(Laurie Barclay, MD, January 2003)

In both men and women, sexual dysfunction (SD) may result from physical or psychological causes and therefore demands thorough evaluation. Often it is underreported because of reluctance by both patients and physicians to discuss sexual issues. Nonetheless, SD affects between 10% to 52% of men and 25% to 63% of women.

Erectile dysfunction (ED), or inability to obtain and or maintain penile erection sufficient for vaginal penetration and satisfactory intercourse, affects 10 to 30 million men in the U.S., and 75 to 100 million men worldwide. It affects about half of men presenting at sex therapy clinics. Incidence increases with age: at age 65, 62% of all men have some degree of ED, which is mild in 18%, moderate in 30%, and severe in 14%.

Psychological causes of ED include performance anxiety, stress, depression, and marital conflict; while organic causes include vascular disease, diabetes mellitus, hypertension, use of certain medications, multiple sclerosis and other neurologic disorders, alcoholism, heavy smoking, pelvic trauma, and prostate and other pelvic surgery.

Physical devices to treat ED, including vacuum constriction devices and penile implants, are typically cumbersome, embarassing, or uncomfortable. Testosterone and other hormone injections are indicated only in patients with documented low testosterone levels, and are generally ineffective, with occasional serious side effects.

Viagra (sildenafil), from Pfizer Laboratories, is the only oral ED drug approved for marketing in the U.S. It has been prescribed 22 million times for 7 million American patients since its introduction in April of 1998, but patients often fail to renew their prescriptions because it is less effective than they had hoped. Up to one-third of men find no improvement with Viagra. Fears of cardiac adverse events and interaction with nitroglycerin also prevent many from using this drug.

In women, SD includes disorders of libido, arousal, and orgasm, as well as dyspareunia and vaginismus. Chronic medical or gynecological diseases, medication use, and psychosocial difficulties, including prior physical or sexual abuse, may contribute to SD.

For psychosocial causes of female SD, education and counseling may be effective. Hormone replacement therapy may restore levels of estrogen and testosterone affected by age, surgery, or endocrine dysfunction, but is often ineffective, and hormonal interactions often lead to unpredictable outcomes. Viagra is currently being tested in women, and it may restore libido in women using antidepressants.

There is clearly a need for medications that improve libido, sexual performance, and sexual response in both sexes. CenterWatch has identified a pipeline of 31 drugs in various phases of clinical development for SD. These drugs act on different neuroendocrine pathways and are available in a variety of systemic and topical formulations.

Like Viagra, Levitra (vardenafil) and Cialis (tadalafil) are orally administered phosphodiesterase type 5 (PDE5) inhibitors which magnify the natural erectile response to sexual stimulation by relaxing smooth muscle cells in the penile vasculature and increasing penile blood flow. Onset of action is about one hour for Viagra, 30 minutes for Cialis, and 30 to 40 minutes for Levitra. Duration of action is four hours, three days, and 16 hours, respectively.

Bayer has received an FDA approvable letter and expects to launch Levitra in Europe in the first half of 2003. Levitra contains a more efficient PDE5 inhibitor than do Viagra and Cialis, making it more potent. On April 30, 2002, Lilly ICOS received an FDA approvable letter for Cialis, which was approved by the European Commission in November 2002.

In a 26-week phase III trial of Levitra in 805 men with ED, most had a reliable and persistent improvement in erectile function. More than three-quarters of men taking Levitra were able to have intercourse on their first attempt, compared with 45% of those taking placebo. Those men who were successful the first time continued to achieve successful penetration in 91% of subsequent attempts while taking the drug, compared with 77% of those on placebo. A separate phase III clinical trial of 440 men showed that Levitra was equally effective in ED related to prostate surgery.

Side effects were mild to moderate, including headaches, flushing and rhinitis. Unlike Viagra, Levitra was not associated with visual symptoms such as the perception of blue discoloration.

Because of Cialis' long duration of action, the FDA may want Lilly ICOS to conduct additional safety testing, and may be concerned about its potential for recreational use or abuse. In a randomized, placebo-controlled trial in 1,112 men, Cialis was consistently safe and effictive across disease severities and etiologies, as well as in patients of all ages. Headache and dyspepsia were the most frequent adverse events.

Lilly ICOS is also in phase II testing of Cialis for female sexual dysfunction.

An alternative approach to increase penile blood flow is Invicorp, a self-injection formulation of 1 to 2 mg of phentolamine mesylate and vasoactive intestinal peptide (VIP), a 28-amino-acid peptide found naturally in the urogenital tracts of both sexes. VIP causes erection by binding to smooth muscle receptors in the corpus cavernosum, inducing smooth muscle relaxation and increasing blood flow.

Invicorp, manufactured by Senetek, is on partial clinical hold by the FDA but is approved in several European countries. In completed Phase III clinical trials in Europe and Australia, Invicorp was safe and 81% effective overall. The most common side effect was transient facial flushing. Advantages include no known contraindications, onset of erection within two to five minutes, duration of action up to 2 ½ hours after administration, natural termination of an erection after ejaculation, and efficacy in the treatment of organic ED. By using a novel drug delivery system with pre-filled drug delivery cartridges, Invicorp self-injection with the Autoject® Mini is uncomplicated and pain-free.

Late last year, the FDA placed a temporary hold on all clinical trials involving phentolamine mesylate because of carcinogenicity in animal models, although the manufacturer claims this has no relevance in humans.

Also on partial clinical hold as of December, 2001, is Zonagen's product Vasomax, an oral formulation of phentolamine mesylate which blocks alpha receptors. A 1998 study showed that Vasomax was effective in 25% to 40% of men with ED, with onset of action within 20 to 30 minutes.

Vasofem is Zonagen’s corresponding phentolamine product for female SD. Phase II testing was completed in Mexico for this vaginal suppository which improves clitoral and vaginal blood flow, lubrication and sensation.

In October of 2000, Vivus withdrew its NDA application for Alibra in ED, but is now involved in ongoing discussions with the FDA. This combination of alprostadil and prazosin HCl is a urethral microsuppository designed to deliver effective drug levels to erectile tissues while limiting systemic exposure and potential for adverse effects. Alprostadil is a vasodilator which increases penile blood flow, and prazosin is an adrenergic receptor antagonist. In clinical trials involving over 1,000 men at 44 U.S. sites, Alibra has been safe and effective within 5 to 10 minutes of application, with a duration of action of 30 to 60 minutes.

Alprox-TD, in phase III development by NexMed, is a topical preparation containing alprostadil for transdermal delivery. In two randomized, parallel, double-blind, placebo-controlled, Phase II studies in the U.S., up to 83% of 300 subjects reported satisfaction with treatment. Most side effects were transient and only mild to moderate in severity.

A similar product from MacroChem Corporation is Topiglan, a topical gel formulation of 1% alprostadil consisting of prostaglandin E-1. In earlier studies, Topiglan achieved 80% to 90% response rates for achieving erection, or 40% response rates in men with severe ED who only had a 7% response rate to placebo gel. As expected from its first-pass metabolism, systemic effects were minimal, allowing safe use in men with cardiovascular disease. Trials are now on clinical hold because phase III testing showed a positive trend but not statistical significance in the ability to maintain erection to completion of intercourse, which is typically required for approval of an ED drug.

Topical alprostadil may also be useful in female SD because it enhances arousal by increasing genital blood flow. Vivus is in phase II/III testing of Alista, while NexMed is in phase II development of Femprox, which utilizes the NexACT platform drug delivery technology.

While the drugs discussed above work peripherally to stimulate genital blood flow, Uprima (apomorphine HCl) is a dopamine receptor agonist working centrally in the brain and spinal cord to stimulate release of dopamine. This neurotransmitter is involved in pleasure sensations and in the erection response. TAP Pharmaceuticals has submitted an NDA for Uprima, a novel sublingual formulation of apomorphine.

In phase II/III clinical trials in 5,000 men, a Uprima dose of 2-3 mg offered the most favorable risk/benefit ratio. The proportion of attempts resulting in erections firm enough for intercourse was 49.4% with 3 mg, compared with the baseline value of 24.3%. Of Uprima responders, 34% had erections within 10 minutes, and 71% within 20 minutes. Adverse reactions included headache in 7%, nausea in 7%, dizziness in 4%, and vasovagal syncope in less than 0.2%. Despite its central mechanism of action, Uprima does not appear to affect sexual desire.

Nastech Pharmaceutical is in phase II development of an intranasal spray formulation of apomorphine which is being tested in female SD.

An alternative approach to female SD is transdermal testosterone, including a patch in phase III development by Watson Pharmaceuticals; Tostrelle gel in phase II/III testing by Cellegy Pharmaceuticals; and LibiGel, in phase II development by BioSante Pharmaceuticals.

Composite scores of female sexual function may not change significantly with testosterone, although subscales for sexual pleasure and orgasm show selective improvement. Transdermal testosterone delivery does not appear to alter estrogen levels, interfere with hormone replacement therapy, increase acne or hirsutism, or change blood lipid levels. However, many physicians are concerned about the lack of safety data concerning breast cancer, heart disease, and hepatocellular damage or carcinoma.

These concerns are magnified with orally administered hormones such as Estratest, an estrogen/methyltestosterone formulation for which Solvay Pharmaceuticals has completed phase II testing.

Development of new drugs for SD has had its ups and downs. Furthest along the pipeline are PDE5 inhibitors similar to Viagra, which may be partially limited by unwanted cardiovascular and other systemic effects. The use of phentolamine in many topical preparations has hindered their approval due to safety concerns. Hormonal manipulation or use of central agonists such as apomorphine are alternative approaches which offer promise, as of yet unfulfilled. In an area such as SD where the placebo effect is considerable, demonstration of efficacy is another obstacle to approval of many drugs in the SD pipeline.