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| New Treatments for Erectile Dysfunction Promise More Sustained Effects, More Options for Patients |
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Clinical Newswire May 26 2002 − When it was introduced in 1998, sildenafil (Viagra) offered the first effective oral therapy to patients with erectile dysfunction (ED) whose previous options included direct injection into the penis, surgery and vacuum devices.
It has been estimated that approximately 50% of men aged 40 to 70 years may suffer from some degree of ED. In part thanks to increasing awareness of this condition since the introduction of Viagra, ED is now understood to originate more from organic than psychological causes. For example, the incidence of ED increases with age, and is higher in men with diabetes, hypertension and hyperlipidemia.
Viagra inhibits the enzyme phosphodiesterase-5 (PDE-5), thereby elevating cyclic GMP levels which activates penile blood flow, allowing a man to obtain an erection in response to sexual stimulation.
New data presented at the 100th American Urological Association Annual Scientific Meeting in Orlando, Florida on May 26, 2002, may heighten expectations among men with ED that they will soon have further options that may include more sustained effects.
The results of phase III clinical trials for two new oral PDE-5 inhibitors were presented at the AUA meeting.
In one German study of 348 men with mild to severe ED, tadalafil (Cialis) led to a significant improvement in successful intercourse attempts up to 36 hours after taking a single dose of 20mg, over placebo. The percentage of successful intercourse attempts was 57% at 24 hours and 60% at 30 hours post dose, compared to 31% and 30% with placebo, respectively (both p<0.001).
In addition secondary measures of efficacy − penetration ability, hardness of erection, and overall satisfaction − were significantly better with tadalafil at 24 and 36 hours.
Tadalafil has a 4-fold longer half life of approximately 12 hours compared to sildenafil (4-5 hours), and a shorter onset of action of about 15 minutes.
“We are very pleased to see that tadalafil allowed a majority of men in this trial to achieve normal sexual functioning at up to 36 hours after taking the drug,” said Dr. Harmut Porst, Hamburg, Germany, who presented the data at the AUA meeting. “The extended duration of responsiveness may help eliminate the need for planning sexual intimacy,” he said. “This could be a major advantage in the treatment of ED.”
Side effects were mostly mild to moderate in intensity, with few patients discontinuing treatment, and included headache, and dyspepsia (<5% incidence).
“The duration of efficacy did not appear to influence the incidence or severity of side effects,” said Dr. Raymond Rosen, another author of the study, from the University of Medicine and Dentistry, Piscataway, NJ.
Another new PDE-5 inhibitor, vardenafil, has been shown to be effective in men with severe erectile dysfunction, and with co-existing morbidities such as hypertension and diabetes.
A retrospective analysis of pooled data from two randomized phase III studies reported at the AUA meeting by Dr Craig Donatucci, Duke University Medical Center, Durham, NC, included a total of 1357 men, over two-thirds of whom had moderate-to-severe ED by the International Index of Erectile Function. Patients, who were in the US and Europe, were randomized to placebo or vardenafil 5mg, 10mg or 20mg, and were classified according to etiology of ED; organic, psychogenic or mixed.
Vardenafil significantly improved erectile function, regardless of etiology or severity of ED. The response to treatment was significant at all doses tested, and even in patients with severe ED.
The most common side effects were headache, rhinitis and dyspepsia, which were all dose-related and were mostly mild to moderate in intensity.
Vardenafil a new PDE-5 inhibitor, does appear to be both safe and effective in men with organic ED,” said Dr. Donatucci. “Vardenafil could be yet another option to effectively treat this condition.”
Referring to these three different PDE-5 inhibitors, Dr. Horst said that each patient may have different reactions to the different drugs, for example more headache with one inhibitor than another, and therefore may be able to choose the drug that is most appropriate for them.
In addition, two promising novel approaches to treatment of ED were also presented at AUA. An inhibitor of the enzyme Rho-kinase, which modulates contraction of smooth muscle in the penis, was shown to give spontaneous hypertensive rats (SHR) rats significantly better erectile responses. The experimental drug Y-27632 gave a 48-104% increase in erectile response in these animals that normally have marked erectile impairment.
Dr. Mahadevan Rajasekaran, PhD, San Diego, CA, said that these results are important because they show a new pathway for treating ED due to vascular causes such as hypertension.
It may even be possible to eventually get gene therapy for age-related ED. In a rat model, a single injection of naked human maxi-K gene in penile smooth muscle gave a sustained and significant reversal of age-related erectile dysfunction. The treatment effect was also related to dose of DNA given. The Maxi-K gene encodes a membrane-bound potassium channel, which are required for initiation and maintenance of smooth muscle contraction.
As ED becomes increasingly recognized to be mostly due to biological causes, there is a slow increase in awareness that female sexual dysfunction (FSD) may also largely be due to organic reasons.
One study at the AUA meeting showed that women with sexual dysfunction have significantly decreased levels of testosterone and all adrenal androgen precursors compared to women with normal sexual function. Another randomized multi-center study of 78 women with FSD, aged 40 to 70, compared topical alprostadil solution, a local vasodilator, to placebo. All women who received topical alprostadil to the clitoris and vulva had increased localized blood flow to the vulva and increased genital lubrication − both signs of a positive sexual response.
“Female sexual dysfunction is very common, occurring in 20 to 50% of the general population,” said study author Marc Gittelman, Miami, FL. “To date, there are no FDA-approved pharmacological treatments for this disorder, but topical alprostadil may be an appropriate on-demand treatment for women suffering from FSD.”
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