The worldwide prevalence of ED has been estimated at over 152 million males with projections for 2025 being in excess of 320 million. In older males, ED may have a physical cause, such as disease, injury, drug side effects, injury to nerves, arteries, smooth muscles, and fibrous tissues, or impaired blood flow in the penis. Other common causes of organic ED include the metabolic syndrome, diabetes, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, vascular disease, and neurologically related causes.9 The incidence of ED increases with age with approximately 5% of 40-year-old males and 15-25% of 65-year-old males experiencing aspects of ED. Surgery, including radical prostatectomy and bladder cancer surgery, can injure nerves and arteries near the penis, causing ED. Antihypertensives, antihistamines, antidepressants, and hypnotics can produce ED as a side effect. Psychological factors including stress, anxiety, guilt, depression, low self-esteem, and fear of sexual underperformance failure can contribute to 10-20% of ED cases. Quality of life assessments suggest that ED can significantly contribute to the incidence of depression.
Penile erection is a spinal reflex under CNS (supraspinal) inhibitory control. Visual, tactile, olfactory, and imaginative stimuli from the higher cortical areas of the brain are integrated in the medial preoptical area of the hypothalamus via dopaminergic and oxytocinergic neuronal systems. These elicit the release of NO from 'nitrergic neurons' in the corpus cavernosum of the penis that then activates soluble guanylyl cyclase (sGC) in smooth muscle producing vasodilation and venoocclusion with engorging of the penis resulting in rigidity and erection.
Drug targets for the treatment of ED are present in both the brain and periphery. CNS targets include dopamine (DA) and melanocortin (MCH) while peripheral targets are focused on drugs that enhance smooth muscle vasodilation or block the adrenergic or endothelin (ET)-mediated vasoconstriction associated with penile flaccidity.
188.8.131.52.1 Centrally acting treatments for erectile dysfunction
Injection of DA D2 agonists into the rat medial preoptic area of the hypothalamus can induce penile erections. Apomorphine (17), a centrally acting agent, is a nonselective DA D2 agonist approved for use in Europe and Japan for the treatment of ED. The lack of DA receptor selectivity is associated with an emetic response, which to some patients has represented an unacceptable side effect, to others, a reinforcing stimulus. The DA D4 receptor was recently identified as being responsible for the erectile actions of apomorphine leading to the discovery and characterization of the selective DA D4 agonist, ABT-724 (18).10 a-MSH (a-melanocyte-stimulating hormone) and oxytocin in the CNS increase penile erection via supraspinal a-MSH and supraspinal and spinal oxytocin receptors. An a-MSH agonist, PT-141, which produces its actions via melanocortin receptors, is in clinical trials being dosed via the intranasal route.11 THIQ is a small-molecule, nonpeptide melanocortin MC-4 receptor agonist that elicits penile erection.
184.108.40.206.2 Peripherally acting treatments for erectile dysfunction
Sildenafil was the first PDE5 inhibitor found to be effective in promoting spontaneous penile erections. While the mechanistic basis for this effect has become obvious in retrospect, it was initially noted as a frequent side effect of an NCE that originally entered the clinic for the treatment of congestive heart failure. Thus the utility of sildenafil for the treatment of ED was discovered by serendipity.12 PDE5 inhibitors block the hydrolysis of the cGMP produced by sGC in response to NO, prolonging cGMP levels in corpus cavernosum smooth muscle. Sildenafil blocks sGC with an IC50 value of 5.3 nM. The second-generation PDE5 inhibitors tadalafil (16) and vardenafil (15) are also potent PDE5 inhibitors (IC50 = 3.6 and 0.4 nM, respectively) but have different pharmacokinetic profiles and/or selectivity profiles for other members of the PDE enzyme family.13 Allsosteric activators of sGC like A-350619 (19) and BAY 41-2272 (20) can elicit penile erection in animals synergistically enhancing the effects of NO by stimulating cGMP synthesis without altering degradation of the cyclic nucleotide.
Prostaglandin E1 (PGE1) is also used to treat ED, acting via specific PGE receptors EP2 and EP4 on smooth muscle to increase intracellular cAMP synthesis and potentiate smooth muscle relaxation. PGE1 is an useful treatment for ED despite its delivery via penile injection and intraurethral routes. Injecting drugs like alprostadil into the penis can lead to stronger erections by engorging the penis with blood, but can lead to priapism. Blockade of endogenous vasoconstrictor-induced tone in corpus cavernosum smooth muscle can also induce penile erection. However, the nonselective a-adrenoceptor antagonist phentolamine showed only modest efficacy in mild to moderate ED. Endothelin (ET) antagonists were also considered to be a useful treatment option for ED based on the potent contractile activity of ETs in vitro in the penis. However, an ETA-selective receptor antagonist, BMS-193884 (21), that was effective on rabbit and human corpus cavernosa, failed to show efficacy in the clinic.
220.127.116.11 Female Sexual Dysfunction
Female sexual dysfunction (FSD) is a complex and controversial disorder that includes components of desire and arousal and orgasmic and sex pain disorders (dyspareunia and vaginismus).14'15 FSD consists of four recognized disorders: hypoactive sexual desire disorder (HSDD) associated with decreased arousal and sexual aversion; female sexual desire disorder (FSAD) associated with decreased arousal; orgasmic disorder, a difficulty or inability to achieve orgasm; and sexual pain disorder. HSDD can be treated with a transdermal testosterone patch, although a Food and Drug Administration (FDA) advisory panel declined to recommend approval for the Intrinsa transdermal testosterone in 2005 due to concerns with long-term safety and clinical trial endpoint issues.16 While there is a major psychological component in decreased sexual desire, as discussed above, the success of the PDE5 inhibitors in promoting erections in males has led to a hypothesis that FSAD is caused by a decreased blood flow to pelvic tissues and a decrease in muscle relaxation in the tissues that comprise the vaginal tube and clitoris. This hypothesis is based on the concept that the clitoris, given a common embryological origin, is similar to the penis. Thus as ED can be associated with decreased penile blood flow, female sexual dysfunction can be considered to have a similar causality. Decreased blood flow results in a decrease in vaginal lubrication with the vaginal tube fails to dilate adequately in preparation for penetration, resulting in painful intercourse, diminished vaginal sensation, and an inability to achieve an orgasm. While there has been considerable interest in the use of PDE5 inhibitors to treat female sexual dysfunction, this has been challenging, as there is a major challenge in measuring subtle changes in vaginal lubrication and penile rigidity. Blood flow to the sexual organs can however be measured. A noninvasive Doppler ultrasound probe can be used to measure blood flow in the penis, vagina, and clitoris. Vaginal photoplethysmography can also be used to measure changes in vaginal blood flow. Sildenafil has however, shown efficacy in FSAD trials.
The discovery of sildenafil and related PDE5 inhibitors has driven public awareness of sexual dysfunction as a drug-treatable disorder in both males and females and also introduced a richer than usual vocabulary into the staid halls of science, e.g., 'stuffers,' males who take ED medication, fail to achieve an erection but enthusiastically engage in attempting penetration nonetheless. However, after an initial explosion in sales, broad nonprescription use by recreational users, and extensive direct-to-consumer advertising, the ED drug market has failed to achieve projections. One reason for this has been a side effect profile involving 'blue vision' due to inhibition of PDE activity in the eye, another with 500 deaths being attributed to the use of sildenafil12 and yet another the confounding issue of the psychology of sexual performance where 'mood' and fear of failure can color outcomes. In many instances in the clinical trial setting, NCEs have been ineffective when used in a monogamous relationship but extremely effective when a new partner was part of the relationship, reflecting the psychological novelty of the latter as an important component. Similarly, placebo is highly effective in that situation. In other instances, none of the treatment options for ED were effective due to insurmountable psychological or organic dysfunction, while in other situations a single use of an ED drug restored 'normal' sexual performance, acting as the catalyst for addressing sexual problems within a relationship. Once whatever hurdles have been overcome, 'little blue pills' become unnecessary.
Premature ejaculation (PE) affects 21-33% of males aged 18-19.16 It is defined in DSM-IV-TR as 'the persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation, before, on, or shortly after penetration and before the person wishes it.'17 Mechanistically, the ejaculatory response represents a complex interaction between serotonergic and dopaminergic neuronal sytems with additional influences from cholinergic, oxytocinergic, adrenergic, and GABAergic systems. DA, acting via D2 receptors promotes ejaculation while 5HT inhibits ejaculation. The selective serotonin reuptake inhibitor (SSRI) antidepressants, e.g., fluoxetine, have been used for the treatment of PE and this is one of their side effects as a drug class. PDE5 inhibitors and local anesthetic formulations, e.g., NM-100061 and PSD-502, have also been used to treat PE. Dapoxetine is a newer SSRI developed for the treatment of PE as an on-demand oral agent. The pharmacokinetic profile of dapoxetine differs from that of other SSRIs in that peak levels are reached within 1h with an initial half-life of 14h. Other NCEs being evaluated for use in the treatment of PE include: UK 390957, a short-acting SSRI, VI-0162, a 5HT3 receptor antagonist, and LI-301, an SSRI/m opioid agonist combination.16 A major issue involved in finding novel drugs for the treatment of human sexual dysfunction disorders is the benefit-to-risk ratio for drug therapy in what is considered both a non-life-threatening and lifestyle disorder.
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