International Journal of Impotence Research (2001) 13, 303вЂ“308 Гџ 2001 Nature Publishing Group All rights reserved 0955-9930/01 $15.00 www.nature.com/ijir Effects of oral phentolamine, taken before sleep, on nocturnal erectile activity: a double-blind, placebo-controlled, crossover study DG Hatzichristou1*, A Apostolidis1, V Tzortzis1, K Hatzimouratidis1 and D Kouvelas1 1 Department of Urology and Center for Sexual Dysfunction, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece The objective of this study was to determine the effects of oral phentolamine, administered before sleep, on nocturnal penile erectile activity of men with mild to moderate erectile dysfunction (ED). We studied five patients with mild to moderate ED (mean age 34.8 Г† 8.13 and mean duration of ED 31.8 Г† 23.5 months), in a double-blind, placebo-controlled, crossover study. All patients received oral phentolamine (VasomaxTM) at a dose of 40 mg and placebo for three consecutive nights respectively and were submitted to nocturnal penile tumescence and rigidity monitoring (NPTR) with the Rigiscan1 device. NPTR parameters of the two 3-night recordings were evaluated and compared. Administration of oral phentolamine before sleep was associated with a statistically significant increase in the number of erectile events with rigidity ! 60% lasting ! 10 min (P Вј 0.02), as well as the rigidity activity units (RAU) value per hour sleep, both at the base (P Вј 0.023) and the tip of the penis (P Вј 0.019). The number of events as measured by Rigiscan software (20% change in circumference), as well as tumescence activity units (TAU)=h values did not show any statistical difference. No adverse effects were recorded. It is concluded that oral phentolamine administered before sleep enhanced NPTR parameters associated with the quality of the erectile events. Such results provide a pathway for the development of a prevention strategy for ED. Future studies will elucidate whether vasoactive agents taken on a regular basis before sleep, can prevent ED in men at risk, protecting also minimally and moderately impotent patients to become moderately and severely impotent respectively. International Journal of Impotence Research (2001) 13, 303вЂ“308. Keywords: erectile dysfunction; nocturnal erections; prevention; phentolamine Introduction Recent epidemiological data determined that the annual incidence rate of erectile dysfunction (ED) is 26=1000 men=year and about one million new cases are expected annually in the USA alone.1 Such high incidence rate, together with the advances in the treatment of ED вЂ” mainly due to the availability of oral agents in the market вЂ” brought into consideration the urgent need for the development of prevention strategies. An increasing body of evidence suggests that pharmacologic erections may prevent erectile dysfunction (ED).2,3 In their pioneer study, Montorsi et al demonstrated the beneficial effect of postoperative intracavernous injections of alprostadil on the recovery of spontaneous erections after nerve- *Correspondence: DG Hatzichristou, 77 Mitropoleos str., 54 622 Thessaloniki, Greece. E-mail: [email protected] Received 3 January 2001; accepted 12 February 2001 sparing radical retropubic prostatectomy.4 Such data gave us the idea to consider the administration of oral agents for ED prevention. Nocturnal erections have been proposed to play a protective role on the trabecular tissue, increasing tissue oxygenation, specifically during long periods of sexual abstinence.5 As orally taken vasoactive drugs, such as sildenafil and phentolamine have shown to be effective in enhancing erectile capabilities,6,7 it was postulated that it may be possible to pharmacologically manipulate nocturnal erections with regular administration of such agents before sleep. If such a hypothesis proves to be correct, an increase in the nocturnal erectile activity may have a beneficial effect on the overall erectile function, preventing ED in men at risk, as well as restraining further hypoxia-induced tissue damage in men with minimal or moderate corporal pathology. The present study represents the first step in the exploration of the above hypothesis. The objective of the study is to determine the effects of oral phentolamine, administered before sleep in men with mild to moderate erectile dysfunction, on nocturnal penile erectile activity. Effects of phentolamine on nocturnal erection DG Hatzichristou et al 304 Materials and methods This is a double-blind, placebo-controlled, crossover, phase II study designed to evaluate the effects of 40 mg oral phentolamine (VasomaxTM, Zonagen Inc.) on the nocturnal erectile activity in patients with a history of mild to moderate erectile dysfunction. The study sample consisted of patients complaining of ED, who fulfilled the following inclusion criteria: (a) a history of ED of at least 3 months duration; (b) mild to moderate ED, defined by a sum equal to or greater than 13 of the scores recorded in questions 1, 2, 3, 4, 5, and 15 from the International Index for Erectile Function questionnaire (IIEF).8 Exclusion criteria included: (a) impotence caused by untreated endocrine disease; (b) presence of significant penile curvature; (c) clinical history of significant liver or renal disease; (d) symptomatic uncontrolled cardiovascular disease or concomitant nitrate therapy for any underlying condition; (e) sitting or supine systolic blood pressure > 160 mmHg or diastolic blood pressure > 95 mmHg at screening; (f) symptomatic postural hypotension within the last 6 months, (g) psychoses, uncontrolled bipolar disorder or depression; (h) any prior or current use of any therapy for ED. All patients were informed on the scope and the methodology of the study and signed a written informed consent approved by the Ethics Committee. Initial evaluation included a complete medical and sexual history, IIEF score, physical examination, vital signs and electrocardiogram, as well as hemodynamic evaluation (pharmacocavernosometry) to determine potential underlying organic causes. The study design included two nocturnal penile tumescence and rigidity (NPTR) monitorings, performed at the patientвЂ™s home for three consecutive nights each time, using the Rigiscan1 device (Timm Medical Co, USA). According to the study protocol, the interval period between the two 3-night NPTR recordings was ! 6 days and 30 days. Sexual activity, beverages containing alcohol or caffeine, as well as medication use, other than those prescribed for chronic illness, were prohibited during the recording periods. Together with the Rigiscan device, patients were given a container holding three tablets plus a spare of either 40 mg phentolamine mesylate or placebo and were instructed to take one dose before sleep over the next 3 nights. The patients and the investigators were blinded as to the identity of all test medication. Phentolamine mesylate and identical placebo tablets were provided by ScheringPlough Corporation (USA). At the conclusion of each 3-night monitoring, patients were interviewed about adverse events and unused medications were counted. Severe adverse event reports or any International Journal of Impotence Research protocol violation were considered as reasons for study discontinuation. After each monitoring period, all data were transferred to a personal computer and at the end of the study data were analysed with the new Rigiscan Plus1 software (version 4.0, Urohealth Co, USA). Analysis of the recordings was focused on the comparison of the two 3-night recordings (placebo vs phentolamine), based on the following parameters: (1) the number of events recognized by the Rigiscan Plus1 software. As the software recognizes an event if there is a 20% increase in base loop circumference lasting for three minutes or more, these events are referred as tumescence events; (2) the number of the events with ! 60% tip rigidity, lasting for ! 10 min.9 Such events are referred as erectile events; (3) tumescence activity units (TAU) and rigidity activity units (RAU). The software automatically calculates the two parameters, for each night separately. As all NPTR parameters are time-dependent, their values were normalized by hour and expressed per hour (tumescence events=h, erectile events=h, TAU=h and RAU=h), in order to be comparable and independent from the duration of the sessions.9 Statistics Results are expressed as means Г† s.e. The StudentвЂ™s t-test was used for comparative statistical analysis as appropriate. Results Five patients, 29 to 49-y-old (mean Г† s.d: 34.8 Г† 8.13 y), formed the study sample. Duration of ED was 31.8 Г† 23.56 months (range 8 вЂ“ 70). Their medical history revealed pulmonary disease in one patient and a prostatitis-like syndrome in another. IIEF score ranged from 44 to 59, while their sum on questions 1, 2, 3, 4, 5, and 15 ranged between 15 and 21. Pharmacocavernosometry revealed mild arteriogenic ED in one patient (gradients between the left and right brachial and cavernosal arteries systolic blood pressure 55 and 57 mmHg, respectively), mild veno-occlusive dysfunction in two patients (pressures decay from an initial intracavernosal pressure of 150 mmHg at 30 s, 65 and 77 respectively), while two patients had normal hemodynamics. All patients completed the protocol and no side effects or protocol violations were noticed. Overall, 15 sessions (3 nights 6 5 patients) after placebo intake and 15 sessions after phentolamine administration were analysed. The intervals between the two measurements ranged between 7 and 12 days. Effects of phentolamine on nocturnal erection DG Hatzichristou et al 305 Table 1(a) Comparative per patient analysis of the erectile events during the two 3-night recordings (placebo vs phentolamine) Sleep duration (3 nights, in hours) Pts Tumescence events=h (actual number) Erectile events=h (actual number) Duration of erectile events=h (min) Placebo PHE Placebo PHE Placebo PHE Placebo PHE 1 16.3 21.6 2 17.83 18.1 3 21.38 16.65 4 21.13 19.7 5 20.6 16.33 0.24 (4) 0.67 (12) 1.03 (22) 0.19 (4) 0.63 (13) 0.32 (7) 0.49 (9) 1.02 (17) 0.5 (10) 0.67 (11) 0.06 (1) 0.28 (5) 0.05 (1) 0.05 (1) 0.19 (4) 0.18 (4) 0.5 (9) 0.12 (2) 0.05 (1) 0.37 (6) 0.86 (14) 6.06 (108) 0.47 (10) 1.8 (38) 3.78 (78) 1.7 (37) 14.6 (264) 3.24 (54) 0.5 (10) 7.59 (124) Table 1(b) Comparative per patient analysis of RAU and TAU values for the two 3-night recordings (placebo vs phentolamine) TAU=h base (TAU base) Pts 1 2 3 4 5 TAU=h tip (TAU tip) RAU=h base (RAU base) RAU=h tip (RAU tip) Placebo PHE Placebo PHE Placebo PHE Placebo PHE 0.98 (16) 9.25 (165) 4.49 (96) 2.41 (51) 6.55 (135) 2.59 (56) 6.74 (122) 8.83 (147) 2.59 (51) 5.63 (92) 0.92 (15) 6.6 (118) 3.04 (65) 2.31 (49) 7.91 (163) 3.84 (83) 6.3 (114) 6.0 (100) 2.99 (59) 6.67 (109) 2.45 (40) 10.76 (192) 5.19 (111) 2.46 (52) 8.0 (165) 4.77 (103) 11.32 (205) 10.81 (180) 5.18 (102) 9.18 (150) 1.53 (25) 8.63 (154) 5.05 (108) 1.89 (40) 9.12 (188) 2.68 (58) 11.49 (208) 9.3 (155) 3.35 (66) 9.61 (157) The overall duration of sleep for the 3-night recordings with placebo administration was 97.24 h (range 16.3 вЂ“ 21.38 h) and for the phentolamine sessions 92.38 h (range 16.33 вЂ“ 21.6 h). Data per patient are given in Table 1a and b. No statistical significant differences were observed regarding the tumescence events per hour sleep for the placebo (0.55 Г† 0.15) versus the phentolamine (0.6 Г† 0.12) sessions (P Вј 0.29). Phentolamine administration was associated with increased mean number of erectile events per sleep hour (0.13 Гѕ 0.05 vs 0.24 Гѕ 0.08, P Вј 0.02). Increased duration of these erectile events was also noticed (2.6 Г† 1.04 for placebo vs 5.53 Г† 2.57 for phentola- Table 2(a) Comparative group analysis of the erectile events during the two 3-night recordings (placebo vs phentolamine) Sleep duration (h) Tumescence events=h (actual number) Erectile events=h (actual number) Duration of erectile events (min) Placebo PHE Placebo PHE Placebo PHE Placebo PHE 97.24 92.38 0.55 Г† 0.15 (55) 0.6 Г† 0.12 (54) 0.13 Г† 0.05 (12) 0.24 Г† 0.08* (22) 2.6 Г† 1.04 (248) 5.53 Г† 2.57 (489) *P < 0.05. PHE Вј phentolamine. Table 2(b) Comparative group analysis of RAU and TAU values for the two 3-night recordings (placebo vs phentolamine) TAU=h base (TAU base) Placebo 4.74 Г† 1.47 (463) TAU=h tip (TAU tip) RAU=h base (RAU base) RAU=h tip (RAU tip) PHE Placebo PHE Placebo PHE Placebo PHE 5.28 Г† 1.21 (468) 4.16 Г† 1.33 (410) 5.16 Г† 0.73 (465) 5.77 Г† 1.62 (560) 8.25 Г† 1.39* (740) 5.24 Г† 1.6 (515) 7.29 Г† 1.79* (644) *P < 0.05. PHE Вј phentolamine. International Journal of Impotence Research Effects of phentolamine on nocturnal erection DG Hatzichristou et al 306 mine, P Вј 0.07), showing a tendency for statistical significance (Table 2a). A considerable variability in individual measurements of TAU=h values at the base (4.74 Г† 1.47 for placebo vs 5.28 Г† 1.21 for phentolamine, P Вј 0.33) and the tip (4.16 Г† 1.33 vs 5.16 Г† 0.73, P Вј 0.15) of the penis was noticed between patients, without statistically by significant differences (Table 2b). RAU=h values however, increased significantly in all patients. Mean RAU=h values at the base were 5.77 Г† 1.62 for placebo and 8.25 Г† 1.39 for phentolamine (P Вј 0.023). At the tip of the penis, mean RAU=h was 5.24 Г† 1.6 for the placebo, compared with 7.29 Г† 1.79 after phentolamine administration (P Вј 0.019). Overall, statistical significant differences were noticed in all parameters reflective of the quality of the erectile events (number of erectile events, RAU=h both at tip and base of the penis, Figure 1), but not in the parameters associated with the initiation of the erectile process (tumescence events and TAU=h). Discussion Recent epidemiological data from the Massachusetts Male Aging Study (MMAS), has recognized several target groups, who are at risk for ED.1 At the ages between 40 and 49 y the incidence rate of ED is 12.4=1000 men, increasing with each decade of age and reaching 45.8=1000 for males aged between 60 and 69 y. Moreover, men with hypertension, diabetes, and heart disease have a significantly higher incidence rate (42.5, 50.7, 58.3 new cases=1000 men per year, respectively), compared to age-matched controls. Such data clearly demonstrate the urgent need for ED prevention strategy development. Several studies suggested that the use of intracavernosal injection of vasoactive agents (ICI) has a beneficial effect in erectile function.2,3,10 A review of the literature by Sharlip, revealed 15 publications in which restoration of erectile function was reported.3 In a total of 2817 patients in these reports, 9.2% Figure 1 A typical Rigiscan1 recording after placebo (A) and phentolamine administration (B). A significant increase in the duration and the quality of the erectile events is noticed. International Journal of Impotence Research Effects of phentolamine on nocturnal erection DG Hatzichristou et al achieved natural erections, while 29.2% reported reduction in the frequency of ICI or dose of vasoactive drugs needed to achieve functional erections. Another important observation is that the number of patients reporting an increase of the dose needed over time was minimal. Although in the literature data psychogenic mechanisms seem to play the key role in the improvement of the quality of spontaneous erections,3 there is an increasing amount of data showing that pharmacologic erections may prevent ED. In a study in potent patients who underwent nerve-sparing radical retropubic prostatectomy, Montorsi et al reported that alprostadil injections administered three times per week for 12 weeks resulted in the recovery of spontaneous erection in 67% of the patients, compared to 20% for those without any treatment.4 Based on their findings that pharmacologic erections also minimized the incidence of post-operative cavernosal veno-occlusive dysfunction (17% in the treated group vs 53% in those untreated), the authors presumed that pharmacologic erections improved cavernous oxygenation, thereby limiting the development of hypoxiainduced fibrosis. Their results were reproduced by Padma-Nathan et al; in those men who began ICI therapy less than 300 days after radical surgery, 73% reported return to spontaneous erections, compared to 35% of those who began ICI more than 300 days after radical prostatectomy, demonstrating the devastating results of long lasting corporal ischemia.11 Taking into consideration the above literature findings, someone should be sceptical on whether pharmacologic erections are able to reverse pathophysiological changes in the corpora; however, the possibility that pharmacologic erections may protect the corpora from further alterations seems apparent. Although the mechanisms that may account for this protective role remain unknown, the hypothesis on the role of corpora cavernosa oxygenation has been supported also by basic and clinical studies, as oxygen tension has been shown to regulate not only NO synthesis, but also the synthesis of factors involved in the hypoxia-induced penile fibrosis, such as TGF-beta1 and prostanoids.12,13 Such data supported not only an overall hypothesis for the molecular pathology of erectile dysfunction, but also the biological role of nocturnal erections in the preservation of potency,5 specifically during long periods in human life where erotic erections are absent, (childhood or periods of sexual abstinence). During such periods, nocturnal erections are critical to prevent erectile tissue damage. This event becomes important also for patients with ED as well as elderly men, as the association between severity of vasculogenic impotence and aging with impaired nocturnal erections is well established.14,15 The aim of the present study was to explore the hypothesis that the oral pills for ED treatment, administered at low doses before sleep, may increase nocturnal erectile activity. Men with minimal to moderate ED were elected as the target group, as recent epidemiological data derived from the MMAS has shown that 2.6% of the patients suffering moderate ED will develop severe ED every year, clearly establishing the necessity for prevention strategies for this group of patients.1 Oral phentolamine has proven to be an effective and well-tolerated on-demand pharmacological treatment for men with minimal-to-moderate erectile dysfunction,7 and the dose of 40 mg was selected for the purpose of the study, as such low doses of vasoactive agents may be considered appropriate for prevention. Regarding efficacy variables, numerous studies have shown that there is no simple criterion for Rigiscan1 evaluation.9,16 вЂ“ 18 The number of tumescence events, as recognized by the Rigiscan1 software, was included as a variable of circumference changes. However, such events are not always associated with the erectile process and therefore cannot be accepted as erectile events. Rigidity at the tip of the penis ! 60% lasting for at least 10 min has been proposed as a reproducible criterion for NPTR registrations9 and therefore, the number of erectile events with such characteristics was adapted as a parameter for the purposes of the present study. Rigidity Activity Units (RAU), equivalent to a standardized measurement of the area bounded by the time-rigidity tracings of Rigiscan1 and Tumescence Activity Units (TAU), expressing area measurements of the region bounded by the timetumescence tracing and the estimated baseline, were also measured.16 RAU and TAU values, expressed as mean RAU=h and TAU=h values of the 3-night registrations, have shown to be reliable evaluation parameters, expressing the overall erectile activity.9,18 Using the above methodology, it was possible to objectively define overall changes in nocturnal erectile activity in our study group. The results of our study demonstrated that administration of the drug is associated with an increase in the number of erectile events, their duration, as well as the RAU=h values at the base and the tip of the penis. Such results are in favour of the beneficial effect of phentolamine on the quality of nocturnal erections. The number of tumescence events as measured by Rigiscan1, as well as TAU=h values did not show any difference, possibly due to the fact that variability between and within subjects reduced the level of statistical significance achieved. This observation can be also explained by the fact that the tumescence events measured by the software, reflect even minimal changes in penile circumference (20%) and TAU values express changes in the penile circumference associated with the onset of an erectile event. Phentolamine mesylate however, enhances relaxation of the erectile tissue by direct antagonism of alpha-1 and -2 adrenergic receptors and by indirect functional antagonism via a non-adrenergic, endotheliummediated mechanism suggesting nitric oxide 307 International Journal of Impotence Research Effects of phentolamine on nocturnal erection DG Hatzichristou et al 308 synthase activation.19 Such mechanisms of action depend on sexual stimulation.20 Therefore, phentolamine should be considered as a conditioner (enhancer) of the erotic and=or nocturnal erections, rather than an initiator, improving the rigidity and duration of the erectile episodes.21 Based on the results of our study, the question raised is can the available conditioners of the erectile process prevent ED, when administered before sleep for a long time period? Future studies will give the answer. Our study provides the first controlled evaluation of phentolamine effects on nocturnal erectile activity. Although the sample size was small, the pattern of effects observed in our вЂ�proof of the conceptвЂ™ study was highly consistent with the study hypothesis, as phentolamine administration was associated with improvement in the quality of nocturnal erections. Preliminary results showed a similar effect of sildenafil.22 Future research studies may include even combination of the two oral agents to further augment nocturnal erectile episodes, as phosphodiesterasetype 5 inhibitors and alpha-adrenergic receptor antagonist act in concert, promoting smooth muscle relaxation and attenuating smooth muscle contraction, respectively.20,23 Another important aspect is that both sildenafil and phentolamine are not direct mediators of smooth muscle relaxation and, therefore, do not initiate penile erection in the absence of sexual stimulation. It is anticipated that future availability of drugs that initiate erection may act complementary with drugs that facilitate erection. If such a synergistic effect is proven, it will be possible to manipulate more drastically nocturnal erectile activity, by increasing both the number of erections and their quality. Conclusions Oral phentolamine, administered before sleep, increased the quality of the erectile events in all patients tested. It remains to be elucidated if such an approach is able to prevent ED in men at risk, protecting also minimally and moderately impotent patients to become moderately and severely impotent respectively. Large-scale studies with long-term follow-up are needed to prove this hypothesis. Acknowledgement This work was supported by the Schering-Plough Corporation. References 1 Johannes CB et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000; 163: 460 вЂ“ 463. International Journal of Impotence Research 2 Virag R et al. Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases. J Urol 1991; 145: 287 вЂ“ 292. 3 Sarlip ID. Does natural erectile function improve following intracavernous injections of vasoactive drugs? Int J Impot Res 1997; 9: 193 вЂ“ 196. 4 Montorsi F et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997; 158: 1408 вЂ“ 1410. 5 Moreland RB. Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int J Impot Res 1998; 10: 113 вЂ“ 120. 6 Goldstein I et al. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998; 338: 1397 вЂ“ 1404. 7 Goldstein I. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res 2000; 12(Suppl 1): S75 вЂ“ S80. 8 Cappelleri JC et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999; 54: 346 вЂ“ 351. 9 Hatzichristou DG et al. Nocturnal penile tumescence and rigidity monitoring in young potent volunteers: reproducibility, evaluation criteria, and the effects of sexual intercourse. J Urol 1998; 159: 1921 вЂ“ 1926. 10 Hatzichristou DG. Current treatment and future perspectives for erectile dysfunction. Int J Impot Res 1998; 10(Suppl 1): S3 вЂ“ S13. 11 Padma-Nathan H, Linet O, Sheu W. The impact on return of spontaneous erections of short term Alprostadil therapy post nerve sparing prostatectomy. J Urol 1997; 157: 363 (1422A). 12 Nehra A et al. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol 1996; 156: 1320 вЂ“ 1329. 13 Daley JT et al. Prostanoid production in rabbit corpus cavernosum: I. regulation by oxygen tension. J Urol 1996; 155: 1482 вЂ“ 1487. 14 Shabsigh R et al. Comparison of penile duplex ultrasonography with nocturnal penile tumescence monitoring for the evaluation of erectile impotence. J Urol 1990; 143: 924 вЂ“ 927. 15 Chung WS, Park YY, Kwon SW. The impact of aging on penile hemodynamics in normal responders to pharmacological injection: a Doppler sonographic study. J Urol 1997, 157: 2129 вЂ“ 2131. 16 Levine LA, Carroll RA. Nocturnal penile tumescence and rigidity in men without complaints of erectile dysfunction using a new quantitative analysis software. J Urol 1994; 152: 1103 вЂ“ 1107. 17 Sohn MH, Seeger U, Sikora R, Jakse G. Criteria for examinerindependent nocturnal penile tumescence and rigidity monitoring (NPTR): correlations to invasive diagnostic methods. Int J Impot Res 1993; 5: 59 вЂ“ 68. 18 Hatzichristou DG et al. RAUвЂ™s and TAUвЂ™s: more confusion or more information. Int J Impot Res 1996; 8: 109 (A41). 19 Traish A et al. Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res 1998; 10: 215 вЂ“ 223. 20 Lue TF, Goldstein I, Traish A. Comparison of oral and intracavernosal vasoactive agents in penile erection. Int J Impot Res 2000; 12(Suppl 1): S81 вЂ“ S88. 21 Heaton JPW, Adams MA, Morales A. A therapeutic taxonomy of treatments for erectile dysfunction: an evolutionary imperative. Int J Impot Res 1997; 9: 115 вЂ“ 121. 22 Montorsi F et al. Sildenafil taken at bed-time significantly increases nocturnal erectile activity: results of a prospective Rigiscan1 study. J Urol 2000; 163: 148 (657A). 23 Kim NN, Goldstein I, Moreland RB, Traish AM. Alphaadrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum. Int J Impot Res 2000; 12(Suppl 1): S26.
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