common complaint people have about growing older is what the experts politely call “benign” memory loss and the rest of us, less politely, sometimes call CRS, for Can’t Remember You-Know-What.

For men with sluggish memories, the best advice to slow the aging process is tried and true: Exercise (to increase blood flow to the brain); stay mentally active (to enhance connections between brain cells); take nonsteroidal anti-inflammatory drugs such as ibuprofen, vitamin E, and maybe a little gingko (though the data on gingko are less compelling).

For women past a certain age, however, there’s one more potentially powerful option – estrogen, a hormone that is increasingly being touted as a way to ward off not only normal age-related memory loss but Alzheimer’s disease as well.

The bio-logic behind estrogen’s surging popularity as a memory enhancer is respectable. Estrogen improves connections between nerve cells in the brain and enhances cerebral blood flow. It boosts important brain chemicals such as serotonin, acetylcholine and dopamine, and acts as an antioxidant, too, blocking other chemicals that otherwise would damage brain cells.

Even before the memory connection was made, of course, many women were already convinced of estrogen’s virtues: Hormone therapy is a huge industry that’s likely to grow to as much as a $5 billion market by 2005, based on estrogen’s proven ability to reduce menopausal symptoms such as hot flashes and to prevent osteoporosis.

But does it really work on the brain? The answer, unfortunately, depends on whom you ask, how you measure memory, and, perhaps most importantly, whether the researcher conducts actual experiments or simply surveys older women about their memories and estrogen use.

For the moment, the best guess is that estrogen seems to protect against some kinds of normal memory loss and may help prevent Alzheimer’s disease as well. But it probably does no good at all, at least without other drugs, once Alzheimer’s is already established. 

One of the key research problems is that “there is no one, unitary thing called memory,” said Patricia Tun, associate director of the memory and cognition lab at Brandeis University in Waltham. And that, said Dr. Elizabeth Barrett-Connor, a professor of family and preventive medicine at the University of California at San Diego, means “nobody knows exactly what to test for.”

While some kinds of memory decline with age, some – such as vocabulary – actually get better with the years, Tun noted. Estrogen is probably not going to turn out to be a panacea for memory, she said, because men and women show similar patterns of memory change as they age, even though only women experience sharp declines in estrogen at menopause.

Nonetheless, there is a growing body of evidence suggesting that estrogen does play some role in protecting memory and enhancing learning, said Susan Resnick, a neuro-psychologist at the National Institute on Aging. “From our studies, we know that women who use estrogen perform better on memory tests than women who don’t.”

Indeed, recent studies by Resnick and others using brain-imaging technology – not just clinical tests of memory – are encouraging; they show that estrogen seems to affect blood flow to areas of the brain such as the hippocampus, which is known to be involved with memory.

Intensive research on estrogen and memory began more than a decade ago, when researchers in Western Ontario showed that premenopausal women performed better on tests of certain cognitive skills – like being able to pronounce tongue-twisters fluently – during the part of their menstrual cycles when levels of natural estrogen were highest.

In postmenopausal women, too, Barbara Sherwin, a psychologist at McGill University in Montreal, has shown that “scores on tests of memory are better for estrogen-users than nonusers.”

In several randomized studies, Sherwin tested women who were scheduled for surgery to remove their ovaries, which make estrogen, and uteruses. The women were then assigned either to receive estrogen supplements or not. Those who took estrogen were able to maintain their pre-surgery scores on tests of memory, while those who did not showed declines.

In general, Sherwin said, estrogen seems better at protecting verbal memory than visual memory. But last April, a randomized study published in Psychopharmacology suggested estrogen may enhance visual memory, too. Women ages 55 to 75 who had never taken hormone therapy before were assigned either to wear an estrogen skin patch or not for three weeks. And those who did showed benefits in remembering things they had seen.

In addition to such randomized studies, there have been a number of observational studies that don’t assign women to take estrogen or not but simply follow them over time, test their memories and correlate that with estrogen use. These studies are more difficult to interpret.

In one such study, Barrett-Connor of San Diego found no effect of estrogen on awareness and judgment, even though her team used 12 different types of memory tests. The study of about 3,000 women was published in 1993 in the Journal of the American Medical Association.

Last year, an observational study of more than 21,000 women ages 70 to78 – the Nurses’ Health Study – also found no significant differences on several cognitive tests between estrogen users and nonusers, though the estrogen users did have an advantage in verbal fluency.

On the plus side, an observational study of more than 700 women in New York City published in 1998 in Neurology found that women who had taken estrogen performed better on verbal memory tests that those who had not.

Finally, a study of more than 8,000 women who were not taking estrogen by Dr. Kristine Yaffe, an assistant professor of psychiatry, neurology and epidemiology at the University of California in San Francisco, also suggested a link between natural estrogen levels and cognitive function. Published last year, the study showed that women with more severe osteoporosis had poorer cognitive function than those with less-severe cases of the bone-thinning disease. Low natural levels of estrogen are known to trigger osteoporosis and may explain the poorer cognitive function as well.

And what of estrogen’s ability to prevent and treat Alzheimer’s disease, as opposed to protecting against normal, age-related memory loss?

An analysis of data pooled from 10 observational studies published in1998 in the Journal of the American Medical Association showed a 29 percent lower risk of Alzheimer’s disease among estrogen users. Other studies suggest as much as a 50 percent Alzheimer’s risk reduction in women who have ever taken estrogen supplements.

For treatment, however, the results are less rosy. One study published last February followed women taking one of two doses of estrogen for one year. All had been diagnosed with mild to moderate Alzheimer’s. Even at the higher dose, estrogen did not slow progression of the disease, a result echoed in two other studies last year. The findings suggest that, once brain damage occurs, estrogen cannot fix it.

“We were all surprised and disappointed about these findings because some of the prior research had suggested estrogen would help,” said Dr. Marilyn Albert, director of the gerontology research unit at Massachusetts General Hospital.

Better data about estrogen’s effect on memory should be available in about four years when results from big studies – with fanciful names like WHIMS and WHISCA – are in.

“Before long,” Albert said, “we will know whether or not estrogen is effective and what doses people should take if it is.”

For now, it’s still a guessing game. But many women are betting that estrogen could help.

Americans Strive To Live With Chronic Illnesses

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At 68, Helen Freeman of Seattle has more chronic diseases than many of us will face in a lifetime. First, there’s her labored breathing because of extensive scarring from years of lung infections.

Then there’s the diabetes, for which she needs daily medication. The glaucoma is no picnic, either – she’s almost blind in one eye. She’s also had melanoma and breast cancer.

Yet, in 1981, Freeman founded an organization to save the endangered snow leopards of Asia, a job that entailed frequent trips to Asia, where she gasped her way through pollution-clogged cities. She climbed mountains to study the leopards and nearly died twice.

Mountain climbing with a serious lung problem was, “to put it mildly, very difficult,” she said cheerfully. “I basically picked an animal that lives at 12,000 feet and I have trouble breathing at sea level.” But she was determined not to let her illnesses slow her down any more than necessary. 

More and more Americans are finding that, like Helen Freeman, they must learn to cope with chronic illness. Half of all Americans today (20 million more than researchers had previously estimated) have at least one chronic illness and one in five has two or more, according to a recent analysis by researchers from the Johns Hopkins School of Public Health.

Granted, for some of the 125 million people with chronic illnesses, the problems are minor, like allergies that can be stabilized with medications. But 60 million others have multiple chronic conditions such as heart disease, Alzheimer’s disease, cancer, arthritis, epilepsy, mental illness and others that can be serious or life-threatening.

The toll of so much illness is enormous – $510 billion annually, said Jay Hedlund, deputy director of the Partnership for Solutions, a Johns Hopkins project aimed at improving the lives of people with chronic diseases. Indeed, chronic illnesses account for 77 percent of direct medical expenditures in America, he said.  It leads to 70 percent of all deaths, according to the federal Centers for Disease Control and Prevention, and it accounts for one third of the years of potential life lost before age 65.

But chronic illness exacts an emotional toll as well, and it is in that realm that researchers are increasingly looking to the hard-won wisdom of patients such as Helen Freeman to find ways to help others cope with diseases that might once have engulfed them in shame or despair.

Take Dr. Steven J. Kingsbury, a man who is both patient and doctor. Kingsbury, 52, is an associate professor of clinical psychiatry at the Keck School of Medicine at the University of Southern California. At 34, he was diagnosed with multiple sclerosis, a potentially crippling, neurological disease that now forces him to remain in a wheelchair much of the time.

In a recent article in the Harvard Mental Health Letter, Kingsbury stated why he believes that people with chronic illnesses should be neither pitied nor idealized, either by others or themselves.

Pity can come across as condescending, Kingsbury said.  Turning someone into a hero may not help, either: “I didn’t get MS to prevent someone else from getting it, so it was not courageous. And when I go into a nice restaurant with my wife, that’s not courageous, either. It’s because I like good restaurants.”

To keep his disease in check, Kingsbury must take powerful drugs often used in cancer chemotherapy, drugs that cause nausea and diarrhea. Yet, when these side effects struck after one recent treatment, he spent the weekend reviewing articles for publication, writing a chapter on a yearbook for mental health and going over some statistics. And he got to work”bright and early Monday morning, though I did have to spend time in the bathroom.”

The point, Kingsbury said, is that people with chronic illnesses, like anybody else, feel better if they focus on other things. “If I sit around contemplating my navel, why shouldn’t I feel crappy? But if I do other things, I feel better. Anybody will suffer less if they have something better to do.”

Other mental health specialists, such as Ann Webster, a health psychologist at the Mind/Body Medical Clinic at Beth Israel Deaconess Medical Center in Boston, take a somewhat different view. Some people with chronic illnesses do want to be seen as normal, she said, but others do seem truly heroic and may appreciate some recognition of that. Some people, she said, make monumental changes when serious disease strikes.

For many people with chronic illnesses, the diagnosis is a wake-up call to change the things that aren’t working in their life, said Webster, who runs support groups for people with cancer, AIDS and other illnesses. Some people quit jobs they’ve always hated, she said. Others leave bad relationships. Others travel while they can.

“A lot of people grow and change” in profound ways,  Webster said. Some long-term survivors in her AIDS group “have changed and grown and turned into some of the most evolved and spiritual people, and they never were that way before.”

That kind of growth in the face of adversity, whether one considers it heroic or not, is never easy, cautioned Dr. Jimmie Holland, chairman of psychiatry and behavioral science at Memorial Sloan-Kettering Cancer Center in New York.

“It’s really hard having a chronic illness, and knowing it is changing your life and your future,” she said. Initially, the big problem may be learning to live with the uncertainty about how disabled you may become and whether your life expectancy will be shortened.

It’s a real struggle, she said, for people to figure out “how to cope, how to do everything they normally do,” and yet, if the prognosis is grim, keep in the back of their minds that, no matter how well they cope, they may not be able to change the course of their disease.

Some people can throw their energies into beating their disease and returning to normal activities. But others can’t beat the disease, no matter how hard they try. For them, Holland said, the challenge is “how can you put new meaning into your life when your life got shattered?” Many people can do this on their own, she said, but many also find it helpful to join support groups or see individual counselors.

Ultimately, Holland said, the task is to make meaning in the face of disability or imminent death, to reassess what’s still important and what you can still do, when your old goals and dreams can no longer be met.

Like Kingsbury, Holland saidshe believes one key to this meaning is not to let the illness define you. Other people can help buttress this outlook by not treating you as if illness were the essence of your being and by continuing to talk to you about the things you’ve always been interested in.

Helen Freeman would be the first to acknowledge that this can be tough. “It’s not easy to stop thinking you feel rotten when you actually feel rotten,” she said.  “After all, your whole body is yelling at you to pay attention.”

But what works for her, she said, is to find moments of pleasure – even if they last only a few seconds – and to complain a bit when necessary and then to go on living. Perhaps most important, she said, is to be realistic: “Don’t make perfect health the measure of who you are because perfect health is an impossible goal.”

SIDEBAR: Groups That Offer Help

There are numerous organizations to help people cope with chronic diseases.   Among them are:

  • The National Chronic Care Consortium, at 952-858-8999 begin_of_the_skype_highlighting              952-858-8999      end_of_the_skype_highlighting.
  • The Mayo Clinic Health Oasis, at www.mayohealth.org.
  • The National Organization for Rare Disorders Inc., at www.rarediseases.org.  

The Time Has Dawned For `Morning-After’ Contraception

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The time has come to do the obvious about the whole abortion mess: Provide emergency “morning-after” contraception over the counter. Right now. In every state. In every pharmacy. For every woman who needs it. And at a reasonable price.

One way you can tell the time has come is that the American Medical Association, not exactly known for its out-on-a-limb stances, endorsed the idea in December. In Great Britain, Finland and France, emergency contraception already can be obtained without a prescription.

Another way to tell is that even the National Right to Life Committee, which opposes abortion and strenuously opposed RU-486 (the abortion pill), has not opposed emergency contraception – the group takes no position on prevention of fertilization. Like standard birth-control pills, emergency contraception, or EC, pills – commonly called “morning after” pills, even though they work for up to 72 hours – are hormones that act, at least in part, by blocking ovulation, which occurs before fertilization.

So far, only one state – Washington – has gone out of its way to make emergency contraception pills easily accessible to women, 24 hours a day, seven days a week, by allowing them to get them from pharmacists without a doctor’s prescription. Alaska, Oregon and other states (though not Massachusetts) soon may follow suit.

But the real breakthrough would come if the US Food and Drug Administration allows the emergency contraceptives to be sold over the counter like aspirin. The FDA states that it is waiting for either of the two companies that make EC pills – the Women’s Capital Corp., which makes Plan B, and Gynetics Inc., which makes PREVEN – to submit applications to switch their products from prescription to over-the-counter status.

The need for safe, effective and accessible emergency contraception is unarguable. In the United States alone, about 3 million unwanted pregnancies occur a year, half of which are due to broken condoms or other contraceptive failures, according to The Alan Guttmacher Institute in New York, a private, nonprofit group. Half of unwanted pregnancies end in abortion.

In fact, one in every two American women between 15 and 44 has had an unintended pregnancy, though only 1 percent has ever used emergency contraceptive pills, noted James Trussell, a professor of economics and public affairs at Princeton University and a leading scholar on contraception issues.

Indeed, survey data show that only one in 10 American women know that emergency contraceptive pills are available, despite the fact that in 1997 the FDA ruled that some regular birth-control pills – taken in a special pattern that varies by pill type – can be safe and effective methods of emergency contraception if taken within 72 hours of unprotected sex. Or that, since then, the agency has approved two other pills – PREVEN (a combined estrogen and progestin pill) and Plan B (a progestin-only pill) – spe cifically for emergency contraception.

This lack of awareness is a shame because there is now no question that emergency contraception is very safe and highly effective, as a 1998 World Health Organization study of nearly 2,000 women in 21 countries, and other studies, have shown.

Overall, emergency contraception reduces the risk of pregnancy by at least 75 percent, and it works best if taken as soon after unprotected sex as possible.

For instance, if 100 women have unprotected sex once during the second or third week of their monthly cycle – when the chance of pregnancy is highest – eight, on average, will become pregnant. With emergency contraception such as PREVEN or standard birth-control pills that combine progestin and estrogen, only two women would become pregnant. With pills such as Plan B that contain only progestin, only one would, Trussell said.

While half of women who take the combined hormones experience nausea and20 percent of them vomit, these side effects are reduced considerably in women who take progestin-only pills such as Plan B, the WHO study shows. Some women who use the combined hormone approach also take an over-the-counter drug called meclizine (Dramamine II) to control nausea.

Furthermore, emergency contraception does not appear to be dangerous either to a woman or to her fetus, if she turns out to be pregnant. “There is no known contraindication,” said Dr. Phillip Stubblefield, chairman of the department of obstetrics and gynecology at Boston Medical Center. Emergency contraception pills are not advised for women who are sure they are pregnant, but that’s not because they are dangerous; it’s because they would not work. “They will not provoke an abortion,” Stubblefield said.

Even if a woman who took the pills turned out to be pregnant, the pills would have no effect on the fetus because they would have been taken long before fetal organs start forming. Moreover, studies of women who inadvertently took standard birth-control pills without knowing they were pregnant showed no increased risk of birth defects.

Still, scientists acknowledge that they are not quite sure of all the biological pathways through which emergency contraception works. The method clearly can block ovulation, Trussell noted, and that is probably its chief mode of operation. Emergency contraception may also block implantation of a fertilized egg, although data on this point are mixed, and it may block fertilization.

However it works, emergency contraception has been a clear boon to women in Washington state who participated in the 1998-1999 pilot project run by PATH, the Program for Appropriate Technology in Health, a nonprofit, health advocacy group.

In the pilot project, which has now become a standard program throughout the state, women who had had unprotected sex within the previous 72 hours were able to go to a pharmacy, have a 15-minute consultation with a pharmacist, and walk away with EC pills. They never had to see a doctor, thanks to a collaborative agreement between the state’s doctors and pharmacists that allows the pharmacists to write and fill emergency contraception prescriptions.

During 16 months of the pilot program, nearly 12,000 prescriptions for emergency contraception were filled, said Jane Hutchings, senior program office at PATH. That translates to an estimated 720 pregnancies prevented. And since roughly half of unwanted pregnancies end in abortion, by inference, it means 360 abortions were prevented, too.

As one woman wrote: “The easy-access program saved me from a stupid mistake.” Wrote another: “I’m so grateful that this drug is available. I don’t think I could emotionally handle an abortion and am not ready for kids.” A third put it this way: “Abortion, and unwanted pregnancy, is very painful and this saves a lot of tears, money, fear and time.”

Moreover, in the Washington program, 42 percent of the women went to pharmacies after normal business hours. That’s important, said Sharon Camp, founder and chief executive officer of the Women’s Capital Corp., which makes Plan B, “because the `morning after’ is very often Sunday morning, when clinics and doctors offices are closed.

Judy Norsigian, a women’s health advocate at the Boston Womens Health Book Collective in Somerville, applauds the pharmacy-based program. Women who fear they may become pregnant don’t really need contact with a doctor, she said. But talking with pharmacists is important because “pharmacists are noted for giving better information than physicians on many drugs.”

But, ultimately, it’s over-the-counter availability that will make emergency contraception most effective. Many women’s health advocates, including the National Women’s Health Network, an advocacy group based in Washington, D.C., strongly endorse the idea, although they note that women who have a history of migraine headaches or blood clots should probably take pills that do not contain estrogen. Women’s health advocates also urge that EC pills be sold at a reasonable price – perhaps $20 – since over-the-counter drugs are not usually reimbursed by insurance.

Granted, there may be some opposition. In Italy last fall, a church-state battle erupted when emergency contraception pills went on sale. The Vatican condemned the pills as a form of abortion and urged pharmacists not to sell them.

Even in the United States, some doctors may resist being left out of the(income-producing) loop if women can simply go to a drug store and get the emergency contraception they need. But, because emergency contraception pills do not interrupt an established pregnancy, they are unlikely to provoke the kind of furor that accompanied approval of RU-486, the abortion pill.

In other words, there is no reason not to make them widely – and cheaply –         available.

 

Judy Foreman is a Lecturer on Medicine at Harvard Medical School. Her column appears every other week. Past columns are available on www.myhealthsense.com.

SIDEBAR: Existing Alternatives

Even without emergency contraception pills becoming available over the counter, there are several things women can do to prevent pregnancy if they act quickly.

First, you can be prepared in advance. Ask your doctor for a prescription for Plan B, PREVEN or regular birth-control pills to be used as emergency contraception. Fill the prescription and keep it where you can find it at home or in your purse. Emergency contraception works best in the first 12 hours after sex, but it is effective up to 72 hours later.

If you think you would like to use an intrauterine device, or IUD, for regular contraception anyway and you need emergency contraception as well, go to a doctor and ask for a copper IUD. This will prevent pregnancy if inserted up to five to seven days after unprotected sex.

Remember that emergency contraception is designed only to prevent pregnancy; it isn’t a treatment for sexually transmitted diseases. If you think you have been exposed to HIV or another sexually transmitted disease, call a doctor immediately.

Exercise Holds Key To Fountain Of Youth

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Johnny Kelley did everything the expert’s say we should if we want to age well: He started exercising young and never stopped.

Too small to play football for his local team in West Medford, Kelley turned to running at 18, and launched the most storied marathoning career in Boston history. Over the years, he ran in 61 Boston Marathons, winning twice and placing second seven times. He also ran the New York Marathon 15 times (he won it twice), and made three US Olympic teams. Today, at 93, he lives in East Dennis and still jogs, swims and goes to the gym several times a week to work out with his trainer.

Exercise, said Jay Olshansky, a senior scientist at the Center on Aging at the University of Chicago, is the closest thing we’ve got to a fountain of youth.

Granted, even the most conscientious of athletes cannot finally escape the ravages of time. Kelley finally gave up his beloved Boston Marathon at age 84, and, these days, he’s more of a walker than a runner. But his very prowess, even now, suggests that human beings can remain strong and fit for many more years than most people think.

Vigorous exercise such as running and brisk walking can add years to your life – about 2  1/2 years if you start before age 35; six months if you start at 75 – largely by lowering your risk of heart disease, cancer and other chronic diseases. Strength training (weight lifting) has not yet been shown to add years to life, but it clearly boosts the quality of life by giving you the muscle power to move around, take care of yourself and remain independent.

But how far can you push the limits? How good can an aging athlete really be? The short answer, sadly, is probably not quite as fit, fast and strong as you were in your youthful heyday, assuming you had one. But you can be a lot fitter, faster, and stronger than you might think; even if you take up exercise after years of sloth.

No matter what you do, for instance, “VO2-max,” or aerobic capacity – the maximum rate at which the heart, lungs and muscles can burn oxygen to make energy – declines with age. If you don’t do regular, aerobic exercise, it falls 10 percent per decade after age 25, several studies have shown. If you do, it declines at half that rate.

But that’s not as discouraging as it may sound. In fact, some aging jocks nowadays can do what was once thought impossible. A century ago, even world-record holders couldn’t run a mile as fast as some 40-year-old masters athletes do today, according to a recent editorial in the Journal of Gerontology. The increasingly impressive performance of older jocks may be due in part to the fact that, as baby boomers age, there’s a bigger pool of older athletes out there, which allows some to become superstars.

In a sense, the most powerful message emerging from recent research into fitness and aging is a simple one: You have to keep exercising if you want to maintain strength and prolong life, even if you were a star jock early in life.

One study, published in 1996, showed that even men who were elite athletes in their youth were no better off than sedentary folks if they stopped working out. The men were rowers who won a silver medal for the United States at the 1972 Olympics, and researchers subjected them to numerous physiological tests that year, then again in 1982 and 1992. After the Olympics, most of the men put their energies into careers, not rowing, said William Evans, the senior author of the study and an exercise physiologist at the University of Arkansas for Medical Sciences. And their fitness levels declined steadily.

But one man kept training all those years. He was still at 90 percent of his aerobic capacity 20 years after the Olympics, though the tests did show he had lost some muscle power (a measure of combined strength and speed) and that his muscles were more susceptible to fatigue than they had been.

Years ago, when exercise physiologists first began studying fitness and aging, what they most wanted to find out was whether regular exercise reduced the overall risk of death. It clearly does, as two pivotal studies, since confirmed again and again by other research, showed.

One 25-year study of 17,000 Harvard graduates by Dr. Ralph Paffenbarger showed that expending at least 2,000 calories a week in exercise (roughly equivalent to jogging two hours a week) adds a year or more to life.

Another study, by Steven Blair at the Institute for Aerobics, part of the Cooper Aerobics Center in Dallas, was equally dramatic. Blair and his colleagues followed more than 10,000 men and 3,000 women and showed that the least fit men died from all causes  at the rate of 64 per 10,000 compared to 19 per 10,000 among the most fit. Among women, the least fit died at more than four times the rate of the most fit.  Perhaps even more important, said Dr. Ken Cooper, the head of the center, you don’t have to be among the most fit to get the benefits; even moderate fitness has a profound, positive effect on longevity.

But in recent years, exercise physiologists have turned their attention increasingly to muscle strength and power as opposed to overall, aerobic fitness. And they’ve found both good news and bad.

It’s clear that people who don’t keep their muscles strong by lifting weights lose about one third of a pound of muscle per year, said Miriam Nelson, an exercise physiologist at Tufts University. Researchers are still trying to figure out how much of this loss can be offset by regular weight lifting, but a Scandinavian study a decade ago showed that older men who did regular strength training had as much muscle mass as younger men. (Interestingly, older runners and swimmers, who were aerobically fit, did not preserve their muscle mass as well.)

Still, there does appear to be a biological wall: We are born with all the muscle fibers were ever going to have. Muscles can and do get bigger and stronger with use, even among people 100 and older, as a number of studies since 1990 have shown. But the number of fibers doesn’t increase.

“There is immutable decline” in muscle mass in part because of a decrease in the number of motor nerves that activate muscles, said John Faulkner, a muscle physiologist at the University of Michigan who, at age76, still runs 4 to 6 miles a day.

In fact, he said, its atrophy of muscles that is the biggest factor in the decline of athletic performance with age. Even so, he said, it pays to stay active and do everything you can to keep muscles strong as you age.

“The person who is active will reach some threshold at 95 or 100. But the inactive person may reach it at 60.”

In fact, research suggests that exercise can make old muscles look a lot like young ones, both under the microscope and in the gym.

Aerobic exercise makes muscles richer in myoglobin (a substance, like hemoglobin, that carries oxygen), capillaries (small blood vessels) and mitochondria, the structures in cells that produce energy, said Evans of Arkansas. Strength training confers those advantages plus another one: The muscles of people who lift weights regularly are bigger and contract with greater force than those of people who don’t.

Scientists who study aging and fitness are also finding that some types of muscles age faster than others. Fast-twitch muscles, which are light colored (like the white meat in turkey breasts), are the type used for speed. This kind of muscle seems to fatigue more quickly and decline more rapidly with age.

Slow-twitch fibers, on the other hand, which look red because they are rich in myoglobin, are for endurance, and they seem to decline more slowly with aging. This may explain why older athletes can’t run or swim as fast as young ones, but can do quite respectably in endurance events like ultramarathons.

Power, which includes speed as well as strength, is also a growing focus of scientists who study aging athletes. In fact, new research suggests that power may be even more important for maintaining daily activities than strength, said Roger Fielding, an Boston University exercise physiologist.

Power seems to decline faster with age than strength – 20 percent per decade versus 10 percent, in people who don’t do special training. But Fielding and his team have just completed a randomized study showing that in older women (average age, 72) muscles can be trained for increased power. The weight-lifting exercises are much like those used in strength training, but in strength training, the emphasis is on lifting weights slowly, while in power training, the key is lifting weights very fast, Fielding said.

The bottom line, exercise physiologists say, is that inactivity, more than age per se, is the great enemy of fitness and health.

One Dallas study, in fact, showed that male college students forced to stay in bed for three weeks wound up with changes in fitness and muscle mass comparable to 20 years of aging.

Most of us probably don’t have whatever combination of good genes, good habits and good luck that makes Johnny Kelley such a dazzling older athlete.

But you don’t have to run for decades like Kelley to be extremely fit as you age. You can just follow his advice, which is, if you don’t like to run, walk: “Walking is the best exercise in the world.”

Is Moderate Drinking The Answer?

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Until four months ago, Paul Robert, a hard-working, 42-year-old Connecticut businessman, would get home from work and knock back six drinks a night – 45 drinks a week. Sometimes wine, sometimes beer, sometimes the hard stuff.

“It was the stress,” he says, and alcohol “absolutely” helped. He didn’t think he was a true alcoholic. His job was going great, he says, and his family life – he has a wife and two  children,  ages 7 and 10 – was, too. He’d never been arrested for driving drunk. Even his liver showed no damage from all the alcohol it processed night after night.

Deep in his heart, though, Robert knew he was drinking far too much, and he wanted to cut back. What he did not want, however, was to go the Alcoholics Anonymous route and quit completely.

Today, Robert gets counseling and a daily dose of a drug called naltrexone to reduce his craving for alcohol, allowing him to cut back to12 drinks a week. His goal is “to go back to leading a normal life, so I can go out and have a couple of drinks. I am already there.”

But Robert’s treatment at Charles River Hospital in Wellesley raises one of the most controversial questions in medicine. The idea that excessive drinkers can safely return to moderate drinking contradicts the most famous alcohol abuse program, AA, and researchers fear it gives false reassurance to alcoholics.

However, advocates of moderate drinking believe that many alcohol abusers don’t get help because they fear they’ll have to stop drinking altogether. They say moderation could significantly reduce the nation’s most pervasive substance abuse problems.

An estimated 14 million Americans either abuse alcohol – meaning they’re impaired, but not physically dependent – or they are outright alcoholics prone to uncontrolled drinking, tolerance for high doses, and withdrawal symptoms when drinking stops. All told, about 40 million Americans drink more than the recommended moderate levels – one drink a day for women, and two for men, with a drink defined as  5 ounces of wine, 1.5 ounces of spirits or 12 ounces of beer.

So, can a heavy drinker really cut back without quitting totally? Yes, but the odds of success depend on the severity of the drinking problem, and on whether you have a family history of alcohol problems. If you’re an alcohol abuser but not yet alcohol-dependent, your chances are better; if you’re truly alcohol-dependent, they’re almost zero. In fact, doctors at Charles River don’t offer the moderate drinking program to people who are physically dependent on alcohol.

The good news is that most people with alcohol problems are not dependent, according to a 1997 analysis published by the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.

The bad news is that the line between abuse and dependence “is in no way a clean distinction,” says University of New Mexico psychologist William R. Miller, a leading alcoholism researcher. In fact, he says, mental health experts are reconsidering whether it makes sense to maintain this distinction at all.

The problem is that people with drinking problems tend to self-diagnose, to think their problem is less severe than it really is, and to avoid seeking help. That’s one reason why the famous 12-step meetings of AA are filled with people who have tried for years and failed to control their drinking rather than quit.

The research studies on controlled drinking are both encouraging and sobering.

A series of studies by Miller’s team at the University of New Mexico shows that people without alcohol dependence can indeed return to more moderate drinking. In these studies, about two-thirds of heavy drinkers managed to reduce their drinking substantially and to maintain their success for two years. When followed for up to eight years, the success rates decline – just 15 percent had maintained moderate, problem-free drinking, 25 percent had abstained completely for at least a year, 23 percent had cut back but still had some drinking-related problems, and 37 percent were no better than when the study started. Other studies in 1980, 1984, 1988, and 1992 showed similar results.

In a pivotal study of true alcoholics – published 15 years ago in the New England Journal of Medicine but still considered noteworthy by other researchers – Dr. John Helzer, a psychiatrist at the University of Vermont Medical School, showed that only about 2 percent were able to have an occasional drink without becoming dependent again. Curiously, noted Helzer in a telephone interview, a successful return to more moderate drinking was four times more likely in women. Other studies in 1979, 1989, and 1996 also suggest that women may be more successful at cutting back than men.

Cognitive-behavioral techniques, in which people are taught to recognize and change the thinking patterns that underlie their drinking, clearly help people cut back on alcohol intake. In fact, they are among the most successful approaches for people with less severe drinking problems, according to a 1999 review of the data in Alcohol Research & Health, the journal of the Alcohol Abuse and Alcoholism Institute. Cognitive behavior also works for true alcoholics – not to help them cut down but to help them remain abstinent – according to project MATCH, a large federal study in1996.

Brief interventions, in which a doctor or nurse schedules several short appointments to teach a patient about ways to reduce intake, also reduce consumption in people who are not alcohol-dependent, according to the same1999 review. In fact, in Seattle, a 1999 study of people who wound up in the emergency room after alcohol-related accidents showed that 30 minutes of alcohol counseling from a psychologist before discharge reduced the likelihood of readmission for other alcohol-related trauma. But nationwide, many doctors and nurses have yet to incorporate this technique into their practices.

On the more discouraging side, research in 1996 by Dr. George Vaillant, director of research in psychiatry at Brigham and Women’s Hospital, tracked more than 700 college-educated and less-educated male heavy drinkers for more than 50 years. Vaillant found that men who tried to control their drinking usually relapsed while those who managed to stay sober for five years rarely did.

Yet, despite the evidence that moderate drinking leads to relapse for most alcoholics, the idea of controlled alcohol consumption is a powerful lure for alcoholics.

“Nothing is more appealing to a lot of alcoholics than the idea that if they could just figure out how to control their drinking, that would do it,” says Dr. Roger Weiss, clinical director of the alcohol and drug abuse treatment program at McLean Hospital in Belmont.

Dr. Richard K. Fuller, director of clinical and prevention research at the National Institute on Alcohol Abuse and Alcoholism, agrees. With true alcoholics, he says, its very unusual for them to return to moderate drinking. “The reason this is so sensitive, why some alcoholics become livid about this, is because they feel their own recovery was delayed for many years because they struggled, kept chasing this will of the wisp. “Most people can have a drink or two and stop. The alcohol-dependent person can’t,” Fuller added.

The limits of moderate drinking were illustrated dramatically not long ago with the tragic story of Audrey Kishline, who founded a program called Moderation Management in 1993 on the premise that heavy drinkers who are not yet alcoholics can cut back without abstaining altogether.

Last March, Kishline went on a drinking binge and killed two people in a car crash. Afterward, she reportedly called her program an example of “denial in action,” and  pleaded guilty to two counts of vehicular homicide.

Even so, Stanton Peele, a Morristown, N.J., psychologist, lawyer and former board member of Moderation Management, points out that it is ironic that Kishline’s accident happened after she joined AA and tried to abstain. It wasn’t just moderation that failed her, he says, “everything failed her.”

Advocates of  moderate drinking like Anthony Martignetti, an addiction specialist who runs the Alcarrest program at Charles River Hospital, insist that, for selected people, reduced drinking programs work.

In fact, says Martignetti (whose family, ironically enough, owns the Martignetti companies, the New England liquor distributor), it’s the fear of abstinence-only programs that keeps many people from seeking traditional treatment. So far, about 200 problem drinkers have completed Martignetti’s program, and by one year after treatment, 70 percent say they’ve reduced their drinking by 70 percent.

The bottom line? For Paul Robert, at least, things look good. He’s optimistic he can continue to drink moderately.

For others, well, let’s put it this way: If you find yourself saying”Bottoms up!” too often, see a doctor or alcohol counselor to evaluate your drinking. Trying to diagnose yourself is likely to be fraught with denial.

Then, if you and your counselor agree your problem is not severe, try a program aimed at cutting back. However, if your alcohol problem is severe, total abstinence remains the best answer.

SIDEBAR:

There are a number of medications that can help people control or cut down on their drinking, says Dr. Shelly Greenfield, medical director of the alcohol and drug abuse ambulatory treatment program at McLean Hospital in Belmont.

Antabuse (disulfiram) is a so-called “aversive” drug that causes nausea and other unpleasant symptoms if alcohol is also consumed. At high doses, the combination of  Antabuse and alcohol can be dangerous. The idea is to make the drinking experience so unpleasant that a person doesn’t drink, but this only works if people take the drug.

Naltrexone (ReVia) is an opiate-blocking drug long used to combat addiction to drugs such as heroin. In 1994, it was approved by the US Food and Drug Administration to curb craving and prevent relapse in people with alcohol problems.

Acamprosate is a drug that has shown promise in European studies to curb craving for alcohol and help maintain abstinence. It is not approved in the United States, but studies are underway.

Antidepressant drugs  that are SSRIs, or selective serotonin reuptake inhibitors, such as Prozac, have also been shown to help some people who drink too much, especially if they are also depressed.

A Fair Portrait of the Transgender Issue

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Until seven years ago, when she was 40, Nancy Nangeroni lived as a man, which was not all that surprising, given that she was born, as she puts it, with standard male plumbing.

Unlike many transgendered people, who feel they are male but trapped in a female body or female stuck with male anatomy, Nangeroni felt she was male. But she hated it.

 “From the time I was very young, I resented the restrictions that were placed on me because I was not a woman,” said Nangeroni, her skirt and long hair blowing in the breeze one warm, fall afternoon in Cambridge. Now, she said, she takes female hormones, lives with a woman (though she doesn’t “presume” to call herself a lesbian), and feels somewhere in between male and female.

But Nangeroni, a leading figure in the transgender movement and the host of the GenderTalk radio show, has not had sex-change surgery. Instead, she said, “I reserve the right to change my gender tomorrow. That’s part of the freedom that transgenderism advocates for.”

For most of us, answering the question, “What sex are you?” is simple. We feel sure we’re male or female, and we’ve got the anatomy to prove it. 

Indeed, throughout the animal kingdom, most creatures fall neatly into one of two categories: Males, who make sperm and usually carry one X and one Y chromosome, and females, who make eggs and usually carry two X chromosomes.

But it’s the exceptions that make biology interesting – and make life difficult for people who don’t fit so clearly into one category or another. Gender, researchers increasingly realize, encompasses a host of possibilities including men who feel like women and vice versa, and people who are a little bit of both.

Transgendered individuals, who say they comprise about 1 to 2 percent of the population, usually face a conflict between their gender identity (the “Who am I?” question) and sex as defined by their anatomy. In short, many of them feel like they got the wrong sexual plumbing, perhaps because of some misfire in the complex process by which the fetal brain becomes masculinized or feminized. The idea that men and women have different brains is far from roven, although scientists do know that sex hormones do play a role in brain development.

Some seek a sex-change operation to end the conflict, but others live with it, appearing to the world as ordinary heterosexuals.

For Nancy Nangeroni, gender expression certainly involves an element of choice, but it’s not just a political decision. “It’s a very personal decision,” said Nangeroni, who holds a degree in electrical engineering  from the Massachusetts Institute of Technology.

As a young person, Nangeroni spent years dressing as a woman, “something I did as a compulsion.” Then, in her late 20s, she said, “I had a terrible motorcycle accident. And the accident was a direct result of the terrible depression and self-hatred that I had because I was cross-dressing in secrecy and great shame. With that accident, I recognized that it was really important for me to do something about the gender issues. I had to make some kind of change.”

Eventually, she decided to live openly as a woman. But it wasn’t easy, and she never felt that “after living for 38, 39 years as a man that I could just flip a switch and all of a sudden be a woman.”

For other transgendered people, the issues are physical as well. Some people are born intersexed, that is, with features of both male and female anatomy, an agonizing situation in which parents and doctors sometimes try to figure out which tendency is dominant and surgically make the child’s body conform to that.

In some African populations, there are also true hermaphrodites, people with two X chromosomes (the typical female genetic pattern), but who look male because they have penises and  testicular tissue (though they have ovarian tissue as well.).

There are even cultures, such as in the Dominican Republic, where people recognize three sexes: male, female and people who are born looking female (they have no penis or visible testes) but at puberty produce so much testosterone, a male hormone, that the clitoris turns into a penis.

To many lay people, the idea that something as seemingly basic as sexual and gender identity can be so complicated is often disturbing. And scientists are far from being able to explain why there can be such variation. But they do have some clues.

In a basic sense, sexual fate is set at the moment of fertilization by the incoming sperm. The sperm carries either a Y chromosome, which determines maleness,  an X chromosome, said David Page, a geneticist at  the Whitehead Institute in Cambridge. (The egg always contains one X chromosome, resulting in XY chromosomes for boys and XX for girls.)

The fascinating thing, though, is that “for the first six or seven weeks of development after the egg is fertilized by the sperm, XX and XY embryos look exactly alike. There are no differences,” Page said. A 6-week embryo has the full potential to become either a male or a female.

At this stage, the embryo has both male and female internal structures. One of these – the Mullerian ducts – has the potential to become fallopian tubes and a uterus; the other – Wolffian ducts – has the potential to become the sperm-making machinery and tubes to carry sperm.

Early embryos also contain primitive gonads that are capable of turning into either ovaries,  which make eggs, or testes, which make sperm. “But, at about seven weeks, the embryo sort of takes stock of whether it got that Y chromosome seven weeks back at the moment of fertilization,” Page said. On the Y chromosome lies a key gene called SRY, which stimulates the primitive gonads to become testes. If the SRY gene is not present, the gonads become ovaries.

Once testes form, they begin pumping out the male hormone, testosterone, which causes the Wolffian ducts to become the sperm production and transport system. The testes also pump out a chemical called MIS that causes the Mullerian ducts to shrivel up, so they cannot form fallopian tubes and the uterus.

As fetal development continues, male and female hormones then imprint the brain, nudging it toward masculinization or feminization. “One of the things we believe is that it is more common for men to become female in transgender change than for females to become men,” said Dr. Marshall Forstein, medical director of Fenway Community Health in Boston. “If something goes wrong in [the fetal development] process, or something is variable in that process, some of the brains of those men don’t become masculinized at the appropriate development time: Their brains are female, even though their bodies are male.

“So far, however, the idea that incomplete brain imprinting causes transgenderism is merely a hypothesis, and it makes some transgendered people like Nancy Nangeroni and Joan Roughgarden, a Stanford University biologist who now lives as a woman but was born male, cringe because it suggests that there might be something wrong with them. They also strongly dispute that men are more likely to be transgendered than women.

“Medical people are the worst,” Roughgarden said. `They don’t know any biology or zoology. They just superimpose their preconceptions on the data. They try to construct a norm and pathologize all states that differ from the norm.”Instead of speaking of one gender or another, people should think in terms of a “gender rainbow,” she said. Transgendered people “view rigid categories as tools of oppression.”

Nancy Nangeroni agreed: “There’s not just black and white. There’s every color of the spectrum. Likewise, there aren’t just two genders.”The real mission of the transgender movement, she said, is to challenge the way we think of gender and the gender restrictions that we put on individuals.Ultimately, she said, “gender expression is a form of speech. It’s not spoken, but it’s a form of speech that should be constitutionally protected.”

Judy Foreman’s column appears every other week in Health-Science. Her past columns are available on Boston.com and myhealthsense.com. Her e-mail address is foreman@globe.com. 

SIDEBAR: Identity, Orientation Issues Cause Confusion

Many people confuse the terms sex, gender identity and sexual orientation.Sex usually refers to physical characteristics, such as a penis or vagina; sometimes it also refers to the chromosomes – XY for males, XX for females.”Gender identity is how people describe themselves. `I’m a man’ or`I’m a woman,’ ” said Dr. Marshall Forstein, medical director of Fenway Community Health. “So, the term gender is filled with all sorts of social customs.”Sexual orientation is about whom one is attracted to. And “gender identity is a totally separate issue from sexual orientation,” said Laura Berman, a sex therapist in the department of urology at the UCLA Medical Center.In other words, Berman said, a person can have a mixture of traits: “You can be male but feel female and be attracted to either men or women. You can be female and feel male and be attracted to either men or women. You can be male and feel male, but be attracted to men. And you can be female, feel female and be attracted to women.”

Cross-dressing, that is, dressing as the opposite sex, can also cut across categories. For some straight men, dressing as a woman may be erotic. For some transgendered people, it may be the first step in living fully as the opposite sex.