The role of local anaesthetics in premature ejaculation.

UNLABELLED: What's known on the subject? and What does the study add? It is now accepted that both biological and psychological factors are important in the aetiology of premature ejaculation (PE). Of particular interest is the correlation between ejaculatory latency and penile sensory thresholds. Men with PE appear to have a heightened sensory response to penile stimulation and also generally exhibit other abnormal reflex pathways within the ejaculatory process, suggesting a link between penile hypersensitivity and PE. Considering these sensory differences, drugs that selectively produce some degree of penile desensitization or act within the afferent-efferent reflex could delay ejaculatory latency without adversely affecting the sensation of ejaculation. This review evaluates published clinical trial data for local anaesthetics used off-label in PE as well as novel topical agents in development. New analyses of the phase III data are presented for topical eutectic mixture for PE (TEMPE, also known as PSD502, Plethora Solutions Plc., London), a proprietary formulation of lidocaine and prilocaine in a metered-dose aerosol delivery system. OBJECTIVES: • To review the published clinical trial data for local anaesthetics used off-label in premature ejaculation (PE), as well as novel topical agents in development. • To evaluate the safety and efficacy of topical eutectic mixture for PE (TEMPE) in subjects with PE and their sexual partners using all available phase III data. RESULTS: • Topical treatments can be applied as needed and systemic side-effects are unlikely. However, existing off-label topical treatments for PE have several disadvantages: they can be messy, interfere with spontaneity, and could cause numbness in the man or his partner. • Several novel topical agents are in development for the treatment of PE. TEMPE appears to be closest to approval. • TEMPE, applied 5 min before sexual intercourse (539 subjects) resulted in an increase in the geometric mean intra-vaginal ejaculatory time (IELT) from a baseline of 0.58 min to 3.17 min during 3 months of double-blind treatment; a 3.3-fold delay in ejaculation compared with placebo (P < 0.001). • IELT continued to increase further with continued use of TEMPE throughout the double-blind and open-label phases. • Treatment with TEMPE also resulted in marked improvements in subjective measures, e.g. ejaculatory control, sexual satisfaction and distress, with little or no evidence of systemic side-effects and minimal desensitization of the genitalia in subjects or their sexual partners. CONCLUSIONS: • The use of a topical agent could be an acceptable first-line option for PE, given the favourable risk/benefit ratio of these products. • Topical aerosol application of TEMPE may provide safe, effective, on-demand treatment for PE.

The long-term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone-deficient men.

What's known on the subject? and What does the study add? Striant® SR is the only available buccal delivery system for testosterone replacement therapy. Previous pharmacokinetic studies have shown that Striant SR effectively produces physiological serum testosterone levels in hypogonadal men. Efficacy and safety data from previously unpublished studies over 2 years of continuous use indicate that Striant SR is effective long term in maintaining serum testosterone within a physiological range, is well tolerated and has a high level of patient acceptance. Striant® sustained-release (SR) is a mucoadhesive buccal tablet (30 mg testosterone, The Urology Company) that adheres to the gum surface in the mouth providing controlled- and sustained-release of testosterone over a 12-h dosing period, offering a unique and rational method of testosterone delivery. Striant SR is indicated for testosterone-replacement therapy (TRT) for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Pharmacokinetic studies have shown that testosterone is released from Striant SR in a manner similar to the normal daily rhythm of endogenous testosterone secretion, with serum levels rising rapidly after insertion and peak levels reached by the second 12-hourly dose with no accumulation over time. In clinical trials involving hypogonadal men receiving Striant SR for up to 2 years, mean serum testosterone levels have always remained within the normal range. Striant SR is well tolerated, with gum-related disorders (such as irritation, inflammation and gingivitis) and taste perversion being the most commonly reported adverse events, reported by 5.6-16.3% and 3.0-4.1% of patients, respectively. Once patients have become accustomed to it, Striant SR has a high level of patient acceptance. In a long-term study, 90% of patients rated the twice-daily dosing as acceptable, just under half preferred it to other forms of TRT that they have used and 96% found it to be cosmetically acceptable. There is no clinically significant risk of testosterone transfer from Striant SR, as any testosterone that may be present in the saliva when swallowed is subject to extensive first-pass hepatic metabolism. It is pertinent to note that the saliva of eugonadal men contains similar levels of endogenous testosterone. Buccal delivery is particularly suitable where easy and rapid reversal of treatment might be required (such as in late-onset hypogonadism) and where there is a need to avoid the potential for transfer of testosterone to women and young children.

The link between penile hypersensitivity and premature ejaculation.

OBJECTIVES: To investigate the correlation between penile hypersensitivity and premature ejaculation (PE), as defined by the criteria identified by the International Society of Sexual Medicine (ISSM). Penile hypersensitivity as a cause of PE is based on historical clinical neurophysiological data and clinical efficacy of the topical desensitizing agent PSD502 in the treatment of PE. PSD502 is a eutectic-like mixture of two local anaesthetics, lidocaine and prilocaine, whose primary action is to reduce neuronal conduction in sensory afferents. METHODS: Historical neurophysiological data was reviewed, together with data from the recent PSD502 clinical trials, including the first published double-blind clinical trial data evaluating a topical desensitizing agent in a population of men with PE, as per the new ISSM definition. The clinical profile of PSD502, based on its local anaesthetic properties, is used as a surrogate index of the role of sensory afferents in the ejaculatory reflex. RESULTS: The published data does not support unequivocally penile hypersensitivity as the cause of PE. Interpretation of the data is hampered by the variability of the populations described as having PE across studies. Data from the PSD502 clinical trials clearly shows that PSD502 increases ejaculatory latency, and improves control and sexual satisfaction when applied topically to men with PE 5 min before intercourse, enabling subjects to delay ejaculation up to six times longer than those who used a placebo. CONCLUSION: The clinical profile of PSD502 lends credibility to the penile hypersensitivity hypothesis for PE. The predominant action of local anaesthetics is to reduce neuronal firing in sensory afferents; the clinical profile of PSD502, which shows improvement of ejaculatory function in the absence of a generalized reduction in penile sensitivity, can most readily be explained based on an underlying hypersensitivity in patients with PE.

PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study.

OBJECTIVES: To determine the effect of PSD502 applied topically 5 min before intercourse on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency time (IELT) of men with lifelong premature ejaculation (PE) defined according to the International Society of Sexual Medicine (ISSM) definition; secondary objectives were to evaluate the safety and tolerability of PSD502 in patients with PE, and their sexual partners. PATIENTS AND METHODS: Men aged >18 years, in stable heterosexual, monogamous relationships, and with lifelong PE diagnosed according to both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) criteria and the ISSM definition, consented (together with their partners) to enter the baseline period of the study. Patients who documented an IELT of

Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome.

OBJECTIVE: To assess the immediate and sustained relief of the symptoms of interstitial cystitis/painful bladder syndrome (IC/PBlS) after a consecutive 5-day course of treatment with intravesical alkalinized lidocaine (PSD597), and to characterize the pharmacokinetics of single and multiple doses of intravesical PSD597 in a subgroup of patients. PATIENTS AND METHODS: In all, 102 adult patients (99 women) with a clinical diagnosis of IC/PBlS were randomized from 19 centres in the USA and Canada to receive a daily intravesical instillation of PSD597 (200 mg lidocaine, alkalinized with a sequential instillation of 8.4% sodium bicarbonate solution, to a final volume of 10 mL) or placebo (double-blind), for 5 consecutive days. Patients were followed at intervals up to 29 days after the first instillation. Efficacy was assessed by changes in the Global Response Assessment (GRA), Likert scales for bladder pain, urgency and frequency, and validated O'Leary-Sant IC symptom and problem indices. RESULTS: Significantly more patients treated with PSD597 rated their overall bladder symptoms as moderately or markedly improved on the GRA scale 3 days after completing the 5-day course of treatment (30% and 9.6%, respectively, for patients treated with PSD597 and placebo; P = 0.012). The treatment effects were also maintained beyond the end of treatment and are further supported by the secondary endpoints, including symptom and problem indices. The peak serum lidocaine concentration during the study was <2 microg/mL, and well below the toxic level (>5 microg/mL). CONCLUSION: This preliminary study showed that PSD597 was effective for providing sustained amelioration of symptoms of IC/PBlS beyond the acute treatment phase. The drug was safe, well tolerated and devoid of the systemic side-effects often experienced with oral drug administration. Long-term studies are needed to determine the optimum regimen to maintain this favourable treatment effect.