Long Tian¹, Zhong-Cheng Xin², Hua Xin², Jie Fu², Yi-Ming Yuan², Wu-Jiang Liu², Chun Yang²

Premature ejaculation (PE) is the most common type of ejaculatory dysfunction; approximately 35 %-70 % of men experienced PE at certain stage of their sexual life [1]. PE is defined as the inability to delay ejaculation sufficiently to enjoy lovemaking and the persistent or recurrent occurrence of ejaculation with minimal sexual stimulation before, during or shortly after penetration; the orgasm and ejaculation occur before the desired moment [2]. Therefore, it significantly influences the patient's and the partner's sexual satisfaction and thus their life quality [3].

Despite the high prevalence of PE in men, little research has directly focused on the mechanism of its development. Traditionally, it was thought that in the majority of patients, PE was caused by psychological factors, including anxiety, unresolved conflicts, marital difficulties, infrequent intercourse, etc.[4] and the primary treatment involved psychological measures, such as penile-squeezing and counseling [1]. Recently, neurobiological studies suggest that PE may be a neurological and not a psychological disorder [5]. Long continued PE is usually related to faulty central serotonergic neurotransmission conditioned by hereditary factors. Lately, psychotropic medicines, such as selective serotonin re-take inhibitors (SSRIs), were found to be highly effective in delaying ejaculation [6], however, these dugs may decreased the sexual desire and cause erectile difficulty and delayed ejaculation [7, 8]. Rowland et al [9] and Xin et al [10, 11] indicated that primary PE patients showed a lower penile sensory threshold and a higher sensory nerve excitability compared to the controls. The condition is reversed by the application of a topical agent, the SS-cream on the glans penis. The SS-cream is a mixture of nine traditional medicines, including Korean ginseng, bufonoid venom, cinnamon, etc. which have been shown to possess a local desensitizing effect and proved to be safe and effective for PE treatment upon local application on the glans penis [12-15]. Pharmacological research showed that it increased the penile sensory threshold and delayed the GPSEP latency [13, 14]. However, some patients complained of its unpleasant smell and color. It has also been reported that a local anesthetic combination (lidocaine and prilocaine) has a delaying effect on intravaginal ejaculation latency time (IVELT) through desensitizing the glans, but it may cause numbness of the glans and prolong the waiting time [16, 17].

The spinal somatosensory evoked potential (SSEP) has been observed to study the activity of the peripheral penile sensory nerves. Traditionally, the dorsal nerve somatosensory evoked potential (DNSEP) was recorded by stimulating the penile shaft with a ring electrode [18]. However, as the glans penis constitutes the primary erogenic area, we examined the glans penis somatosensory evoked potential (GPSEP) and indicated that GPSEP was more specific to evaluate the sensory nerve function then DNSEP [11].

The renewed SS-cream (RSSC) is a new topical agent composed of the two main components of the original SS-cream (OSSC), Korean ginseng and bufonoid venom, mixed in a hydrobase with a special enhancer without smell and color [19, 20]. RSSC has been shown to be an excellent desensitizing agent.

The present invesgation was designed to study the mechanism of RSSC (and OSSC) in the treatment of PE.

The ingredients of SS-cream were indicated in our previous paper [21]. The RSSC contains Bufonoid venom, Korean Ginseng extract and a hydrobase with a special enhancer consisting of ethylalcohol, propylene glycol monolaurate, N-methyl pyrrolidinone, diethylene glycol monoethyl ether, carbopol 940 and sodium hydroxide. The RSSC, the OSSC and the placebo (provided by the CJ Co. LTD, Seoul, Korea) at 0.2 mg each were enveloped separately in paper bags printed only with their allocation numbers.

Electrophysiologic recordings were performed using an electromyograph (Poseidomn Co., Shanghai, China).

Sixty male White New Zealand rabbits, weighing
2.5-3.0 kg, were divided at random into the RSSC, OSSC and placebo groups of 20 animals each. The Principles of Laboratory Animal Care (NIH publication No 86-23, revised 1985) as well as the Chinese Government Rule on the Protection of Laboratory Animals were followed.

The SSEP was successfully elicited before and after drug or placebo application (Figure 1). Before applica-tion, the mean Onset latency of the 3 groups showed no significant difference (P>0.05). After application (10 and 30 min), it was significantly delayed (P<0.05) in the RSSC and OSSC groups, while no significant change was noted in the placebo group (P>0.05). Comparing with the placebo group, the mean Onset latency of the RSSC (at 10 and 30 min) and the OSSC group (at 30 min) were significantly delayed (P<0.05) (Table 1).

Before drug or placebo application, the mean N1 latency of the three groups showed no significant difference (P>0.05). After application (10, 30 and 60 min), it was significantly delayed in the RSSC and OSSC groups (P<0.05), while the placebo group had no significant change (P>0.05). Comparing with the placebo group, the mean N1 latency of the RSSC group (at 30 and 60 min) and OSSC (at 30 min) were significantly delayed (P<0.05) (Table 2).

Table 2. SSEP N1 latency (ms). ^bP<0.05, compared with pre-application, ^eP<0.05, compared with placebo.

Both the RSSC and OSSC groups showed a tendency of a decrease in SSEP amplitude, but statistically insignificant (P>0.05) (data not listed).

Although some psychotropic medications(phenothi-azines and antiaxiolytics) are highly efficacious for delaying ejaculation, however, they have their limitation because of systematic [7] and sexual function side effects [8].

It has been indicated that in PE patients the sensory threshold of the glans penis is significantly lowered [10] and the GPSEP latency significantly delayed compared with the controls [11]. In recent studies, topical administration of certain desensitizing drugs had satisfactory results for PE treatment [16, 17]. These results suggested that penile hypersensitivity and/or hyperexcitability may be the organic basis of PE. Another study evaluated the penile sensitivity of 18 patients with a long history of PE and 15 controls and suggested that penile hypersensitivity does not appear to be a major factor contributing to premature ejaculation [22]. The inconsistency may be due to the limited sample size of that study and/or the difference in patient entry criteria.

In the study on DNSEP, cortical recording via surface electrodes is employed and in animal study, intravenous anesthesia has to be used, therefore, may influence on cortical evoked potential [18]. In this study, GPSEP was observed with the stimulating electrode at the glans and the recording electrodes at L1 and L5. It may avoid the influence of intra-venous anesthesia on the cortical evoked potential, therefore, appears to be more appropriate for assessing the sensory nerve function of the glans.

The present study indicated that the local application of RSSC significantly delayed the Onset and N1 latencies of SSEP: the Onset latencies of RSSC at 10 and 30 min and the N1 latencies at 30 and 60 min were significantly delayed. These results show that the local desensitizing effect of RSSC will be initiated at 10 min after application and maintained at least for 50 min. For future clinical application, PE patients may be advised to use RSSC 10 min before intercourse and a maintainence period of 60 min will be enough for lovemaking. Both the Onest and N1 latencies of SSEP had their highest value at 30 min after application, suggesting that RSSC had its peak action time at 30 min. The OSSC also significantly delayed the SSEP Onset and N1 latencies, but only at 30 min after application

In conclusion, RSSC delays the latencies of SSEP more effectively than OSSC, suggesting a better effect in the treatment of PE.