The growing sexual dysfunction market

April 1, 1999
Pharmaceutical Representative

With the incredible media coverage and potentially huge market for impotence drugs, more and more research is now being conducted in this area. Center Watch found 19 drugs presently in clinical testing.

The launch of Viagra in late 1997 has expanded the market for sexual dysfunction treatments. An estimated 48 million men between the ages of 40 and 70 in the United States, Canada and Europe could suffer from male erectile dysfunction, according to the Massachusetts male aging study published in 1994. With the incredible media coverage and this potentially huge market for impotence drugs, more and more research is now being conducted in this area. Center Watch found 19 drugs presently in clinical testing.

Male erectile dysfunction can be defined as the inability to attain an erection with sufficient rigidity for vaginal penetration. According to the Merck manual, it can be classified as either primary or secondary impotence. Primary impotence is rare while secondary impotence occurs when male erectile dysfunction prohibits successful sexual intercourse in about 25% of the attempts made. About 80% of secondary impotence cases can be attributed to mental and emotional factors.

In order to understand the treatments for this problem, it is important to recognize the pathway of an erection. An erection is the result of a complex process in which the brain sends it arousal signals to the penile nerves. These nerve impulses go to the corpora cavernosa, or the two erection chambers of the penis. Here, the impulses cause relaxation of the penis and the expansion of arterial blood vessels. The blood can then flow into the erectile chambers, causing the penis to become erect. The maintenance of the erection occurs when the blood is trapped against the wall of the tunica albugenia, or the dense, elastic envelope which covers the corpora cavernosa.

Many men are interested in learning about the cause of impotence and how it is diagnosed. Researchers have found various factors that may cause the condition. There could be cardiovascular issues in which the penis cannot receive the proper amount of blood or cannot maintain the blood supply. Certain medical conditions such as diabetes, injuries to the spinal column and hardening of the arteries to the pelvic organs also lead to male erectile dysfunction. Other risk factors are smoking, excessive alcohol consumption and obesity, which are quite manageable. Often, if a man stops smoking and drinking or learns to control his weight, he can continue to lead a healthy sex life.

Changing a patient's lifestyle does not always help. If the patient's erection is painful or severely bent, then it is possible he may have Peyronie's disease, a condition caused by scar tissue in the penis. Several lab tests may be required, such as determining the levels of testosterone or using high frequency sound waves to check the condition of the penile arteries. Many times, the patient's nocturnal penile tumescence and rigidity will be checked. Here, a patient attaches a pair of spherical gauges to his penis before sleeping to measure the number of erections that occur throughout the night. If the patient is not experiencing erections, the doctor will diagnose that the erectile dysfunction is probably a physical one.

Female sexual dysfunction

Although it is not as widely researched, females also experience sexual dysfunction. Unlike the explainable physical pathway of the erection in males, the mechanism of female excitement is not so completely documented. Female excitement is also prompted by an arousal signal that should produce adequate vaginal lubrication and clitoral swelling, leading to orgasm. Female sexual arousal disorder is often accompanied by decreased sexual desire and inhibited orgasm.

The causes of female sexual arousal disorder are not so clearly defined as the causes of male erectile dysfunction. It is known that [it] may result from a lack of vaginal lubrication, and using a water-based lubricant is often the recommended treatment. Other problems arise when the vagina is too snug for intercourse or when the uterus is improperly raised, causing the penis to press the cervix during penetration. Once again, a lubricant is suggested, or a doctor might be able to explain more comfortable positions for the couple to lessen the pain.

There also may be physical conditions, such as vaginismus, when vaginal muscles are extremely tight due to nervousness or anxiety. In this case, the woman is taught certain mental and physical practices to relax her vaginal muscles. A woman might also experience female sexual arousal disorder as a result of conditions such as yeast infections, herpes or sexually transmitted diseases which lead to inflammation of the vagina. A doctor must prescribe medication to alleviate symptoms of these diseases before intercourse is attempted.

Alternatives

Before Pfizer launched Viagra (sildenafil), men had few oral treatments to relieve their impotence. One substance, yohimbine hydrochloride, is derived from an African tree bark, pausinystalia johimbe. This treatment is believed to increase the the parasympathetic tone while decreasing the sympathetic tone in the central nervous system, therefore producing an increase in the blood flow to the penis. Since this is a central nervous system stimulant, it could lead to side effects such as dizziness, nervousness and anxiety. NitroMed is currently in phase I with its oral drug NMI-861. This compound attempts to relieve male erectile dysfunction and female sexual dysfunction by combining yohimbine with a nitric oxide-donor using NitroMed proprietary technology.

Another form of therapy is intracorporal pharmacological injection therapy. Here, a man injects himself 15 minutes prior to erection with a thin needle into the shaft of his penis. Pharmacia & Upjohn received regulatory clearance in July of 1998 to market Caverject (alprostadil), a prostaglandin that causes the smooth muscles to relax. When the smooth muscles relax, blood can flow into the penis, resulting in an erection. The most common side effect of Caverject is penile pain, occurring in about 50% of the men using it. MacroChemical Corp. is currently in phase IIB in testing a topical form of alprostadil.

Other forms of treatment include vacuum constriction devices and surgical prosthetic devices. The vacuum constriction device works through the use of a tube placed over the penis. A vacuum is then created, which draws the blood into the penis, causing an erection. A rubber constriction ring is placed at the base of the penis to maintain the erection. The most invasive treatment is the implantation of a penile prosthetic device. The device is actually inserted into the penis itself and frequently provides a permanent solution to the problem of impotence.

Viagra vs. Vasomax

Pfizer was the first to get its male erectile dysfunction drug approved in March of 1997, and it stunned the industry with Viagra's success. Another drug, Zonagen's Vasomax (phentolamine), was racing with Viagra for FDA approval. These two drugs supposedly produce the same result - an erection - but it is important to highlight the differences between the two. The mechanistic pathway for Viagra is based on the fact that penile erection is mediated by nitric oxide via cyclic guanosine monophosphate. Viagra works as a selective inhibitor of type 5 phosphodiesterase, the major isozyme responsible for the inactivation of cGMP in the corpus cavernosa. By elevating the levels of cGMP in the penis, Viagra helps produce an erection.

Viagra needs to be administered orally one hour before anticipated sexual activity. Its most common side effects include headache, vasodilatation, dyspepsia and diarrhea. However, a far more serious effect has been reported since the drug's introduction. The Viagra package insert warns that patients using nitroglycerin or other nitrate drugs should not take Viagra. Mixing these drugs could cause a sudden, possibly lethal, drop in blood pressure. The solution seems simple - these men should heed the warnings and not take the drug. Unfortunately, there is a high correlation between male erectile dysfunction and men with hypertension. In less than two and a half months, The FDA reported that at least 69 Americans taking Viagra died, with 46 cases linked to cardiovascular occurrences.

Zonagen claims that Vasomax does not interact with nitrate drugs. Vasomax was originally used as an injectable treatment for hypertension and to diagnose tumors of the adrenal gland. The patients reported they were surprised when the drug also caused involuntary erections. In April 1994, Zonagen purchased the rights to a pending patent application for the use of this drug orally.

In November of 1997, Zonagen and Schering-Plough signed a worldwide agreement (with Zonagen earning a $5 million payment) to comarket Vasomax once it is approved. Zonagen submitted an NDA to the FDA in July 1998 and is currently waiting approval.

Other drugs in development

Pfizer and Zonagen are not the only companies researching impotence. ICOS and Eli Lilly recently completed phase II trials in the United States and Europe for the drug, IC351. This drug works like Viagra by inhibiting PDE5.

Takeda Chemicals Industries is in phase III testing for its drug aphomorphine HCl, a mixture of morphine and hydrochloride acid, which stimulates the receptors linked to sexual arousal and helps males with psychological male erectile dysfunction. It is already used in Australia to treat Parkinson's disease. It is dissolved under the tongue, therefore giving a quicker response time - reportedly about 15 minutes.

As for drugs being tested to aid female sexual arousal disorder, doctors are realizing that Viagra may potentially treat women experiencing similar blood flow problems as men. Doctors at Johns Hopkins and other major medical centers are currently observing Viagra on women. Zonagen is also testing its female version of Vasomax, or Vasofem, currently in phase I trials. PR