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PFIZER'S VIAGRA

VIAGRA: SEX DRUGS & ROCK 'N' ROLL

The Sunday Times Magazine (London) September 6 1998

Viagra is the sex sensation of the century. Launched as a cure for impotence, it has now become the latest lifestyle accessory. But for some men it is useless, or much worse: the side-effects include death.

BRIAN DEER INVESTIGATES

The drug company's instructions are simple enough, but Dr Harin Padma-Nathan fears missing his engagement, and anxiously seeks advice. "Where's Chino?" he demands, via his hand-held cellphone, as we hammer through Los Angeles at 75mph in a dark blue BMW. "My passenger from England here tells me that the map you've given us runs out at Ponoma."

A voice reassures him: go the way you're told. He repeats this. I read the instructions. From his office at the Male Clinic in Santa Monica to the Chino Medical Group, 50 miles east, you follow I-10 onto California 60, shoot through Ponoma head south on Central Avenue, then left onto Walnut. Our destination is just past the hospital building. Street number 5475.

Pfizer's note actually says right onto Walnut - the wrong way - and one of its sales representatives, a dark-haired young man lurking in Padma-Nathan's parking garage, had earlier piled on extra stress by reckoning that we would be late. But at the frantic pace at which everyone is working, errors are bound to occur. We make one double-back, but look in good shape. We will reach our goal as planned.

It's a sweltering Thursday lunchtime, and the doctor is on assignment promoting Viagra: the selective phosphodiesterase inhibitor launched euphorically last March in America and now heading in Europe's direction. He's one of an elite core of paid Pfizer "consultants" who are hurtling through a punishing campaign of talks and media pronouncements. At Chino, a town of 48,000, he will lecture to a gathering of health professionals and offer a soundbite for network news.

In the light of the world-wide Viagra hysteria you wouldn't think he needed to bother. Not since the banning of Coke containing coke have people sweated so much for a drug. Even the launch ten years ago of Eli Lilly's selective seratonin reuptake inhibitor, Prozac, never saw a buzz like this. "Forget mind-altering drugs," Padma-Nathan tells me. "The new vogue is penis-altering drugs."

But today the doctor has a task on his hands that contradicts Viagra's image. There are signs of the frenzy spinning out of control, and the product's downside may be starting to show. Not only has it picked up the label "recreational drug", for which health insurers and governments are reluctant to pay, but potentially life-threatening side-effects have hit the news. So his goal, like that of Pfizer people all over the world, is to refocus the campaign on impotence.

Although paid by Pfizer, he's not a salesperson. The company has 15,000 of those. Rather, this 42-year-old Sri Lankan-born urologist is one of a new breed of doctor: a sort of freelance expert-entrepreneur, leasing their services and reputation. From his Male Clinic, which he set up for such purposes, he was the major contractor for Viagra's pivotal tests, submitted to the Food and Drug Administration. He advises the company. He makes company training videos. He travels at the company's expense. If you want to find a man to call "Dr Viagra", he's sitting at the wheel of this car.

His schedule is crazy, media pressure intense and I'm lucky to ride shotgun for the day. Pfizer itself says next to nothing on the record about its billion-dollar baby, leaving its hard-pressed consultants to feed the public's interest - so far with spectacular success. Padma-Nathan has recently done Newsweek (twice), Time, People Weekly, the New York Times, the Los Angeles Times, The Wall Street Journal, Nova, CBS News (six times) and NBC News (four times).

He asks my opinion about London-based press, which are also clamouring for interviews. With US Viagra consumption already down by one quarter from the peak of America's hysteria, the focus has now shifted to the upcoming European launch, especially in Germany, France and Britain. He has patients ready and waiting with testimonial anecdotes, and he wants to make the most of their material.

As we turn off the freeway, however, he's still grappling with the unremitting domestic appetite for the topic. He has a 43-frame slide show in his doctor's black briefcase, and there is the television appearance to psyche-up for. This morning, another Pfizer consultant, his friend Dr Irwin Goldstein from Boston, was quoted on the front of USA Today as prescribing the drug to women as well as men, and an NBC crew is driving from Burbank to Chino to record an item on this for tonight's news.

*****

Inside the two-story cream-and-pink Chino Medical Group building, a room is filling with 60 doctors and nurses who have come to hear Padma-Nathan. There's a Pfizer buffet behind them, a Pfizer promotions stand to the left and a grey-lettered white banner on the wall. "VIAGRA (sildenafil citrate) tablets," it announces, in case anyone forgot why they came.

For a paid consultant, his performance is impressive. Committed and yet subtly detached. "I am not a stockholder in Pfizer or anything," he declares at the outset, pacing back and forth in black suit-trousers, grey shirt and yellow tie. "I have no financial interest in Pfizer, Viagra or any of the products I'm going to mention."

It's the kind of lecture that the company's consultants are putting on everywhere. It redefines impotence as "erectile dysfunction", then cuts to a cover of Newsweek. Then to a list of obsolete therapies that were the options before the new product. Vacuum devices. Penile implants. Injections. Urethral pellets.

"1998 is a wonder year for this area of medicine," he announces. "At last, erectile dysfunction is starting to come out into the open and to be talked about."

Slides five and six give another angle on the change: an upward revision of numbers. Using bar charts in primary colours, there are estimates of erectile dysfunction incidence which have, apparently, soared in recent years. Post-war studies from the famous Kinsey Institute reckoned that 15% of men in their 50s were impotent. In 1986, a study of ageing in Baltimore said 8% at age 45. But according to a May research paper co-authored by Padma-Nathan, with Goldstein, in the prestigious New England Journal of Medicine, the incidence is very much higher. "The disorder is age-associated," his paper declares, "with estimated prevalence rates of 39% percent among men 40 years old."

This figure seems extraordinary, but the slides move on. Numbers nine through 12 zoom in on the penis: firstly in cross section then microscopically, to reveal how Viagra works. Here are the corpora cavernosa - the two spongy tubes, one either side of the urethra, that are pumped with blood during erections. Here are the smooth muscles that become relaxed to permit this flow. Then come more technical slides. Viagra alters the balance of nitric oxide, which is produced in response to sexual stimulation and which activates an enzyme called guanylate cyclase, which in turn gets on with the job. More specifically, the drug inhibits yet another enzyme, called phosphodiesterase type 5, which degrades yet another, called cyclic guanosine monophosphate, which is otherwise inclined to suppress nitric oxide and throw all this into reverse. Phew.

He speaks for precisely 30 mins, takes questions and hurries downstairs. The NBC crew have set up their lights and are anxious to get back to Burbank. They're working on segment called "The Clamour for Viagra", apparently triggered by Goldstein's remarks.

Padma-Nathan sits stiffly with his fingers clasped and subtly contradicts his friend. He's not against prescribing to women in principle, but argues that more work is needed. "It's irrational for Viagra to be used in women without any safety data," he says. "It's irrational to use a drug that is being used off-label without clinical research."

Nathan's clip is in the can. The lights go out. We scurry to the car.

Back in Santa Monica, he hits the phones to square me a testimonial anecdote. A Santa Barbara couple had initially looked good, but were so freaked out by the BBC that they grumpily went to ground. "They wanted to film us on the beach," the patient's wife berated me. "It was something more like an entertainment."

While he calls on my behalf, I poke around the clinic, starting with the doctor's office. On the walls by his desk are 18 framed certificates which proclaim his various achievements. They look nice enough, but there's nothing very startling. A British doctor would put them in a drawer. The industry usually calls on full professors, department chairmen and medical school deans. But my Dr Viagra looks like a middle-rank urologist: more successful than distinguished, I'd say.

On a cherrywood sideboard are a pile of reprints of the May New England Journal of Medicine paper with the dramatic impotence statistics. There are six authors named, including Nathan and Goldstein. Five of them are Pfizer consultants. It mostly describes two Viagra trials, the results of which were vital for its license. One involved 532 volunteers, the other 329. A Dr Ian Osterloh, of Pfizer's British research centre, at Sandwich, Kent, helped to design the tests.

The 2000-square-foot Male Clinic has nine rooms, in shades of grey, and since opening in October 1996, Padma-Nathan and his staff have used them intensively to test 11 impotence remedies. On shelves and in cupboards, everywhere you look, are the accumulated patient data: more than 700 3-inch spines labelled "Pfizer", "Zonagen", "Schwarz", "Eli Lilly". Padma-Nathan, it seems, isn't only Dr Viagra, he's Dr Impotence Product in General.

But today, and tomorrow, he's on the road for Pfizer, with his biggest impact tonight. From my room at the Century Courtyard hotel, I watch Tom Brokaw anchor NBC News with the latest update on the product. He trails it teasingly across three commercial breaks. I wonder how much that helps the ratings? "It's the drug that has changed the lives of millions of American men," he begins the item, "restoring the sexual potency they thought they'd lost forever."

It's a bad news story about the giant insurers who are either refusing to pay or are rationing Viagra supplies. The chairman of the biggest, the 9m-member Kaiser Permanente, says that his company would need $100m a year if everyone's requests were met. A Viagra user appears and says he'll sue his insurer. A Pfizer consultant comes on and says that Kaiser's action is "incredible".

The company's worst nightmare is that European governments will take the same stance as Kaiser, but time is short and now comes the good news: "The Clamour for Viagra" segment. In Saudi Arabia, tablets cost $100 - ten times the US price. Japanese companies fly men to Hawaii. Doctors sell it on the Internet. Others, such as Goldstein, prescribe it to women, before any benefits are proved.

"It's irrational for Viagra to be used in women without any safety data," Padma-Nathan's soundbite slots in. "It's irrational to use a drug that is being used off-label without clinical research."

Pfizer's consultants provide both sides of the story. That strikes me as kind of smart.

*****

Padma-Nathan finds me a man called Bob Pollyea, who is shouting from the roof about how Viagra has given him back a sex life. Not literally from the roof, but he goes one better: he recounts his story for media. During the summer he appeared on NBC and, towards the end of July, when I call to see him, the BBC has just been in touch. He's passionate, articulate, good-looking, middle-class. He's just the kind of person to encourage European governments to make health services pay for the drug.

He lives with his wife, Sharlene, on West 4th Street in the heart of Los Angeles. They've a first floor condominium with big airy rooms, polished floors and a deck at the front. For my visit they nestle on a couch to praise Pfizer's remarkable blue diamond-shaped pill.

They met at university in 1955 and have been married for 41 years. Bob is 66 and grew up in Chicago; Sharlene is 61, a Californian. He retired as a psychology lecturer recently. She teaches business studies. They have two daughters and a squad of grandchildren. They seem to be in love.

Everything was fine until October 1994, when Bob had prostate cancer surgery. Though most of the nerves around the area were spared, he had a problem with sex after that. He could get erections, but lost them quickly. He couldn't see his lovemaking through. "You lose your self confidence," he tells me. "You feel less adequate."

Padma-Nathan helped during the operation, and 18 months back Bob went to see him to get a prescription for Caverject. This was the first licensed impotence medicine, manufactured by Upjohn and approved for sale in August 1995. Known generically as alprostidil, it's injected into the base of the penis and causes erections, without stimulation. "You have to leave your lovemaking, go to the refrigerator and inject yourself," Bob explains its biggest drawback. "Your partner is lying there thinking 'what's going on?'.

Then, on 27th March this year, Viagra got its license. It was approved by the US government's Food and Drug Administration (FDA) on a Friday, Bob went to Padma-Nathan the following Monday, got the prescription filled on Tuesday and tried it out with Sharlene on Wednesday.

"It's very natural," he says. "You take the pill. It's working in about 45 minutes. You get your erection as you did before. You have intercourse like you did as a young man. And in our case there were no side-effects."

The couple's bad news is that their medical insurer, Blue Cross of California, has issued an edict that rations them to only six 100mg tablets a month. And such is the change they report in Bob's erections that they aren't pleased about this restriction. He tells me that Padma-Nathan is lobbying government on this. Trying to get something done.

"Its renewed our relationship," Sharlene says. "We always had a loving relationship and a very good sex life. And now we've been able to have all that back. I think it's so amazing they could come up with something like this."

Padma-Nathan tells me that their are many such stories, bringing impotence out of the closet. But I wonder about the danger of relying on anecdotes: is the experience common or rare? Human interest trumps statistics. And the doctor wasn't telling me about any of his patients for whom Viagra failed to please.

Yet such failures are bound to be out there, as they are for any pharmaceutical product. And when I turn to the research - sponsored stuff, admittedly - it shows that the story of the drug's effectiveness can't be told through personal accounts. It also reveals that for many men who suffer from impotence, sadly, Viagra doesn't work.

I find the facts buried in a stack of reports that I obtain from the FDA. Agency staff analysed all Viagra's trials - including the material for Padma-Nathan's paper in the New England Journal of Medicine - and they came to the conclusion that the drug's effects are significant, but despite testimonials such as Bob and Sharlene's, it's by no means the answer for all.

The first trial in Padma-Nathan's paper starkly reveals its shortcomings. It involved 532 men, randomly allocated to get Viagra for 24 weeks in fixed doses of 25mg, 50mg, or 100mg, or alternatively a dummy, placebo, pill. Among volunteers on the "standard" 50mg dose, or 100mg like Bob's, only half (51%) of attempts at sexual intercourse were reported to be a success.

In the second study, of 329 men, the volunteers got Viagra or placebo for 12 weeks. In this case, however, they started on 50mg, but could vary the dose, if they wanted. The FDA's assessors reckon that fewer than half (47%) of attempts were successful among those on the drug.

A further, and maybe depressing, complication is that there was a big boost for sex among men whose pills had no active ingredient. In the first trial, nearly one quarter (24%) of attempts at sex were successful among those on placebo. In the second it was 13%. Figures in the paper suggest that between one quarter and one half of Viagra's benefits may have psychological roots.

These were short trials, but independent researchers suspect that such numbers might be right. "There's no doubt that this drug is very effective," Dr Ronald Lewis, head of urology at the Medical College of Georgia and president of the International Society of Impotence Research, tells me on the phone. "For patients who really do have impotence, I think when it's sorted out it's going to be about 40%-50% helped."

Pfizer, however, doesn't stress these results, but instead locks onto a measure which makes Viagra look a whole lot better. Despite FDA orders that the fairly objective "successful sex" measurement be the yardstick, the company prefers to use a more commercial and more subjective question about how hard or big the penis appears. On this scale, 74% of men on 50mg Viagra (and 24% on placebo) say that they experienced an "improvement in erection".

This is nearly three-quarters, a great headline figure, but redefining the goal is proving a double-edged sword for the company. Although men wanting a harder or larger penis is an infinitely more profitable market than men who have unsuccessful sex, wanting a harder or larger penis isn't exactly a medical complaint. And in the face of the fun-drug buzz around Viagra, insurers and governments are finding it easy to refuse to pay for it. Britain's gargantuan National Health Service, for instance, is determined to avoid coughing up.

Dealing with this dilemma needs more than anecdotes and, fortunately for Pfizer, there is help from science, which it deploys at every turn. First, there is the explosion in the incidence of impotence, as described in Padma-Nathan's slide show and based on the New England Journal of Medicine report. It points to what amounts to an impotence epidemic, which insurers and governments can't ignore.

Another forceful paper, published 15 months ago, unveils a new diagnostic tool. It's called the International Index of Erectile Function and using this, impotence is no longer judged a yes-or-no matter, but is placed on a sliding scale and becomes subjective like "improvement in erection". The index is based on a 15-point questionnaire, like you find in lifestyle magazines. "Over the last month," for instance, "when you attempted sexual intercourse how often was it satisfactory to you?" Again, this produces an increase in numbers. Through science, the market expands.

But if insurers and governments look carefully at this stuff, they may see what a small world it is. The terrifyingly high impotence figures can be traced through the footnotes to another journal paper, dated January 1994. It's co-authored by Dr Goldstein, Padma-Nathan's friend in Boston and is based on a mere 303 subjects, who are deemed by Goldstein to suffer from impotence even if they say that it's "minimal".

There's also credit due to two men involved in the widely-used erectile index. First, to Dr Raymond Rosen, a Pfizer consultant and New Jersey psychology professor. He's also one of the six authors of the New England Journal of Medicine paper. And second, Dr Osterloh, of Pfizer research in England, who led the team which developed Viagra.

The upshot of their efforts is to help shift the boundaries between those who think they're impotent and those who don't. It encourages doctors to write more prescriptions. And if a wave of anxiety is provoked around the globe about the hardness or size of erections, well apparently, in tests, 74% of men say their penis looks better on Viagra.

*****

It's a Monday evening. I'm now in New York, at the Downtown Holiday Inn. The television is tuned to NBC, where funnyman Jay Leno is starting his Tonight Show with fast-pace monologue gags. "It's so hot," he says, referring to the heat wave which currently grips the United States. "It's so hot," (two, three, four...) "men are taking Viagra just to get some shade."

Laughs, cheers. And he doesn't change the subject. NBC, a General Electric subsidiary, has sildenafil on the brain. "You see this new book? Viagra Nation?" (Two, three, four...) "I just hope it's not one of those pop-up books."

Then Leno produces a manila folder and holds it up for a camera. It's stencilled with the words "Pfizer Pharmaceuticals". He namechecks the company six times. Here he explains are rejected slogans from its new promotional campaign.

"Hot dog helper."

"Sex... in about an hour."

"Church won't be the only place that granny shouts 'bingo'."

Leno has done a Viagra joke almost every other night since the spring - which makes you wonder whether Pfizer needs a promotional campaign at all. But it has earmarked $35m to rally the public against the insurers. One of the first to get a share has been Time magazine, which helped launch the hysteria with a May cover story and package of excitable reports. One article concluded that claims for new products may have the familiar ring of "youth-in-a-bottle" advertising, "only this time, the stuff will really work."

At Pfizer's stainless steel and tinted glass world headquarters on East 82nd Street, Manhattan, the company's board and management must think they've died and gone to heaven. By mid-May, the hysteria had propelled weekly sales to a staggering 278,000 new prescriptions and, although by the end of June they had already slipped back to 150,000 weekly, there's never been anything like it. The company's stock bobbed around $50 on Wall Street a year ago (after profits of $2.2bn on sales of $12.5bn), but has recently topped $120.

Meanwhile, in the research department at Sandwich, England, celebrations must centre on the one-in-a-thousand fluke with which the sildenafil goal was scored. Patents filed in London as recently as 1991, 1992 and 1994 show that the compound - coded UK-92,480-10 - was one of a number which grew from the work of other drug firms, notably Warner Lambert and Abbott Laboratories. And they were synthesised before Osterloh's team had the foggiest about what they were supposed to do.

"Thus," the patents declare, "the compounds have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, eg post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, eg irritable bowel syndrome."

But this summer the toasts will be most raucous in Pfizer's marketing departments. For 30 years, the industry's holy grail has been products which get as close as possible to potential universal consumption. While high-price medicines for rare ailments can make money and those for common, and preferably incurable, conditions can yield unbelievable returns, what makes pharmaceutical salespeople shout 'bingo' is something to be swallowed by us all. The contraceptive pill was the great leap forward. Antidepressants were a sprightly hop.

Here's the great glory of Pfizer's riser: it's declared to be everyone's tonic. With men on a sliding scale of erectile dysfunction and the market primed with breathless stories about potential benefits for women, the reason for its license, dreary old impotence, need detain the world's attention no more. Even with Bob and Sharlene in the shop window, everyone knows that the big-time target is men with nothing much wrong.

"The best way I can describe the feeling of the sensation of Viagra is to compare it to when you're a 12-year-old boy and you're having your first erections," is how Clark, a Californian man in his 20s expresses a more typical anecdote. "It feels like you have an erection that can't be tied down with a rope."

Viagra isn't niched with sickness and disease products, but rather with those for fitness and lifestyle. And as a trip through a typical bookstore reveals, they are doing some incredible trade. In one New York Barnes & Noble I see browsers with Viagra: The Potency Pill, by the editors of the Consumer Guide; Viagra: A Guide to the Phenomenal Potency-Promoting Drug, by Susan C Vaughan, MD; Viagra - The Potency promise, by Larry Katzenstein; and The Virility Solution, by Steven Lamm, MD, with a do-it-yourself erectile index.

Lamm's book is the most revealing in its portrait of target users. Say goodbye to Bob and Sharlene and bid hello to "Dennis" and "Jennifer". These are stressed-out achievers in California's silicon valley who appear to be looking for thrills. He portrays Dennis coming home on a Friday evening to unexpected soft music and his wife preparing to make a dramatic entrance in the lounge.

"Very soon she did," Lamm gushes, "carrying a tray with a bottle of wine, two glasses, and a small china plate with a small blue pill for Dennis. Both he and Jennifer knew that it would ensure them a night of intense sexual pleasure, and the anticipation of those events brought a flush to both their faces. With that pill, their weekend, their sex lives, and most of all their ongoing relationship would be enhanced and enriched.

"Jennifer poured the wine and passed Dennis a glass. He leaned over, picked up the pill and, toasting his wife, swallowed it. Both Jennifer and Dennis were willing participants in the new world of sexual medicine, which gave them the security of knowing that they could have what they wanted, when they wanted it."

Lamm concludes: "Everyone can."

Gripped by his prose and by three references to Padma-Nathan I journey to the doctor's Upper East Side office, 20 yards from Central Park. He's also the author of Thinner at Last (1995) and Younger at Last (1997) and claims 100 network appearances. His room is emblazoned with signed celebrity photographs: Frank Sinatra, Rod Stewart, Steve Martin. He charges $150 for a first consultation. He dispatches Viagra by FedEx.

Lamm, who is 49, calls his speciality "vitality medicine" and he pursues the same holy grail as the industry: customers who are basically well. "I have a vision of the doctor as a coach, rather than just as a repairman," he tells me. "How do I take someone like you and get you to come and see me? Vitality medicine is getting people like you to function at a higher level, at peak performance."

This sounds good, but when I take the Viagra challenge - picking up twenty 50mg tablets elsewhere at a cost of $180.69 - to be honest I feel let down. Despite a first-time rush from consuming a sex-related product - producing more or less what Clark describes - on the next occasion, three days later, it doesn't make a great deal of difference. For my third experiment, after another few days, I take two (ie 100gms). But this time nothing seems harder or bigger. On the fourth time there's no effect.

Studying the science in my reporter's identity, this experience makes sense to me. The mechanism involved in the cavernosal smooth muscle is only a link in an elaborate chain - understood by experts with about as much clarity as how our minds control our bodies. There are countless messages flashing round our nerves, hormones generated in obscure glands and any number of chemical events. Blocking one enzyme, even phosphodiesterase type 5, is no more of a conclusive penis-booster than oil is the certain solution for grinding or funny smells in the car.

I also feel cheated that the drug isn't an aphrodisiac. It has the kick of decaffeinated coffee. And, in my case, it seems to have a deadening effect on sexual sensitivity. Although encouraging more blood into the penis sounds like fun, the sensation to me is something like wearing an invisible extra condom.

Then, when I consider why my penis is often soft, I think maybe it's because I'm not turned on.

Sales figures suggest that I'm not alone in my disappointment. Even my doctor in New York says the same. "I tried it when it first came out, but I don't take it any more," he explains. "I'm reasonably functional for a man of 65."

There's no pill yet for an unattractive partner (except possibly cyanide) and Viagra's limitations may wreck a few marriages when it fails to galvanise. But from Pfizer's point of view there need be no alarm. The market may still get bigger. The influential Dr Goldstein, professor of urology at Boston University Medical Center, argues that Viagra may be used to prevent impotence and be consumed on a just-in-case basis. "People take aspirin to prevent heart attacks," he tells Reuters. "Is Viagra the aspirin of the penis? We think it is."

Then there is the much-hyped use by women, which Padma-Nathan thinks needs more research. As The Sunday Times reported on 7th June, the campaign is on to convince the world that the wonder drug is not just for men. "Initial results from the secret clinical trials commissioned by Pfizer," the newspaper says,. "suggest the treatment is impressively effective, heralding a sexual revolution."

Whether this is true remains to be seen, and in the meantime many experts are cautious. When I catch a cab uptown to the 800-bed Montefiore Medical Center and Albert Einstein School of Medicine, in the Bronx, the professor and chairman of urology, Dr Arnold Melman, 56, sits behind his desk in a red-striped shirt and trashes the theory - in code. He's the past president of the International Society of Impotence Research and avoids inflammatory quotes.

"It's like the repeat dose of shampoos," he says.

"Err?" is my reply. I assume that he's setting-up a gag.

"Viagra for women," Melman continues (two, three, four). "It's the same as shampooing twice."

"How's that?" I'm still confused. A punchline missing?.

"It doubles the market." No joke.

*****

We're back in Los Angeles, two miles from Bob and Sharlene's (and as many light years from their lifestyle) at a gay men's sex club called The Zone. It's on Sycamore Avenue in Hollywood. Admission costs $8, plus $10 membership. Notices adorn the lobby. One warns of pickpockets. Another concerns condoms. And there's advice about the new craze drug.

"If you are taking Viagra," it shouts in red and black, "don't use poppers. The combination is deadly and frankly we don't feel like hauling your dead ass out of here."

It raises smiles, but the advice is for real. California has been rocked by three such deaths. When combined with sildenafil, the amyl nitrite or nitrate in the recreational chemical poppers can cause a blood-pressure slump and instant cardiovascular collapse.

Gay men are good Viagra customers, yet research for anti-Aids campaigns reveals that in sexual situations, whether at clubs or more privately, quite often health advice goes ignored. Maybe half are drunk. A good many are on grass. A few take harder drugs. If a little brown bottle containing poppers passes round, some will find it hard to say no.

There are also other Viagra users who appear to be running into trouble. Most conspicuous to date are heart condition patients who summon an ambulance. Medicinal nitrates are often carried in emergency vehicles to help relieve angina and other symptoms. So a man on Viagra who is administered this treatment may die as a consequence.

When a medicine is taken and a bad event follows, you can't assume cause-and-effect. But a string of fatal incidents has worried observers since Viagra went on American sale. At the end of July, the FDA announced that it knew of 77 deaths between March and June in which the drug may have played some role. Facts are thin for many of the reports, but 39 cases are solid enough to trigger a short review.

"Age was specified for 31 individuals, who had an average age of 66 years (median = 64, range = 48-87)," the agency says. "Of 18 with the dose reported, all but one had taken the 50mg dose. Six patients were administered nitro-glycerine or a nitrate medication that is contraindicated with the use of Viagra. Of reports that provided information on sexual activity, 14 men died or developed symptoms that led to death during or within 2 hours of sexual activity; 3 died or developed symptoms that led to death more than 2 hours after sexual activity."

These figures mean something, but nobody knows what, since there's no proper side-effects monitoring in America. Partly due to doctors' terror of being sued, fewer than 1% of suspected bad events are reckoned to be reported to watchdogs. But any drug's benefits are balanced against its risks, and Viagra's are no exception.

A possible pointer to the degree of risk is that of 3,700 men in pre-marketing trials such as Padma-Nathan's, two of them died of heart attacks for which no conclusive explanation was found. One was a 66-year-old taking just 10mg, but who was noted to have a history of smoking. The second was aged 53, on 100mg, and with no "pertinent" medical history.

For a drug with the benefits described for Viagra, a death rate of 1 in 3,700 would be considered to be alarmingly high. But Pfizer insists that the product is safe and that associated deaths may be due to older men resuming a strenuous sex life. Padma-Nathan agrees and points out that this age group has a high "background" death rate in any case. "If you took 330,000 men in the general population over the age of 49 and followed them over the course of a month," he says, "400 to 700 of them would die of natural causes."

But questions nag - not least because of the speed of Viagra's approval. Both the FDA and Europe's safety watchdogs have been slimmed and quickened during the 1990s, mainly in order to deregulate medicine and boost returns on research investment. Viagra's application, which totalled hundreds of thousands of documents, stormed through the FDA in just six months, compared with the two years which were common in the past.

More uncertainties lurk in the nature of the relatively small clinical trials. Tests such as those at the Male Clinic may show that the product seems to work, but its safety profile won't be clear until millions of people try it. "You just don't know all you need to know from the few thousand people who get a drug before marketing," explains Dr Robert Woosley, professor of pharmacology at Georgetown University, Washington. "I've called for educational programmes to let people know that, after they're on the market, drug side-effects are to be expected. And drug removals are to be expected."

A case of removal is a drug from Sanofi Winthrop called oral milrinone. It was taken off the market in 1992 despite getting the green light from watchdogs. This was a phosphodiesterase type 3 inhibitor, licensed for treating heart patients. But after special trials at 119 hospitals, independent researchers concluded that it "was associated with a 28% INCREASE in mortality".

As a phosphodiestarase type 5 inhibitor, Viagra is only roughly in the same class of medicine. But there have also been recent problems with other drugs with pharmaceutical similarities. In February, the antihistamine Seldane was withdrawn by its manufacturer, Hoechst Marion Roussel, after fatal heart-rhythm reports. In June, Roche withdrew the anti-angina/hypertension drug Posicor after a "three-year long-term study". And, also in June, following 38 death reports, Janssen Pharmaceutica alerted doctors about risks with Propulsid, for heartburn.

What these products have in common with sildenafil is the way in which they're metabolised, or processed, in the body. What concerns some specialists is that all four are taken up by a particular enzyme (cytochrome P450 3A4) which has a finite ability to process foreign chemicals, causing a potential toxic "back-up", or overload.

Related to this worry is that impotent men are often ill or taking medications. Yet pre-marketing tests for Viagra were designed to specifically exclude many of them. FDA documents that I read show that men were excluded from tests for as many as 17 different health reasons - and so the drug's effects on them after marketing are pretty much anyone's guess. These include people with a "history of alcohol or drug abuse", those with major liver or kidney disorders, uncontrolled diabetes, unstable angina, abnormal blood pressure, peptic ulcers, a history of retinitis, and what Pfizer's trial designers call "any clinically significant baseline laboratory abnormality."

In addition to not being tested on so many of its potential consumers, there's a well-itemised shopping list of acknowledged Viagra side-effects. Analyses of company data, which will soon be released in the European Union, shows that the commonest of these during placebo-controlled trials were:

	50gms	100gms
Headache	24%	29%
Vasodilation	20%	20%
Dyspepsia	8.1%	12%
Abnormal vision	2.3%	8.7%
Rhinitis	3.1%	5.2%

Most of these appear to be mild and brief. Users are often willing to accept them. "On my third time with Viagra my stomach got so upset there was no time for an 'afterglow' because I had to run to the bathroom," is how Gary, aged 37, recounts his experience with 50mg to an Internet discussion group. "This last time I was practically side-effects free. About 30 minutes after taking Viagra, I took two Tylenol and a Tums and started drinking water. After about 15 minutes I took another Tums and used a nasal spray for my stuffiness. The water seemed to help with the facial flushing. All I got was a great erection when the time came."

*****

With the FDA's approval in the bag last March, Pfizer now looks to Canary Wharf in London and the offices of the second most powerful licensing body: the European Medicines Evaluation Agency. Under gentle pressure from the company's management and from the ferocious media frenzy, officials are finishing the paperwork on Viagra, faxing and phoning back and forth with Brussels, which must give the go-ahead for marketing. An advisory committee has already said "Yes", although stronger safety warnings have been ordered.

Pfizer bosses declare that the decision is imminent, yet Brussels has been dragging its feet as the problems in America are closely analysed. When Viagra was first released in the US, fewer than 550 people had taken it for more than 12 months, leaving big holes in regulators' knowledge about what may happen during long-term use.

One concern which has prompted strengthened warnings is the drug's possibly damaging effect on the eyes. As well as inhibiting the phosphodiesterase type 5 enzyme, it also inhibits the closely-related type 6, which is found in the retina. Among users this sometimes leads to blue vision and light sensitivity.

"Blue vision and light sensitivity are somewhat unusual and mildly worrisome symptoms," explains Michael Marmor, professor of ophthalmology at Stanford University, California, who believes that Europe still has time to ask Pfizer for more safety data. "I don't tell people not to use it. I just think the public should be informed that it does affect the eye directly, that we don't have all of the information that we might have about potential damage, and that this might be a greater risk to people who have underlying eye disease."

But if problems such as retinal damage arise, there's a good chance they won't become public knowledge until after Europeans take the drug. Compared with America's hopeless side-effects monitoring, several European countries have reasonably clever and well-tried systems for tracking deaths and other adverse reactions. In that sense, the Germans, the French and the British will be Viagra's guinea pigs.

Britain's arrangements have been in place since 1964. Using so-called "yellow cards", which are given out to doctors, those patients who complain of adverse reactions can be notified to the Department of Health. In France, meanwhile, Europe's best-regarded system, called Pharmacovigilance, involves 31 regional centres which collect reports and also give advice. Both schemes have flaws, but they pick up problems. Only New Zealand's is thought to be better.

But even such schemes can't tackle another difficulty that doctors told me about: the extent to which Viagra may cause medical problems to be overlooked. A drop-off in erectile function can be a warning about serious underlying conditions. Atherosclerosis, heart disease and diabetes are three examples. Avoidable matters can also cause it: such as smoking, bad nutrition and stress.

Nor can safety watchdogs pick up risks which aren't classified as adverse reactions. There can, for instance, be risks of psychological dependence, or of losing pre-existing physical function. Pharmacology's history is littered with medicines which in time stop working or even worsen the condition for which they are prescribed. And while sildenafil isn't suspected of failing over time, I notice one mildly interesting fact. In Padma-Nathan's second New England Journal of Medicine trial, where men started on 50mg but could vary their dose, only 2% halved it to 25mg, while 74% upped it to 100mg - or twice the standard prescription.

Pfizer is confident, doesn't expect problems and hopes for a long life for its product. The company's exclusive patent rights extend to 2011, during which, some predict, Viagra sales will top $1bn a year. But its window of opportunity may not be quite as wide as such optimistic forecasts suggest. Sildenafil will soon have rivals from other products. And Pfizer's frantic foot soldiers, the Drs Viagra, will shortly roll on, with mass media in tow, to impotence remedies new.

If you recall the Chino slide-show where Padma-Nathan and I began, he had 17 frames full of facts about Viagra, but he also flashed a pair on alternatives. From the Zonagen Corporation comes oral phentolamine, a fast-absorbed version of an old medication which acts at a different stage in the erection process by blocking neurotransmitter action. Next, from TAP Holdings, is sublingual apomorphine, which works on a spot in the centre of the brain thought to be involved with arousal. Both are now with the FDA. The first license is imminent.

The doctor also had a slide with a passing reference to the potential for gene therapies. In New York I heard of one, for which a patent has been sought, entailing local, but infrequent, injections. And then there was a mention for a prostaglandin ointment, which developers hope can be massaged into the penis (without making your hands get bigger, boom, boom).

One of Padma-Nathan's next contracts is to look at a phosphodiesterase inhibitor which is less likely to affect the eyes. It's being developed by the Washington State-based ICOS Corporation, in which Microsoft's chairman Bill Gates is said to be the largest individual investor. "It works for 24 hours instead of Viagra's 3-5 hours, so there would be less need to time the administration," Padma-Nathan tells me, when I call him on the phone from London. "You could even take it once a day."

But before that happens, if happen it will, he has something else on his plate. Padma-Nathan is about to move to a new Santa Monica office which, at 6,000 square feet, is triple the space he has now. And he plans to dump the label "Male Clinic" from the business and take female patients as well. He believes in the need to test Viagra in women and that he is just the man to do it. He is drawn to the name Sexual Medicine Research Institute. He says: "We need to broaden it out, obviously."

Pick up the story by Brian Deer five years later in Sexual Interest Disorder

Copyright, Brian Deer. All rights reserved. No portion of this article on Pfizer's Viagra (sildenafil citrate) may be copied, retransmitted, reposted, duplicated or otherwise used without the express written approval of the author. Responses, information and other feedback are appreciated - via Brian Deer's homepage.