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International Journal of Urology (2014)
doi: 10.1111/iju.12471
Original Article
Resiniferatoxin for treatment of lifelong premature ejaculation: A preliminary study Bentao Shi,1 Xuesong Li,2 Jing Chen,1 Boxing Su,2 Xianxin Li,1 Shangqi Yang,1 Zhichen Guan1 and Run Wang3 1 Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 2Department of Urology, Peking University First Hospital, Beijing, China; and 3Department of Urology, University of Texas Medical School at Houston and University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Abbreviations & Acronyms CIPE-5 = Chinese Index of Sexual Function for Premature Ejaculation IELT = intravaginal ejaculation latency time PE = premature ejaculation RP = redundant prepuce RTX = resiniferatoxin Correspondence: Zhichen Guan M.D., Ph.D., Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Street, Shenzhen, Guangdong 518038, China. Email: [email protected] Received 3 October 2013; accepted 30 March 2014.
Objectives: To evaluate the efficacy of resiniferatoxin in the treatment of patients with lifelong premature ejaculation. Methods: A total of 41 outpatients (mean age 26.14 ± 4 years) with premature ejaculation completed the present study. They were randomly separated into the resiniferatoxin group and the placebo group. The resiniferatoxin group included 11 patients with redundant prepuce and 10 patients without redundant prepuce, whereas the placebo group contained 10 patients with redundant prepuce and 10 patients without. For the treatment, the glans were respectively soaked in 30 mL of resiniferatoxin with a concentration of 100 nmol/L or 10% alcohol solution for 30 min before sexual intercourse. Clinical efficacy was assessed by using the Chinese Index of Sexual Function for Premature Ejaculation-5 and the intravaginal ejaculation latency time before or 4 weeks after the treatment. The side-effects were also evaluated. Results: In the resiniferatoxin group, the effective rate of patients with redundant prepuce was 63.6%, and both the intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 significantly increased (P < 0.05). However, the effective rate of patients without redundant prepuce was 20%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the resiniferatoxin treatment (P > 0.05). The total effective rate of patients treated with resiniferatoxin was 42.9%. In the placebo group, the effective rate of patients with or without redundant prepuce was 20% and 10%, respectively. The total effective rate of patients treated with placebo was 15%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the placebo treatment (P > 0.05). The side-effects included a slight burning sensation for the glans penis and dysuria. Conclusions: These preliminary results show that resiniferatoxin might be suitable for treating patients with lifelong premature ejaculation and particularly those with redundant prepuce.
Key words:
Chinese Index of Sexual Function for Premature Ejaculation, intravaginal ejaculation latency time, premature ejaculation, redundant prepuce, resiniferatoxin.
Introduction PE is considered to be one of the most common male sexual dysfunctions, and affects 20–30% of adult males.1 However, the exact etiology of PE remains unknown. Some studies suggested that penile hypersensitivity or increased excitability of the penile sensory nerve might be one of the reasons associated with PE.2 A total of 80–90% of sensory nerves in the glans penis are C type amyelinic nerve fibers.3 RTX, a representative of the vanilloids family, is extracted from a cactus-like plant. Not only does RTX have a similar structure to capsaicin, but it is also 1000-fold spicier than capsaicin.4 Animal studies have shown that RTX can act on peripheral sensory nerve terminals, mainly amyelinic C fibers, that can reduce the excitability and sensitivity of afferent sensory nerves by releasing substance P.5 RTX and other vanilloid substances have been used to treat overactive bladder and interstitial cystitis.6–10 To the best of our knowledge, there has been no report of using RTX to treat PE. This placebo-controlled study was designed to assess the efficacy and safety of RTX therapy for PE. © 2014 The Japanese Urological Association
1
B SHI ET AL.
Methods
Criterion of curative effect
Patients selection and clinical data
The effects and adverse effects were assessed 4 weeks after treatment. The CIPE-5 scores were obtained before and after treatment. The IELT was recorded using stopwatch chronometry. Patients were considered to be cured when normal CIPE-5 scores or prolonged IELT >4 min were achieved after treatment. The one to two grade decrease of the CIPE-5 score or prolonged IELT of 3–4 min were considered as improvements. No change of CIPE-5 score or prolonged IELT 18 years with a stable female sexual partner; (ii) uncontrollable ejaculation caused by genital stimulation either before penetration or shortly after penetration with IELT less than 2 min; (iii) lifelong PE; (iv) normal erectile function; (v) partner dissatisfied with sexual life; (vi) total CIPE-5 score 0.05) and in the placebo group. Comparing the two groups treated with RTX and placebo, the change of IELT was significant (P < 0.05), and the PE patients with redundant prepuce had a longer IELT (Table 1).
CIPE-5 scores The CIPE-5 scores are also summarized in Table 1. The baseline CIPE-5 scores in the two groups were nearly the same. After the RTX treatment, there was a significant change of CIPE-5 scores from 11.82 ± 5.19 to 16.00 ± 4.22 in patients with redundant prepuce (P < 0.05). However, there was no significant change of CIPE-5 score in patients without redundant prepuce (P > 0.05) and in the placebo group. Comparing the two groups treated with RTX and placebo, the change of CIPE-5 score was significant (P < 0.05), and the PE patients with redundant prepuce had a higher CIPE-5 score (Table 1).
Adverse events All patients reported a tolerable burning sensation at the glans and dysuria while soaking the penis in the RTX solution or 10% alcohol solution. The uncomfortable sensations generally disappeared 1–2 h after the treatment. There was no patient dropped out of the study as a result of the side effects, and no adverse vaginal events were reported by the patients’ sexual partners. Neither the patients nor their partners reported systemic adverse effects.
Discussion Recently, lifelong PE has been defined by the International Society of Sexual Medicine.11 Referring to this definition, the 1-min IELT cut-off point is not applied in the most absolute sense, as approximately 10% of men seeking treatment for lifelong PE have IELT of 1–2 min.11 In the present study, all patients with lifelong PE and IELT less than 2 min expressed emotional distress in regard to their sexual life. Therefore, this © 2014 The Japanese Urological Association
cohort of patients became the ideal candidates for studying novel pharmaceutical therapy for PE. Current treatments are largely based on logical solutions (decreasing sensory input), behavior modification therapies and observations of drug sideeffects (those with serotonin reuptake inhibiting activity, such as dapoxetine), phosphodiesterase type 5 inhibitors, combination modalities or alternative medicine. Unfortunately, most of therapies are off-label uses without specific indications for PE.12 Therefore, an ideal medical treatment for PE has yet to be found. Local therapy is a very attractive option for treatment of PE, as studies suggest that the glans penis of a patient with PE is more sensitive with higher excitability in the sensory nerves and lower ejaculation threshold when compared with a normal man.13 Therefore, many local therapies utilized anesthetic effects to prolong the IELT. These included 1% dyclonine ointment,14 2% lidocaine15 and SS-cream (severance secret cream).16 Unfortunately, these treatments often resulted in a lack of orgasm or erectile dysfunction due to the decrease of pleasurable sensation.13 The treatment failure is also common as a result of the short acting time associated with these medications. RTX is not an anesthetic. It reduces the excitability and sensibility of afferent sensory nerves by releasing substance P with particular effect to amyelinic nerves.5 As mentioned previously, 80–90% of sensory nerve terminals at the glans are amyelinic, with only a small amount of medullated nerves. These nerves are equipped with either C type or A type nerve fibers.3 Therefore, using RTX to temporarily block the penile sensory nerve can theoretically reduce the sensitivity of the glans, and might increase the ejaculation threshold for patients with PE. Indeed, the present study showed a 42.9% overall response rate for the entire cohort and a 63.6% effective rate in PE patients with redundant prepuce when IELT and CIPE-5 were used as the evaluation instruments. However, the exact pharmacokinetic mechanism of RTX for lifelong PE is unclear. In our previous study, RTX was used for treatment of overactive bladder and interstitial cystitis, the purpose of treatment might be achieved through blocking the C type nerve fibers by RTXinduced release of substance P.6 Maybe the mechanism of RTX therapy for lifelong PE is similar to this. The association of redundant prepuce with PE is not clear. There are studies showing prolonged pudental-evoked potential latency by circumcision with improvement of PE.17,18 Recently, the short frenulum was also proposed as a common genital anomaly associated with lifelong PE, and the frenulectomy 3
B SHI ET AL.
could significantly increase the IELT.12 However, the effect of circumcision on male sexual function is controversial because of the concern that denuding the penis with full exposure of corona to direct stimulation can cause PE.19 In the present study, patients with redundant prepuce had better improvement. We do not know whether the anatomical difference (with or without redundant prepuce) affects the nerve sensitivity or the absorption of the RTX. Further studies are necessary to address this question. The 100 nmol/L of RTX used in the present study was based on our experience in the treatment of overactive bladder or interstitial cystitis, as the studies showed that the higher the concentration of RTX, the more severe the adverse reaction would be, mainly presenting as the dysuria and hypogastric discomfort.6–8 The dose of 100 nmol/L is considered as the ideal concentration for the best results and minimal adverse reaction in animal and patient studies.6,20 Whether 100 nmol/L of RTX is the ideal concentration for treatment of PE requires further study. However, the safety of this concentration is obvious, as no patients reported any serious adverse event and no patients dropped out from the study as a result of side-effects. Even though all patients experienced burning during the treatment, the burning sensation generally disappeared 1 h after the treatment. Because of the short study period, the small number of patients and no concentration escalation of drugs, the present study had limitations to some extent. Nevertheless, this is the first study, to our knowledge, that shows a potentially effective method using RTX for PE treatment, particularly, for patients with redundant prepuce.
Acknowledgments The study was funded by Shenzhen Science and Technology Innovation Committee. We are grateful to Dr Feng Xie and Dr Shangqi Yang for their valuable advice and suggestions.
Conflict of interest None declared.
References 1 Carson C, Gunn K. Premature ejaculation: definition and prevalence. Int. J. Impot. Res. 2006; 18 (Suppl 1): S5–13.
4
2 Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK. Penile sensitivity in patients with primary premature ejaculation. J. Urol. 1996; 156: 979–81. 3 Yang CC, Bradley WE. Peripheral distribution of the human dorsal nerve of the penis. J. Urol. 1998; 159: 1912–16; discussion 1916–17. 4 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816–24. 5 Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 1999; 51: 159–212. 6 Guan ZC, Ye JX, Cai ZM. Intravesical instillation of resiniferatoxin for the treatment of overactive bladder. Chin. J. Urol. 2004; 25: 194–5. 7 Guan ZC, Zhang DH, Chen T, Wei JX. A preliminary study on intravesical capsaicin for the treatment of obstinate urethral syndrome. Chin. J. Urol. 2002; 23: 282–4. 8 Guan ZC, Zhou JT. Intrabladder medication on overactive bladder. Chin. J. Urol. 2007; 28: 68–70. 9 Haferkamp A, Hohenfellner M. Intravesical treatment of overactive bladder syndrome. Urologe A 2006; 45: 1283–8. 10 Takahashi S, Yanase M, Inoue R et al. Intravesical instillation of resiniferatoxin for the patients with interstitial cystitis. Hinyokika Kiyo 2006; 52: 911–13. 11 McMahon CG, Althof SE, Waldinger MD et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. J. Sex. Med. 2008; 5: 1590–606. 12 Gallo L, Perdona S, Gallo A. The role of short frenulum and the effects of frenulectomy on premature ejaculation. J. Sex. Med. 2010; 7: 1269–76. 13 Zhang CY, Yao ZM, Li XH et al. The effect of selective dorsal penile nerve neurectomy on the penis sensitivity. Chin. J. Androl. 2009; 23: 46–9. 14 Ying J, Yao DH, Jiang YQ, Ren XM. Clinical study on treatment of premature ejaculation with Dyclonine. Chin. J. Androl. 2004; 18: 37–9. 15 Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J. Urol. 1995; 154: 1360–1. 16 Choi HK, Xin ZC, Choi YD, Lee WH, Mah SY, Kim DK. Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study. Int. J. Impot. Res. 1999; 11: 261–4. 17 Senol MG, Sen B, Karademir K, Sen H, Saracoglu M. The effect of male circumcision on pudendal evoked potentials and sexual satisfaction. Acta Neurol. Belgica. 2008; 108: 90–3. 18 Zhang SJ, Zhao YM, Zheng SG, Xiao HW, He YS. Correlation between premature ejaculation and redundant prepuce. Zhonghua Nan Ke Xue 2006; 12: 225–7. 19 Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensitivity, or satisfaction? – a systematic review. J. Sex. Med. 2013; 10: 2644–57. 20 Guan ZC, Li XX. The histopathologic features of rat bladder with capsaicin intravesical instillation. Chin. J. Urol. 2006; 27: 181–3.
© 2014 The Japanese Urological Association
International Journal of Urology (2014)
doi: 10.1111/iju.12471
Original Article
Resiniferatoxin for treatment of lifelong premature ejaculation: A preliminary study Bentao Shi,1 Xuesong Li,2 Jing Chen,1 Boxing Su,2 Xianxin Li,1 Shangqi Yang,1 Zhichen Guan1 and Run Wang3 1 Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 2Department of Urology, Peking University First Hospital, Beijing, China; and 3Department of Urology, University of Texas Medical School at Houston and University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Abbreviations & Acronyms CIPE-5 = Chinese Index of Sexual Function for Premature Ejaculation IELT = intravaginal ejaculation latency time PE = premature ejaculation RP = redundant prepuce RTX = resiniferatoxin Correspondence: Zhichen Guan M.D., Ph.D., Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Street, Shenzhen, Guangdong 518038, China. Email: [email protected] Received 3 October 2013; accepted 30 March 2014.
Objectives: To evaluate the efficacy of resiniferatoxin in the treatment of patients with lifelong premature ejaculation. Methods: A total of 41 outpatients (mean age 26.14 ± 4 years) with premature ejaculation completed the present study. They were randomly separated into the resiniferatoxin group and the placebo group. The resiniferatoxin group included 11 patients with redundant prepuce and 10 patients without redundant prepuce, whereas the placebo group contained 10 patients with redundant prepuce and 10 patients without. For the treatment, the glans were respectively soaked in 30 mL of resiniferatoxin with a concentration of 100 nmol/L or 10% alcohol solution for 30 min before sexual intercourse. Clinical efficacy was assessed by using the Chinese Index of Sexual Function for Premature Ejaculation-5 and the intravaginal ejaculation latency time before or 4 weeks after the treatment. The side-effects were also evaluated. Results: In the resiniferatoxin group, the effective rate of patients with redundant prepuce was 63.6%, and both the intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 significantly increased (P < 0.05). However, the effective rate of patients without redundant prepuce was 20%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the resiniferatoxin treatment (P > 0.05). The total effective rate of patients treated with resiniferatoxin was 42.9%. In the placebo group, the effective rate of patients with or without redundant prepuce was 20% and 10%, respectively. The total effective rate of patients treated with placebo was 15%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the placebo treatment (P > 0.05). The side-effects included a slight burning sensation for the glans penis and dysuria. Conclusions: These preliminary results show that resiniferatoxin might be suitable for treating patients with lifelong premature ejaculation and particularly those with redundant prepuce.
Key words:
Chinese Index of Sexual Function for Premature Ejaculation, intravaginal ejaculation latency time, premature ejaculation, redundant prepuce, resiniferatoxin.
Introduction PE is considered to be one of the most common male sexual dysfunctions, and affects 20–30% of adult males.1 However, the exact etiology of PE remains unknown. Some studies suggested that penile hypersensitivity or increased excitability of the penile sensory nerve might be one of the reasons associated with PE.2 A total of 80–90% of sensory nerves in the glans penis are C type amyelinic nerve fibers.3 RTX, a representative of the vanilloids family, is extracted from a cactus-like plant. Not only does RTX have a similar structure to capsaicin, but it is also 1000-fold spicier than capsaicin.4 Animal studies have shown that RTX can act on peripheral sensory nerve terminals, mainly amyelinic C fibers, that can reduce the excitability and sensitivity of afferent sensory nerves by releasing substance P.5 RTX and other vanilloid substances have been used to treat overactive bladder and interstitial cystitis.6–10 To the best of our knowledge, there has been no report of using RTX to treat PE. This placebo-controlled study was designed to assess the efficacy and safety of RTX therapy for PE. © 2014 The Japanese Urological Association
1
B SHI ET AL.
Methods
Criterion of curative effect
Patients selection and clinical data
The effects and adverse effects were assessed 4 weeks after treatment. The CIPE-5 scores were obtained before and after treatment. The IELT was recorded using stopwatch chronometry. Patients were considered to be cured when normal CIPE-5 scores or prolonged IELT >4 min were achieved after treatment. The one to two grade decrease of the CIPE-5 score or prolonged IELT of 3–4 min were considered as improvements. No change of CIPE-5 score or prolonged IELT 18 years with a stable female sexual partner; (ii) uncontrollable ejaculation caused by genital stimulation either before penetration or shortly after penetration with IELT less than 2 min; (iii) lifelong PE; (iv) normal erectile function; (v) partner dissatisfied with sexual life; (vi) total CIPE-5 score 0.05) and in the placebo group. Comparing the two groups treated with RTX and placebo, the change of IELT was significant (P < 0.05), and the PE patients with redundant prepuce had a longer IELT (Table 1).
CIPE-5 scores The CIPE-5 scores are also summarized in Table 1. The baseline CIPE-5 scores in the two groups were nearly the same. After the RTX treatment, there was a significant change of CIPE-5 scores from 11.82 ± 5.19 to 16.00 ± 4.22 in patients with redundant prepuce (P < 0.05). However, there was no significant change of CIPE-5 score in patients without redundant prepuce (P > 0.05) and in the placebo group. Comparing the two groups treated with RTX and placebo, the change of CIPE-5 score was significant (P < 0.05), and the PE patients with redundant prepuce had a higher CIPE-5 score (Table 1).
Adverse events All patients reported a tolerable burning sensation at the glans and dysuria while soaking the penis in the RTX solution or 10% alcohol solution. The uncomfortable sensations generally disappeared 1–2 h after the treatment. There was no patient dropped out of the study as a result of the side effects, and no adverse vaginal events were reported by the patients’ sexual partners. Neither the patients nor their partners reported systemic adverse effects.
Discussion Recently, lifelong PE has been defined by the International Society of Sexual Medicine.11 Referring to this definition, the 1-min IELT cut-off point is not applied in the most absolute sense, as approximately 10% of men seeking treatment for lifelong PE have IELT of 1–2 min.11 In the present study, all patients with lifelong PE and IELT less than 2 min expressed emotional distress in regard to their sexual life. Therefore, this © 2014 The Japanese Urological Association
cohort of patients became the ideal candidates for studying novel pharmaceutical therapy for PE. Current treatments are largely based on logical solutions (decreasing sensory input), behavior modification therapies and observations of drug sideeffects (those with serotonin reuptake inhibiting activity, such as dapoxetine), phosphodiesterase type 5 inhibitors, combination modalities or alternative medicine. Unfortunately, most of therapies are off-label uses without specific indications for PE.12 Therefore, an ideal medical treatment for PE has yet to be found. Local therapy is a very attractive option for treatment of PE, as studies suggest that the glans penis of a patient with PE is more sensitive with higher excitability in the sensory nerves and lower ejaculation threshold when compared with a normal man.13 Therefore, many local therapies utilized anesthetic effects to prolong the IELT. These included 1% dyclonine ointment,14 2% lidocaine15 and SS-cream (severance secret cream).16 Unfortunately, these treatments often resulted in a lack of orgasm or erectile dysfunction due to the decrease of pleasurable sensation.13 The treatment failure is also common as a result of the short acting time associated with these medications. RTX is not an anesthetic. It reduces the excitability and sensibility of afferent sensory nerves by releasing substance P with particular effect to amyelinic nerves.5 As mentioned previously, 80–90% of sensory nerve terminals at the glans are amyelinic, with only a small amount of medullated nerves. These nerves are equipped with either C type or A type nerve fibers.3 Therefore, using RTX to temporarily block the penile sensory nerve can theoretically reduce the sensitivity of the glans, and might increase the ejaculation threshold for patients with PE. Indeed, the present study showed a 42.9% overall response rate for the entire cohort and a 63.6% effective rate in PE patients with redundant prepuce when IELT and CIPE-5 were used as the evaluation instruments. However, the exact pharmacokinetic mechanism of RTX for lifelong PE is unclear. In our previous study, RTX was used for treatment of overactive bladder and interstitial cystitis, the purpose of treatment might be achieved through blocking the C type nerve fibers by RTXinduced release of substance P.6 Maybe the mechanism of RTX therapy for lifelong PE is similar to this. The association of redundant prepuce with PE is not clear. There are studies showing prolonged pudental-evoked potential latency by circumcision with improvement of PE.17,18 Recently, the short frenulum was also proposed as a common genital anomaly associated with lifelong PE, and the frenulectomy 3
B SHI ET AL.
could significantly increase the IELT.12 However, the effect of circumcision on male sexual function is controversial because of the concern that denuding the penis with full exposure of corona to direct stimulation can cause PE.19 In the present study, patients with redundant prepuce had better improvement. We do not know whether the anatomical difference (with or without redundant prepuce) affects the nerve sensitivity or the absorption of the RTX. Further studies are necessary to address this question. The 100 nmol/L of RTX used in the present study was based on our experience in the treatment of overactive bladder or interstitial cystitis, as the studies showed that the higher the concentration of RTX, the more severe the adverse reaction would be, mainly presenting as the dysuria and hypogastric discomfort.6–8 The dose of 100 nmol/L is considered as the ideal concentration for the best results and minimal adverse reaction in animal and patient studies.6,20 Whether 100 nmol/L of RTX is the ideal concentration for treatment of PE requires further study. However, the safety of this concentration is obvious, as no patients reported any serious adverse event and no patients dropped out from the study as a result of side-effects. Even though all patients experienced burning during the treatment, the burning sensation generally disappeared 1 h after the treatment. Because of the short study period, the small number of patients and no concentration escalation of drugs, the present study had limitations to some extent. Nevertheless, this is the first study, to our knowledge, that shows a potentially effective method using RTX for PE treatment, particularly, for patients with redundant prepuce.
Acknowledgments The study was funded by Shenzhen Science and Technology Innovation Committee. We are grateful to Dr Feng Xie and Dr Shangqi Yang for their valuable advice and suggestions.
Conflict of interest None declared.
References 1 Carson C, Gunn K. Premature ejaculation: definition and prevalence. Int. J. Impot. Res. 2006; 18 (Suppl 1): S5–13.
4
2 Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK. Penile sensitivity in patients with primary premature ejaculation. J. Urol. 1996; 156: 979–81. 3 Yang CC, Bradley WE. Peripheral distribution of the human dorsal nerve of the penis. J. Urol. 1998; 159: 1912–16; discussion 1916–17. 4 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816–24. 5 Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 1999; 51: 159–212. 6 Guan ZC, Ye JX, Cai ZM. Intravesical instillation of resiniferatoxin for the treatment of overactive bladder. Chin. J. Urol. 2004; 25: 194–5. 7 Guan ZC, Zhang DH, Chen T, Wei JX. A preliminary study on intravesical capsaicin for the treatment of obstinate urethral syndrome. Chin. J. Urol. 2002; 23: 282–4. 8 Guan ZC, Zhou JT. Intrabladder medication on overactive bladder. Chin. J. Urol. 2007; 28: 68–70. 9 Haferkamp A, Hohenfellner M. Intravesical treatment of overactive bladder syndrome. Urologe A 2006; 45: 1283–8. 10 Takahashi S, Yanase M, Inoue R et al. Intravesical instillation of resiniferatoxin for the patients with interstitial cystitis. Hinyokika Kiyo 2006; 52: 911–13. 11 McMahon CG, Althof SE, Waldinger MD et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. J. Sex. Med. 2008; 5: 1590–606. 12 Gallo L, Perdona S, Gallo A. The role of short frenulum and the effects of frenulectomy on premature ejaculation. J. Sex. Med. 2010; 7: 1269–76. 13 Zhang CY, Yao ZM, Li XH et al. The effect of selective dorsal penile nerve neurectomy on the penis sensitivity. Chin. J. Androl. 2009; 23: 46–9. 14 Ying J, Yao DH, Jiang YQ, Ren XM. Clinical study on treatment of premature ejaculation with Dyclonine. Chin. J. Androl. 2004; 18: 37–9. 15 Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J. Urol. 1995; 154: 1360–1. 16 Choi HK, Xin ZC, Choi YD, Lee WH, Mah SY, Kim DK. Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study. Int. J. Impot. Res. 1999; 11: 261–4. 17 Senol MG, Sen B, Karademir K, Sen H, Saracoglu M. The effect of male circumcision on pudendal evoked potentials and sexual satisfaction. Acta Neurol. Belgica. 2008; 108: 90–3. 18 Zhang SJ, Zhao YM, Zheng SG, Xiao HW, He YS. Correlation between premature ejaculation and redundant prepuce. Zhonghua Nan Ke Xue 2006; 12: 225–7. 19 Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensitivity, or satisfaction? – a systematic review. J. Sex. Med. 2013; 10: 2644–57. 20 Guan ZC, Li XX. The histopathologic features of rat bladder with capsaicin intravesical instillation. Chin. J. Urol. 2006; 27: 181–3.
© 2014 The Japanese Urological Association
