Lifestyle Drugs: What's After Viagra?

There's a big difference between being sick and not feeling your best. Doctors and pharmaceutical companies used to know the difference. If you were sick, they were there to help. If other aspects of your life weren't perfect, well, you should just learn to live with them.

That type of thinking has gone the way of carbon paper and wine coolers. Today, drug manufacturers realize there's big money in curing things that aren't generally considered illnesses—such as baldness or shyness. Thanks to Viagra, they see the enormous profit potential in improving your sex life. The rush is on to develop lifestyle drugs—medications that help you achieve the life you feel you deserve. Whether you need better sex, more hair, less weight, an improved memory, a good night's sleep or some cheering up, there's a medication on the horizon for you.

Getting it up

Last year's king of the lifestyle drugs was Viagra, Pfizer's blockbuster solution to male—and, likely, female—sexual dysfunction. But, hey, nothing's perfect, and while most patients keep renewing their prescriptions (seven out of ten are happy warriors), enthusiasm has slowed somewhat as Viagra's limitations have become better known. Viagra isn't for men with serious heart problems, low or high blood pressure, peptic ulcers or the eye disease retinitis pigmen-tosa. And for some men, Viagra doesn't deliver the goods, or it takes too long. The other most commonly prescribed drugs are Caverject and Muse. One requires sticking a needle into the penis and the other is a small pellet placed in the urethra through a plastic tube.

That means there's room for improved drugs (for us) and more profits (for the drug companies). Here's what the researchers are working on now:

"Clearly, the first-line therapies will still be oral drugs," says Dr. Harin Padma-Nathan, director of the Male Clinic in Beverly Hills. Dr. Padma-Nathan and other researchers believe we've only just begun to treat such sexual problems as impotence and premature ejaculation.

The likeliest new pills—that is, those closest to FDA approval—are two promising tabs that could work for some men who can't use Viagra.

Vasomax: Submitted to the FDA last summer, this pill is based on phentolamine, one of the drugs currently used in penile injections. Phentolamine relaxes smooth-muscle cells in the penis, allowing that hot intake of blood that brings us such pride of ownership. Nobody likes to talk specifics when the FDA is scrutinizing a drug, but tests so far apparently show that Vasomax works faster than Viagra, with fewer side effects. It also appears to be effective on milder cases of impotence. Under the name Z-Max, Vasomax has already been approved by Mexican authorities and is for sale across the border.

Spontane: A sublingual (placed under the tongue) drug that is quickly sucked into your system through blood vessels in the mouth. That may mean a faster erection. But results reported so far suggest that Spontane may work best either in combination with Viagra or for men whose big problem is the somewhat limited one of getting messages from brain to penis. Apparently Spontane also has a few side effects, including headaches.

IC351: Dr. Padma-Nathan sees enormous potential in one pill that's not so far along in development. IC351, another fast-acting tablet, seems to work like Viagra, but with a more focused concentration on the penis. It could eliminate some pesky side effects. Icos, which makes IC351, is running clinical studies in the U.S. and Europe and plans to include female patients at some point. If testing stays on track, and the FDA approves it, IC351 could be on the market in the year 2001.

Viagra under the tongue: Meanwhile, Pfizer is researching other delivery systems for Viagra's key ingredient, including a sublingual wafer.

Topiglan and Alprox-TD: Two other near-term contenders are gels to be rubbed on the penis. The big advantage here is direct application. Both gels deliver alprostadil—the same well-tested drug in the Muse pellet and most injections—directly to the whanger, so the drug doesn't wander through the rest of the body stirring up side effects. Until now, however, this delivery method hasn't worked as well as one might expect, because it is difficult to get a drug from the penis surface to the erectile chambers inside, where it counts. But the new gels contain compounds that are highly absorbable. Both have shown decent results so far in tests in doctors' clinics, where men apply gel to the head of their members and use X-rated movies and vibrators for inspiration. Even sitting in examination rooms all by their lonesomes, 66 percent to 75 percent of the men tested achieved serviceable erections. And the gels don't seem to harm female partners. In fact, companies expect to test versions formulated for sexually challenged women as well. (continued on page 80)lifestyle drugs(continued from page 72)

Gene Therapy: Gene therapy introduces a new, or remodeled, batch of genes into a person to correct a genetic disease or flaw. Genes give the body orders. In an organ that is basically isolated from the rest of the body—the penis being one low-hanging example—this could mean that by injecting a bunch of new genes with the orders to stand erect and be counted, the new genes could overwhelm the existing genes. This could be the best treatment for many men. A couple of times a year, a guy would drop by his doctor's office to get a tune-up injection. (You can guess where he would get the needle.) One prominent gene researcher, Dr. Arnold Melman, chairman of urology at Montefiore Medical Center/Albert Einstein College of Medicine in New York, believes that human trials of gene therapy could begin as early as the end of 1999, with a drug on the market several years after that.

The Herpes Complex

There is some good news regarding gonorrhea and syphilis: Antibiotic pills and injections that need to be taken only once are already on the market. While there's no known cure for herpes, three drugs—acyclovir (Zovirax, or generic versions) and the newer Valtrex and Famvir—will help suppress outbreaks.

Within the next year, expect better blood tests that make highly accurate diagnoses by herpes type. Dr. Penny Hitchcock, chief of the Sexually Transmitted Disease branch of the National Institute of Allergy and Infectious Diseases, is particularly interested in developing at-home tests for the full range of STDs. "My goal is to one day have these tests done in your bathroom, just like a home pregnancy test," says Dr. Hitchcock.

Pockit: This blood test has been submitted to the FDA and could be available this year. If it's approved, doctors could tell you in ten minutes whether you're infected with herpes type II, the most common genital variety.

Vaccines: Far more exciting to the uninfected among us is the prospect of a vaccine. Herpes is more easily thwarted by a vaccine than other viruses because it doesn't mutate—it doesn't keep changing the rules on the researchers. Research on a herpes vaccine focuses not only on the traditional preventative vaccine—a treatment to keep people from being infected—but also on a therapeutic vaccine, which would strengthen the immune system of the afflicted, potentially lessening symptoms and infectiousness. Not a cure, but a much better treatment.

One promising vaccine has already bitten the dust. Another, produced by SmithKline Beecham, is in advanced testing, but many researchers predict it will suffer the same fate. If it succeeds, however, a vaccine could be available in as little as a year. Other vaccines being developed are probably at least five years away, according to Dr. John Douglas Jr., a visiting scientist at the Centers for Disease Control and director of STD control at the Denver Department of Public Health.

A Cure: That's even farther down the road, says Douglas. Some research has suggested that patients treated with Famvir soon after their first herpes outbreak may throw off the virus before it settles into nerve cells near the brain and spinal cord. "But I think that's somewhat of a long shot," says Douglas.

STD Stoppers

Why not find a way to thwart all obnoxious sexually transmitted diseases at once? Hitchcock is researching a simple solution—an STD killer called a topical microbicide. In its ideal form, this would be a tasteless, odorless, colorless substance that could be applied to the vagina. Without being noticed by either partner, the gel, cream or ointment would stop most STDs in their tracks. In theory, topical microbicides would be long-lasting, needing reapplication only every so often—for instance, when one changed lovers.

One product in clinical trials is a suppository that contains good bacteria called lactobacillus. Lactobacillus in the vagina protects against some STDs, but it can also act as a carrier for other disease killers. "There's no reason that we couldn't add a whole cocktail of molecules to the lactobacillus," says Hitchcock. This product could be used by women at their discretion, to protect themselves without making an issue of it with their partners.

The following microbicide products are being tested:

Lactin-Vaginal: A lactobacillus suppository produced by GyneLogix, with encouragement from the National Institutes of Health. Lactin-Vaginal is being developed to protect women and their partners against HIV, gonorrhea and bacterial vaginosis, but not herpes. It would have to be reapplied with each new sexual partner. Women would test themselves every so often to see that the lactobacillus count is still sufficient. Men would have to depend on the conscientiousness of their partners.

Pro 2000: A gel developed by Procept in Cambridge, Massachusetts as a contraceptive and a microbicide. In the lab, the gel worked against HIV and herpes II, as well as chlamydia. In 1997, in two tests on European women, the drug appeared to be safe. Testing among women in the U.S. and South Africa is scheduled to begin this year, supported by the National Institute of Allergy and Infectious Diseases. Some of these women will already be infected with HIV, so the question will be whether Pro 2000 prevents viral transfer to a partner.

Buffer Gel: A spermicidal microbicide in a lubricant, being tested as protection against STDs. It was developed by ReProtect, in Baltimore. Buffer Gel works by maintaining the naturally protective acidity of the vagina that can kill sperm and many STDs. Semen has an alkaline component that neutralizes that acidity and allows the sperm to swim to the egg. This lubricant blocks the semen's alkaline component, keeps the vagina's acidity intact and should keep sperm and STD organisms—including syphilis, gonorrhea, genital herpes and HIV—at bay. The first phase of clinical trials, at Brown University, has been completed and the next stage is expected to begin this year. Buffer Gel could be available as a contraceptive in about three years, and about a year later as an STD fighter.

Plantibodies: ReProtect and another small research company, EPIcyte Pharmaceutical in San Diego, have joined to work on a contraceptive and disease-stopper—but using a different mechanism. Plantibodies are plant antibodies. Human genes are put into a plant, where they are reproduced and harvested. This method produces drugs a (continued on page 152)lifestyle drugs(continued from page 80) lot more cheaply than some current recombinant methods. Various plantibodies would cause sperm to clump together, limiting their motility, and also to stick to viruses and other pathogens to prevent them from entering cells. Clinical trials could begin next year, with an over-the-counter gel or lubricant available about four years later.

Deflating your spare tire

In September 1997, after being tied to a sometimes fatal lung condition as well as heart-valve damage, the weight-loss drugs Redux (dexfenfluramine) and Pondimin (fenfluramine, the "fen" in the phen-fen combo) were withdrawn from the market. There are better ways to lose weight.

"You've got an awful lot of stuff in the gyms out there that promises to promote lean muscle mass and body definition, and flush out fat," says Dr. Peter Vash. "And most of that is dishwater. Really." Dr. Vash, executive medical director of Lindora Medical Clinics in Costa Mesa, California, is a clinical expert on obesity management.

The key armaments in Vash's arsenal are appetite suppressants, both common over-the-counter pills (most of which use phenylpropanolamine) and new prescription drugs:

Meridia controls the appetite by imparting a sense of being full; Phentermine is the good half of phen-fen, and is still available under various brand names (Oby-trim, Ionamin, Fastin, Adipex-P). If taken half an hour before eating, phentermine decreases hunger and increases a general sense of optimism.

Tenuate works by manipulating nerve transmitters.

But there are more-intriguing weight-loss possibilities in the future.

Xenical: If approved, this fat blocker will be sold by Hoffman-LaRoche. Unlike appetite suppressants, this drug works directly on the gut, reducing fat absorption by 30 percent—no matter how much fat you eat. Where does this fat go? Out your nether end as an "oily discharge," says Vash. (Other researchers have reported an unfortunate side effect described as "anal leakage.") In clinical trials, patients lost 10 percent or more of their body weight over the course of a year, and experienced lower cholesterol and lower blood pressure.

Leptin: This is even farther down the pipeline, perhaps five years off. Leptin is a hormone produced in fat cells. Amgen is testing to see if a synthesized form of leptin can cause weight loss. Lab mice got fatter when they didn't have enough leptin in their systems, thinner when they did. In early testing, humans on high doses lost an average of 16 pounds in six months.

Neuropeptide Y blockers: Pfizer, in collaboration with Neurogen, is testing a group of drugs that decrease appetite by shutting off the neurotransmitter neuropeptide Y, which stimulates hunger. "Whether this will make any difference to the human whose brain overrides these things and says, 'Oh, the hell with that, I'm still going to eat that doughnut,' we don't know," says Vash.

CP-644, 673: Pfizer's possible anti-obesity drug, derived from a South African plant, encourages people to eat less. It's being researched by Phytopharm, in collaboration with Pfizer. CP-644, 673 is considered an appetite suppressant. It works in rats and is now being tested in humans.

CP-331, 684: Another Pfizer drug in testing fights weight gain by increasing a person's metabolism so they burn more calories. It's now in human trials that will show whether it works or not.

Hair today and tomorrow

Hair transplants and surgical cover-ups for male pattern baldness have improved a lot recently, but thousands of years of trying have yielded only two drugs that work on men—neither of which is 100 percent effective, and both of which require six months or more to find out if they're doing any good.

Minoxidil: The active ingredient in Rogaine is now available without prescription in two percent and five percent solutions. Rogaine's maker reported that a quarter of men get moderate or better results—74 percent see minimal or no hair regrowth. More often, Rogaine halts further loss of hair, and that's an accomplishment. Minoxidil also comes in a pill, as a blood-pressure medicine. But this form can have heart-damaging side effects. It can also grow hair on places other than your head—"werewolf kind of hair," says one doctor, "all over."

Propecia: Studies have found that 36 percent of male patients who use Propecia show moderate or better regrowth, while 83 percent at least maintain their current hairlines. Propecia's side effects, which are often temporary, include lowered sexual desire, trouble getting an erection and a decrease in semen amount—each of which occurs in fewer than two percent of users.

Perhaps the most discouraging word about hair growth is that no improved drugs are expected for at least five years.

Getting your beauty rest

Everyone has trouble sleeping at one time or another. There's a booming over-the-counter business in sleep aids. No wonder pharmaceutical companies are turning up the heat to market pills that help you get a good night's sleep.

Sonata: Under FDA scrutiny since December 1997, this sleep medication will likely be on the market this spring. Wyeth-Ayerst Laboratories, makers of the new drug, says that because Sonata is metabolized more than twice as fast as other drugs, it is less likely to cause next-day drowsiness. On the other hand, the new pill may not keep all insomniacs asleep through the entire night, for the same reason. Sonata patients apparently have fewer withdrawal symptoms when they go back to drugless attempts at slumber.

NGD 96-1: Farther behind, this unnamed drug, another joint project of Neurogen and Pfizer, is scheduled to begin human trials this year. Neurogen researchers expect it to work quickly, but not so quickly that it leaves you awake again at four A.M. It shouldn't interact dangerously with alcohol, and isn't supposed to be addictive.

Forget me not

A decade ago, smart drugs were a medical trend. Purported to enhance memory, intelligence, perception, mood and sexual interest, smart drugs have encouraged few researchers to study their often faint effects.

Smart drugs: There are two distinct points of view about smart drugs. The smart drug people, who meet each other at smart drug parties and watering holes, say their experiences confirm the findings (claims) of the Cognitive Enhancement Research Institute that non-prescription drugs such as Hydergine, Piracetam, Deprenyl, GHB and pyeoglutamate make our brains function better. What the drugs lack, says CERI executive director Steven William Fowkes, is the "perception of legitimacy" that would come from FDA-accepted studies. But the FDA isn't of a mind to give its stamp of approval to a drug that may only make us operate better. And drug companies don't see much profit in paying out $50 million or more to take a smart drug they can't patent through the FDA approval process. Still, says Fowkes, Piracetam and Deprenyl have developed such a following that they may, over the next decade, become acceptable to the mainstream.

The other camp, traditional researchers, says that nobody knows whether smart drugs work. "But they're certainly not used extensively in psychiatric and neurological practice," says James McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California–Irvine. "And believe me, if they were effective, they'd be used. There's a crying need."

So, the search for drugs to preserve and strengthen memory—cognition enhancers—has been pushed by conventional researchers. Big drug manufacturers have calculated the economic opportunity from such drugs among baby boomers as they approach Alzheimer's age. Only two drugs for cognitive enhancement have so far been approved by the FDA: Cognex and Aricept. Both improve patients' brains, but not sufficiently. McGaugh evaluates them: On a scale of one to 20, normal people are 17 in cognitive terms. The average Alzheimer's patient is a 3. With Cognex or Aricept, the Alzheimer's patient moves up to 5.

But pharmaceutical houses have a much bigger market in mind. "The major companies are looking at a very large population of people who either have, or believe they have, a deficit in memory," says McGaugh. These are people, he says, who notice the natural decline in cognitive function that comes with age. "And they say," adds McGaugh, "'I just want to remember better. Who's to keep me from doing that? If I can have Viagra, why can't I have this?'" So, here's the name of a disease you may want to commit to memory: mild cognitive impairment. Mild cognitive impairment is what will happen to most of us as time goes on. The FDA considers this a disease worth developing drugs for. "Many companies are developing such drugs," says McGaugh. "Most of us believe that in the next decade or so some powerful new ones will appear." At least two major trends are thriving at the moment:

Brain receptors: Receptors receive and send messages in the brain, and different receptors react to different drugs. Prozac, for instance, works on the serotonin receptors. But 70 percent or more of the brain's receptors are glutamate receptors, and researchers are hunting for drugs that can manipulate the function of glutamate receptors. As we age, we have fewer brain cells. If receptors would work harder, they would make up for some of that loss. This process may even cause the growth of new cells. But most potential glutamate-receptor drugs have too many side effects to be safe.

McGaugh is hunting for better receptor drugs, as are a lot of other researchers, including two from UC–Irvine (Gary Lynch and Richard Granger). The University of California, in fact, has taken out patents on a family of glutamate-receptor drugs. Lynch and Granger are working with Cortex Pharmaceuticals, a small Irvine company that has licensed the patents. The drugs have proved safe so far, and are now being tested to see if they work for people. Granger estimates that these drugs could be available in a couple of years.

Gene switch: Researchers are looking for a drug that would use genetic manipulation to switch long-term–memory formation on and off. One protein (called CREB) controls whether we have a long-term memory of an event. Eric Kandel, a neuroscientist at Columbia University, has founded Memory Pharmaceuticals to develop a pill that will work with CREB to improve our memory. Another CREB researcher, Tim Tully, an investigator at Cold Spring Harbor Laboratory in New York, has used a CREB switch to give fruit flies a photographic memory. He believes that a drug can eventually be found that will switch memory on when needed—or off, when not wanted. Tully gives an example of an unwanted memory: the traumatic experience of the day-care-center kids who survived the Oklahoma City bombing. "If you could administer a memory suppressor to those kids in the hospital within a few hours of the event," he says, "you could block the formation of that emotional memory." Tully is a founder of Helicon Therapeutics, a co-venture with the Cold Spring Harbor Lab, Oncogene Sciences and Hoffman-LaRoche that is working to develop such pills. These memory drugs could be 15 to 20 years off.

In your Head

At least 85 new drugs are under development in the U.S. to treat mental disorders. And the existing pharmaceutical armory—from Prozac to Depakote—is already formidable. "We have great medications—that's been a real success story in the last five or ten years," says Glen Stimmel, professor of clinical pharmacy and psychiatry at the University of Southern California Schools of Pharmacy and Medicine.

No one wants to feel bad, physically or emotionally. And the existing mood enhancers have proven extremely profitable for drug companies. That's why there's no shortage of new miracle pills. Some drugs in development:

NGD 91-2: This drug is for sufferers of generalized anxiety disorder, the most common of the anxieties and one that many of us can identify with. Existing anxiety drugs like Valium have side effects that include sleepiness, memory impairment and a dangerous interaction with alcohol. The new drug, aimed at a brain neurotransmitter, is expected to lower anxiety with fewer side effects. In a collaboration between Neurogen and Pfizer, it is being tested on humans. Wall Street pharmaceutical analysts expect that if this drug is successful, it will be on the market in the next four years.

MK-869: Also aimed at the big market for anxiety (as well as depression and schizophrenia), this is a new type of anti-depressant intended to block a brain peptide called substance P. Merck Research Laboratories is developing the drug, which is already being tested with humans. MK-869 aspires to be the new Prozac, with fewer side effects.

Paxil: When it was approved for use in the UK to treat a widespread anxiety disorder called social phobia, this SmithKline Beecham antidepressant was scoffed at in the British press as a "shyness drug." Still fending off unsporting charges that the drug is more for parties than party phobes, the drugmaker has asked the FDA for approval to use it on the same disorder in the U.S. (To use it for a party, you'll have to think ahead; it takes a couple of weeks before the drug's liberating effects begin.)

NDG 98-1, NPY2: The first of these two drugs from Neurogen aimed at treating depression and anxiety focuses on the corticotropin releasing factor, a neurotransmitter not yet targeted by existing drugs. Testing should start this year in human subjects. The second drug, which will be a longer time coming to market, aims at the neuropeptide Y receptor, and it could work faster and with fewer side effects than existing pills. Proponents also hope it will work with some patients who don't respond to current medication.

R-Fluoxetine: It's already known as Son of Prozac. The rights to produce a sort of mirror image of Prozac were bought late last year by Eli Lilly as a way of continuing the company's stake in the depression-drug market. The patent protection on Prozac will end in 2004. R-Fluoxetine's patent stretches to 2015. Lilly plans to apply to the FDA for approval by 2001.

"The drug works directly on the gut, reducing fat absorption by 30 percent—no matter how much fat you eat."