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Biological Chemistry

Viagra

Purpose Vasodilator

by Rick Mullin
June 20, 2005 | A version of this story appeared in Volume 83, Issue 25

WORKING BLUE
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Credit: PFIZER PHOTO
Nascar's Mark Martin is a celebrity front man for Viagra.
Credit: PFIZER PHOTO
Nascar's Mark Martin is a celebrity front man for Viagra.

Researchers in Ian Osterloh's lab at Pfizer stopped work on developing sildenafil citrate as a therapy for chest pain in men in 1992 following unpromising results in a Phase I angina study. They noticed, however, that some of the men taking 50- and 75-mg doses in the trial reported an increased tendency to get erections, suggesting a surprise "act two" for sildenafil. "Gradually, a consensus grew that research should shift from angina to the drug's erectile angle, and the rest is, as they say, history," says Daniel J. Watts, a spokesman for Pfizer.

Viagra was approved by the Food & Drug Administration in 1998 as a therapy for erectile dysfunction (ED), a term for impotence that surfaced in the 1990s. The drug rose swiftly to blockbuster status, achieving sales of $1 billion in its first full year on the market.

Physically, Viagra works by inhibiting an enzyme called phosphodiesterase type 5 (PDE5), which normally cleaves cyclic guanosine monophosphate (cGMP), a compound that promotes smooth-muscle relaxation in the corpus cavernosum, thus enhancing blood flow. This enhances the effect of nitric oxide, a chemical released in response to sexual stimulation. Nitric oxide activates guanylate cyclase, an enzyme that boosts levels of cGMP. Cialis, marketed jointly by Eli Lilly & Co. and Icos, and Bayer Pharmaceutical's Levitra are also PDE5 inhibitors.

The likelihood that PDE5 inhibitors could be applied to the treatment of ED had been noted by Peter Ellis and Nick Terrett, researchers in Pfizer's Discovery Biology Laboratory, Sandwich, England. Both are named in the patent for Viagra.

The drug's psychological mechanism is far more nebulous and is still being studied. Abraham Morgentaler, in his book "The Viagra Myth: The Surprising Impact on Love and Relationships," focuses on the drug's effect on relationships. "In particular, it forces couples to decide what is real in their relationships and what is not," he writes. "I have come to see Viagra as providing a window into the psyche of men, and perhaps indirectly into the psyche of women, since women are not immune from unduly high expectations regarding the benefits of Viagra and its potential to provide sexual healing."

As it turns out, drugmakers' expectations from Viagra may also be unduly high. Sales figures last year provide some indication that the drug-induced sexual revolution is sputtering. Sales for all impotence drugs reached $2.7 billion in 2004, at least $1 billion lower than industry analysts forecast two years ago. Viagra's sales slipped 11% last year from the 2003 sales figures. This can partly be blamed on competition from Cialis and Levitra.

There are other pressures, such as the fact that most health insurers do not cover prescriptions for ED medication. It won't help that federal officials recently began looking into reports that Viagra and other impotence drugs are linked to 43 cases of blindness. And some analysts claim that many men are too embarrassed to seek treatment.

Whatever embarrassment exists might be dissipating, according to Ira D. Sharlip, a urologist and spokesman for the American Urology Association. Sharlip says Viagra has promoted a liberalization in attitudes toward sexuality, and that patients are likely to be more forthcoming regarding ED or other problems now that they know there is a pill that they can take. He suggests that patients, to a large extent, will themselves determine whether they need to take the drug. "Patients are looking for a drug that will improve sexual performance," Sharlip says. "If you are looking to improve your performance, then you have a problem with your performance."

Sharlip says Viagra has been a key catalyst for the formation of a formal area of medical practice called sexual medicine. He says other drugs targeting male performance, including a Johnson & Johnson therapy for premature ejaculation, are in the pipeline, and that the field of female sexual performance is garnering a lot of attention.

The drug has also had an impact in diagnosing other health problems in men. Sharlip says, for example, that an increasing body of literature suggests that ED may be a marker for cardiac disease such as arterial sclerosis. Recently, in fact, FDA approved sildenafil citrate as a therapy for pulmonary hypertension. Viagra has also had the effect of bringing patients into urologists' offices, which is important given the reticence of men to be checked for prostate cancer, according to Sharlip and other physicians.

This would please former Sen. Bob Dole, who, like Nascar's Mark Martin, is a celebrity pitchman for Viagra. Explaining on his website why he added Viagra to the other products he has promoted--such as Pepsi and Dunkin' Donuts--Dole points to his advocacy of early screening, prevention, and treatment of prostate cancer.

Viagra has, in fact, made history. It pioneered a new category of drugs that now includes Cialis, marketed jointly by Eli Lilly & Co. and Icos, and Bayer Pharmaceuticals Levitra. Intended for patients who have trouble achieving and sustaining erections, these drugs are also at the vanguard of lifestyle drugs, a fast-growing category of pharmaceuticals that are often taken to enhance appearance, physical and sexual performance, or mood.

More important, Viagra has opened a window on the complexity of human sexuality and relationships, sparking what some have called a second drug-induced sexual revolution, following the wave of change brought on by birth control pills in the 1960s.

The societal impact of Viagra can be measured in many ways. One might, for instance, compare the number of unsolicited Viagra e-mails he or she receives to the number of e-mails illegally hawking any other drug. Or compare the number of Viagra jokes Jay Leno tells to the number of jokes he tells about other drugs, including Vioxx and Prozac. Go to the Nascar track and see how many racers are, like Mark Martin, sponsored by a pill.

A drug designed to enhance male sexual performance—and self-esteem—is bound to be big. The market for patients it supposedly targets, older men beset with the diagnosis of ED, is estimated at about 189 million worldwide. The market of men—and women—who are simply interested in enhanced sexual experience by taking a pill is much larger.

This aspect was not lost on Pfizer. The company last year ran a television advertisement known for its opening line of voice-over, Remember that guy who used to be called Wild Thing? The ad— in which a middle-aged man, watching his wife window-shopping for stiletto heels, sprouts horns the blue color of Viagra pills—makes no mention of ED. Instead, it promotes the drug as an almost purely recreational means of returning to a previous level of sexual desire and activity.

FDA, in a letter to Pfizer, noted that there is no substantial clinical evidence that the drug provides a return to previous levels of sexual desire and performance. FDA also complained that the ad left out the required catalog of side effects and contraindications—including possible exacerbation of heart problems—and the advice to seek medical help in case an erection lasts more than four hours.But Pfizer, which complied with FDAs request that it pull Wild Thing, had put its finger on the real significance of its drug with an ad appealing to male libido and the centrality of sex to self-image.

Abraham Morgentaler in his book The Viagra Myth: The Surprising Impact on Love and Relationships writes that Viagra has a significant psychological as well as an erectile angle. Morgentaler, a professor at Harvard Medical School and director of Mens Health Boston, documents the extent to which men and women have turned to Viagra as a quick and easy fix to a range of personal problems related to relationships and self-esteem, which are heavily affected by sexuality. Morgentaler says Viagra has added a significant new dimension to his urology practice. With expertise on the anatomy of the penis, of all things, he writes, I came full circle to the intricacies of the mind.


Sildenafil Citrate


Name: 1-{[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazine citrate


CAS Registry: 171599-83-0


Other names: Viagra


Sales: $1.87 billion in 2004


Did you know that Viagra inhibits the enzyme that breaks down cyclic GMP, and that it keeps flowers erect and alive for up to seven days beyond their normal life span?


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