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 Efficacy and safety data from previously unpublished studies over 2 years of continuous use indicate that Striant SR is effective long term in maintaining serum testosterone within a physiological range, is well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 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 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.

Improved ejaculatory latency, control and sexual satisfaction when PSD502 is applied topically in men with premature ejaculation: results of a phase III, double-blind, placebo-controlled study.

INTRODUCTION: PSD502 is a novel aerosolized, lidocaine-prilocaine, spray being developed for the treatment of lifelong premature ejaculation. The clinical profile of PSD502 is described in one of two double-blind, placebo-controlled, phase III studies. AIM: To determine the effect of PSD502 on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency (IELT) of men with lifelong PE. METHODS: Men with lifelong PE who documented an IELT ≤ 1 minute with two or more of the first three sexual encounters during a 4-week baseline period were randomized to receive double-blind treatment with PSD502 or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile questionnaires at entry and monthly visits, and recorded stop-watch timed IELT during each encounter. Safety was assessed by collecting adverse event data and standard safety measures. MAIN OUTCOME MEASURES: Stopwatch timed IELT recordings and a patient-reported outcome questionnaire the IPE were used in this study to determine the effect of PSD502 applied topically 5 minutes before intercourse. RESULTS: Two hundred fifty-six men with PE were randomized from 38 centers in the U.S., Canada, and Poland. The geometric mean IELT over the 3-month treatment period increased from a baseline of 0.56 minute and 0.53 minute in the PSD502 and placebo group respectively to 2.60 and 0.80 minute. There were significantly greater increases in the scores for the IPE domains of ejaculatory control, sexual satisfaction and distress in the PSD502 group than in the placebo group, with a mean 5.0 point difference between treatments in change from baseline in the IPE domain for ejaculatory control, 4.6 point difference in change from baseline in the IPE domain for sexual satisfaction, and a 2.5 point difference in change from baseline in the IPE domain for distress. This was supported by improvements in all secondary endpoints. CONCLUSION: In this study, PSD502 applied topically to the glans penis 5 minutes before intercourse showed significantly improved ejaculatory latency, ejaculatory control, sexual satisfaction and distress and was shown to be well tolerated by patients and partners.

Standards for clinical trials in male sexual dysfunctions.

INTRODUCTION: Clinical trials in male sexual dysfunction (MSD) are expanding. Consequently, there is a need for consensus standards in this area. AIM: To develop an evidence-based, state-of-the-art consensus report on standards for clinical trials in MSD. METHODS: A literature review was performed examining clinical trials in erectile dysfunction (ED), premature ejaculation (PE), delayed/absent ejaculation, libido disorders/loss of desire, hypogonadism, and Peyronie's disease, focusing on publications published in the last 20 years. This manuscript represents the opinions of eight experts from seven countries developed in a consensus process. This document was presented for peer review and debate in a public forum and revisions were made based on recommendations of chairpersons to the International Consultation on Sexual Medicine. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: According to experience and recent publications in dealing with clinical trials in sexual dysfunction, recommendations have been made for conducting trials in patients with ED, PE, delayed ejaculation, libido disorders, hypogonadism, and Peyronie's disease. CONCLUSIONS: It is important that future clinical trials are conducted using standards upon which investigators can rely when reading manuscripts or conducting new trials in this field.

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.

Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction.

Erectile dysfunction (ED) is becoming an increasingly common problem and although oral therapies offer first-line treatment for many men, they are contraindicated or ineffective in substantial groups of patients. Intracavernosal injection (ICI) therapy is the most effective nonsurgical treatment for ED and offers an effective alternative to oral therapy. Sufficient arterial blood supply and a functional veno-occlusive mechanism are prerequisites in the attainment and maintenance of a functional erection. Invicorp (Plethora Solutions, London, UK) is a combination of vasoactive intestinal polypeptide (VIP) 25 microg and phentolamine mesylate 1 or 2 mg for ICI in the management of moderate to severe ED. The two active components have complementary modes of action; VIP has a potent effect on the veno-occlusive mechanism, but little effect on arterial inflow, whereas phentolamine increases arterial blood flow with no effect on the veno-occlusive mechanism. Clinical studies showed that Invicorp is effective in >or=80% of men with ED, including those who have failed to respond to other therapies and, unlike existing intracavernosal therapies, is associated with a very low incidence of penile pain and virtually negligible risk of priapism. We estimate that there are >5.9 million men in the USA alone for whom oral ED drugs are not a viable treatment option, and for whom Invicorp might offer a safe and effective alternative.

TEMPE: Topical Eutectic-Like Mixture for Premature Ejaculation.

BACKGROUND: Premature ejaculation (also known as rapid or early ejaculation) is the most common form of sexual dysfunction experienced by men, but there is presently an unmet need for a licensed pharmaceutical product that can be used on demand and that is effective from the first dose. OBJECTIVE: TEMPE (Topical Eutectic-Like Mixture for Premature Ejaculation; Plethora Solutions Plc.) is a proprietary metered-dose aerosol containing a combination of the well-known local anaesthetics lidocaine and prilocaine in a novel formulation. The authors evaluate here the progress that has been made towards the reformulation of these local anaesthetic agents into a unique eutectic-like formulation for use as a desensitising agent in the treatment of premature ejaculation, as well as examining other potential uses for the spray, such as pain relief at skin-graft donor sites. METHODS: Both lidocaine and prilocaine are soluble in the hydrofluoroalkane (HFA-134a) propellant, providing a unique formulation in which the pressurised liquid propellant is used as the solvent. Deployment of the metered-dose chamber vaporises the propellant, spraying lidocaine and prilocaine, now forced into a eutectic-like combination that remains in liquid form at temperatures well below their individual melting points, onto the target surface. The site is thus easily covered in a controlled dose of pure local anaesthetic in base form, providing ideal circumstances for optimised absorption through non- or poorly-keratinised skin, mucus membranes and wound surfaces. RESULTS/CONCLUSION: TEMPE has been developed for use in premature ejaculation and preliminary results show promising improvements in intravaginal ejaculatory latency, as well as patient-reported outcomes.