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In the Works: Pharmacological Treatment for Premature Ejaculation

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In the Works: Pharmacological Treatment for Premature Ejaculation SEXUAL FUNCTION 20 In the works: pharmacological treatment for premature ejaculation MICHAEL G. WYLLIE The ideal treatment for premature to be having sex on a daily basis (indeed, it ejaculation – the most common male sexual may be a relatively infrequent event), the ideal treatment for PE has often been dysfunction – would be an approved, described as one that can be taken or discreet and on-demand therapy that is administered ‘on-demand’. It is interesting, effective from the first dose and has no however, to note that surveys of the prescribing patterns of urologists indicate side-effects. The author takes a look at that similar proportions of urologists are what is available. prescribing on-demand dosing as daily dosing.2 remature ejaculation (PE) has been AETIOLOGY OF PE AND DRUG TARGETS Pdefined by the wise men and women of In contrast to ED, no organic disease the International Society for Sexual has been firmly associated with PE, Medicine (ISSM) as ‘a male sexual except perhaps some evidence that dysfunction characterised by ejaculation prostatitis, hyperthyroidism and penile which always or nearly always occurs prior hypersensitivity may play a role in the to or within about one minute of vaginal aetiology of PE in some men,3 with penetration; and inability to delay a possible familial genetic overlay.4 ejaculation on all or nearly all vaginal Many different pathways are involved penetrations; and negative personal (Figure 1)3 and the relative importance consequences, such as distress, bother, of these is incompletely understood. frustration and/or the avoidance of sexual A particular focus has been on serotonin intimacy’.1 (5-hydroxytryptamine, 5-HT), which appears to be a key mediator in the Premature ejaculation is a more common neurophysiology of ejaculation, with problem than erectile dysfunction (ED), at least three 5-HT receptor subtypes although the prevalence data depend on (5-HT1A, 5-HT1B, and 5-HT2C) so far the definition used. In a study in the USA implicated. The final common path, of men aged 18–59 years, around 30 per however, is undoubtedly the afferent- cent of men reported that they ‘climaxed efferent reflex, which can be influenced too early’ compared to 10 per cent of men like any other by local anaesthetics. who reported that they ‘had trouble achieving or maintaining an erection’. This ASSESSMENT OF CLINICAL BENEFIT article gives a flavour of the differing Drug companies tend to present data in pharmacological options for treating PE. many different ways, which can make ‘ON-DEMAND’ VERSUS DAILY Dr M.G. Wyllie, PhD, PHARMACOTHERAPY Chief Scientific Officer, Given that PE is not a life-threatening Plethora Solutions, London condition and that most men are unlikely www.trendsinurology.com TRENDS IN UROLOGY & MEN’S HEALTH DECEMBER 2010 SEXUAL FUNCTION 21 OT, oxytocin; 5-HT, 5-hydroxytryptamine; ACh, acetylcholine; NO, nitric oxide; BS, bulbospongiosus muscle. Figure 1. Pathways involved in ejaculation3 interpretation and drug–drug comparison As PE is generally not life-threatening, studies using ‘on-demand’ dosing with problematic. A more reliable index of drug the regulators are insistent on wide clomipramine have shown some degree performance can be an analysis of what therapeutic ratios, ie potential drugs of benefit. the regulatory authorities require for have to be squeaky clean. marketing authorisation. To circumvent some of the issues relating It is not anticipated that the endpoints used to the use of an antidepressant in non- The efficacy of therapy in clinical trials is in clinical trials will have any real diagnostic depressed patients and the limitations of generally based on a change in intravaginal value in the work-up of patients with PE. clomipramine, other formulations of the ejaculatory latency time (IELT), which is drug have been evaluated. One such assessed by stopwatch measurement, ORAL THERAPIES example is VR776 (Vectura Group plc, sometimes coupled with a patient-reported Traditionally, as in most therapeutic areas, Chippenham, UK), a novel proprietary outcome, such as the index of PE. The latter patients with PE prefer oral medication to formulation of clomipramine delivered by is used to capture ‘bother’ or ‘distress’, other routes. oral inhalation via Vectura’s dry powder which may not be directly related to inhaler (Aspirair). Although having some ejaculation time. One potentially useful Tricyclic antidepressants effect, VR776 has a high level of benchmark in evaluating clinical data is that Clomipramine is a tricyclic antidepressant respiratory side-effects, which suggest that the ISSM uses a cut-off point in their PE that inhibits the uptake of noradrenaline the drug may not reach the market. definition of ‘within about one minute’. It and 5-HT by adrenergic and 5-HT neurons. would appear that the regulatory authorities Daily dosing with 25mg or 50mg Selective serotonin reuptake inhibitors require to see at least a doubling of time as clomipramine can significantly increase The use of selective serotonin reuptake the index of an effective drug. IELT compared with placebo,5 and several inhibitors (SSRIs) in PE, like many TRENDS IN UROLOGY & MEN’S HEALTH DECEMBER 2010 www.trendsinurology.com SEXUAL FUNCTION 22 good drug discoveries, started with short-active agents are being developed to Opioid receptor agonists clinical observation rather than rational optimise on-demand benefit. Dapoxetine Tramadol, a centrally acting agonist of drug design. Delayed ejaculation is a (Johnson & Johnson, Mountain View, µ-opioid receptors, is a narcotic analgesic common side-effect of the SSRI class of California, USA) is a short-acting SSRI in indicated for the management of moderate antidepressant drugs (such as paroxetine, development for the on-demand treatment to severe pain. Its mode of action in PE is fluoxetine, sertraline and citalopram) when of PE.8 On-demand administration of not completely understood; however, in used to treat depressed patients, and this dapoxetine three hours before intercourse animal models it binds to opioid receptors serendipitous discovery has led to the use resulted in an up to four-fold increase in and is suggested to inhibit noradrenaline of SSRIs as a treatment for PE. IELT. Dapoxetine was also relatively well and serotonin reuptake. tolerated compared to longer-acting SSRIs, SSRIs inhibit the reuptake of 5-HT into the although nausea, diarrhoea, headache and Tramadol 25 or 50mg has been shown to presynaptic cell as a result of blockade of dizziness were commonly reported adverse be effective in prolonging IELT when used 5-HT transporters, increasing levels of 5-HT events. In spite of these promising findings, on-demand (one to two hours before within the synaptic cleft. The use of SSRIs the Food and Drug Administration issued a anticipated intercourse) in patients with in the treatment of PE has been the subject non-approvable letter for dapoxetine in PE, although interestingly, a recent study of a number of comprehensive reviews 2005, although a European marketing showed that daily treatment with one and a meta-analysis,6 with the general authorisation has been obtained. 100mg sustained-release tablet for four conclusion that, with daily treatment, all weeks was no better at prolonging IELT the SSRIs produced an increase in IELT. Several other novel short-acting SSRIs than placebo.9 have reached preclinical and early clinical In spite of a lack of regulatory authority development. These include UK-390,957 Phosphodiesterase-5 inhibitors approval, the off-label use of SSRIs in the (Pfizer Inc., New York, USA) and BMS- On-demand oral phosphodiesterase-5 management of PE is currently endorsed 505130 (Bristol-Myers Squibb, New York, (PDE-5) inhibitors are a popular and by the American Urological Association USA). However, Pfizer has withdrawn effective treatment for ED, but there is guidelines as well as the Second International UK-390,957 from further clinical studies, no pharmacological rationale for their Consultation on Sexual Dysfunctions. and there appears to be no further news use in the treatment of PE. A review of of BMS-505130, possibly as a result of 14 clinical trials of PDE-5 inhibitors in the Although daily SSRIs are highly effective problems with low oral bioavailability. treatment of PE concluded that there is no in the treatment of PE, there are Similarly, VI-0134, an oral 5-HT4 agonist convincing evidence to support their role accompanying nuisance side-effects (such developed by Vivus Inc. (Mountain View, in the treatment of men with lifelong PE as dry mouth, headaches and dizziness) and California, USA) for on-demand use in PE and normal erectile function.10 However, the risk of more serious consequences also appears to have been abandoned. there is limited evidence to support a (including psychiatric and neurological as potential role for PDE-5 inhibitors alone or well as the potential for drug interactions 5-HT1A receptor antagonists combined with daily or on-demand SSRIs and problems related to SSRI withdrawal The time taken to desensitise 5-HT1A in the treatment of acquired PE in men and the potential for suicidal ideation). receptors is thought to be the reason for with comorbid ED. These may be important considerations the delay of several weeks in the clinical when SSRIs are used outside our normal improvement of depression with SSRIs. Other potential drug targets for oral comfort zone in the treatment of depression, 5-HT1A antagonists have therefore been therapy ie for the management of PE. investigated as potential treatments for As ejaculation is a sympathetic spinal PE on the basis that they could mimic cord reflex (see Figure 1), sympatholytic The use of continuous versus on-demand the desensitisation of the receptor and agents such as alpha-1 adrenoreceptor administration of SSRIs for managing PE speed up the onset of action of the SSRI, antagonists could theoretically be used in has recently been reviewed by Giuliano thereby inducing strong immediate the treatment of PE, and there has been 7 and Hellstrom, with the conclusion ejaculatory delay.
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