Current Status And New Progress Of Drug Therapy For Premature Ejaculation

ABSTRACT: Premature ejaculation(PE)is the most common male sexual dysfunction with a high incidence, which seriously affects the relationship between husband and wife and family harmony. Drug therapy is a first-line treatment method for patients with premature ejaculation, and has achieved good efficacy, but the clinically available drugs are single and the abandonment rate is high, coupled with the ineffective treatment of some patients, new drug research and development is imminent. This paper systematically reviews the current status of drug treatment for premature ejaculation, focusing on the research and development of new drugs and research progress, in order to provide a reference for clinicians,

KEYWORDS: Premature ejaculation; drug treatment; new drug research and development; sexual dysfunction

Premature ejaculation (PE) is one of the most commonly reported male sexual dysfunctions. The incidence of premature ejaculation in adult men worldwide is about 20% to 30%, which seriously affects the relationship between husband and wife and family harmony. In 2014, The International Society for Sexual Medicine (ISSM) proposed the first comprehensive evidence-based definition of idiopathic premature ejaculation [1]. According to this definition, premature ejaculation is a male sexual dysfunction and is divided into two types: primary premature ejaculation and secondary premature ejaculation. In addition, WALDINGER et al2 proposed a classification scheme for premature ejaculation based on the duration of intra-vaginal ejaculation latency time (IELT) and proposed two new classifications of premature ejaculation: natural variability premature ejaculation and subjective ejaculation Premature ejaculation. The addition of these new subtypes may help overcome the limitations of individual definitions and may support more flexible stratification, diagnosis, and treatment of patients. The drugs currently in clinical use are mainly dapoxetine, long-acting selective serotonin reuptake inhibitors (SSRIs), local anesthetics, etc., which have opened up new opportunities for the drug treatment of premature ejaculation. path of. However, these drugs have the problems of poor efficacy, many adverse reactions, and a high discontinuation rate. To address these issues, some research is accelerating the development of new drugs. This article will discuss the current status and new progress of premature ejaculation treatment drugs from the following aspects.

1 Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants SSRIs block axonal reuptake of 5-HT at synapses of central 5-HT neurons through 5-HT transporters, resulting in Stimulation of postsynaptic membrane 5-HT2C receptors and delayed ejaculation. Tricyclic antidepressants (the tricyclic antidepressants, TCAs) block the reuptake of alpha-1 adrenergic receptors and 5-HT in peripheral sympathetic nerves. The off-label use of antidepressants, including paroxetine, sertraline, fluoxetine, citalopram, and the tricyclic antidepressant clomipramine, has revolutionized the treatment of premature ejaculation.

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1.1 Dapoxetine

Dapoxetine is a short-acting SSRIs with a rapid peak time and short half-life, little accumulation in the body and a dose-dependent pharmacokinetic change [3]. It has been approved for on-demand treatment of premature ejaculation in more than 50 countries or regions around the world, including the European Union and China. Randomized, placebo-controlled, phase III clinical trials showed that taking 30 mg or 60 mg 1-2 hours before intercourse was significantly better than placebo, resulting in a 2.5 or 3.0-fold increase in IELT, improved ejaculation control, less pain, and increased satisfaction*0. Dapoxetine is quite effective in the treatment of patients with primary premature ejaculation and patients with secondary premature ejaculation [Dapoxetine 30mg and 60mg were well tolerated throughout clinical trials, side effects were uncommon, It is dose-dependent, including nausea, diarrhea, headache, insomnia, etc., but there are also reported serious adverse reactions with very low incidence, such as syncope [7]. Dapoxetine discontinuation rates are high in the clinical setting, with cumulative discontinuation rates increasing over time and reaching >90% 2 years after initiation of therapy. The reasons for drug discontinuation were high cost (29.9%), disappointment that PE could not be cured and drug on-demand (25.0%), adverse reactions (11.6%), etc. [1]. The poor bioavailability of dapoxetine is an important reason for the poor efficacy and low patient satisfaction of dapoxetine, which leads to a high clinical discontinuation rate.

Using the drug-loaded form of nanostructured dapoxetine-loaded polymeric micelles (PMs), plasma pharmacokinetic parameters have been reported to significantly increase the area under the drug concentration-time curve in plasma and brain tissue (P<0.05), improved delivery across the blood-brain barrier, improved brain delivery 00. Using the drug-loaded form of dapoxetine-zein-a lipoic acid nanoparticles (NPs), the relative bioavailability was increased by 194% [1]. Novel drug-loaded forms of dapoxetine may lead to lower therapeutic doses and improved patient compliance due to improved bioavailability [10-1].

1.2 SSRIs and TCAs that can be used off-label The daily treatment of patients can effectively delay ejaculation, and paroxetine has the strongest ejaculation delay effect [12-16].

According to the relevant meta-analysis, SSRIs can increase the geometric mean multiple of IELT, and their efficacy ranks are as follows: ① Paroxetine (8.8 times 95% CI 5.9-13.2) ② Clomipramine (4.6 times 95% CI: 3.0-7.4 ); ③ sertraline (4.1 times; 95% CI: 2.6-7.0) ④ Fluoxetine (2.9 times 95% CI: 3.0-5.4) [17].

The daily therapeutic dose of paroxetine is 10 to 40 mg, clomipramine is 12.5 to 50 mg, sertraline is 50 to 200 mg, fluoxetine is 20 to 40 mg, and citalopram is 20 to 40 mg. It occurs only after 5 to 10 days, and clinically significant ejaculation delay usually occurs gradually after 1 to 3 weeks. Delayed ejaculation usually persists for several years, but the effect sometimes subsides after 6 to 12 months, and the reason for this tachyphylaxis is unclear. Daily SSRI treatment was effective in delaying ejaculation, but it did not delay ejaculation to the same extent in every patient. Delayed ejaculation occurs in 70% to 80% of men, while approximately 20% of patients with primary premature ejaculation do not experience delayed ejaculation associated with SSRIs.

Short-term side effects of SSRIs include fatigue, yawning, mild nausea, loose stools, or sweating. Several small studies have shown that SSRIs have potentially harmful effects on sperm. It is recommended that patients who intend to become pregnant gradually reduce the dose of SSRIs and stop taking the drug for 3 to 4 months09. Post-SSRI sexual dysfunction (PSSD) may occur in some patients using SSRIs, so patients using SSRIs should be advised to discontinue use immediately after undergoing genital anesthesia [20].

Patients treated with SSRIs should be careful not to stop the drug suddenly, and the dose should be gradually reduced within 2 to 3 months to prevent SSRIs withdrawal syndrome. It is characterized by tremors, a shock-like feeling when turning the head, nausea, and dizziness.

1.2.2 On-demand therapy An obvious advantage of on-demand oral drug therapy is the absence of the risk of long-term drug therapy side effects. Another advantage is that the drug should only be used when better sex is needed. On-demand paroxetine, sertraline, and fluoxetine administered 3 to 6 hours before sexual activity were moderately effective and well tolerated, but in most studies, ejaculation delay was significantly less than daily therapy [1]. Multiple clinical trials and meta-analyses show the efficacy and safety of tramadol in the treatment of premature ejaculation, and the efficacy of on-demand treatment for premature ejaculation is superior to paroxetine

2 local anesthetics

Studies have found that local anesthetics can delay ejaculation time by reducing the sensitivity of the glans penis, but do not affect the pleasure of ejaculation [20]. 2.1 Lidocaine-prilocaine cream local anesthetic eutectie mixture of local anesthetie (EMLA) cream is 2.5% lidocaine (volume fraction) and 2.5% prilocaine (volume fraction) in a cream base in the mixture. The use of EMLA 20 minutes before sexual intercourse has a certain effect in the treatment of premature ejaculation, but it is inconvenient to use, tends to soil the body, and has a slow onset of effect, and it has not been approved for the treatment of premature ejaculation in terms of indications. Due to the possible cytotoxic effects of lidocaine/prilocaine on fresh human sperm cells, topical lidocaine/prilocaine-containing medications are not recommended for couples who want to have children.

2.2 Lidocaine and prilocaine sprays

Lidocaine and prilocaine sprays (FORTACIN, TEMPE, PSD502) are the first officially approved topical treatments for premature ejaculation. TEMPE is a metered aerosol spray containing the local anesthetic lidocaine in the form of soda ash (uncharged) at 150 mg/mL and prilocaine at 0 mg/mL. The dose of the spray delivery system can maximize the degree of nerve blockage while reducing the occurrence of numbness, and the drug penetrates the intact keratinized skin very slowly and is not absorbed through the skin of the penile body. Relevant phase II and III studies have shown that TEM-PE significantly improved the IELT of patients compared with placebo and showed a good safety profile, did not reduce sexual satisfaction, and was unlikely to be associated with systemic adverse reactions [26] ]. 3 Type 5 phosphodiesterase inhibitors Currently, phosphodiesterase inhibitor type 5 (PDE-5i) drugs have been tested for the treatment of premature ejaculation, including sildenafil, tadalafil, and vardenafil. Nafe. A randomized, double-blind, placebo-controlled study comparing sildenafil and placebo in patients with premature ejaculation. Although there was no significant improvement in IELT, patients in the sildenafil group improved ejaculation confidence, decreased anxiety, and decreased the refractory period to achieve a second erection after ejaculation [7]. A number of randomized controlled trials have shown that tadalafil 5 mg once a day for several weeks can effectively improve IELTs and patient self-reported outcomes (PROs) in patients with premature ejaculation, and it is well tolerated [m]. The latest meta-analysis showed the efficacy and safety of PDE5-i in the treatment of premature ejaculation [3]. Several trials and meta-analyses have shown that combination therapy with PDE5-i and SSRI was found to be superior to other treatment modalities (including topical lidocaine gel, behavioral therapy, PDE5-Is, tramadol, dapoxetine 30/60 mg, clomipramine, citalopram, and placebo) with tolerable adverse reactions Antagonists are of interest as an alternative treatment option because of their inhibitory effects on the direct peripheral effector organs that induce ejaculation, including the seminal vesicles, vas deferens, and prostate and associated muscles.*0 Results of a prospective, open-label, multicenter trial of 26 patients with secondary premature ejaculation supported the clinical use of silodosin as an alternative therapy for premature ejaculation, but silodosin reversibly reduced semen volume, which was also reported in this study. This phenomenon occurs

5 Oxytocin receptor antagonists

Oxytocinergic neurotransmission plays a role in both male and female sexual responses. Numerous studies have shown that oxytocin has a stimulating effect on the ejaculation process, suggesting that blocking oxytocin receptors may be a promising approach to treating premature ejaculation. After finding that the oxytocinergic antagonist Epelsi-ban failed to significantly improve IELT, the researchers focused on another oxytocin antagonist, Cligosiban [3].

Cligosiban (formerly IX-01) is an oral small molecule oxytocin receptor antagonist that has been shown in studies to have good CNS penetration37. Its pharmacokinetic properties are suitable for once-daily dosing or Administer as needed before intercourse.

Two phase II trials of Cligosiban (the PEPIX and PEDRIX trials) were published simultaneously, but reported conflicting results. In the PEPIX study, over 8 weeks, patients were randomized to receive either Cligosiban (n=58) or placebo (n=30), administered 1 to 6 hours before intercourse. The initial dose was 400 mg, and after 2 and/or 4 weeks, patients were allowed to increase (800 mg) or decrease (200 mg) the dose; in the Cligosiban group, the geometric mean IELT value increased 2.1-fold, which was significantly higher than that in the placebo group (1.1 times, P=0.079). There were also significant improvements in patient-reported prognostic indicators in the Cligosiban group compared with the placebo group (P<0.05). No serious treatment-related adverse events were reported**. Considering the favorable results of this proof-of-concept trial, the authors conducted another phase IIb trial (the PEDRIX study) including 239 patients with PE. The design was very similar to the PEPIX study, and patients were randomized to receive a fixed dose of Cligosiban (400, 800 or 1200 mg) or a placebo. However, unlike the PEPIX trial, there were no significant differences in efficacy endpoints and patient-reported outcomes between the Cligosiban arm and the placebo arm. Similar to the PEPIX trial, Cligosi-ban was well tolerated with an acceptable safety profile [3].

The two studies were well designed and were almost identical in methodology, but some obvious differences may explain these contradictory results, such as the division of the experimental groups and the different amounts and forms of drugs taken, which may lead to differences in the trial results. In addition, the small number of patients included in the trial and the fact that the patients included in the trial may not be all patients with premature ejaculation may cause differences in the trial results [39]. Therefore, further larger studies are needed to establish the optimal dosing form and dosage of Cligosiban and to answer unanswered questions about the potential value of CNS-penetrating oxytocin receptor antagonists in the treatment of premature ejaculation . At present, some scholars are also designing and exploring new oxytocin receptor antagonists with good pharmacokinetic characteristics to treat CNS-related premature ejaculation.

6 Other drugs

6.1 5-HT1A receptor antagonists

A double-blind, placebo-controlled study showed that 35 subjects were divided into a single oral 3 mg, 7 mg GSK958108 and placebo 3 groups, using the masturbation model to measure ejaculation latency (ELT), the results showed that 5HT1A receptors The antagonist GSK958108, 3 mg daily and 7 mg daily, was well tolerated, safe, and effective in treating PE subjects and demonstrated a strong association between the 5HT1A receptor and ejaculation control in humans. A total of 4 subjects in the 7 mg group had minor adverse events: 3 cases of somnolence, 1 case of headache, and 1 case of tinnitus. The use of a masturbation model and the small sample size are the main limitations of this study.

6.2 Cistanche

 Cistanche deserticola is a proprietary blend of Chinese herbal ingredients, a multi-target formulation containing the appropriate proportions of Morel, Fenugreek, Fenugreek, Water Lily and 1-Arginine, which is synergistic in treating the psychological and biological causes of PE It exerts its activity by increasing testosterone levels, NO levels, and neurotransmitters (dopamine and serotonin) involved in PE management, and can also reduce stress and anxiety [2]. A randomized, double-blind, placebo-controlled study of 60 patients with premature ejaculation who were randomly assigned to receive OLNP-05 or placebo twice a day for 8 weeks showed significantly greater improvement in IELT scores in the OLNP-05 group than with placebo at the end of treatment , the significant improvement of the premature ejaculation profile (PEP) subscale score confirmed the safety and efficacy of Cistanche deserticola, thus indicating that OLNP-05 may be a safe and effective intervention for the management of premature ejaculation.

6.3 Pregabalin

Pregablin) The mechanism of action of pregablin is not fully understood. Studies by BONNET and SCHERBAUMIS have not demonstrated its addictive properties. Delayed ejaculation has been described as a side effect of pregabalin therapy in one study [1]. Accordingly, researchers evaluated pregabalin as a novel treatment for premature ejaculation. The first double-blind, placebo-controlled, randomized trial of pregabalin on the treatment of premature ejaculation showed that 116 patients were divided into 3 groups and required to take 150 mg, 75 mg of pregabalin and placebo 1 to 2 hours before intercourse, respectively. Symptoms improved in 82% of patients in the 150 mg pregabalin group, and a multiple study showed a 2.4-fold improvement in baseline IELT; fewer, tolerable adverse events occurred [*]. Based on the trial results, oral pregabalin appears to be a promising treatment for premature ejaculation, and more research is needed to assess the appropriate dose, duration, and safety of this drug.

6.4 Modafinil

Modafinil (2-[(diphenylmethyl)sulfoxide]acetamide) is a wake-promoting drug. The neurochemical properties of modafinil appear to have effects on the catecholaminergic and 5-HT systems. A randomized, double-blind, placebo trial showed that modafinil 100 mg administered approximately 6 hours before intercourse in patients with premature ejaculation improved premature ejaculation over a 4-week period compared with placebo. The most common side effects of modafinil were insomnia and decreased appetite, but no related adverse events were reported in this study. Given the strong effects of modafinil on attention, alertness, and executive control, it can be speculated that modafinil affects premature ejaculation through physiological and cognitive processes, which corroborate with the experimental results.

7 Conclusion and Outlook

Premature ejaculation seriously affects the relationship between husband and wife and family harmony because of its high incidence and difficulty to cure. At present, drug therapy is the first-line treatment for patients with premature ejaculation, including SSRIs, TCA, local anesthetics, PDE-5i, α-1 adrenergic receptor antagonists, etc., which have improved the symptoms of premature ejaculation to varying degrees in clinical practice. However, there are not many clinically available drugs at present, and some patients have poor efficacy, resulting in a high abandonment rate. Therefore, new drug development is imperative. Oxytocin receptor antagonists, 5-HT1A receptor antagonists, OLNP-05, pregabalin, modafinil, botulinum toxin and other new drugs have achieved certain therapeutic effects against new therapeutic targets. In the future, it can be applied to the clinic.

This paper systematically reviews the latest research progress on the mechanism of action and therapeutic effect of drugs for the treatment of premature ejaculation, in order to provide reference for clinicians. Get a more harmonious sex life.

If you have any questions or PE problems when you take medicine, please send us an Email at: wallence.suen@wecistanche.com