The use of drugs for the treatment of impotence and other sexual disorders is very old. Yohimbine has been used in folk medicine by men and women for various forms of sexual dysfunction, mainly as an aphrodisiac for over a century. In the United States, yohimbine hy-drochloride has been marketed and prescribed by doctors for more than 75 years (154). Be cause the mainstream medical use of yohimbine pre-dated the Food and Drug Act, the drug did not go through the formal FDA review and approval process, and hence, there are no well-controlledclinical trials with a sufficient number of patients to allow for conclusive results on its efficacy and long-term safety. The lack of conclusive clinical data and the daily dosing schedule that has been practiced for decades, rather than a more convenient on-demand use, are the main reasons for the low level of interest in yohimbine by medical practitioners. Needless to say, pharmaceutical companies lack the interest in conducting expensive large-scale clinical trials of yohimbine, because the ancient drug is non-patentable.
Because of the absence of clinically proven safe and effective pharmacotherapy for erectile dysfunction, psychotherapy was until recently the core treatment for most patients, except for a few cases where a surgically correctable cause could be identified. The results of psychotherapy have been disappointing and often times, the goal of psychotherapy was to help men accept their sexual dysfunction rather than to correct it. The widespread belief that erection failure is primarily of psychological origin, and hence the acceptance of psychotherapy as the primary treatment, continued until the early 1980s.
In 1982, a new era for erectile dysfunction started when Virag (156) showed that penile injection of a vasoactive amine — papaverine (9)-could result in erection without sexual
stimulation. In 1983, Brindley (157) reported the clinical efficacy of cavernosal a-blockade in the treatment of erectile dysfunction. As a re-
sult of the extensive research on the mechanism of erection that followed Virag's and Brindley's pioneer work, it was established that underlying organic causes are responsible for approximately 80% of persistent erectile dysfunction cases (142). This resulted in changing the primary treatment from psychotherapy to pharmacotherapy and stimulated further research in this area. Intracavernosal injections of papaverine and phentolamine (10) became a common treatment for erectile
dysfunction in addition to vacuum/constriction devices. As a result of the growing interest and increased understanding of the condition, the U.S. National Institute of Health (NIH) advocated the use of the term erectile dysfunction (ED) rather than impotence in 1992 (158).
The first pharmacological agent for ED to be approved by the FDA was intracavernosal alprostadil. It was approved in June 1995 for the treatment of erectile dysfunction caused by neurogenic, vasculogenic, psychogenic, or mixed etiology. Despite its clinical efficacy, the high cost, and more importantly, fear of self injection limited the use of intracavernosal therapy. The search for a less invasive therapy led to the development of a novel transure-dosage form of alprostadil, which gained FDA approval in 1997. This was still far from the ideal therapy. The main disadvantages of alprostadil therapy are loss of spontaneity, because erection occurs even without sexual stimulation, and rapid onset of action, which does not allow for discreet administration and also contributes to the loss of spontaneity.
In 1985, the story of sildenafil discovery (159) started when two chemists at Pfizer's site in Kent, U.K. proposed to look for antihy-pertensive and antianginal compounds that would work by inhibiting phosphodiesterase (PDE) and thus promoting the vasodilator action of cGMP. The project started with the usual literature review to identify a chemical starting point. Zaprinast (11), a compound
that was developed as an antiallergic by May and Baker (later part of Rhone-Poulenc Rorer, which is now part of Aventis), was selected. Zaprinast, which was never commercialized, was not selective enough to PDE; however, it provided a satisfactory starting point for the Pfizer team. In their effort to modify the Zap-rinast structure to make it more selective and more potent, Pfizer chemists explored other ring systems and varied the side-chain substitutions. A total of about 1600 compounds were synthesized. In 1989, sildenafil (UK 92480) was identified as a promising candidate based on its in vitro selectivity to PDE and its potency (159).Sildenafil had a more than 500fold affinity to PDE than the starting compound (149). Phase I clinical trials of sildenafil started in 1991. In 1992, the results of a limited phase II clinical study in patients with severe coronary heart disease were disappointing, but at the same time, the first report of sildenafil's effect on erectile function came from a parallel high dose phase I study. The "side effect" of erection caught the team's interest; however, the decision to change the direction of the sildenafil development program from cardiovascular to erectile dysfunction came only after long deliberations (159). The discovery of nitric oxide and the understanding of its role as a signaling molecule in the early 1990s helped Pfizer's researchers to understand the mechanism of sildenafil's effect on erection and therefore helped in making that decision. The first phase II clinical trial for erectile dysfunction started in 1994 and included 12 men with ED. Ten of 12 patients showed improvement. The next trial, which took place in 1994 and 1995, was an outpatient trial. This was followed by a large open-label multi-center clinical trial in which 225 patients were assessed for over 32 weeks. Eighty-eight percent of patients reported improvement, and over 90% expressed interest in continuing the treatment. In total, the drug was tested in about 4000 men, ages 19-87, who suffered from erectile dysfunction of organic, psychogenic, or mixed origin, or with no identified etiology (117). In all of the studies, sildenafil exhibited superior efficacy over placebo. The NDA was submitted to the FDA in September 1997, and sildenafil was approved in March 1998 after a fast track review.
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